Профессор Александр Д. Кулагин, главный редактор журнала «Клеточная Терапия и Трансплантация» (СТТ)
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Он безвременно ушел из жизни 16 марта 2020 г. Издание журнала CTT было одним из приоритетов Бориса Владимировича, что сделало журнал признанным инструментом международного сотрудничества, форумом для обсуждения наиболее сложных клинических проблем и актуальных аспектов онкологии, гематологии, трансплантации стволовых клеток, иммунологии, а также смежных областей иммунологии, молекулярной биологии, клеточной и генной терапии. </p> <p style="text-align: justify;"> Широкий спектр проблем, освещаемых в СТТ с 2008 г., продиктован интегрирующей ролью трансплантации гемопоэтических клеток (ТГСК), которая использует мультидисциплинарные диагностические подходы для повышения безопасности и эффективности данного метода лечения. Прогресс в результатах ТГСК базируется на огромном числе новых фундаментальных данных в разных областях биологии и медицины, что выражается в клинических достижениях. </p> <p style="text-align: justify;"> Теперь мы располагаем большей информацией о механизмах развития всех тяжелых клинических ситуаций, при которых проводится ТГСК, в том числе – лейкозов, лимфом, других состояний клонального гемопоэза, синдромов костномозговой недостаточности, иммунодефицитов, аутоиммунных заболеваний, наследственных болезней. </p> <p style="text-align: justify;"> Новые возможности таргетного фармакологического контроля и иммунотерапии позволяют нам точнее определять показания к ТГСК, лучше подготовить больных, что повышает выживаемость пациентов и минимизирует возможные побочные эффекты терапии. Поэтому научные приоритеты и тематика журнала CTT являются откликом на возрастающую потребность в новых знаниях, широком и эффективном междисциплинарном взаимодействии. </p> <p style="text-align: justify;"> Существенной особенностью и преимуществом журнала является освещение новых клинических данных как при лечении детей, так и у взрослых пациентов. Постоянный обмен знаниями и сравнительным опытом во взрослой и детской практике, взаимно полезен и абсолютно необходим для определения роли возрастного фактора в клинической онкологии, гематологии и трансплантации гемопоэтических клеток. Это – еще одна важная традиция, связанная с историей основания и развития НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой Первого Санкт-Петербургского государственного медицинского университета им. И. П. Павлова в 2007 г. </p> <p style="text-align: justify;"> Журнал постоянно развивается, издание представляет весь спектр жанров научных публикаций – научные обзоры, оригинальные клинические и экспериментальные исследования, рекомендации и описания редких клинических наблюдений. Среди авторов журнала СТТ всегда можно найти как известных экспертов, освещающих крупные теоретические и клинические проблемы, так и молодых ученых и клиницистов, сосредоточенных на своих отдельных актуальных вопросах. Этот принцип является одной из ключевых традицией журнала, заложенных Борисом В. Афанасьевым, который придавал огромное значение преемственности поколений в фундаментальных разработках и клинической практике. </p> <p style="text-align: justify;"> Журнал СТТ традиционно освещает и публикует тезисы докладов Международного симпозиума «Трансплантация гемопоэтических стволовых клеток. Генная и клеточная терапия», посвященного памяти Р. М. Горбачевой. Симпозиум уже на протяжении 14 лет является авторитетным научным форумом в области лечения онкогематологических заболеваний и трансплантации гемопоэтических клеток. В этом году наш симпозиум пройдет с активным использованием онлайн-формата на специально разработанной платформе с виртуальным и реальным участием ведущих российских и зарубежных экспертов в области трансплантации гемопоэтических стволовых клеток и клеточной терапии. Несмотря на необходимость социального дистанцирования и сложности очного участия, мы вновь ожидаем большую аудиторию симпозиума и интересные научные дискуссии. </p> <p style="text-align: justify;"> В этот трудный для всего медицинского сообщества период, редакция журнала СТТ желает всем нашим читателям и авторам крепкого здоровья и, особенно – быстрейшего преодоления пандемии, надеется на перспективы будущих научных встреч, а также обсуждение новых экспериментальных данных, текущих клинических проблем гематологии, трансплантологии и смежных областей исследования на страницах журнала «Клеточная Терапия и Трансплантация». </p> <br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(8314) "
Уважаемые авторы и читатели журнала СТТ!
Первичную подготовку этого номера журнала «Клеточная Терапия и Трансплантация» (CTT) проводил главный редактор, профессор Борис Владимирович Афанасьев. Он безвременно ушел из жизни 16 марта 2020 г. Издание журнала CTT было одним из приоритетов Бориса Владимировича, что сделало журнал признанным инструментом международного сотрудничества, форумом для обсуждения наиболее сложных клинических проблем и актуальных аспектов онкологии, гематологии, трансплантации стволовых клеток, иммунологии, а также смежных областей иммунологии, молекулярной биологии, клеточной и генной терапии.
Широкий спектр проблем, освещаемых в СТТ с 2008 г., продиктован интегрирующей ролью трансплантации гемопоэтических клеток (ТГСК), которая использует мультидисциплинарные диагностические подходы для повышения безопасности и эффективности данного метода лечения. Прогресс в результатах ТГСК базируется на огромном числе новых фундаментальных данных в разных областях биологии и медицины, что выражается в клинических достижениях.
Теперь мы располагаем большей информацией о механизмах развития всех тяжелых клинических ситуаций, при которых проводится ТГСК, в том числе – лейкозов, лимфом, других состояний клонального гемопоэза, синдромов костномозговой недостаточности, иммунодефицитов, аутоиммунных заболеваний, наследственных болезней.
Новые возможности таргетного фармакологического контроля и иммунотерапии позволяют нам точнее определять показания к ТГСК, лучше подготовить больных, что повышает выживаемость пациентов и минимизирует возможные побочные эффекты терапии. Поэтому научные приоритеты и тематика журнала CTT являются откликом на возрастающую потребность в новых знаниях, широком и эффективном междисциплинарном взаимодействии.
Существенной особенностью и преимуществом журнала является освещение новых клинических данных как при лечении детей, так и у взрослых пациентов. Постоянный обмен знаниями и сравнительным опытом во взрослой и детской практике, взаимно полезен и абсолютно необходим для определения роли возрастного фактора в клинической онкологии, гематологии и трансплантации гемопоэтических клеток. Это – еще одна важная традиция, связанная с историей основания и развития НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой Первого Санкт-Петербургского государственного медицинского университета им. И. П. Павлова в 2007 г.
Журнал постоянно развивается, издание представляет весь спектр жанров научных публикаций – научные обзоры, оригинальные клинические и экспериментальные исследования, рекомендации и описания редких клинических наблюдений. Среди авторов журнала СТТ всегда можно найти как известных экспертов, освещающих крупные теоретические и клинические проблемы, так и молодых ученых и клиницистов, сосредоточенных на своих отдельных актуальных вопросах. Этот принцип является одной из ключевых традицией журнала, заложенных Борисом В. Афанасьевым, который придавал огромное значение преемственности поколений в фундаментальных разработках и клинической практике.
Журнал СТТ традиционно освещает и публикует тезисы докладов Международного симпозиума «Трансплантация гемопоэтических стволовых клеток. Генная и клеточная терапия», посвященного памяти Р. М. Горбачевой. Симпозиум уже на протяжении 14 лет является авторитетным научным форумом в области лечения онкогематологических заболеваний и трансплантации гемопоэтических клеток. В этом году наш симпозиум пройдет с активным использованием онлайн-формата на специально разработанной платформе с виртуальным и реальным участием ведущих российских и зарубежных экспертов в области трансплантации гемопоэтических стволовых клеток и клеточной терапии. Несмотря на необходимость социального дистанцирования и сложности очного участия, мы вновь ожидаем большую аудиторию симпозиума и интересные научные дискуссии.
В этот трудный для всего медицинского сообщества период, редакция журнала СТТ желает всем нашим читателям и авторам крепкого здоровья и, особенно – быстрейшего преодоления пандемии, надеется на перспективы будущих научных встреч, а также обсуждение новых экспериментальных данных, текущих клинических проблем гематологии, трансплантологии и смежных областей исследования на страницах журнала «Клеточная Терапия и Трансплантация».
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Professor Alexander D. Kulagin, Editor-in-Chief, Cellular Therapy and Transplantation Journal
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Afanasyev who untimely passed away on March 16, 2020. The CTT edition was one of his priorities, which made the journal a recognizable tool of international cooperation, a forum for discussing the most difficult clinical issues and challenging aspects of oncology, hematology, stem cell transplantation, and relevant areas of immunology, molecular biology, cellular and gene therapy.</p> <p style="text-align: justify;">A wide range of problems highlighted in CTT since 2008, was determined by integrative role of hematopoietic stem cell transplantation (HSCT) which applies multidisciplinary diagnostic approaches to improve safety and efficiency of the procedure. This progress in HSCT is based on huge number of new fundamental data obtained in adjacent fields of biology and medicine, then translated into clinical achievements. Now we are more informed about the mechanisms underlying the development of all severe clinical situations in which hematopoietic cell transplants are performed, including leukemias, lymphomas, other conditions with clonal hematopoiesis, bone marrow failure syndromes, immune deficiencies, autoimmune disorders, hereditary diseases. Molecular biology studies enabled us to detect marker genes which could be used for improved diagnostics and risk stratification of the patients.</p> <p style="text-align: justify;">New options of targeted pharmacological control and immunotherapy permitted us more accurately determine indications for HSCT, thus increasing survival and minimizing possible adverse effects from the treatment. Therefore, the scientific priorities and topics of CTT journal represent a response to the growing needs for new knowledge, wide and effective interdisciplinary interaction.</p> <p style="text-align: justify;">An essential feature and advantage of the journal is the coverage of new clinical data in both pediatric and adult patients. A constant exchange of knowledge and comparative experience gained in seek children and adults, is mutually enriching and absolutely necessary when assessing the role of age factor in clinical oncology, hematology and hematopoietic cell transplantation. This is another notable tradition which stems from the history of founding and development of Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation established at the Pavlov University in 2007.</p> <p style="text-align: justify;">The journal is a permanently developing edition, and it presents the whole range of scientific publications – scientific reviews, original clinical and experimental studies, guidelines, and descriptions of rare clinical observations. Among CTT authors, you will always find widely known experts covering major theoretical and clinical problems, along with young researchers and clinicians who focus on their individual topics. This principle is one of the key CTT traditions established by Professor Boris V. Afanasyev, who attached great importance to continuity of generations in fundamental research and clinical practice.</p> <p style="text-align: justify;">CTT journal traditionally highlights and publishes abstracts of the Raisa Gorbacheva Memorial Meeting <i>Hematopoietic Stem Cell Transplantation. Gene and Cellular Therapy</i>. Over 14 years, the Symposium has become a renowned scientific forum in the field of blood cancer treatment and hematopoietic cell transplantation. This year, our symposium will take place with the active use of online format on a specially developed platform with virtual and real participation of leading Russian and foreign experts in the field of hematopoietic stem cell transplantation and cellular therapy. Despite a required social distancing and difficulties of the face-to-face participation, we again expect a large audience and interesting scientific discussions.</p> <p style="text-align: justify;">During these hard times for the medical community, the editors wish good health to all our readers and authors, and, especially, faster overcoming the pandemic, hoping for opportunities of future scientific meetings, as well as discussing new experimental data and current clinical problems of hematology, transplantation and adjacent research fields on the pages of <i>Cellular Therapy and Transplantation.</i></p> " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4545) "Dear CTT authors and readers,
The initial design for this issue of Cellular Therapy and Transplantation (CTT) was prepared by the Editor-in-Chief, Professor Boris V. Afanasyev who untimely passed away on March 16, 2020. The CTT edition was one of his priorities, which made the journal a recognizable tool of international cooperation, a forum for discussing the most difficult clinical issues and challenging aspects of oncology, hematology, stem cell transplantation, and relevant areas of immunology, molecular biology, cellular and gene therapy.
A wide range of problems highlighted in CTT since 2008, was determined by integrative role of hematopoietic stem cell transplantation (HSCT) which applies multidisciplinary diagnostic approaches to improve safety and efficiency of the procedure. This progress in HSCT is based on huge number of new fundamental data obtained in adjacent fields of biology and medicine, then translated into clinical achievements. Now we are more informed about the mechanisms underlying the development of all severe clinical situations in which hematopoietic cell transplants are performed, including leukemias, lymphomas, other conditions with clonal hematopoiesis, bone marrow failure syndromes, immune deficiencies, autoimmune disorders, hereditary diseases. Molecular biology studies enabled us to detect marker genes which could be used for improved diagnostics and risk stratification of the patients.
New options of targeted pharmacological control and immunotherapy permitted us more accurately determine indications for HSCT, thus increasing survival and minimizing possible adverse effects from the treatment. Therefore, the scientific priorities and topics of CTT journal represent a response to the growing needs for new knowledge, wide and effective interdisciplinary interaction.
An essential feature and advantage of the journal is the coverage of new clinical data in both pediatric and adult patients. A constant exchange of knowledge and comparative experience gained in seek children and adults, is mutually enriching and absolutely necessary when assessing the role of age factor in clinical oncology, hematology and hematopoietic cell transplantation. This is another notable tradition which stems from the history of founding and development of Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation established at the Pavlov University in 2007.
The journal is a permanently developing edition, and it presents the whole range of scientific publications – scientific reviews, original clinical and experimental studies, guidelines, and descriptions of rare clinical observations. Among CTT authors, you will always find widely known experts covering major theoretical and clinical problems, along with young researchers and clinicians who focus on their individual topics. This principle is one of the key CTT traditions established by Professor Boris V. Afanasyev, who attached great importance to continuity of generations in fundamental research and clinical practice.
CTT journal traditionally highlights and publishes abstracts of the Raisa Gorbacheva Memorial Meeting Hematopoietic Stem Cell Transplantation. Gene and Cellular Therapy. Over 14 years, the Symposium has become a renowned scientific forum in the field of blood cancer treatment and hematopoietic cell transplantation. This year, our symposium will take place with the active use of online format on a specially developed platform with virtual and real participation of leading Russian and foreign experts in the field of hematopoietic stem cell transplantation and cellular therapy. Despite a required social distancing and difficulties of the face-to-face participation, we again expect a large audience and interesting scientific discussions.
During these hard times for the medical community, the editors wish good health to all our readers and authors, and, especially, faster overcoming the pandemic, hoping for opportunities of future scientific meetings, as well as discussing new experimental data and current clinical problems of hematology, transplantation and adjacent research fields on the pages of Cellular Therapy and Transplantation.
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Kulagin, Editor-in-Chief, <i>Cellular Therapy and Transplantation Journal</i></p> " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(109) "Professor Alexander D. Kulagin, Editor-in-Chief, Cellular Therapy and Transplantation Journal
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(109) "Professor Alexander D. Kulagin, Editor-in-Chief, Cellular Therapy and Transplantation Journal
" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "26427" ["VALUE"]=> array(2) { ["TEXT"]=> string(4757) "<p style="text-align: justify;">Dear CTT authors and readers,</p> <p style="text-align: justify;">The initial design for this issue of <i>Cellular Therapy and Transplantation</i> (CTT) was prepared by the Editor-in-Chief, Professor Boris V. Afanasyev who untimely passed away on March 16, 2020. The CTT edition was one of his priorities, which made the journal a recognizable tool of international cooperation, a forum for discussing the most difficult clinical issues and challenging aspects of oncology, hematology, stem cell transplantation, and relevant areas of immunology, molecular biology, cellular and gene therapy.</p> <p style="text-align: justify;">A wide range of problems highlighted in CTT since 2008, was determined by integrative role of hematopoietic stem cell transplantation (HSCT) which applies multidisciplinary diagnostic approaches to improve safety and efficiency of the procedure. This progress in HSCT is based on huge number of new fundamental data obtained in adjacent fields of biology and medicine, then translated into clinical achievements. Now we are more informed about the mechanisms underlying the development of all severe clinical situations in which hematopoietic cell transplants are performed, including leukemias, lymphomas, other conditions with clonal hematopoiesis, bone marrow failure syndromes, immune deficiencies, autoimmune disorders, hereditary diseases. Molecular biology studies enabled us to detect marker genes which could be used for improved diagnostics and risk stratification of the patients.</p> <p style="text-align: justify;">New options of targeted pharmacological control and immunotherapy permitted us more accurately determine indications for HSCT, thus increasing survival and minimizing possible adverse effects from the treatment. Therefore, the scientific priorities and topics of CTT journal represent a response to the growing needs for new knowledge, wide and effective interdisciplinary interaction.</p> <p style="text-align: justify;">An essential feature and advantage of the journal is the coverage of new clinical data in both pediatric and adult patients. A constant exchange of knowledge and comparative experience gained in seek children and adults, is mutually enriching and absolutely necessary when assessing the role of age factor in clinical oncology, hematology and hematopoietic cell transplantation. This is another notable tradition which stems from the history of founding and development of Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation established at the Pavlov University in 2007.</p> <p style="text-align: justify;">The journal is a permanently developing edition, and it presents the whole range of scientific publications – scientific reviews, original clinical and experimental studies, guidelines, and descriptions of rare clinical observations. Among CTT authors, you will always find widely known experts covering major theoretical and clinical problems, along with young researchers and clinicians who focus on their individual topics. This principle is one of the key CTT traditions established by Professor Boris V. Afanasyev, who attached great importance to continuity of generations in fundamental research and clinical practice.</p> <p style="text-align: justify;">CTT journal traditionally highlights and publishes abstracts of the Raisa Gorbacheva Memorial Meeting <i>Hematopoietic Stem Cell Transplantation. Gene and Cellular Therapy</i>. Over 14 years, the Symposium has become a renowned scientific forum in the field of blood cancer treatment and hematopoietic cell transplantation. This year, our symposium will take place with the active use of online format on a specially developed platform with virtual and real participation of leading Russian and foreign experts in the field of hematopoietic stem cell transplantation and cellular therapy. Despite a required social distancing and difficulties of the face-to-face participation, we again expect a large audience and interesting scientific discussions.</p> <p style="text-align: justify;">During these hard times for the medical community, the editors wish good health to all our readers and authors, and, especially, faster overcoming the pandemic, hoping for opportunities of future scientific meetings, as well as discussing new experimental data and current clinical problems of hematology, transplantation and adjacent research fields on the pages of <i>Cellular Therapy and Transplantation.</i></p> " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4545) "Dear CTT authors and readers,
The initial design for this issue of Cellular Therapy and Transplantation (CTT) was prepared by the Editor-in-Chief, Professor Boris V. Afanasyev who untimely passed away on March 16, 2020. The CTT edition was one of his priorities, which made the journal a recognizable tool of international cooperation, a forum for discussing the most difficult clinical issues and challenging aspects of oncology, hematology, stem cell transplantation, and relevant areas of immunology, molecular biology, cellular and gene therapy.
A wide range of problems highlighted in CTT since 2008, was determined by integrative role of hematopoietic stem cell transplantation (HSCT) which applies multidisciplinary diagnostic approaches to improve safety and efficiency of the procedure. This progress in HSCT is based on huge number of new fundamental data obtained in adjacent fields of biology and medicine, then translated into clinical achievements. Now we are more informed about the mechanisms underlying the development of all severe clinical situations in which hematopoietic cell transplants are performed, including leukemias, lymphomas, other conditions with clonal hematopoiesis, bone marrow failure syndromes, immune deficiencies, autoimmune disorders, hereditary diseases. Molecular biology studies enabled us to detect marker genes which could be used for improved diagnostics and risk stratification of the patients.
New options of targeted pharmacological control and immunotherapy permitted us more accurately determine indications for HSCT, thus increasing survival and minimizing possible adverse effects from the treatment. Therefore, the scientific priorities and topics of CTT journal represent a response to the growing needs for new knowledge, wide and effective interdisciplinary interaction.
An essential feature and advantage of the journal is the coverage of new clinical data in both pediatric and adult patients. A constant exchange of knowledge and comparative experience gained in seek children and adults, is mutually enriching and absolutely necessary when assessing the role of age factor in clinical oncology, hematology and hematopoietic cell transplantation. This is another notable tradition which stems from the history of founding and development of Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation established at the Pavlov University in 2007.
The journal is a permanently developing edition, and it presents the whole range of scientific publications – scientific reviews, original clinical and experimental studies, guidelines, and descriptions of rare clinical observations. Among CTT authors, you will always find widely known experts covering major theoretical and clinical problems, along with young researchers and clinicians who focus on their individual topics. This principle is one of the key CTT traditions established by Professor Boris V. Afanasyev, who attached great importance to continuity of generations in fundamental research and clinical practice.
CTT journal traditionally highlights and publishes abstracts of the Raisa Gorbacheva Memorial Meeting Hematopoietic Stem Cell Transplantation. Gene and Cellular Therapy. Over 14 years, the Symposium has become a renowned scientific forum in the field of blood cancer treatment and hematopoietic cell transplantation. This year, our symposium will take place with the active use of online format on a specially developed platform with virtual and real participation of leading Russian and foreign experts in the field of hematopoietic stem cell transplantation and cellular therapy. Despite a required social distancing and difficulties of the face-to-face participation, we again expect a large audience and interesting scientific discussions.
During these hard times for the medical community, the editors wish good health to all our readers and authors, and, especially, faster overcoming the pandemic, hoping for opportunities of future scientific meetings, as well as discussing new experimental data and current clinical problems of hematology, transplantation and adjacent research fields on the pages of Cellular Therapy and Transplantation.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(4545) "Dear CTT authors and readers,
The initial design for this issue of Cellular Therapy and Transplantation (CTT) was prepared by the Editor-in-Chief, Professor Boris V. Afanasyev who untimely passed away on March 16, 2020. The CTT edition was one of his priorities, which made the journal a recognizable tool of international cooperation, a forum for discussing the most difficult clinical issues and challenging aspects of oncology, hematology, stem cell transplantation, and relevant areas of immunology, molecular biology, cellular and gene therapy.
A wide range of problems highlighted in CTT since 2008, was determined by integrative role of hematopoietic stem cell transplantation (HSCT) which applies multidisciplinary diagnostic approaches to improve safety and efficiency of the procedure. This progress in HSCT is based on huge number of new fundamental data obtained in adjacent fields of biology and medicine, then translated into clinical achievements. Now we are more informed about the mechanisms underlying the development of all severe clinical situations in which hematopoietic cell transplants are performed, including leukemias, lymphomas, other conditions with clonal hematopoiesis, bone marrow failure syndromes, immune deficiencies, autoimmune disorders, hereditary diseases. Molecular biology studies enabled us to detect marker genes which could be used for improved diagnostics and risk stratification of the patients.
New options of targeted pharmacological control and immunotherapy permitted us more accurately determine indications for HSCT, thus increasing survival and minimizing possible adverse effects from the treatment. Therefore, the scientific priorities and topics of CTT journal represent a response to the growing needs for new knowledge, wide and effective interdisciplinary interaction.
An essential feature and advantage of the journal is the coverage of new clinical data in both pediatric and adult patients. A constant exchange of knowledge and comparative experience gained in seek children and adults, is mutually enriching and absolutely necessary when assessing the role of age factor in clinical oncology, hematology and hematopoietic cell transplantation. This is another notable tradition which stems from the history of founding and development of Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation established at the Pavlov University in 2007.
The journal is a permanently developing edition, and it presents the whole range of scientific publications – scientific reviews, original clinical and experimental studies, guidelines, and descriptions of rare clinical observations. Among CTT authors, you will always find widely known experts covering major theoretical and clinical problems, along with young researchers and clinicians who focus on their individual topics. This principle is one of the key CTT traditions established by Professor Boris V. Afanasyev, who attached great importance to continuity of generations in fundamental research and clinical practice.
CTT journal traditionally highlights and publishes abstracts of the Raisa Gorbacheva Memorial Meeting Hematopoietic Stem Cell Transplantation. Gene and Cellular Therapy. Over 14 years, the Symposium has become a renowned scientific forum in the field of blood cancer treatment and hematopoietic cell transplantation. This year, our symposium will take place with the active use of online format on a specially developed platform with virtual and real participation of leading Russian and foreign experts in the field of hematopoietic stem cell transplantation and cellular therapy. Despite a required social distancing and difficulties of the face-to-face participation, we again expect a large audience and interesting scientific discussions.
During these hard times for the medical community, the editors wish good health to all our readers and authors, and, especially, faster overcoming the pandemic, hoping for opportunities of future scientific meetings, as well as discussing new experimental data and current clinical problems of hematology, transplantation and adjacent research fields on the pages of Cellular Therapy and Transplantation.
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Профессор Александр Д. Кулагин, главный редактор журнала «Клеточная Терапия и Трансплантация» (СТТ)
" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "26423" ["VALUE"]=> array(2) { ["TEXT"]=> string(8518) "<p style="text-align: justify;"> Уважаемые авторы и читатели журнала СТТ! </p> <p style="text-align: justify;"> Первичную подготовку этого номера журнала «Клеточная Терапия и Трансплантация» (CTT) проводил главный редактор, профессор Борис Владимирович Афанасьев. Он безвременно ушел из жизни 16 марта 2020 г. Издание журнала CTT было одним из приоритетов Бориса Владимировича, что сделало журнал признанным инструментом международного сотрудничества, форумом для обсуждения наиболее сложных клинических проблем и актуальных аспектов онкологии, гематологии, трансплантации стволовых клеток, иммунологии, а также смежных областей иммунологии, молекулярной биологии, клеточной и генной терапии. </p> <p style="text-align: justify;"> Широкий спектр проблем, освещаемых в СТТ с 2008 г., продиктован интегрирующей ролью трансплантации гемопоэтических клеток (ТГСК), которая использует мультидисциплинарные диагностические подходы для повышения безопасности и эффективности данного метода лечения. Прогресс в результатах ТГСК базируется на огромном числе новых фундаментальных данных в разных областях биологии и медицины, что выражается в клинических достижениях. </p> <p style="text-align: justify;"> Теперь мы располагаем большей информацией о механизмах развития всех тяжелых клинических ситуаций, при которых проводится ТГСК, в том числе – лейкозов, лимфом, других состояний клонального гемопоэза, синдромов костномозговой недостаточности, иммунодефицитов, аутоиммунных заболеваний, наследственных болезней. </p> <p style="text-align: justify;"> Новые возможности таргетного фармакологического контроля и иммунотерапии позволяют нам точнее определять показания к ТГСК, лучше подготовить больных, что повышает выживаемость пациентов и минимизирует возможные побочные эффекты терапии. Поэтому научные приоритеты и тематика журнала CTT являются откликом на возрастающую потребность в новых знаниях, широком и эффективном междисциплинарном взаимодействии. </p> <p style="text-align: justify;"> Существенной особенностью и преимуществом журнала является освещение новых клинических данных как при лечении детей, так и у взрослых пациентов. Постоянный обмен знаниями и сравнительным опытом во взрослой и детской практике, взаимно полезен и абсолютно необходим для определения роли возрастного фактора в клинической онкологии, гематологии и трансплантации гемопоэтических клеток. Это – еще одна важная традиция, связанная с историей основания и развития НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой Первого Санкт-Петербургского государственного медицинского университета им. И. П. Павлова в 2007 г. </p> <p style="text-align: justify;"> Журнал постоянно развивается, издание представляет весь спектр жанров научных публикаций – научные обзоры, оригинальные клинические и экспериментальные исследования, рекомендации и описания редких клинических наблюдений. Среди авторов журнала СТТ всегда можно найти как известных экспертов, освещающих крупные теоретические и клинические проблемы, так и молодых ученых и клиницистов, сосредоточенных на своих отдельных актуальных вопросах. Этот принцип является одной из ключевых традицией журнала, заложенных Борисом В. Афанасьевым, который придавал огромное значение преемственности поколений в фундаментальных разработках и клинической практике. </p> <p style="text-align: justify;"> Журнал СТТ традиционно освещает и публикует тезисы докладов Международного симпозиума «Трансплантация гемопоэтических стволовых клеток. Генная и клеточная терапия», посвященного памяти Р. М. Горбачевой. Симпозиум уже на протяжении 14 лет является авторитетным научным форумом в области лечения онкогематологических заболеваний и трансплантации гемопоэтических клеток. В этом году наш симпозиум пройдет с активным использованием онлайн-формата на специально разработанной платформе с виртуальным и реальным участием ведущих российских и зарубежных экспертов в области трансплантации гемопоэтических стволовых клеток и клеточной терапии. Несмотря на необходимость социального дистанцирования и сложности очного участия, мы вновь ожидаем большую аудиторию симпозиума и интересные научные дискуссии. </p> <p style="text-align: justify;"> В этот трудный для всего медицинского сообщества период, редакция журнала СТТ желает всем нашим читателям и авторам крепкого здоровья и, особенно – быстрейшего преодоления пандемии, надеется на перспективы будущих научных встреч, а также обсуждение новых экспериментальных данных, текущих клинических проблем гематологии, трансплантологии и смежных областей исследования на страницах журнала «Клеточная Терапия и Трансплантация». </p> <br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(8314) "
Уважаемые авторы и читатели журнала СТТ!
Первичную подготовку этого номера журнала «Клеточная Терапия и Трансплантация» (CTT) проводил главный редактор, профессор Борис Владимирович Афанасьев. Он безвременно ушел из жизни 16 марта 2020 г. Издание журнала CTT было одним из приоритетов Бориса Владимировича, что сделало журнал признанным инструментом международного сотрудничества, форумом для обсуждения наиболее сложных клинических проблем и актуальных аспектов онкологии, гематологии, трансплантации стволовых клеток, иммунологии, а также смежных областей иммунологии, молекулярной биологии, клеточной и генной терапии.
Широкий спектр проблем, освещаемых в СТТ с 2008 г., продиктован интегрирующей ролью трансплантации гемопоэтических клеток (ТГСК), которая использует мультидисциплинарные диагностические подходы для повышения безопасности и эффективности данного метода лечения. Прогресс в результатах ТГСК базируется на огромном числе новых фундаментальных данных в разных областях биологии и медицины, что выражается в клинических достижениях.
Теперь мы располагаем большей информацией о механизмах развития всех тяжелых клинических ситуаций, при которых проводится ТГСК, в том числе – лейкозов, лимфом, других состояний клонального гемопоэза, синдромов костномозговой недостаточности, иммунодефицитов, аутоиммунных заболеваний, наследственных болезней.
Новые возможности таргетного фармакологического контроля и иммунотерапии позволяют нам точнее определять показания к ТГСК, лучше подготовить больных, что повышает выживаемость пациентов и минимизирует возможные побочные эффекты терапии. Поэтому научные приоритеты и тематика журнала CTT являются откликом на возрастающую потребность в новых знаниях, широком и эффективном междисциплинарном взаимодействии.
Существенной особенностью и преимуществом журнала является освещение новых клинических данных как при лечении детей, так и у взрослых пациентов. Постоянный обмен знаниями и сравнительным опытом во взрослой и детской практике, взаимно полезен и абсолютно необходим для определения роли возрастного фактора в клинической онкологии, гематологии и трансплантации гемопоэтических клеток. Это – еще одна важная традиция, связанная с историей основания и развития НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой Первого Санкт-Петербургского государственного медицинского университета им. И. П. Павлова в 2007 г.
Журнал постоянно развивается, издание представляет весь спектр жанров научных публикаций – научные обзоры, оригинальные клинические и экспериментальные исследования, рекомендации и описания редких клинических наблюдений. Среди авторов журнала СТТ всегда можно найти как известных экспертов, освещающих крупные теоретические и клинические проблемы, так и молодых ученых и клиницистов, сосредоточенных на своих отдельных актуальных вопросах. Этот принцип является одной из ключевых традицией журнала, заложенных Борисом В. Афанасьевым, который придавал огромное значение преемственности поколений в фундаментальных разработках и клинической практике.
Журнал СТТ традиционно освещает и публикует тезисы докладов Международного симпозиума «Трансплантация гемопоэтических стволовых клеток. Генная и клеточная терапия», посвященного памяти Р. М. Горбачевой. Симпозиум уже на протяжении 14 лет является авторитетным научным форумом в области лечения онкогематологических заболеваний и трансплантации гемопоэтических клеток. В этом году наш симпозиум пройдет с активным использованием онлайн-формата на специально разработанной платформе с виртуальным и реальным участием ведущих российских и зарубежных экспертов в области трансплантации гемопоэтических стволовых клеток и клеточной терапии. Несмотря на необходимость социального дистанцирования и сложности очного участия, мы вновь ожидаем большую аудиторию симпозиума и интересные научные дискуссии.
В этот трудный для всего медицинского сообщества период, редакция журнала СТТ желает всем нашим читателям и авторам крепкого здоровья и, особенно – быстрейшего преодоления пандемии, надеется на перспективы будущих научных встреч, а также обсуждение новых экспериментальных данных, текущих клинических проблем гематологии, трансплантологии и смежных областей исследования на страницах журнала «Клеточная Терапия и Трансплантация».
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Уважаемые авторы и читатели журнала СТТ!
Первичную подготовку этого номера журнала «Клеточная Терапия и Трансплантация» (CTT) проводил главный редактор, профессор Борис Владимирович Афанасьев. Он безвременно ушел из жизни 16 марта 2020 г. Издание журнала CTT было одним из приоритетов Бориса Владимировича, что сделало журнал признанным инструментом международного сотрудничества, форумом для обсуждения наиболее сложных клинических проблем и актуальных аспектов онкологии, гематологии, трансплантации стволовых клеток, иммунологии, а также смежных областей иммунологии, молекулярной биологии, клеточной и генной терапии.
Широкий спектр проблем, освещаемых в СТТ с 2008 г., продиктован интегрирующей ролью трансплантации гемопоэтических клеток (ТГСК), которая использует мультидисциплинарные диагностические подходы для повышения безопасности и эффективности данного метода лечения. Прогресс в результатах ТГСК базируется на огромном числе новых фундаментальных данных в разных областях биологии и медицины, что выражается в клинических достижениях.
Теперь мы располагаем большей информацией о механизмах развития всех тяжелых клинических ситуаций, при которых проводится ТГСК, в том числе – лейкозов, лимфом, других состояний клонального гемопоэза, синдромов костномозговой недостаточности, иммунодефицитов, аутоиммунных заболеваний, наследственных болезней.
Новые возможности таргетного фармакологического контроля и иммунотерапии позволяют нам точнее определять показания к ТГСК, лучше подготовить больных, что повышает выживаемость пациентов и минимизирует возможные побочные эффекты терапии. Поэтому научные приоритеты и тематика журнала CTT являются откликом на возрастающую потребность в новых знаниях, широком и эффективном междисциплинарном взаимодействии.
Существенной особенностью и преимуществом журнала является освещение новых клинических данных как при лечении детей, так и у взрослых пациентов. Постоянный обмен знаниями и сравнительным опытом во взрослой и детской практике, взаимно полезен и абсолютно необходим для определения роли возрастного фактора в клинической онкологии, гематологии и трансплантации гемопоэтических клеток. Это – еще одна важная традиция, связанная с историей основания и развития НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой Первого Санкт-Петербургского государственного медицинского университета им. И. П. Павлова в 2007 г.
Журнал постоянно развивается, издание представляет весь спектр жанров научных публикаций – научные обзоры, оригинальные клинические и экспериментальные исследования, рекомендации и описания редких клинических наблюдений. Среди авторов журнала СТТ всегда можно найти как известных экспертов, освещающих крупные теоретические и клинические проблемы, так и молодых ученых и клиницистов, сосредоточенных на своих отдельных актуальных вопросах. Этот принцип является одной из ключевых традицией журнала, заложенных Борисом В. Афанасьевым, который придавал огромное значение преемственности поколений в фундаментальных разработках и клинической практике.
Журнал СТТ традиционно освещает и публикует тезисы докладов Международного симпозиума «Трансплантация гемопоэтических стволовых клеток. Генная и клеточная терапия», посвященного памяти Р. М. Горбачевой. Симпозиум уже на протяжении 14 лет является авторитетным научным форумом в области лечения онкогематологических заболеваний и трансплантации гемопоэтических клеток. В этом году наш симпозиум пройдет с активным использованием онлайн-формата на специально разработанной платформе с виртуальным и реальным участием ведущих российских и зарубежных экспертов в области трансплантации гемопоэтических стволовых клеток и клеточной терапии. Несмотря на необходимость социального дистанцирования и сложности очного участия, мы вновь ожидаем большую аудиторию симпозиума и интересные научные дискуссии.
В этот трудный для всего медицинского сообщества период, редакция журнала СТТ желает всем нашим читателям и авторам крепкого здоровья и, особенно – быстрейшего преодоления пандемии, надеется на перспективы будущих научных встреч, а также обсуждение новых экспериментальных данных, текущих клинических проблем гематологии, трансплантологии и смежных областей исследования на страницах журнала «Клеточная Терапия и Трансплантация».
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Prediction is very difficult, especially if it's about the future.
Niels Bohr
Introduction
Immune therapy is a safe and effective therapy of diverse cancers. In haematology this efficacy is limited predominately to B-cell lymphoid cancers including acute lymphoblastic leukemia (ALL), lymphomas and plasma cell myeloma. Effective therapies include monoclonal antibodies such as rituximab, antibody-drug conjugates such as brentuximab vedotin, antibody-radionuclide conjugates such as 131-iodine tositumomab, bi-specific monoclonal antibodies (BiTE® antibodies) such as blinatumomab (CD20/CD3) and chimeric antigen receptor T-cells (CAR-T-cells) to CD19, CD20 and to B-cell maturation antigen (BCMA). The target of these immune therapies are B-cell lineage antigens rather than cancer-specific antigens. These interventions are more effective than checkpoint-inhibition directed antibodies such as those to PD-1, or PD-1L or antibodies to CTLA-4 active in solid cancers.
One might expect equal success using immune therapy to treat myeloid cancers such as acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). However, this is not so. Early attempts to use immunotherapy for AML treatment (with BCG, C.parvum, or leukemia blast antigens) were not successful [1]. At the present time, there is only one FDA-approved therapy of myeloid cancers, gemtuzumab ozogamicin (Myelotarg®) for AML which was first approved >10 years ago, withdrawn and re-approved. Why this discordance?
What are the reasons for successful immune therapy of different blood cancers?
There are two important differences between myeloid and lymphoid cancers. First is the different structures and kinetics of myelopoiesis and lymphopoiesis. Lymphoid and myeloid lineages are divided (dichotomized) at the level of early progenitors. About at 600 billion cells myeloid cells are produced per day in contrast to only about 10 million lymphoid cells per day, a 60-fold difference. Also, granulocytes and platelets survive only a few hours or days in contrast to lymphoid cells which live years. The implication of these differences is a disruption of myelopoiesis is much more serious than a disruption of lymphopoiesis. One be reasonably well without B-cells, somewhat well without T- and NK-cells but you will die immediately without granulocytes and platelets.
Second this the different targetability of myeloid versus lymphoid antigens. As indicated, the target of immune therapy of lymphoid cancers is B-lineage antigens. These antigens are not cancer-specific such that normal B-cells are targeted along with the cancer cells. Fortunately killing all normal B-cells is compatible with life (normal B-cell function can be reversed by giving intravenous immune globulin [IVIG]). In contrast, it is impossible to replace normal granulocyte production, a situation is incompatible with life.
Is there immune surveillance against AML?
Figure 1. Low levels of myeloid leukemia evolving after kidney transplants [2, 3]
Figure 2. Cumulative incidence of relapse after allo-transplants for leukaemia [3]
Considerable data indicate the immune system is effective in controlling lymphomas. For example, lymphoma-risk is markedly increased in persons with immune deficiency or suppression such as those with severe combined immune deficiency (SCID), acquired immune deficiency syndrome (AIDS) and solid organ and hematopoietic transplant recipients. Most of these lymphomas are Epstein-Barr virus (EBV)-related. However, there is a only a small if any increased risk of AML, CML or myelodysplastic syndrome (MDS) in similar populations and amongst solid organ transplant recipients receiving life-long immune suppression (Fig. 1) [2, 3]. These data imply immune surveillance does not operate effectively against myeloid cancers.
Are there convincing data of an immune response to AML?
Considerable data indicate a strong immune response to myeloid cancers in the setting of a hematopoietic cell transplant. For example, among persons with AML receiving an HLA-identical sibling transplant, cumulative incidence of relapse (CIR) is highest among recipients of a transplant from a genetically-identical twins and lowest among recipients of allotransplants with acute and chronic graft-versus-host disease (GvHD) [4]. This difference correlates with histo-incompatibility between donor and recipient. Graft-versus-host disease (GvHD) and graft-versus-leukemia effect (GvL) may be identical or overlap to different degree in individuals.
Therefore, the answer on targetability of AML immune therapy lies in two considerations: (1) lack of a convincing AML-specific target antigen(s); and (2) unacceptable adverse effects from non-specificity of target antigens used in AML immune therapy such as CD33 and CD124. Therapy against these target antigens can potentially kill AML cells but will unavoidably destroy normal bone marrow cells resulting in death absent a transplant or using synthetic biology techniques.
What is the role of AML-specific antigens in graft-versus-leukaemia (GvL)?
There are several potential targets of anti-AML activity in the context of an allotransplant including: (1) HLA antigens; (2) minor histocompatibility antigens; (3) leukemia-associated antigens; and (4) leukemia-specific antigens (if they exist). All of these are potential targets of the so-called GvL-effect seen after allotransplants and after donor lymphocyte infusions (DLI). Elsewhere my colleague and I discuss whether this effect is leukemia-specific or against HLA and/or non-HLA antigens and not leukemia-specific [5].
Several variables correlate with success of immune therapy: (1) antigenicity; (2) immunogenicity; (3) accessibility; (4) sensitivity to killing; and (5) collateral damage to normal cells. The major current limitation of these approaches is lack of an AML-specific target antigen. In many models, probability of response to immune therapy correlates with mutation frequency and with estimated numbers of potential cancer-specific neo-antigens [6]. AML cells have an average of 0.28 mutation per megabase of DNA compared with 8.15 mutations for lung cancer, 40-fold less. For this reason checkpoint-inhibitor antibodies and antibodies to CTLA-4 are unlikely to be effective when used alone in persons with AML.
Figure 3. Correlation between coding somatic mutation frequency and objective response rates in diverse cancers [6]
Clinical trials
We can envision any potential immune therapy of blood cancer using along two strategies: antibody therapies and cell therapies. Antibody therapies can be further divided by technology such as unmodified antibodies, antibody-drug conjugates, antibody-radionuclide conjugates (radio-immunotherapy), bi-specific antibodies, and other more advanced techniques [7]. These data are summarized in the Table 1.
An example is gemtuzumab ozogamycin [8]. Clinical trials data are shown in Figure 4.
Table 1. Antibody-based therapies of acute myeloid leukemia (adapted from [7])
Figure 4. Improved long-term survival in persons with AML receiving or not receiving gemtuzumab ozogamycin [9]
PD-1 and CTLA-4 inhibitors
Clinical studies of immune checkpoint inhibitors like anti-PD-1 antibodies report little or no benefit. Current studies combine anti-PD-1 antibodies with anti-leukemic drugs [10]. A study in 22 subjects reported complete responses in 4 subjects with extra-medullary relapse of AML but not in subjects with bone marrow relapse [11].
Cell-based immune therapy
Cellular immune therapies use NK-cells and CAR-T- and CAR-NK cells and cytokine-induced NK-cells (CIK). My colleagues and I recently reviewed the current state of cell therapy of AML [12]. We discussed several approaches and concluded that although there are interesting preliminary data, there are no convincing data these approaches are a safe and effective treatment of AML. Perhaps the strongest current data are for NK-cells [13].
Synthetic biology techniques may allow use of anti-CD33 antibodies in AML by using CRISP/Cas9 to edit out CD33 from normal myeloid cells [14].
Conclusions
In summary, immune therapy of AML poses challenges different from immune therapy of lymphoid-lineage cancers. There is progress, for example with gemtuzumab ozogamicin, but major challenges remain. There are potential advantages to immune therapy of AML compared with other cancers such as accessibility of AML cells and susceptibility to killing. However, negative aspects of immune therapy are requirements for antigenicity, immunogenicity, a low mutation rate and unacceptable reduced collateral damage to normal myeloid cells. Whether these challenges can be overcome is unknown. Hopefully so.
References
- Foon KA, Smalley RV, Riggs CW, Gale RP. The role of immunotherapy in acute myelogenous leukemia. Arch Intern Med 1983;143:1726-1731.
- Gale RP, Opelz G. Commentary: does immune suppression increase risk of developing acute myeloid leukemia? Leukemia. 2012; 26(3):422-423.
- Gale RP, Opelz G. Is there immune surveillance against chronic myeloid leukaemia? Possibly, but not much. Leuk Res. 2017;57:109-111.
- Horowitz MM, Gale RP, Sondel PM, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990;75(3):555-562.
- Gale RP, Fuchs EJ. Is there really a specific graft-versus-leukaemia effect? Bone Marrow Transplant 2016;51(11): 1413-1415.
- Yarchoan M, Hopkins A, Jaffee EM. Tumor Mutational Burden and Response Rate to PD-1 Inhibition. N Engl J Med. 2017; 377(25):2500-2501.
- Assi R, Kantarjian H, Ravandi F, Daver N. Immune therapies in acute myeloid leukemia: a focus on monoclonal antibodies and immune checkpoint inhibitors. Curr Opin Hematol. 2018, 25 (2), 136-145.
- Godwin CD, Gale RP, Walter RB. Gemtuzumab ozogamycin in acute myeloid leukemia. Leukemia, 2017; 31(9): 1855-1868.
- Lambert J, Pautas C, Terré C, Raffoux E, Turlure P, Caillot D, Legrand O, Thomas X, Gardin C, Gogat-Marchant K, Rubin SD, Benner RJ, Bousset P, Preudhomme C, Chevret S, Dombret H, Castaigne S. Gemtuzumab Ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, Phase III ALFA-0701. Trial. 2019;104(1):113-119. doi: 10.3324/haematol.2018.188888.
- Boddu P, Kantarjian H, Garcia-Manero G, Allison J, Sharma P, Daver N. The emerging role of immune checkpoint based approaches in AML and MDS. Leuk Lymphoma. 2018; 59 (4): 790-802.
- Davids MS, Kim HT, Bachireddy P, Costello C, Liguori R, Savell A, Lukez AP, Avigan D, Chen YB, McSweeney P, LeBoeuf NR, Rooney MS, Bowden M, Zhou CW, Granter SR, Hornick JL, et al. Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med. 2016; 375(2):143-153.
- Hansrivijit P, Gale RP, Barrett J, Ciurea SO. Cellular therapy for acute myeloid leukemia – current status and future prospects. Blood Rev 2019;doi.org/10.1016j. blre.2019.05.002.
- Miller JS, Soignier Y, Panoskaltsis-Mortari A, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 2005;105(8):3051-3057.
- Kim MY, Yu KR, Kenderian SS, Tsai SO, Dunbar CE, Saar Gill. Genetic inactivation of CD33 in hematopoietic stem cells to enable CAR T Cell immunotherapy for acute myeloid leukemia. Cell 2018;173:1439-1453.
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Prediction is very difficult, especially if it's about the future.
Niels Bohr
Introduction
Immune therapy is a safe and effective therapy of diverse cancers. In haematology this efficacy is limited predominately to B-cell lymphoid cancers including acute lymphoblastic leukemia (ALL), lymphomas and plasma cell myeloma. Effective therapies include monoclonal antibodies such as rituximab, antibody-drug conjugates such as brentuximab vedotin, antibody-radionuclide conjugates such as 131-iodine tositumomab, bi-specific monoclonal antibodies (BiTE® antibodies) such as blinatumomab (CD20/CD3) and chimeric antigen receptor T-cells (CAR-T-cells) to CD19, CD20 and to B-cell maturation antigen (BCMA). The target of these immune therapies are B-cell lineage antigens rather than cancer-specific antigens. These interventions are more effective than checkpoint-inhibition directed antibodies such as those to PD-1, or PD-1L or antibodies to CTLA-4 active in solid cancers.
One might expect equal success using immune therapy to treat myeloid cancers such as acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). However, this is not so. Early attempts to use immunotherapy for AML treatment (with BCG, C.parvum, or leukemia blast antigens) were not successful [1]. At the present time, there is only one FDA-approved therapy of myeloid cancers, gemtuzumab ozogamicin (Myelotarg®) for AML which was first approved >10 years ago, withdrawn and re-approved. Why this discordance?
What are the reasons for successful immune therapy of different blood cancers?
There are two important differences between myeloid and lymphoid cancers. First is the different structures and kinetics of myelopoiesis and lymphopoiesis. Lymphoid and myeloid lineages are divided (dichotomized) at the level of early progenitors. About at 600 billion cells myeloid cells are produced per day in contrast to only about 10 million lymphoid cells per day, a 60-fold difference. Also, granulocytes and platelets survive only a few hours or days in contrast to lymphoid cells which live years. The implication of these differences is a disruption of myelopoiesis is much more serious than a disruption of lymphopoiesis. One be reasonably well without B-cells, somewhat well without T- and NK-cells but you will die immediately without granulocytes and platelets.
Second this the different targetability of myeloid versus lymphoid antigens. As indicated, the target of immune therapy of lymphoid cancers is B-lineage antigens. These antigens are not cancer-specific such that normal B-cells are targeted along with the cancer cells. Fortunately killing all normal B-cells is compatible with life (normal B-cell function can be reversed by giving intravenous immune globulin [IVIG]). In contrast, it is impossible to replace normal granulocyte production, a situation is incompatible with life.
Is there immune surveillance against AML?
Figure 1. Low levels of myeloid leukemia evolving after kidney transplants [2, 3]
Figure 2. Cumulative incidence of relapse after allo-transplants for leukaemia [3]
Considerable data indicate the immune system is effective in controlling lymphomas. For example, lymphoma-risk is markedly increased in persons with immune deficiency or suppression such as those with severe combined immune deficiency (SCID), acquired immune deficiency syndrome (AIDS) and solid organ and hematopoietic transplant recipients. Most of these lymphomas are Epstein-Barr virus (EBV)-related. However, there is a only a small if any increased risk of AML, CML or myelodysplastic syndrome (MDS) in similar populations and amongst solid organ transplant recipients receiving life-long immune suppression (Fig. 1) [2, 3]. These data imply immune surveillance does not operate effectively against myeloid cancers.
Are there convincing data of an immune response to AML?
Considerable data indicate a strong immune response to myeloid cancers in the setting of a hematopoietic cell transplant. For example, among persons with AML receiving an HLA-identical sibling transplant, cumulative incidence of relapse (CIR) is highest among recipients of a transplant from a genetically-identical twins and lowest among recipients of allotransplants with acute and chronic graft-versus-host disease (GvHD) [4]. This difference correlates with histo-incompatibility between donor and recipient. Graft-versus-host disease (GvHD) and graft-versus-leukemia effect (GvL) may be identical or overlap to different degree in individuals.
Therefore, the answer on targetability of AML immune therapy lies in two considerations: (1) lack of a convincing AML-specific target antigen(s); and (2) unacceptable adverse effects from non-specificity of target antigens used in AML immune therapy such as CD33 and CD124. Therapy against these target antigens can potentially kill AML cells but will unavoidably destroy normal bone marrow cells resulting in death absent a transplant or using synthetic biology techniques.
What is the role of AML-specific antigens in graft-versus-leukaemia (GvL)?
There are several potential targets of anti-AML activity in the context of an allotransplant including: (1) HLA antigens; (2) minor histocompatibility antigens; (3) leukemia-associated antigens; and (4) leukemia-specific antigens (if they exist). All of these are potential targets of the so-called GvL-effect seen after allotransplants and after donor lymphocyte infusions (DLI). Elsewhere my colleague and I discuss whether this effect is leukemia-specific or against HLA and/or non-HLA antigens and not leukemia-specific [5].
Several variables correlate with success of immune therapy: (1) antigenicity; (2) immunogenicity; (3) accessibility; (4) sensitivity to killing; and (5) collateral damage to normal cells. The major current limitation of these approaches is lack of an AML-specific target antigen. In many models, probability of response to immune therapy correlates with mutation frequency and with estimated numbers of potential cancer-specific neo-antigens [6]. AML cells have an average of 0.28 mutation per megabase of DNA compared with 8.15 mutations for lung cancer, 40-fold less. For this reason checkpoint-inhibitor antibodies and antibodies to CTLA-4 are unlikely to be effective when used alone in persons with AML.
Figure 3. Correlation between coding somatic mutation frequency and objective response rates in diverse cancers [6]
Clinical trials
We can envision any potential immune therapy of blood cancer using along two strategies: antibody therapies and cell therapies. Antibody therapies can be further divided by technology such as unmodified antibodies, antibody-drug conjugates, antibody-radionuclide conjugates (radio-immunotherapy), bi-specific antibodies, and other more advanced techniques [7]. These data are summarized in the Table 1.
An example is gemtuzumab ozogamycin [8]. Clinical trials data are shown in Figure 4.
Table 1. Antibody-based therapies of acute myeloid leukemia (adapted from [7])
Figure 4. Improved long-term survival in persons with AML receiving or not receiving gemtuzumab ozogamycin [9]
PD-1 and CTLA-4 inhibitors
Clinical studies of immune checkpoint inhibitors like anti-PD-1 antibodies report little or no benefit. Current studies combine anti-PD-1 antibodies with anti-leukemic drugs [10]. A study in 22 subjects reported complete responses in 4 subjects with extra-medullary relapse of AML but not in subjects with bone marrow relapse [11].
Cell-based immune therapy
Cellular immune therapies use NK-cells and CAR-T- and CAR-NK cells and cytokine-induced NK-cells (CIK). My colleagues and I recently reviewed the current state of cell therapy of AML [12]. We discussed several approaches and concluded that although there are interesting preliminary data, there are no convincing data these approaches are a safe and effective treatment of AML. Perhaps the strongest current data are for NK-cells [13].
Synthetic biology techniques may allow use of anti-CD33 antibodies in AML by using CRISP/Cas9 to edit out CD33 from normal myeloid cells [14].
Conclusions
In summary, immune therapy of AML poses challenges different from immune therapy of lymphoid-lineage cancers. There is progress, for example with gemtuzumab ozogamicin, but major challenges remain. There are potential advantages to immune therapy of AML compared with other cancers such as accessibility of AML cells and susceptibility to killing. However, negative aspects of immune therapy are requirements for antigenicity, immunogenicity, a low mutation rate and unacceptable reduced collateral damage to normal myeloid cells. Whether these challenges can be overcome is unknown. Hopefully so.
References
- Foon KA, Smalley RV, Riggs CW, Gale RP. The role of immunotherapy in acute myelogenous leukemia. Arch Intern Med 1983;143:1726-1731.
- Gale RP, Opelz G. Commentary: does immune suppression increase risk of developing acute myeloid leukemia? Leukemia. 2012; 26(3):422-423.
- Gale RP, Opelz G. Is there immune surveillance against chronic myeloid leukaemia? Possibly, but not much. Leuk Res. 2017;57:109-111.
- Horowitz MM, Gale RP, Sondel PM, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990;75(3):555-562.
- Gale RP, Fuchs EJ. Is there really a specific graft-versus-leukaemia effect? Bone Marrow Transplant 2016;51(11): 1413-1415.
- Yarchoan M, Hopkins A, Jaffee EM. Tumor Mutational Burden and Response Rate to PD-1 Inhibition. N Engl J Med. 2017; 377(25):2500-2501.
- Assi R, Kantarjian H, Ravandi F, Daver N. Immune therapies in acute myeloid leukemia: a focus on monoclonal antibodies and immune checkpoint inhibitors. Curr Opin Hematol. 2018, 25 (2), 136-145.
- Godwin CD, Gale RP, Walter RB. Gemtuzumab ozogamycin in acute myeloid leukemia. Leukemia, 2017; 31(9): 1855-1868.
- Lambert J, Pautas C, Terré C, Raffoux E, Turlure P, Caillot D, Legrand O, Thomas X, Gardin C, Gogat-Marchant K, Rubin SD, Benner RJ, Bousset P, Preudhomme C, Chevret S, Dombret H, Castaigne S. Gemtuzumab Ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, Phase III ALFA-0701. Trial. 2019;104(1):113-119. doi: 10.3324/haematol.2018.188888.
- Boddu P, Kantarjian H, Garcia-Manero G, Allison J, Sharma P, Daver N. The emerging role of immune checkpoint based approaches in AML and MDS. Leuk Lymphoma. 2018; 59 (4): 790-802.
- Davids MS, Kim HT, Bachireddy P, Costello C, Liguori R, Savell A, Lukez AP, Avigan D, Chen YB, McSweeney P, LeBoeuf NR, Rooney MS, Bowden M, Zhou CW, Granter SR, Hornick JL, et al. Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med. 2016; 375(2):143-153.
- Hansrivijit P, Gale RP, Barrett J, Ciurea SO. Cellular therapy for acute myeloid leukemia – current status and future prospects. Blood Rev 2019;doi.org/10.1016j. blre.2019.05.002.
- Miller JS, Soignier Y, Panoskaltsis-Mortari A, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 2005;105(8):3051-3057.
- Kim MY, Yu KR, Kenderian SS, Tsai SO, Dunbar CE, Saar Gill. Genetic inactivation of CD33 in hematopoietic stem cells to enable CAR T Cell immunotherapy for acute myeloid leukemia. Cell 2018;173:1439-1453.
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Роберт П. Гэйл
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" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "26439" ["VALUE"]=> array(2) { ["TEXT"]=> string(3467) "<p style="text-align: justify;">Достигнут значительный прогресс в иммунотерапии различных злокачественных заболеваний. В области гематологии эти успехи ограничены в основном лимфоидными неоплазиями. Эффективные методы терапии включают моноклональные антитела и Т-клетки с химерным антигенным рецептором (CAR-T-клетки) к антигенам клеток лимфоидного ряда, таким, как CD19, CD20 и антигенам созревания В-клеток (BCMA). Гемтузумаб озогамицин (Миелотарг®) является единственным препаратом, одобренным FDA для иммунотерапии острого миелобластного лейкоза (ОМЛ). Сообщают о нескольких клинических исследованиях антител к CD38 и CD123 с невысокой эффективностью и проблемами безопасности применения. Причинами являются: высокий уровень продукции миелоидных клеток и существенные повреждения нормальных кроветворных клеток в связи с недостаточной специфичностью в отношении клеток ОМЛ. Потенциальными мишенями для анти-ОМЛ терапии являются: (1) антигены системы HLA; (2) минорные антигены гистосовместимости; (3) лейкоз-ассоциированные антигены и (4) лейкоз-специфические антигены.</p> <p style="text-align: justify;">Данные в пользу эффективного аллогенного анти-ОМЛ эффекта основаны на исследованиях реципиентов гемопоэтических клеток с реакцией «трансплантат против хозяина» и реципиентов инфузий донорских лимфоцитов. Особой проблемой является относительный дефицит неоантигенов ОМЛ, по сравнению с солидными новообразованиями, что связано с низкой частотой накопленных мутаций. Исследования по клеточной иммунной терапии продолжаются, включая CAR-T-клетки, CAR-NK-клетки и аллогенные NK-клетки. Развиваются подходы с применением синтетической биологии. В настоящее время, кроме гемтузумаба озогамицина, отсутствуют убедительные данные об эффективности иммунной терапии при ОМЛ. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Острый миелобластный лейкоз, мутации, неоантигены, иммунотерапия.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3389) "Достигнут значительный прогресс в иммунотерапии различных злокачественных заболеваний. В области гематологии эти успехи ограничены в основном лимфоидными неоплазиями. Эффективные методы терапии включают моноклональные антитела и Т-клетки с химерным антигенным рецептором (CAR-T-клетки) к антигенам клеток лимфоидного ряда, таким, как CD19, CD20 и антигенам созревания В-клеток (BCMA). Гемтузумаб озогамицин (Миелотарг®) является единственным препаратом, одобренным FDA для иммунотерапии острого миелобластного лейкоза (ОМЛ). Сообщают о нескольких клинических исследованиях антител к CD38 и CD123 с невысокой эффективностью и проблемами безопасности применения. Причинами являются: высокий уровень продукции миелоидных клеток и существенные повреждения нормальных кроветворных клеток в связи с недостаточной специфичностью в отношении клеток ОМЛ. Потенциальными мишенями для анти-ОМЛ терапии являются: (1) антигены системы HLA; (2) минорные антигены гистосовместимости; (3) лейкоз-ассоциированные антигены и (4) лейкоз-специфические антигены.
Данные в пользу эффективного аллогенного анти-ОМЛ эффекта основаны на исследованиях реципиентов гемопоэтических клеток с реакцией «трансплантат против хозяина» и реципиентов инфузий донорских лимфоцитов. Особой проблемой является относительный дефицит неоантигенов ОМЛ, по сравнению с солидными новообразованиями, что связано с низкой частотой накопленных мутаций. Исследования по клеточной иммунной терапии продолжаются, включая CAR-T-клетки, CAR-NK-клетки и аллогенные NK-клетки. Развиваются подходы с применением синтетической биологии. В настоящее время, кроме гемтузумаба озогамицина, отсутствуют убедительные данные об эффективности иммунной терапии при ОМЛ.
Ключевые слова
Острый миелобластный лейкоз, мутации, неоантигены, иммунотерапия.
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Correspondence
Robert Peter Gale MD, PhD, DSc(hc), FACP, FRCP, Visiting Professor Haematology, Centre for Haematology Research, Department of Immunology and Inflammation Imperial College London, London, UK
E-mail: robertpetergale@gmail.com
There is considerable progress in immune therapy of diverse cancers. In haematology these advances are mostly limited to lymphoid cancers. Effective therapies include monoclonal antibodies and chimeric antigen receptor (CAR)-T-cells to lymphoid lineage-antigens such as CD19, CD20 and B-cell maturation antigen (BCMA). Gemtuzumab ozogamicin (Myelotarg®) is the only FDA-approved immune-based therapy for acute myeloid leukemia (AML). Several clinical trials of antibodies to CD38 and CD123 are reported with unimpressive efficacy and safety concerns. Reasons are higher daily production rates of myeloid cells and unacceptable collateral damage to normal haematopoietic cells because of imperfect specificity for AML cells. Potential targets of anti-AML immune therapy are (1) HLA antigens; (2) minor histocompatibility antigens; (3) leukemia-associated antigens; and (4) leukemia-specific antigens. Data supporting an effective allogeneic anti-AML effect come from studies in recipients of haematopoietic cell transplants with graft-versus-host disease (GvHD) and recipients of donor lymphocyte infusions (DLI). A special problem is a relative paucity of neo-antigens in AML compared with solid cancers because of a low cumulative mutation frequency. Cell immune therapy trials are in progress including CAR-T-cells, CAR-NK-cells and allogeneic NK-cells. Approaches using synthetic biology are being developed. Presently, except for gemtuzumab ozogamicin there are no convincing data of efficacy of immune therapy in AML.
Keywords
Acute myeloid leukemia, mutations, neoantigens, immune therapy.
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" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "26442" ["VALUE"]=> array(2) { ["TEXT"]=> string(1736) "<p style="text-align: justify;">There is considerable progress in immune therapy of diverse cancers. In haematology these advances are mostly limited to lymphoid cancers. Effective therapies include monoclonal antibodies and chimeric antigen receptor (CAR)-T-cells to lymphoid lineage-antigens such as CD19, CD20 and B-cell maturation antigen (BCMA). Gemtuzumab ozogamicin (Myelotarg®) is the only FDA-approved immune-based therapy for acute myeloid leukemia (AML). Several clinical trials of antibodies to CD38 and CD123 are reported with unimpressive efficacy and safety concerns. Reasons are higher daily production rates of myeloid cells and unacceptable collateral damage to normal haematopoietic cells because of imperfect specificity for AML cells. Potential targets of anti-AML immune therapy are (1) HLA antigens; (2) minor histocompatibility antigens; (3) leukemia-associated antigens; and (4) leukemia-specific antigens. Data supporting an effective allogeneic anti-AML effect come from studies in recipients of haematopoietic cell transplants with graft-versus-host disease (GvHD) and recipients of donor lymphocyte infusions (DLI). A special problem is a relative paucity of neo-antigens in AML compared with solid cancers because of a low cumulative mutation frequency. Cell immune therapy trials are in progress including CAR-T-cells, CAR-NK-cells and allogeneic NK-cells. Approaches using synthetic biology are being developed. Presently, except for gemtuzumab ozogamicin there are no convincing data of efficacy of immune therapy in AML.</p> <h2>Keywords</h2> <p style="text-align: justify;">Acute myeloid leukemia, mutations, neoantigens, immune therapy.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1680) "There is considerable progress in immune therapy of diverse cancers. In haematology these advances are mostly limited to lymphoid cancers. Effective therapies include monoclonal antibodies and chimeric antigen receptor (CAR)-T-cells to lymphoid lineage-antigens such as CD19, CD20 and B-cell maturation antigen (BCMA). Gemtuzumab ozogamicin (Myelotarg®) is the only FDA-approved immune-based therapy for acute myeloid leukemia (AML). Several clinical trials of antibodies to CD38 and CD123 are reported with unimpressive efficacy and safety concerns. Reasons are higher daily production rates of myeloid cells and unacceptable collateral damage to normal haematopoietic cells because of imperfect specificity for AML cells. Potential targets of anti-AML immune therapy are (1) HLA antigens; (2) minor histocompatibility antigens; (3) leukemia-associated antigens; and (4) leukemia-specific antigens. Data supporting an effective allogeneic anti-AML effect come from studies in recipients of haematopoietic cell transplants with graft-versus-host disease (GvHD) and recipients of donor lymphocyte infusions (DLI). A special problem is a relative paucity of neo-antigens in AML compared with solid cancers because of a low cumulative mutation frequency. Cell immune therapy trials are in progress including CAR-T-cells, CAR-NK-cells and allogeneic NK-cells. Approaches using synthetic biology are being developed. Presently, except for gemtuzumab ozogamicin there are no convincing data of efficacy of immune therapy in AML.
Keywords
Acute myeloid leukemia, mutations, neoantigens, immune therapy.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1680) "There is considerable progress in immune therapy of diverse cancers. In haematology these advances are mostly limited to lymphoid cancers. Effective therapies include monoclonal antibodies and chimeric antigen receptor (CAR)-T-cells to lymphoid lineage-antigens such as CD19, CD20 and B-cell maturation antigen (BCMA). Gemtuzumab ozogamicin (Myelotarg®) is the only FDA-approved immune-based therapy for acute myeloid leukemia (AML). Several clinical trials of antibodies to CD38 and CD123 are reported with unimpressive efficacy and safety concerns. Reasons are higher daily production rates of myeloid cells and unacceptable collateral damage to normal haematopoietic cells because of imperfect specificity for AML cells. Potential targets of anti-AML immune therapy are (1) HLA antigens; (2) minor histocompatibility antigens; (3) leukemia-associated antigens; and (4) leukemia-specific antigens. Data supporting an effective allogeneic anti-AML effect come from studies in recipients of haematopoietic cell transplants with graft-versus-host disease (GvHD) and recipients of donor lymphocyte infusions (DLI). A special problem is a relative paucity of neo-antigens in AML compared with solid cancers because of a low cumulative mutation frequency. Cell immune therapy trials are in progress including CAR-T-cells, CAR-NK-cells and allogeneic NK-cells. Approaches using synthetic biology are being developed. Presently, except for gemtuzumab ozogamicin there are no convincing data of efficacy of immune therapy in AML.
Keywords
Acute myeloid leukemia, mutations, neoantigens, immune therapy.
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Correspondence
Robert Peter Gale MD, PhD, DSc(hc), FACP, FRCP, Visiting Professor Haematology, Centre for Haematology Research, Department of Immunology and Inflammation Imperial College London, London, UK
E-mail: robertpetergale@gmail.com
Imperial College London, London, UK
Correspondence
Robert Peter Gale MD, PhD, DSc(hc), FACP, FRCP, Visiting Professor Haematology, Centre for Haematology Research, Department of Immunology and Inflammation Imperial College London, London, UK
E-mail: robertpetergale@gmail.com
Роберт П. Гэйл
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В области гематологии эти успехи ограничены в основном лимфоидными неоплазиями. Эффективные методы терапии включают моноклональные антитела и Т-клетки с химерным антигенным рецептором (CAR-T-клетки) к антигенам клеток лимфоидного ряда, таким, как CD19, CD20 и антигенам созревания В-клеток (BCMA). Гемтузумаб озогамицин (Миелотарг®) является единственным препаратом, одобренным FDA для иммунотерапии острого миелобластного лейкоза (ОМЛ). Сообщают о нескольких клинических исследованиях антител к CD38 и CD123 с невысокой эффективностью и проблемами безопасности применения. Причинами являются: высокий уровень продукции миелоидных клеток и существенные повреждения нормальных кроветворных клеток в связи с недостаточной специфичностью в отношении клеток ОМЛ. Потенциальными мишенями для анти-ОМЛ терапии являются: (1) антигены системы HLA; (2) минорные антигены гистосовместимости; (3) лейкоз-ассоциированные антигены и (4) лейкоз-специфические антигены.</p> <p style="text-align: justify;">Данные в пользу эффективного аллогенного анти-ОМЛ эффекта основаны на исследованиях реципиентов гемопоэтических клеток с реакцией «трансплантат против хозяина» и реципиентов инфузий донорских лимфоцитов. Особой проблемой является относительный дефицит неоантигенов ОМЛ, по сравнению с солидными новообразованиями, что связано с низкой частотой накопленных мутаций. Исследования по клеточной иммунной терапии продолжаются, включая CAR-T-клетки, CAR-NK-клетки и аллогенные NK-клетки. Развиваются подходы с применением синтетической биологии. В настоящее время, кроме гемтузумаба озогамицина, отсутствуют убедительные данные об эффективности иммунной терапии при ОМЛ. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Острый миелобластный лейкоз, мутации, неоантигены, иммунотерапия.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3389) "Достигнут значительный прогресс в иммунотерапии различных злокачественных заболеваний. В области гематологии эти успехи ограничены в основном лимфоидными неоплазиями. Эффективные методы терапии включают моноклональные антитела и Т-клетки с химерным антигенным рецептором (CAR-T-клетки) к антигенам клеток лимфоидного ряда, таким, как CD19, CD20 и антигенам созревания В-клеток (BCMA). Гемтузумаб озогамицин (Миелотарг®) является единственным препаратом, одобренным FDA для иммунотерапии острого миелобластного лейкоза (ОМЛ). Сообщают о нескольких клинических исследованиях антител к CD38 и CD123 с невысокой эффективностью и проблемами безопасности применения. Причинами являются: высокий уровень продукции миелоидных клеток и существенные повреждения нормальных кроветворных клеток в связи с недостаточной специфичностью в отношении клеток ОМЛ. Потенциальными мишенями для анти-ОМЛ терапии являются: (1) антигены системы HLA; (2) минорные антигены гистосовместимости; (3) лейкоз-ассоциированные антигены и (4) лейкоз-специфические антигены.
Данные в пользу эффективного аллогенного анти-ОМЛ эффекта основаны на исследованиях реципиентов гемопоэтических клеток с реакцией «трансплантат против хозяина» и реципиентов инфузий донорских лимфоцитов. Особой проблемой является относительный дефицит неоантигенов ОМЛ, по сравнению с солидными новообразованиями, что связано с низкой частотой накопленных мутаций. Исследования по клеточной иммунной терапии продолжаются, включая CAR-T-клетки, CAR-NK-клетки и аллогенные NK-клетки. Развиваются подходы с применением синтетической биологии. В настоящее время, кроме гемтузумаба озогамицина, отсутствуют убедительные данные об эффективности иммунной терапии при ОМЛ.
Ключевые слова
Острый миелобластный лейкоз, мутации, неоантигены, иммунотерапия.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(3389) "Достигнут значительный прогресс в иммунотерапии различных злокачественных заболеваний. В области гематологии эти успехи ограничены в основном лимфоидными неоплазиями. Эффективные методы терапии включают моноклональные антитела и Т-клетки с химерным антигенным рецептором (CAR-T-клетки) к антигенам клеток лимфоидного ряда, таким, как CD19, CD20 и антигенам созревания В-клеток (BCMA). Гемтузумаб озогамицин (Миелотарг®) является единственным препаратом, одобренным FDA для иммунотерапии острого миелобластного лейкоза (ОМЛ). Сообщают о нескольких клинических исследованиях антител к CD38 и CD123 с невысокой эффективностью и проблемами безопасности применения. Причинами являются: высокий уровень продукции миелоидных клеток и существенные повреждения нормальных кроветворных клеток в связи с недостаточной специфичностью в отношении клеток ОМЛ. Потенциальными мишенями для анти-ОМЛ терапии являются: (1) антигены системы HLA; (2) минорные антигены гистосовместимости; (3) лейкоз-ассоциированные антигены и (4) лейкоз-специфические антигены.
Данные в пользу эффективного аллогенного анти-ОМЛ эффекта основаны на исследованиях реципиентов гемопоэтических клеток с реакцией «трансплантат против хозяина» и реципиентов инфузий донорских лимфоцитов. Особой проблемой является относительный дефицит неоантигенов ОМЛ, по сравнению с солидными новообразованиями, что связано с низкой частотой накопленных мутаций. Исследования по клеточной иммунной терапии продолжаются, включая CAR-T-клетки, CAR-NK-клетки и аллогенные NK-клетки. Развиваются подходы с применением синтетической биологии. В настоящее время, кроме гемтузумаба озогамицина, отсутствуют убедительные данные об эффективности иммунной терапии при ОМЛ.
Ключевые слова
Острый миелобластный лейкоз, мутации, неоантигены, иммунотерапия.
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Target drug delivery systems find increasingly wide application in medicine. Use of these systems requires high stability of encapsulated MC, low dosage and toxicity, prolonged therapeutic action. Porous vaterites (one of three calcium carbonate polymorphs) have been used as carriers in delivery systems (DS) for biologically active compounds and medicinal compounds since 2004 [1]. In many research works, they were used as "sacrificed" matrices. Porous carbonate cores were saturated with biologically active compounds using different methods, then their surface was coated layer-by-layer with polyelectrolytes; polymers with opposite excess charges were applied by turns. After dissolution of СаСО3 cores in the presence of chelate compounds (e.g., ethylenediaminetetraacetic acid), these multilayered shells were used as capsules for delivery of biologically active compounds [2]. In some cases, carbonate cores were not dissolved, but used together with their PE shells [3-5]. Since one of the objectives of employing delivery systems is to provide prolonged release of an encapsulated MC, preservation of the porous core increases resistance of the structure against external influence and thus helps attain this goal. Another way of using СаСО3 as a component of DS consists in including carbonate cores into alginate granule, which significantly simplifies DS preparation [6].
A number of research papers [7-9] report preparation of DS with СаСО3 in combination with various polymers; antitumor drug doxorubicin was used as an active substance. In vitro experiments demonstrated prolonged pH-dependent release of the drug.
Note that synthesis of СаСО3 cores is relatively simple. It is believed that they are completely biocompatible and biodegradable; they show neither toxicity nor immunogenicity, and thus are well tolerated by a recipient organism [10]. This opinion was confirmed by the studies of behavior of СаСО3-based delivery systems in various model environments as well as upon administration of these DS into living rabbits, rats and mice by various methods. Configurations of DS based on СаСО3 cores depend on the method used for their administration. The influence of various environments on the DS containing СаСО3 cores is described in the papers that are quoted below.
In water or physiological solution (0.9% NaCl), СаСО3 vaterites undergo morphological transformations [11]. At medium temperatures, porous vaterites turn into calcites (which are more thermodynamically stable), and at elevated temperatures (above 37-40°С), they are transformed into aragonites [12]. Since these polymorphs are not porous, recrystallization is accompanied by release of drugs encapsulated in vaterites. The drug release profiles correlate with percentages of calcites formed [13].
Oral administration is the most convenient method for patients. However, vaterite cores dissolve in acidic medium of a stomach; therefore, the cores with encapsulated MC should be protected. This protection can be provided both by PE shells (on condition that their components are stable in acidic stomach environment) and alginate granules surrounding СаСО3 cores. Since it is necessary to provide penetration of MC from intestinal tract into main blood flow, a polymer shell should swell or dissolve in the middle division of intestinal tract, thus releasing СаСО3 with MC. Model experiments involving 0.15 M phosphate buffer with рН=7.4 (model intestinal fluid) demonstrated that CaCO3 enters into ion-exchange reaction with phosphate ions; as a result, rather compact porous vaterites are transformed into loose macroporous СаНРО4 structures. This process facilitates release of the encapsulated MC. Scanning electron microscopy (SEM) and energy-dispersive spectroscopy (EDS) studies revealed structural changes in СаСО3 vaterites [14]. Similar transformation also occurs with time in the case of two-level DS that consist of alginate granules and carbonate cores. The presence of fragments of СаСО3 cores in blood and plasma of experimental animals (rats) was confirmed by elemental analysis of the samples [15].
The requirements for size of DS intended for parentheral administration are more rigid, but in this case the carrier should not be necessary protected (unlike the systems used in oral delivery). The СаСО3 vaterites that were synthesized according to the technique described in [1] have sizes of 3-5 μm. Diameter of cores may be reduced by various methods: change in the basic synthesis conditions – increasing concentration of the initial solutions of salts (Na2CO3 and CaCl2), and stirring intensity [16]; increase in viscosity of starting solutions by adding ethylene glycol [17]; addition of a polyelectrolyte during co-precipitation of the salts [18-20]. Unfortunately, the latter method gives low yield of the final product and requires monitoring interaction between MC and polymer.
The authors of [21] used intratracheal administration of СаСО3 cores that contained BSA protein labeled with Cy7 fluorophore. It was demonstrated that efficiency of penetration into lungs for carriers of various diameters decreased with increasing core size from 0.65 to 3.15 μm. Penetration of the labeled protein into lungs with the aid of СаСО3 vaterites of different sizes was confirmed by confocal microscopy of mouse lung cryocut sections. The lower DS size, the deeper they penetrate into lung tissue. Confocal microscopy makes it possible to localize СаСО3 carriers in a sample. Recrystallization of vaterites was observed in the model environment that included physiological solution and bronchoalveolar lavage (containing proteins and surfactants). It was shown that the components of lavage covering vaterite surface protect them from recrystallization.
The authors of [22] demonstrated possibility of penetration of СаСО3 vaterites with encapsulated loperamide through blood-brain barrier of rats after intranasal administration. In order to enhance mucoadhesion, СаСО3 cores were covered with mucoadhesive polymers (hyaluronic acid or poly-L-lysine).
It was suggested [10] to use СаСО3 cores with encapsulated superoxide dismutase enzyme as an ophthalmic delivery system. According to the authors, no undesirable effects were observed after injections of vaterite microcrystals (concentration 10 mg/mL) into eye tissues of rabbits.
In vivo transdermal administration of СаСО3 particles (diameter: 4 μm) to a depth of 200 μm was performed via laser ablation followed by massage. These relatively large particles did not penetrate into the underlying derma. In 1 week after beginning of the experiment, СаСО3 particles dissolved in rat body and released the encapsulated compound [23].
It was revealed [24] that porous СаСО3 cores degraded completely in three months after introducing them into rat bone tissue.
Along with other calcium-containing inorganic nanostructured materials, СаСО3 vaterites find increasing applications in regenerative medicine and tissue engineering [25].
To summarize, all methods for introducing DS based on СаСО3 vaterites are aimed at providing absorption of cores by cells. The influence of size and shape of СаСО3 particles on cell uptake was studied in [26]. It was demonstrated that internalization is more effective for spherical particles with the lowest volume, and for elongated particles.
Currently, there are no literature data on the studies of behavior of vaterite-based DS in human blood plasma and upon their intramuscular administration. When using the majority of the above-mentioned methods, it is necessary to study transformations of DS in blood plasma. The second method may be efficient when DS with MC are introduced directly into tumor tissue. Thus, the goal of the present work was to study behavior of spherical СаСО3 vaterites (components of target delivery systems for antitumor drugs) in vitro (in human blood plasma) and in vivo (in rat muscle tissue).
Abbreviations: DS, delivery systems; MC, medicinal compounds; EDS, energy dispersive spectroscopy; SEM, scanning electron microscopy; EDTA, ethylenediaminetetraacetic acid; BSA, bovine serum albumin.
Materials and methods
Synthesis of carbonate cores
Porous vaterites (СаСО3 cores) were prepared by co-precipitation according to the technique described in [1] with some modifications. Equal volumes of 1 M aqueous solutions of CaCl2×2H2O and Na2CO3 were rapidly mixed at stirring with an RW 20 anchor-type mechanical stirrer (Kika-Werk, Switzerland) (1000 rpm). The mixture was stirred for 30 s. Then the suspension was filtered through Schott filter glass (#16), washed thrice with distilled water, then with acetone/water mixtures with increasing acetone concentrations (33%, 50%, and 100%). The precipitate was dried in thermostat at 40-50°C until a constant weight was achieved. Diameter of the obtained cores varies from 1 to 3 μm.
Interaction between СаСО3 and human blood plasma
Interaction between carbonate cores and human blood plasma was performed at continuous stirring of the suspension. When the reaction was complete, the cores were centrifuged (5 min at 3000 rpm); the supernatant was poured out and substituted for distilled water. The procedure was performed twice. The cores were dried at 40°C until a constant weight was achieved.
Scanning electron microscopy (SEM)
SEM microphotographs of СаСО3 cores were obtained with the help of a Supra 55VP scanning electron microscope (Carl Zeiss, Germany) using secondary electron imaging; before the experiments, the samples were coated with thin platinum layer.
Energy dispersive spectroscopy (EDS)
Elemental compositions of the samples were determined by energy-dispersive spectroscopy (EDS) using an X-Max 80 detector (Oxford Instruments, UK).
Experiments with animals
The experiments involving animals were performed according to the laboratory animal welfare policy accepted in Russian Federation and European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes (ETS 123, Strasbourg, 1986).
In vivo experiments involved 10 male Wistar rats (weight: 200-250 g, age: 3 months). Before studies of bioresorption in vivo, СаСО3 cores were sterilized in autoclave at 110°С for 1 h. Each weighed amount of СаСО3 (10 mg) intended for an experiment in each of two locations in one animal was carefully hermetically packed in aluminum foil. The animals were operated under general anesthesia (intraperitoneal injections of Zoletil 100 (0.1 mL) and Rometar (20 mg/mL) solutions, 0.0125 mL per 0.1 kg of animal body mass). The samples were placed into thigh great adductor muscles (musculus adductor magnus) of both hind extremities. Then the wounds were sutured layer by layer using atraumatic needles and Prolene 4-0 suture. After outer suturing, the rats were caged individually, were fed standard diet, and had free access to water. All animals were active after surgery; no inflammation in the implantation area was observed, which is indicative of the absence of detrimental effects of implantation.
Histological studies
In 1 and 2 weeks after operation, samples of muscle tissue containing СаСО3 were fixed with 10% neutral formalin in phosphate buffer (рН=7.4) for not less than 24 hrs, dehydrated using a series of ethanol solutions with increasing concentrations, and enclosed in paraffin blocks according to the standard histological technique. The paraffin cuts (5 μm in width) transverse to muscular fibers were obtained with the use of an Accu-Cut SRT 200 microtome (Sakura, Japan) and stained with Mayer hematoxylin and eosin (Bio-Optica, Italy). The connective tissue was visualized according to the Mallory method (BioVitrum, Russia). Microscopic analysis was performed using a Leica DM750 light microscope (Germany) with a 10× ocular and 4, 10, 40, and 100× objectives. Images were recorded with an ICC50 camera (Leica, Germany).
Results
Influence of human blood plasma on the structure of СаСО3 cores
Table 1. Phosphorus content (P) in CaCO3 samples that contacted with blood plasma for various periods of time
Blood plasma contains phosphate ions, which enter into reaction with СаСО3 vaterites; as a result, macroporous СаНРО4 structures are gradually formed [14]. It is seen in the SEM images of СаСО3 vaterites (Fig. 1) that the objects with increasingly loose structure are formed with time; they consist of needle-like subunits less than 1 μm in diameter.
Phosphorus content in the studied structures was determined by energy-dispersive spectroscopy (see Table 1).
The EDS data show that phosphorus content in transformed structures increases with time; this result confirms that ion exchange reaction indeed occurs in СаСО3 vaterites.
Figure 1. Microphotographs of СаСО3 vaterites taken upon interaction with human blood plasma for various periods of time: A – 2 hrs; B – 24 hrs; C – 50 hrs
Transformation of СаСО3 vaterites upon intramuscular administration
After injection of СаСО3 vaterites into thigh great adductor muscles (musculus adductor magnus) of both hind extremities in rats, needle-like structures were formed (Fig. 2) and then gradually disappeared in two weeks due to bioresorption. Presumably, these needles are aragonites (one of three СаСО3 polymorphs). Fig. 2B presents the magnified image of the area where vaterites were introduced and then transformed into aragonites (1 week after operation). As was mentioned in Introduction, aragonites (non-porous elongated structures) are one of three morphological modifications of calcium carbonate, along with non-porous (usually cubic) calcites and porous spherical vaterites (which are used as components of target drug delivery systems). Transformation of vaterites during their use in delivery systems into calcites is frequently observed [13]. Formation of aragonite-like structures in the process of bioresorption of СаСО3 vaterites was revealed in the present work for the first time.
Figure 2. Histological cuts of rat muscle tissue obtained in 1 week after implantation of СаСО3 vaterites. Staining with hematoxylin and eosin; objectives 10× (а), 40× (b)
Discussion
he reason for transformation of porous СаСО3 vaterites (diameter: 1 – 3 μm) into needle-like aragonites (length: 30 – 150 μm, width: 10 – 40 μm) in muscle tissue still remains unclear. It may be suggested that morphological transformation of vaterites is influenced by the following factors. First, there is a difference between pH values of muscle tissue and blood or its components (pH of muscle tissue is lower). The second factor involves peculiarities of metabolic processes, mainly, exchange of carbon dioxide. Upon interaction with water, carbon dioxide forms carbonic acid, which reacts with calcium carbonate. Among other factors are intensive action of immune cells, and, finally, mechanic action related to muscle contraction. This issue should be investigated further.
The comparison between our results and the literature data on transformation of СаСО3 vaterites with encapsulated Fe3O4 nanoparticles (which occurred after shallow transdermal injection into rat body [23]) shows that no vaterite modification in muscle tissue was observed. The histological sections prepared in one week after transdermal administration show spherical structures almost similar to the initial cores. In two weeks after operation, vaterites underwent bioresorption, and Fe3O4 nanoparticles were released. These data may indirectly confirm our hypothesis concerning the influence of the above factors on transformation of CaCO3 vaterites in muscle tissue.
Bioresorption of vaterites in blood plasma in vitro is also completed in relatively short period of time (several weeks), while plasma composition remains mostly unchanged.
The main advantage of the DS based on CaCO3 vaterites intended for intramuscular administration of antitumor preparations is the fact that modified carbonate cores undergo complete bioresorption in 2 weeks in vivo and exert no negative influence on the surrounding tissues. The fact that aragonites are formed in the muscles once again indicates the ambiguity of applying the conclusions obtained from in vitro experiments to the in vivo behavior of the studied objects.
The obtained results confirm ability of porous calcium carbonate cores for bioresorption and their safety for medicinal use, which allows us to recommend porous CaCO3 vaterites for further experimental studies as components of target drug delivery systems.
Conflict of interests
None declared.
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- Zhao D, Zhuo R, Cheng S. Alginate modified nanostructured calcium carbonate with enhanced delivery efficiency for gene and drug delivery. Mol Biosystems. 2012; 8:753-759.
- Gusliakova O, Atochina-Vasserman EN, Sindeeva O, Sindeev S, Pinyaev S, Pyataev N, Revin V, Sukhorukov GB, Gorin D, Gow AJ. Use of submicron vaterite particles serves as an effective delivery vehicle to the respiratory portion of the lung. Front Pharmacol: Exp Pharmacol and Drug Discovery. 2018; 9: Article 559. DOI: 10.3389/fphar.2018.00559.
- Borodina, TN, Trushina DB, Marchenko IV, Bukreeva TV. Calcium carbonate-based mucoadhesive microcontainers for intranasal delivery of drugs bypassing the blood-brain barrier. BioNanoScience. 2016; 6: 261-268. DOI: 10.1007/s12668-016-0212-2.
- Genina EA, Svenskaya YI, Yanina IY, Dolotov LE, Navolokin NA, Bashkatov AN, Terentyuk GS, Bucharskaya AB, Maslyakova GN, Gorin DA, Tuchin VV, Sukhorukov GB. In vivo optical monitoring of transcutaneous delivery of calcium carbonate microcontainers. Biomed Opt Express. 2016; 7: 2082-2087. DOI: 10.1364/BOE.7.002082.
- Ohgushi H, Okumura M, Yoshikawa T, Inboue K, Senpuku N, Tamai S, Shors EC. Bone formation process in porous calcium carbonate and hydroxyapatite. J Biomed Mater Res. 1992; 26 (7): 885-895. DOI: 10.1002/jbm.820260705.
- Trushina DB, Bukreeva TV, Kovalchuk MV, Antipina MN. CaCO3 vaterite microparticles for biomedical and personal care applications. Materials Sci Engineering C. 2014; 45: 644-658. DOI: 10.1016/j.msec.2014.04.050.
- Parakhonskiy B, Zyuzin MV, Yashchenok A, Carregal-Romero S, Rejman J, Möhwald H. The influence of the size and aspect ratio of anisotropic, porous CaCO3 particles on their uptake by cells. J Nanobiotechnol. 2015; 13: Article 53. doi: 10.1186/s12951-015-0111-7.
Introduction
Target drug delivery systems find increasingly wide application in medicine. Use of these systems requires high stability of encapsulated MC, low dosage and toxicity, prolonged therapeutic action. Porous vaterites (one of three calcium carbonate polymorphs) have been used as carriers in delivery systems (DS) for biologically active compounds and medicinal compounds since 2004 [1]. In many research works, they were used as "sacrificed" matrices. Porous carbonate cores were saturated with biologically active compounds using different methods, then their surface was coated layer-by-layer with polyelectrolytes; polymers with opposite excess charges were applied by turns. After dissolution of СаСО3 cores in the presence of chelate compounds (e.g., ethylenediaminetetraacetic acid), these multilayered shells were used as capsules for delivery of biologically active compounds [2]. In some cases, carbonate cores were not dissolved, but used together with their PE shells [3-5]. Since one of the objectives of employing delivery systems is to provide prolonged release of an encapsulated MC, preservation of the porous core increases resistance of the structure against external influence and thus helps attain this goal. Another way of using СаСО3 as a component of DS consists in including carbonate cores into alginate granule, which significantly simplifies DS preparation [6].
A number of research papers [7-9] report preparation of DS with СаСО3 in combination with various polymers; antitumor drug doxorubicin was used as an active substance. In vitro experiments demonstrated prolonged pH-dependent release of the drug.
Note that synthesis of СаСО3 cores is relatively simple. It is believed that they are completely biocompatible and biodegradable; they show neither toxicity nor immunogenicity, and thus are well tolerated by a recipient organism [10]. This opinion was confirmed by the studies of behavior of СаСО3-based delivery systems in various model environments as well as upon administration of these DS into living rabbits, rats and mice by various methods. Configurations of DS based on СаСО3 cores depend on the method used for their administration. The influence of various environments on the DS containing СаСО3 cores is described in the papers that are quoted below.
In water or physiological solution (0.9% NaCl), СаСО3 vaterites undergo morphological transformations [11]. At medium temperatures, porous vaterites turn into calcites (which are more thermodynamically stable), and at elevated temperatures (above 37-40°С), they are transformed into aragonites [12]. Since these polymorphs are not porous, recrystallization is accompanied by release of drugs encapsulated in vaterites. The drug release profiles correlate with percentages of calcites formed [13].
Oral administration is the most convenient method for patients. However, vaterite cores dissolve in acidic medium of a stomach; therefore, the cores with encapsulated MC should be protected. This protection can be provided both by PE shells (on condition that their components are stable in acidic stomach environment) and alginate granules surrounding СаСО3 cores. Since it is necessary to provide penetration of MC from intestinal tract into main blood flow, a polymer shell should swell or dissolve in the middle division of intestinal tract, thus releasing СаСО3 with MC. Model experiments involving 0.15 M phosphate buffer with рН=7.4 (model intestinal fluid) demonstrated that CaCO3 enters into ion-exchange reaction with phosphate ions; as a result, rather compact porous vaterites are transformed into loose macroporous СаНРО4 structures. This process facilitates release of the encapsulated MC. Scanning electron microscopy (SEM) and energy-dispersive spectroscopy (EDS) studies revealed structural changes in СаСО3 vaterites [14]. Similar transformation also occurs with time in the case of two-level DS that consist of alginate granules and carbonate cores. The presence of fragments of СаСО3 cores in blood and plasma of experimental animals (rats) was confirmed by elemental analysis of the samples [15].
The requirements for size of DS intended for parentheral administration are more rigid, but in this case the carrier should not be necessary protected (unlike the systems used in oral delivery). The СаСО3 vaterites that were synthesized according to the technique described in [1] have sizes of 3-5 μm. Diameter of cores may be reduced by various methods: change in the basic synthesis conditions – increasing concentration of the initial solutions of salts (Na2CO3 and CaCl2), and stirring intensity [16]; increase in viscosity of starting solutions by adding ethylene glycol [17]; addition of a polyelectrolyte during co-precipitation of the salts [18-20]. Unfortunately, the latter method gives low yield of the final product and requires monitoring interaction between MC and polymer.
The authors of [21] used intratracheal administration of СаСО3 cores that contained BSA protein labeled with Cy7 fluorophore. It was demonstrated that efficiency of penetration into lungs for carriers of various diameters decreased with increasing core size from 0.65 to 3.15 μm. Penetration of the labeled protein into lungs with the aid of СаСО3 vaterites of different sizes was confirmed by confocal microscopy of mouse lung cryocut sections. The lower DS size, the deeper they penetrate into lung tissue. Confocal microscopy makes it possible to localize СаСО3 carriers in a sample. Recrystallization of vaterites was observed in the model environment that included physiological solution and bronchoalveolar lavage (containing proteins and surfactants). It was shown that the components of lavage covering vaterite surface protect them from recrystallization.
The authors of [22] demonstrated possibility of penetration of СаСО3 vaterites with encapsulated loperamide through blood-brain barrier of rats after intranasal administration. In order to enhance mucoadhesion, СаСО3 cores were covered with mucoadhesive polymers (hyaluronic acid or poly-L-lysine).
It was suggested [10] to use СаСО3 cores with encapsulated superoxide dismutase enzyme as an ophthalmic delivery system. According to the authors, no undesirable effects were observed after injections of vaterite microcrystals (concentration 10 mg/mL) into eye tissues of rabbits.
In vivo transdermal administration of СаСО3 particles (diameter: 4 μm) to a depth of 200 μm was performed via laser ablation followed by massage. These relatively large particles did not penetrate into the underlying derma. In 1 week after beginning of the experiment, СаСО3 particles dissolved in rat body and released the encapsulated compound [23].
It was revealed [24] that porous СаСО3 cores degraded completely in three months after introducing them into rat bone tissue.
Along with other calcium-containing inorganic nanostructured materials, СаСО3 vaterites find increasing applications in regenerative medicine and tissue engineering [25].
To summarize, all methods for introducing DS based on СаСО3 vaterites are aimed at providing absorption of cores by cells. The influence of size and shape of СаСО3 particles on cell uptake was studied in [26]. It was demonstrated that internalization is more effective for spherical particles with the lowest volume, and for elongated particles.
Currently, there are no literature data on the studies of behavior of vaterite-based DS in human blood plasma and upon their intramuscular administration. When using the majority of the above-mentioned methods, it is necessary to study transformations of DS in blood plasma. The second method may be efficient when DS with MC are introduced directly into tumor tissue. Thus, the goal of the present work was to study behavior of spherical СаСО3 vaterites (components of target delivery systems for antitumor drugs) in vitro (in human blood plasma) and in vivo (in rat muscle tissue).
Abbreviations: DS, delivery systems; MC, medicinal compounds; EDS, energy dispersive spectroscopy; SEM, scanning electron microscopy; EDTA, ethylenediaminetetraacetic acid; BSA, bovine serum albumin.
Materials and methods
Synthesis of carbonate cores
Porous vaterites (СаСО3 cores) were prepared by co-precipitation according to the technique described in [1] with some modifications. Equal volumes of 1 M aqueous solutions of CaCl2×2H2O and Na2CO3 were rapidly mixed at stirring with an RW 20 anchor-type mechanical stirrer (Kika-Werk, Switzerland) (1000 rpm). The mixture was stirred for 30 s. Then the suspension was filtered through Schott filter glass (#16), washed thrice with distilled water, then with acetone/water mixtures with increasing acetone concentrations (33%, 50%, and 100%). The precipitate was dried in thermostat at 40-50°C until a constant weight was achieved. Diameter of the obtained cores varies from 1 to 3 μm.
Interaction between СаСО3 and human blood plasma
Interaction between carbonate cores and human blood plasma was performed at continuous stirring of the suspension. When the reaction was complete, the cores were centrifuged (5 min at 3000 rpm); the supernatant was poured out and substituted for distilled water. The procedure was performed twice. The cores were dried at 40°C until a constant weight was achieved.
Scanning electron microscopy (SEM)
SEM microphotographs of СаСО3 cores were obtained with the help of a Supra 55VP scanning electron microscope (Carl Zeiss, Germany) using secondary electron imaging; before the experiments, the samples were coated with thin platinum layer.
Energy dispersive spectroscopy (EDS)
Elemental compositions of the samples were determined by energy-dispersive spectroscopy (EDS) using an X-Max 80 detector (Oxford Instruments, UK).
Experiments with animals
The experiments involving animals were performed according to the laboratory animal welfare policy accepted in Russian Federation and European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes (ETS 123, Strasbourg, 1986).
In vivo experiments involved 10 male Wistar rats (weight: 200-250 g, age: 3 months). Before studies of bioresorption in vivo, СаСО3 cores were sterilized in autoclave at 110°С for 1 h. Each weighed amount of СаСО3 (10 mg) intended for an experiment in each of two locations in one animal was carefully hermetically packed in aluminum foil. The animals were operated under general anesthesia (intraperitoneal injections of Zoletil 100 (0.1 mL) and Rometar (20 mg/mL) solutions, 0.0125 mL per 0.1 kg of animal body mass). The samples were placed into thigh great adductor muscles (musculus adductor magnus) of both hind extremities. Then the wounds were sutured layer by layer using atraumatic needles and Prolene 4-0 suture. After outer suturing, the rats were caged individually, were fed standard diet, and had free access to water. All animals were active after surgery; no inflammation in the implantation area was observed, which is indicative of the absence of detrimental effects of implantation.
Histological studies
In 1 and 2 weeks after operation, samples of muscle tissue containing СаСО3 were fixed with 10% neutral formalin in phosphate buffer (рН=7.4) for not less than 24 hrs, dehydrated using a series of ethanol solutions with increasing concentrations, and enclosed in paraffin blocks according to the standard histological technique. The paraffin cuts (5 μm in width) transverse to muscular fibers were obtained with the use of an Accu-Cut SRT 200 microtome (Sakura, Japan) and stained with Mayer hematoxylin and eosin (Bio-Optica, Italy). The connective tissue was visualized according to the Mallory method (BioVitrum, Russia). Microscopic analysis was performed using a Leica DM750 light microscope (Germany) with a 10× ocular and 4, 10, 40, and 100× objectives. Images were recorded with an ICC50 camera (Leica, Germany).
Results
Influence of human blood plasma on the structure of СаСО3 cores
Table 1. Phosphorus content (P) in CaCO3 samples that contacted with blood plasma for various periods of time
Blood plasma contains phosphate ions, which enter into reaction with СаСО3 vaterites; as a result, macroporous СаНРО4 structures are gradually formed [14]. It is seen in the SEM images of СаСО3 vaterites (Fig. 1) that the objects with increasingly loose structure are formed with time; they consist of needle-like subunits less than 1 μm in diameter.
Phosphorus content in the studied structures was determined by energy-dispersive spectroscopy (see Table 1).
The EDS data show that phosphorus content in transformed structures increases with time; this result confirms that ion exchange reaction indeed occurs in СаСО3 vaterites.
Figure 1. Microphotographs of СаСО3 vaterites taken upon interaction with human blood plasma for various periods of time: A – 2 hrs; B – 24 hrs; C – 50 hrs
Transformation of СаСО3 vaterites upon intramuscular administration
After injection of СаСО3 vaterites into thigh great adductor muscles (musculus adductor magnus) of both hind extremities in rats, needle-like structures were formed (Fig. 2) and then gradually disappeared in two weeks due to bioresorption. Presumably, these needles are aragonites (one of three СаСО3 polymorphs). Fig. 2B presents the magnified image of the area where vaterites were introduced and then transformed into aragonites (1 week after operation). As was mentioned in Introduction, aragonites (non-porous elongated structures) are one of three morphological modifications of calcium carbonate, along with non-porous (usually cubic) calcites and porous spherical vaterites (which are used as components of target drug delivery systems). Transformation of vaterites during their use in delivery systems into calcites is frequently observed [13]. Formation of aragonite-like structures in the process of bioresorption of СаСО3 vaterites was revealed in the present work for the first time.
Figure 2. Histological cuts of rat muscle tissue obtained in 1 week after implantation of СаСО3 vaterites. Staining with hematoxylin and eosin; objectives 10× (а), 40× (b)
Discussion
he reason for transformation of porous СаСО3 vaterites (diameter: 1 – 3 μm) into needle-like aragonites (length: 30 – 150 μm, width: 10 – 40 μm) in muscle tissue still remains unclear. It may be suggested that morphological transformation of vaterites is influenced by the following factors. First, there is a difference between pH values of muscle tissue and blood or its components (pH of muscle tissue is lower). The second factor involves peculiarities of metabolic processes, mainly, exchange of carbon dioxide. Upon interaction with water, carbon dioxide forms carbonic acid, which reacts with calcium carbonate. Among other factors are intensive action of immune cells, and, finally, mechanic action related to muscle contraction. This issue should be investigated further.
The comparison between our results and the literature data on transformation of СаСО3 vaterites with encapsulated Fe3O4 nanoparticles (which occurred after shallow transdermal injection into rat body [23]) shows that no vaterite modification in muscle tissue was observed. The histological sections prepared in one week after transdermal administration show spherical structures almost similar to the initial cores. In two weeks after operation, vaterites underwent bioresorption, and Fe3O4 nanoparticles were released. These data may indirectly confirm our hypothesis concerning the influence of the above factors on transformation of CaCO3 vaterites in muscle tissue.
Bioresorption of vaterites in blood plasma in vitro is also completed in relatively short period of time (several weeks), while plasma composition remains mostly unchanged.
The main advantage of the DS based on CaCO3 vaterites intended for intramuscular administration of antitumor preparations is the fact that modified carbonate cores undergo complete bioresorption in 2 weeks in vivo and exert no negative influence on the surrounding tissues. The fact that aragonites are formed in the muscles once again indicates the ambiguity of applying the conclusions obtained from in vitro experiments to the in vivo behavior of the studied objects.
The obtained results confirm ability of porous calcium carbonate cores for bioresorption and their safety for medicinal use, which allows us to recommend porous CaCO3 vaterites for further experimental studies as components of target drug delivery systems.
Conflict of interests
None declared.
References
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- Ohgushi H, Okumura M, Yoshikawa T, Inboue K, Senpuku N, Tamai S, Shors EC. Bone formation process in porous calcium carbonate and hydroxyapatite. J Biomed Mater Res. 1992; 26 (7): 885-895. DOI: 10.1002/jbm.820260705.
- Trushina DB, Bukreeva TV, Kovalchuk MV, Antipina MN. CaCO3 vaterite microparticles for biomedical and personal care applications. Materials Sci Engineering C. 2014; 45: 644-658. DOI: 10.1016/j.msec.2014.04.050.
- Parakhonskiy B, Zyuzin MV, Yashchenok A, Carregal-Romero S, Rejman J, Möhwald H. The influence of the size and aspect ratio of anisotropic, porous CaCO3 particles on their uptake by cells. J Nanobiotechnol. 2015; 13: Article 53. doi: 10.1186/s12951-015-0111-7.
Наталья Н. Сударева1,2, Павел В. Попрядухин1,2, Наталья Н. Сапрыкина1, Ольга М. Суворова1, Галина Ю. Юкина2, Олег В. Галибин2, Александр Д. Вилесов1,2
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2 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
Успехи в лечении большинства онкологических заболеваний связаны с применением действенных и в различной мере токсичных противоопухолевых препаратов. Во многих случаях химиотерапия требует максимальной локализации препарата в зоне опухоли. Поэтому наиболее эффективным методом является введение медицинских препаратов (MП) непосредственно в опухоль или применение таргетных систем их доставки. Второй из этих методов дает возможность снизить общую токсичность МП и достичь пролонгированного терапевтического эффекта из-за равномерного, контролируемого по времени выхода МП в опухолевую ткань. В данной работе мы исследовали поведение пористых сферических частиц ватерита СаСО3 (компонентов системы доставки противоопухолевых препаратов) в различных средах (плазма крови человека, мышечная ткань крыс). Было показано, что исследуемый носитель МП подвергается морфологической трансформации и со временем разрушается. В плазме крови, благодаря ионному обмену, ватериты превращаются в постепенно распадающиеся иглоподобные структуры, что показано с помощью сканирующей электронной микроскопии и энергорассеивающей спектроскопии. Сходные процессы наблюдались в мышечной ткани: в течение 3 дней сферические частицы превращались в иглоподобные структуры и затем подвергались полной биологической резорбции.
Ключевые слова
Противоопухолевые препараты, системы доставки, СаСО3, ватериты, плазма крови, внутримышечное введение, биорезорбция.
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2 Pavlov University, St. Petersburg, Russia
Correspondence
Dr. Natalia N. Sudareva, Research Institute of Macromolecular Compounds, Bolshoi Prosp. 31 (V.O.), 199004, St. Petersburg, Russia
E-mail: nnsas@mail.ru
Successful treatment of the majority of oncological diseases that affect solid organs is related to appropriate use of potent and (to varying degrees) toxic antitumor drugs. In a number of cases, chemotherapy requires the maximum localized action of a drug in the tumor area. The most efficient methods of drug administration are introducing medicinal compounds (MC) directly into the tumor or use of target drug delivery systems. The second method makes it possible to decrease general toxicity of MC, and to reach prolonged therapeutic action due to uniform and time-controlled release of a MC into tumor tissue.
In the present work, we studied behavior of porous spherical СаСО3 vaterites (components of delivery systems for antitumor drugs) in various environments (human blood plasma, rat muscle tissue). It was demonstrated that the studied drug carriers undergo morphological transformations and are destructed with time. In blood plasma, due to ion exchange reactions, vaterites are transformed into gradually disintegrating needle-like structures (as shown by scanning electron microscopy and energy dispersive spectroscopy). Similar processes were observed in muscle tissue: in three days, spheres were transformed into needle-like structures and then underwent complete bioresorption.
Keywords
Anticancer drugs delivery systems, СаСО3 vaterites, blood plasma, intramuscular administration, bioresorption.
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Sudareva<sup>1,2</sup>, Pavel V. Popryadukhin<sup>1,2</sup>, Natalia N. Saprykina<sup>1</sup>, Olga M. Suvorova<sup>1</sup>, Galina Yu. Yukina<sup>2</sup>, Oleg V. Galibin<sup>2</sup>, Aleksandr D. Vilesov<sup>1,2</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(237) "Natalia N. Sudareva1,2, Pavel V. Popryadukhin1,2, Natalia N. Saprykina1, Olga M. Suvorova1, Galina Yu. Yukina2, Oleg V. Galibin2, Aleksandr D. Vilesov1,2
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(237) "Natalia N. Sudareva1,2, Pavel V. Popryadukhin1,2, Natalia N. Saprykina1, Olga M. Suvorova1, Galina Yu. Yukina2, Oleg V. Galibin2, Aleksandr D. Vilesov1,2
" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "26454" ["VALUE"]=> array(2) { ["TEXT"]=> string(1668) "<p style="text-align: justify;">Successful treatment of the majority of oncological diseases that affect solid organs is related to appropriate use of potent and (to varying degrees) toxic antitumor drugs. In a number of cases, chemotherapy requires the maximum localized action of a drug in the tumor area. The most efficient methods of drug administration are introducing medicinal compounds (MC) directly into the tumor or use of target drug delivery systems. The second method makes it possible to decrease general toxicity of MC, and to reach prolonged therapeutic action due to uniform and time-controlled release of a MC into tumor tissue.</p> <p style="text-align: justify;">In the present work, we studied behavior of porous spherical СаСО<sub>3</sub> vaterites (components of delivery systems for antitumor drugs) in various environments (human blood plasma, rat muscle tissue). It was demonstrated that the studied drug carriers undergo morphological transformations and are destructed with time. In blood plasma, due to ion exchange reactions, vaterites are transformed into gradually disintegrating needle-like structures (as shown by scanning electron microscopy and energy dispersive spectroscopy). Similar processes were observed in muscle tissue: in three days, spheres were transformed into needle-like structures and then underwent complete bioresorption.</p> <h2>Keywords</h2> <p style="text-align: justify;">Anticancer drugs delivery systems, СаСО<sub>3</sub> vaterites, blood plasma, intramuscular administration, bioresorption.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1566) "Successful treatment of the majority of oncological diseases that affect solid organs is related to appropriate use of potent and (to varying degrees) toxic antitumor drugs. In a number of cases, chemotherapy requires the maximum localized action of a drug in the tumor area. The most efficient methods of drug administration are introducing medicinal compounds (MC) directly into the tumor or use of target drug delivery systems. The second method makes it possible to decrease general toxicity of MC, and to reach prolonged therapeutic action due to uniform and time-controlled release of a MC into tumor tissue.
In the present work, we studied behavior of porous spherical СаСО3 vaterites (components of delivery systems for antitumor drugs) in various environments (human blood plasma, rat muscle tissue). It was demonstrated that the studied drug carriers undergo morphological transformations and are destructed with time. In blood plasma, due to ion exchange reactions, vaterites are transformed into gradually disintegrating needle-like structures (as shown by scanning electron microscopy and energy dispersive spectroscopy). Similar processes were observed in muscle tissue: in three days, spheres were transformed into needle-like structures and then underwent complete bioresorption.
Keywords
Anticancer drugs delivery systems, СаСО3 vaterites, blood plasma, intramuscular administration, bioresorption.
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In the present work, we studied behavior of porous spherical СаСО3 vaterites (components of delivery systems for antitumor drugs) in various environments (human blood plasma, rat muscle tissue). It was demonstrated that the studied drug carriers undergo morphological transformations and are destructed with time. In blood plasma, due to ion exchange reactions, vaterites are transformed into gradually disintegrating needle-like structures (as shown by scanning electron microscopy and energy dispersive spectroscopy). Similar processes were observed in muscle tissue: in three days, spheres were transformed into needle-like structures and then underwent complete bioresorption.
Keywords
Anticancer drugs delivery systems, СаСО3 vaterites, blood plasma, intramuscular administration, bioresorption.
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2 Pavlov University, St. Petersburg, Russia
Correspondence
Dr. Natalia N. Sudareva, Research Institute of Macromolecular Compounds, Bolshoi Prosp. 31 (V.O.), 199004, St. Petersburg, Russia
E-mail: nnsas@mail.ru
1 Institute of Macromolecular Compounds RAS, St. Petersburg, Russia
2 Pavlov University, St. Petersburg, Russia
Correspondence
Dr. Natalia N. Sudareva, Research Institute of Macromolecular Compounds, Bolshoi Prosp. 31 (V.O.), 199004, St. Petersburg, Russia
E-mail: nnsas@mail.ru
Наталья Н. Сударева1,2, Павел В. Попрядухин1,2, Наталья Н. Сапрыкина1, Ольга М. Суворова1, Галина Ю. Юкина2, Олег В. Галибин2, Александр Д. Вилесов1,2
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Во многих случаях химиотерапия требует максимальной локализации препарата в зоне опухоли. Поэтому наиболее эффективным методом является введение медицинских препаратов (MП) непосредственно в опухоль или применение таргетных систем их доставки. Второй из этих методов дает возможность снизить общую токсичность МП и достичь пролонгированного терапевтического эффекта из-за равномерного, контролируемого по времени выхода МП в опухолевую ткань. В данной работе мы исследовали поведение пористых сферических частиц ватерита СаСО<sub>3</sub> (компонентов системы доставки противоопухолевых препаратов) в различных средах (плазма крови человека, мышечная ткань крыс). Было показано, что исследуемый носитель МП подвергается морфологической трансформации и со временем разрушается. В плазме крови, благодаря ионному обмену, ватериты превращаются в постепенно распадающиеся иглоподобные структуры, что показано с помощью сканирующей электронной микроскопии и энергорассеивающей спектроскопии. Сходные процессы наблюдались в мышечной ткани: в течение 3 дней сферические частицы превращались в иглоподобные структуры и затем подвергались полной биологической резорбции.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Противоопухолевые препараты, системы доставки, СаСО<sub>3</sub>, ватериты, плазма крови, внутримышечное введение, биорезорбция.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2767) "Успехи в лечении большинства онкологических заболеваний связаны с применением действенных и в различной мере токсичных противоопухолевых препаратов. Во многих случаях химиотерапия требует максимальной локализации препарата в зоне опухоли. Поэтому наиболее эффективным методом является введение медицинских препаратов (MП) непосредственно в опухоль или применение таргетных систем их доставки. Второй из этих методов дает возможность снизить общую токсичность МП и достичь пролонгированного терапевтического эффекта из-за равномерного, контролируемого по времени выхода МП в опухолевую ткань. В данной работе мы исследовали поведение пористых сферических частиц ватерита СаСО3 (компонентов системы доставки противоопухолевых препаратов) в различных средах (плазма крови человека, мышечная ткань крыс). Было показано, что исследуемый носитель МП подвергается морфологической трансформации и со временем разрушается. В плазме крови, благодаря ионному обмену, ватериты превращаются в постепенно распадающиеся иглоподобные структуры, что показано с помощью сканирующей электронной микроскопии и энергорассеивающей спектроскопии. Сходные процессы наблюдались в мышечной ткани: в течение 3 дней сферические частицы превращались в иглоподобные структуры и затем подвергались полной биологической резорбции.
Ключевые слова
Противоопухолевые препараты, системы доставки, СаСО3, ватериты, плазма крови, внутримышечное введение, биорезорбция.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2767) "Успехи в лечении большинства онкологических заболеваний связаны с применением действенных и в различной мере токсичных противоопухолевых препаратов. Во многих случаях химиотерапия требует максимальной локализации препарата в зоне опухоли. Поэтому наиболее эффективным методом является введение медицинских препаратов (MП) непосредственно в опухоль или применение таргетных систем их доставки. Второй из этих методов дает возможность снизить общую токсичность МП и достичь пролонгированного терапевтического эффекта из-за равномерного, контролируемого по времени выхода МП в опухолевую ткань. В данной работе мы исследовали поведение пористых сферических частиц ватерита СаСО3 (компонентов системы доставки противоопухолевых препаратов) в различных средах (плазма крови человека, мышечная ткань крыс). Было показано, что исследуемый носитель МП подвергается морфологической трансформации и со временем разрушается. В плазме крови, благодаря ионному обмену, ватериты превращаются в постепенно распадающиеся иглоподобные структуры, что показано с помощью сканирующей электронной микроскопии и энергорассеивающей спектроскопии. Сходные процессы наблюдались в мышечной ткани: в течение 3 дней сферические частицы превращались в иглоподобные структуры и затем подвергались полной биологической резорбции.
Ключевые слова
Противоопухолевые препараты, системы доставки, СаСО3, ватериты, плазма крови, внутримышечное введение, биорезорбция.
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2 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
1 Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия
2 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
Introduction
Over the past decade, international hematological community has been actively engaged in clinical research to standardize medical treatment of patients with chronic Ph-negative myeloproliferative neoplasms (MPNs) and improve the quality of care for this category of patients [1–5].
To identify the problems and areas of concern in management of the Ph(-) MPN patients, a large-scale Landmark Survey of patients and physicians was initiated in USA in 2014 [6, 7]. A total of 813 Ph(-) MPN patients and 457 physicians who treated this cohort participated in this survey. The results of this study were reported for each of the most common Ph(-) MPNs, i.e., myelofibrosis (MF), polycythemia vera (PV) and essential thrombocythemia (ET) in the following sections: understanding of the disease diagnosis by patients and physicians; symptoms experienced by patients and their impact on daily activities, as reported by patients and physicians; disease burden with relation to the patient's quality of life and work productivity reported by patients and physicians; patient’s and physician’s attitudes to the treatment goals; and perception of bilateral physician-patient relationships [8]. The independent responses submitted by patients and physicians were used to find distinct similarities or differences between MF, PV, and ET. In 2016, the project became international, and the electronic survey forms were completed by Ph(-) MPN patients and hematologists who treated these diseases in Australia, Japan, Canada, Germany, Italy, and the UK [9]. The data collected in this survey enabled the researchers to evaluate perception of the physical, psychological, social and other problems that Ph(-) MPN patients face in their daily life, and to improve the awareness of hematologists about these problems.
The next stage of this project took place in 2018, as a research program, to conduct an online survey of 560 Ph(-) MPN patients and 260 hematologists in the emerging market countries: China, Turkey, Russia, Taiwan, South Korea, and Saudi Arabia [10, 11] The results of this survey, along with previous studies conducted in 2014-2016, are of importance for improving Ph(-) MPN medical care and developing standardized approaches to diagnosis and treatment of these chronic disorders. The project could potentially promote the multidisciplinary efforts, working together with patients and their relatives, in order to maximize effects of the Ph(-) MPN therapy.
The aim of this paper is to analyze and systematize the data from the Russian patient and physician survey arranged as part of the Landmark Survey in the emerging market countries.
Patients and methods
Forty Ph(-) MPN patients and physicians residing in the Russian Federation took part in the international Landmark Survey between September and November 2018. The criteria for engaging a physician for the survey were as follows: (1) managing of least 2 patients with MF, 5 patients with PV, and 5 patients with ET over last 12 months; (2) professional experience in hematology over 1 year; at least 25% of patients treated by the physician had to have hematological disorders. The patients with MF, PV and ET aged 18 years and older were enrolled with the physician at their routine clinic visits. Patients were eligible to complete the survey, being, however, excluded if they were participating in any clinical trials.
The survey checklists consisted of the following sections: for patients – patient demographics, patient awareness and perception of symptoms, impact of disease on daily living, work productivity/activity impairment, disease history and treatment, patient satisfaction, disease information availability; for physicians – physician demographics and caseload, patient disease burden, patient management and treatment decisions, physician perceptions [11]. This was an exploratory survey; no any special standardized questionnaires were applied during the survey.
Before completing the survey, patients and physicians consented to participate in the project. Both patients and physicians participated in the online survey independently of each other. To keep confidentiality, all physicians and patients were assigned identification numbers. Before the start of the survey, all the participants were given instructions on the procedure and principles of electronic questionnaire completion. The survey took 25-30 minutes.
The results survey are presented as descriptive statistics with estimation of mean values, standard deviations, and percentages for each position tested. Analyses were conducted in Stata statistical software version 16.0 or later (StataCorp, 2015. Stata statistical software: Release 16 (College Station, TX, StataCorp LP)). Where missing values were found in a particular variable, any participant with missing values was removed from all pieces of analysis where that variable was used. However, patients and physicians removed from one piece of analysis were still eligible for inclusion in other analyses. It was expected that the base of patients and physicians would vary from variable to variable for this reason.
Results
Characteristics of the patients and attending physicians
Overall, 40 patients with Ph(-) MPNs and 30 physicians completed the online survey. The characteristics of the patients included in the survey are summarized in Table 1. The distribution by diagnosis was as follows: PV, 42.5%; MF, 37.5%, and ET, 20% of patients. Twelve (80%) of the 15 MF patients were diagnosed with primary MF. Mean age of the patients at the time of diagnosis was 54.9 ± 9.7 years, duration of the disorder was 3.0 ± 2.2 years. Hence, their mean age at the survey was 57.9 ± 10.4 years. Diabetes mellitus (38% of ET patients), congestive heart failure (20% of MF patients), peptic ulcer (18% of PV patients), deep vein thrombosis (18% of PV patients) and liver disease (18% of PV patients) were the most common comorbidities in this group.
It is worth of note that over a half of the patients (55%) exhibited symptoms for a year prior to diagnosis, 17.5% during two years, and almost 1/3 of patients (27.5%) felt them over two years prior to the clinical diagnosis.
Of 30 physicians participating in the survey, 24 (80%) were hematologists, and 6 (20%) were hematologists-oncologists. Approximately half of the physicians (47%) had 3 to 15 years of professional experience, 40% had 15 to 25 years, and 13% had experience of 25 to 33 years. Over the period of 12 months preceding the survey, each of the physicians treated, on average, 10 MF cases, 16 PV patients, and 14 ET cases. 63% of physicians worked in regional clinic hospitals, 30% in specialized referral centers, and 7%, at the University clinics.
Table 1. Clinical and demographic characteristics of the patients
Symptoms in Ph(-) MPN patients
Figure 1. Most commonly reported symptoms across all Ph(-) MPNs during last 12 months: A – myelofibrosis, B – polycythemia vera, and С – essential thrombocythemia
At diagnosis, the patients reported fatigue (63%) and weakness (53%) as the most common Ph(-) MPN symptoms. Other symptoms post-diagnosis included pruritus (33%) and night sweats (30%). On average, Ph(-) MPN patients mentioned seven symptoms ever experienced during their illness. The MF patients complained about eight symptoms, compared with six symptoms usually reported by PV and ET patients.
The five most common symptoms reported by MF, PV and ET patients over the past 12 months are listed in Figure 1. Over half of the MF patients reported fatigue (80%), weakness (67%), and night sweats (60%). Worth of note, not all patients believed these symptoms were related to the disease. In particular, the patients did not associate fatigue, weakness, and night sweats with the disease in 33%, 40% and 56% cases, respectively. As for PV symptoms, 59% of patients felt weakness, and 41% experienced fatigue and pruritus. Hence, 20% and 14% of the patients did not relate weakness and fatigue, respectively, to specific symptoms of their disease. Meanwhile, all the patients believed that pruritus was associated with the disease. 50% of ET patients experienced fatigue and numbness/tingling. Of note, all the patients associated fatigue with the disease; as for numbness/tingling, 12.5% of patients did not associate this symptom with the disease. At the same time, most physicians (69%) believed that the vast majority of the patients associated their symptoms with myeloproliferative disease.
The patients also evaluated severity of their symptoms in the past 12 months using a 10-point numerical rating scale (NRS). Some symptoms were severe: ≥7 points on the NRS scale. Patients with Ph(-) MPN reported the following severe symptoms: fatigue (n=18), weakness (n=15), headache (n=9), night sweats (n=8), abdominal pain (n=7), fever (n=5), dizziness (n=5), bone pain (n=2), nose bleeding (n=2) and facial flushing (n=2).
Attending physicians also answered some questions about symptoms in their patients. They were asked to list five most significant symptoms for the patients with each type of Ph(-) MPNs. For MF, the physicians mentioned fatigue (72%), unintentional weight loss (59%), weakness (45%), abdominal discomfort (34%), and night sweats (31%). Of note, only half of the physicians, when compared to their patients, reported night sweats in these cases. In PV, physicians pointed to itching (59%), headaches (45%), hypertension (41%), facial flushing and numbness/tingling in hands and feet (38%). Moreover, as opposed to patients, none of the physicians mentioned weakness or fatigue. For ET, the physicians noted fatigue (59%), nasal bleeding and thrombotic events clot (48%), headaches (37%), and weakness (33%). Unlike patients, physicians did not mention numbness/tingling. As evidenced by the above data, there are discrepancies in the patient and physician perception of the most significant symptoms experienced by Ph(-) MPN patients, while 77% of physicians believed that they have correctly assessed the symptom burden.
As a separate task, both physicians and patients were asked to choose from the list of symptoms experienced by patients those traits that, according to the patient, were most likely to be resolved (1 to 3). The MF patients mentioned fatigue (47%) and pruritus (33%); physicians chose weakness (45%) and fatigue (31%). Patients with PV pointed to pruritus (41%), whereas, in opinion of physicians, pruritus (52%) and hypertension (48%) were most likely to be resolved. As for ET, the patients chose fatigue (38%), while physicians highlighted fatigue, tingling in the hands/feet, and predisposal for thrombosis (44%).
These discrepancies in the physician and patient description of the symptoms that are most significant to patients can be partially explained using the survey data, with regard of the physician’s strategies when discussing symptoms and general well-being during the patients’ clinical visit. The majority of patients mentioned in the survey that the physicians were interested in their symptoms and overall well-being. Patients noticed the following: during the clinic visit, attending physician was actively interested in their well-being and symptoms (55% of patients); the doctor asked them about specific, most important symptoms (25%); the physician expected patients to report their concerns (15%); the physician asked them to fill out questionnaires and discussed existing problems with them on the basis of their answers (5%). All the patients stated that the physician was interested in their well-being and existing symptoms.
In addition, significant differences between physicians and patients were revealed, regarding the time that physicians spent discussing blood test results and well-being with the patients. The vast majority of patients (93%) believed that during the visit the physician spent most of the time discussing blood test results with them. At the same time, only 43% of physicians believed that they spent more time discussing blood test results with the patient rather than their well-being.
According to the survey of physicians, they received information about the patient’s symptoms and overall well-being in the following way: 43% of physicians were actively interested in the patient’s problems during the visit; 37% discussed the most important symptoms with the patient, and 13% expected reporting of any alarming symptoms from patients. Only 7% of physicians told that they asked patients to fill out questionnaires to record their symptoms. At the same time, 83% of physicians stated that they assessed patient's symptoms at each visit. When evaluating the severity of symptoms, 43% of physicians considered the impact of disease on the daily life of the patient, and 27% of physicians based it on their own assessment. Only 20% of physicians used questionnaires for standard assessment of the symptoms.
Disease impact on the quality of life in Ph(-) MPN patients
The list of questions in the patient’s and physician’s survey checklists focused on the impact of symptoms on patient’s quality of life and daily activities [9, 11]. Most Ph(-) MPN patients (81%) believed that the symptoms reduced their quality of life (Table 2). All the MF patients, 65% of PV patients, and 75% of ET patients agreed with this statement. Physicians also shared the view that the disease symptoms lead to worsening of quality of life of patients. Furthermore, 77% of physicians believed that even mild or moderate symptoms in patients could be associated with reduced quality of life.
Table 2. Symptom interference with quality of life in Ph(-) MPN patients
As a special point, the effect of symptoms on daily life activities was evaluated by the survey. Figure 2 shows the distribution of the patient’s and physician’s answers about impact of the symptoms upon daily activities of patients, their family and social life, relationships with caregivers, as well as limitations of activities caused by pain/discomfort. As evidenced in the Figure 2, most patients and physicians believed that disease symptoms affect the mentioned daily activities of patients. Most patients and physicians also indicated that pain/discomfort limits patient's daily activities, especially in MF patients, compared to PV and ET. In MF, the reported symptoms had a higher impact on their daily activities, family and social life. Pain/discomfort also significantly limited their daily activities. In general, the discrepancy between physicians and patients in assessing the impact of disease symptoms on daily life was not significant.
Figure 2. Patient and physician perceptions of the disease symptom burden on daily activities in Ph(-) MPN patients; A, myelofibrosis; B polycythemia vera; C, essential thrombocythemia
The patients were also asked in what way the disease affected various aspects of their quality of life (Figure 3). For the vast majority of Ph(-) MPN patients, the disease had a significant impact on physical (95%) and emotional (87%) functioning. Almost all of the patients (95%) experienced anxiety, because of their condition and were worried that their condition would worsen. It is noteworthy that 80% of patients believed that their health was worse, if compared to their condition evaluated by treating physician, and 77% felt helpless.
Figure 3. Disease impact on various aspects of quality of life as assessed by Ph(-) MPN patients
As for different forms of Ph(-) MPNs, all the patients with MF and ET, as well as 88% of patients with PV, experienced some degree of physical problems caused by their condition. All the ET patients, 87% of MF patients, and 82% of PV patients reported emotional burden associated with the disease. All the MF patients, 94% of PV patients and 87% of ET patients experienced anxiety related to their condition. At the same time, 93%, 71% and 75% of patients with MF, PV and ET, respectively, believed that they felt worse than perceived by their treating physician. Moreover, 93%, 71% and 62% of patients with MF, IP and ET, respectively, indicated that they felt helpless.
All surveyed physicians believed that MF and PV patients had physical and emotional limitations; 7% of physicians believed that ET patients did not experience such restrictions.
Disease impact on work productivity in Ph(-) MPN patients
The patient survey contained questions about employment, disability, limitations in overall activity and support from caregivers. From the proposed list of employment options, over one-third of patients (35%) stated that they worked full time, 13% were in part-time employment, and 5% were on sick leave. Other patients claimed they were pensioners (43%) or unemployed (6%). Overall, 53% of patients reported that they continued to work at the time of the survey. Over past 7 days, the patients had to miss, on average, 2.8 hours of working time, due to their disease. To assess the impact of the disease on productivity at work and overall activity, patients were asked to choose a number on a scale from 0 to 10, where 0 means "no effect of the disease on work/overall activity" and 10 means "completely unable to work/illness completely interferes with overall activity". According to the survey results, 32% of patients indicated that their disease significantly (score 7-10) limited their productivity at work; the disease significantly affected overall activity in 48% of patients.
Overall, 48% of Ph(-) MPN patients reported requiring assistance from a caregiver, with 46% of MF patients, 36% of PV patients and 13% of ET patients needed for support often or sometimes. Half of these patients were supported by their children. In 47% of cases, a support for the patients was provided by the people who continued to work. Assistance with housework (79%) and transportation (74%) were the main forms of support.
Treatment of Ph(-) MPNs and physician’s and patient’s perspectives on treatment goals
The surveys for physicians contained the following questions regarding treatment: 1) treatment strategy at the time of diagnosis; 2) therapy prescribed anytime in the past; 3) treatment that physicians currently prescribed for their patients. Physicians had to choose the answers from the proposed list of treatment options separately for patients with MF, PV and ET. According to their answers, the physicians chose a strategy of waiting and observation in 12% of MF patients, in 15% of PV cases, and in 18% of ET patients at the time of diagnosis. Details of previous treatment for patients with MF, PV and ET, and currently prescribed therapies, as well as reasons for changing therapy are summarized in Table 3. In general, there is no much difference between the past and current therapies prescribed by physicians to treat specific MF, PV and ET patients. Some differences between the past and current therapies were observed for MF treatment with epoetin-α, androgens and glucocorticosteroids, for PV treatment with epoetin-α, for ET treatment with glucocorticosteroids and BMT/HSCT.
Table 3. Treatment prescribed in the past, currently prescribed therapy, and the reasons for changing therapy in patients with MF, IP and ET
Worth of note, half of the physicians reported an increase in symptoms of a specific Ph(-) MPN as the reason for the change of treatment.
The questionnaire for physicians also included questions concerning prognostic risk assessment in patients with Ph(-) MPN, and criteria for assessing the disease progression. According to the survey, 70% of physicians used different tools to calculate prognostic risk scores in their practice. IPSS was the most commonly used scale for assessing prognostic risk (43%). Among those physicians who did not use the available risk assessment tools, 33% considered these methods useful, but did not have enough time to use them in clinical practice; the same number of physicians (33%) were familiar with these assessment tools, but did not consider them practically useful; 11% of physicians stated that they were not familiar with these tools. The physicians pointed to the following main criteria for the disease progression: in MF, deterioration of the patient's condition (86%), increasing splenomegaly (86%), and continued weight loss (79%); in PV, changes of hemoglobin levels (83%), changing severity of symptoms (79%), evolving new symptom(s) (72%); in ET, changes in platelet levels (85%), development of new symptom(s) (78%), and deterioration of the patient's condition (70%).
Both physicians and patients were given a separate block of questions related to the main treatment goals. Physicians and patients were asked to select the main treatment goals (except for a curation) from a list of statements. The physician and patient survey results regarding goals for MF, PV and ET treatment are shown in Figure 4. Information is shown as the percentages of patients and physicians who have chosen the definite treatment goals. As seen in Figure 4, the MF, PV and ET patients have selected the following main treatment goals: better quality of life (60%, 76%, and 75%, respectively), reduction of symptoms (60%, 47%, and 50%, respectively), normal blood counts (53%, 53%, and 50%, respectively), and slower progression of the disease (47%, 41%, 50%, respectively). Physicians indicated the following main treatment goals (except for a cure) in Ph(-) MPN patients: in MF, improved quality of life (66%), slower disease progression (55%) and reduction in spleen size (52%); in PV and ET, better quality of life (69% and 59%, respectively), prevention of thrombotic events (48% and 67%), retarded disease progression (48% and 48%), and reduced frequency of phlebotomies in the PV patients (48%).
Figure 4. Ph(-) MPN treatment goals (other than cure), as reported by physicians and patients
In addition, the patients filled a list of supplementary statements on how successful or unsuccessful the treatment could be. When evaluating the success of treatment, patients used the following criteria: quality of life improvement or relief of symptoms (68%), reduced number of the symptoms (48%), physician’s conclusion (48%), and blood testing results (43%).
Moreover, the physicians were also given a list of statements describing challenges in Ph(-) MPN treatment. With regard to the treatment of MF, PV and ET patients, physicians selected the following unresolved issues: chances for cure (41%, 31% and 41%, respectively), and ability to delay progression of the disease (21%, 21% and 19%, respectively). Furthermore, 22% of physicians stated that a search for new effective drugs is an important aspect of ET treatment.
Perception of the physician-patient relationship by physicians and Ph(-) MPN patients
Both physician’s and patient’s surveys contained questions about patient satisfaction with the treatment, effectiveness of the physician in management of the disease, as well as the physician-patient relationship. In terms of treatment satisfaction, 98% of Ph(-) MPN patients were generally satisfied with the treatment (65% were completely satisfied and 33% were somewhat satisfied). Overall, 85% of patients were satisfied with efficiency of the disease control achieved by their physician (75% were completely satisfied and 10% were somewhat satisfied). As for physicians, 90% of them were satisfied with their management of the disease. Similarly, 90% of physicians reported that their priority goals concerning treatment agreed with the patients' perspectives: 37% believed that they completely agreed, 53% agreed to some extent. In general, all the patients were satisfied with the communication with their physician. When asked about the physician-patient relationship, 84% of physicians stated that they were satisfied with their communication with patients. Whereas 95% of patients indicated that they were generally satisfied with the awareness of various aspects of the disease, 5% were not satisfied. When asked about patient awareness of the disease, 87% of physicians believed that patients were well informed.
The majority of patients (95%) reported that they received information about their disease directly from their physician; 20% of patients indicated that they had difficulties with finding information about their disease.
Discussion
This paper presents data on survey of Russian patients and physicians evaluating the impact of chronic Ph(-) MPNs on various aspects of patients' well-being, conducted as a part of the international Landmark Survey. One of the main aims of the Landmark Survey is to study the symptoms experienced by Ph(-) MPN patients and their impact on daily activities as assessed by patients and physicians. The survey was also designed to investigate how the disease affects the patient’s quality of life and work productivity, both from the patient’s and physician's perspective. The analysis was based on the survey completed by 40 patients with Ph(-) MPN and 30 attending physicians.
The results of the survey revealed a significant impact of Ph(-) MPNs on quality of life of the patients. Accordingly, the disease symptoms in majority of Ph(-) MPN patients (100% of MF cases, 65% of PV cases, and 75% of ET patients), led to impairment of their quality of life. In general, these data are consistent with results of the original Landmark study conducted in the USA, where 81% of MF patients, 66% of PV patients and 56% of ET patients reported worsening of their quality of life due to the disease [8]. However, compared with the original study, a higher number of MF (100% versus 81%) and ET (75% versus 56%) patients in the Russian sample reported the negative effect of the disease symptoms on their quality of life.
In terms of the most common symptoms after diagnosis, Ph(-), the MPN patients noted fatigue (63%) and weakness (53%), thus being consistent with the data from the Landmark Survey in other countries [8-11]. It is worth of note that over a half of the patients (54%) experienced symptoms for a year prior to diagnosis, and the remaining patients had symptoms for two or more years before receiving the diagnosis, which is significantly more than in other countries [8-10].
When analyzing the symptoms exhibited by Ph(-) MPN patients over the past 12 months, it was shown that most patients, regardless of the disease, noted weakness or fatigue. Other common symptoms were different, depending on the specific Ph(-) MPN subtype. It is important to note that not all patients believed these symptoms were related to the disease.
This data is in line with the published results of Landmark survey in the countries with development markets according to which many patients also did not recognize that their symptoms could be MPN-related. For example, in this study 18% MF and 25% PV did not think their fatigue/tiredness resulted from MPNs [10]. According to our data, 33% and 14% of MF and PV patients, respectively, did not recognize fatigue as a symptom of the disease. It should also be noted that the analysis of the physician’s and patient’s responses regarding the most important patient’s symptoms revealed a discrepancy in their assessments. To some extent, these differences can be explained by the fact that only a half of the physicians actively discussed well-being and symptoms with patients during clinic visits. Moreover, the results show that only 20% of asked physicians use standardized questionnaires to assess the severity of symptoms, i.e., a significantly smaller proportion compared to their colleagues in other countries [8-10].
The analyzed results of the patient’s and physician’s surveys evaluating the effect of disease symptoms on daily lives of patients, including their everyday activities, family or social life, relationships with caregivers, and pain/discomfort that limits activity, revealed that, in the opinion of most patients and physicians, the disease burden affects daily lives of patients. It is worth of note that, in general, the discrepancy between physicians and patients in assessing the impact of disease symptoms on daily life was not significant. These results are consistent with previous reports that included non-US patients [12-14], as well as the recent US Landmark survey [6].
In a separate subset of questions, patients and physicians evaluated how the disease affected various aspects of their physical and emotional functioning. In the overwhelming majority of cases both patients and physicians reported that the disease caused significant physical and emotional hardship for Ph(-) MPN patients. The following data requires a special consideration: almost all the patients experienced anxiety because of their condition and were worried that their condition would worsen; moreover, 80% believed that their health was worse than what their treating physician perceived.
It was also shown that Ph(-) MPNs affect working ability and overall activity of patients. Thus, 32% of patients indicated that their disease significantly (score 7-10) limited their productivity at work; the disease had a significant impact on the overall activity of 48% of patients. Similar data was collected by the Landmark Survey in other countries [11].
Overall, almost a half of Ph(-) MPN patients reported requiring assistance from a caregiver, with 46% of MF patients, 36% of PV patients and 13% of ET patients needing support often or sometimes. These results are consistent with data obtained in other countries [11].
A separate analysis was conducted on the responses of physicians regarding treatment strategies at the time of diagnosis, treatments that were prescribed in the past, and treatments currently prescribed for their patients. It is interesting to note that half of the physicians reported an increase in symptoms as the reason for changing treatment, which emphasizes the importance of improving approaches to symptom management in Ph(-) MPN patients.
Responses of physicians on the approaches of Ph(-) MPN prognostic risk assessment were also analyzed. It should be noted that 70% of physicians used different tools to assess prognostic risk in their practice, but a third of physicians did not resort to their use due to lack of time, doubts about the usefulness of these tools or simply due to insufficient information about them.
Patient’s and physician’s responses regarding the MF, PV and ET therapy goals are of particular interest. It is important to note that both patients and physicians chose the improvement of the quality of life and symptom relief, as well as slowing the progression of the disease as the main treatment goals. In terms of evaluating treatment success, most patients (68%) mentioned the improvement in quality of life and symptom relief. This fact highlights the relevance of patient quality of life assessments as one of the important treatment outcomes. Besides, the international guidelines on assessing clinical response of Ph(-) MPN patients to treatment suggest the use of information on patient’s quality of life and symptoms [15, 16].
Satisfaction with the treatment as well as with the physician-patient relationship was also analyzed. With regard to the physician-patient relationship, 84% of physicians and 100% of patients were satisfied with it. According to the majority of the physicians (87%), patient awareness of the disease was rather high. Overall, 95% of patients were satisfied with their knowledge of the various aspects of the disease. At the same time, the issues identified in the survey of physicians and patients in relation to significant discrepancies between physician’s and patient’s assessment of burdensome symptoms, and specific perception of certain symptoms as not related to their disease by the patients highlight the importance of further improvement of symptom assessment strategies in Ph(-) MPN patients and raising awareness about the disease among the medical community, Ph(-) MPN patients and their relatives.
Despite the fact that the results were obtained in a limited sample of respondents (40 patients with Ph(-) MPN and 30 physicians), it is the first comprehensive analysis of the problems associated with the disease and treatment of Ph(-) MPN obtained in the Russian population of these patients, and the information is presented from the viewpoint of both patients and physicians. In general, the results of our survey demonstrate that patients with Ph(-) MPN feel a significant negative impact of the disease on various aspects of their life, have impaired quality of life and reduced work productivity. This data confirm the previously published results of the Landmark Survey conducted in other countries [6-11]. At the same time, this analysis enabled us to identify features of the disease impact and treatment upon various aspects of daily life of Ph(-) MPN patients in Russia, to describe their perceptions of the treatment goals, to assess the degree of satisfaction with treatment and disease control, and also to gain an insight into the physician-patient relationship and the strategies that physicians use in real clinical practice to obtain information about the impact of the disease and treatment on various aspects of the patient’s life. Overall, the results obtained support the value of patient’s perspective about the disease and its treatment for Ph(-) MPN to improve quality of care of this patients’ population [17-19].
Conclusion
Evaluation and synthesis of the survey data collected among Russian Ph(-)MPN patients and their attending physicians as part of the Landmark Survey constitute an important contribution to this project conducted in different countries. This data revealed that the patients with different Ph(-) MPNs have serious disease-related restrictions in everyday life, altered quality of life and reduced work productivity. In addition, the survey has revealed discordance in physician’s and patient’s assessment of the problems that patients face in relation to the disease and treatment. These differences indicate a need for new approaches, in order to improve of quality of care for this patients’ population, as well as for raising knowledge on the Ph(-) MPNs among the medical community and patients. Further clinical research is required to substantiate the development of patient-centered treatment programs for chronic Ph-negative myeloproliferative neoplasms in Russian Federation, as well as to provide detailed information for the patients and their relatives about the disease and its treatment.
Acknowledgements
No conflict of interest declared.
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Introduction
Over the past decade, international hematological community has been actively engaged in clinical research to standardize medical treatment of patients with chronic Ph-negative myeloproliferative neoplasms (MPNs) and improve the quality of care for this category of patients [1–5].
To identify the problems and areas of concern in management of the Ph(-) MPN patients, a large-scale Landmark Survey of patients and physicians was initiated in USA in 2014 [6, 7]. A total of 813 Ph(-) MPN patients and 457 physicians who treated this cohort participated in this survey. The results of this study were reported for each of the most common Ph(-) MPNs, i.e., myelofibrosis (MF), polycythemia vera (PV) and essential thrombocythemia (ET) in the following sections: understanding of the disease diagnosis by patients and physicians; symptoms experienced by patients and their impact on daily activities, as reported by patients and physicians; disease burden with relation to the patient's quality of life and work productivity reported by patients and physicians; patient’s and physician’s attitudes to the treatment goals; and perception of bilateral physician-patient relationships [8]. The independent responses submitted by patients and physicians were used to find distinct similarities or differences between MF, PV, and ET. In 2016, the project became international, and the electronic survey forms were completed by Ph(-) MPN patients and hematologists who treated these diseases in Australia, Japan, Canada, Germany, Italy, and the UK [9]. The data collected in this survey enabled the researchers to evaluate perception of the physical, psychological, social and other problems that Ph(-) MPN patients face in their daily life, and to improve the awareness of hematologists about these problems.
The next stage of this project took place in 2018, as a research program, to conduct an online survey of 560 Ph(-) MPN patients and 260 hematologists in the emerging market countries: China, Turkey, Russia, Taiwan, South Korea, and Saudi Arabia [10, 11] The results of this survey, along with previous studies conducted in 2014-2016, are of importance for improving Ph(-) MPN medical care and developing standardized approaches to diagnosis and treatment of these chronic disorders. The project could potentially promote the multidisciplinary efforts, working together with patients and their relatives, in order to maximize effects of the Ph(-) MPN therapy.
The aim of this paper is to analyze and systematize the data from the Russian patient and physician survey arranged as part of the Landmark Survey in the emerging market countries.
Patients and methods
Forty Ph(-) MPN patients and physicians residing in the Russian Federation took part in the international Landmark Survey between September and November 2018. The criteria for engaging a physician for the survey were as follows: (1) managing of least 2 patients with MF, 5 patients with PV, and 5 patients with ET over last 12 months; (2) professional experience in hematology over 1 year; at least 25% of patients treated by the physician had to have hematological disorders. The patients with MF, PV and ET aged 18 years and older were enrolled with the physician at their routine clinic visits. Patients were eligible to complete the survey, being, however, excluded if they were participating in any clinical trials.
The survey checklists consisted of the following sections: for patients – patient demographics, patient awareness and perception of symptoms, impact of disease on daily living, work productivity/activity impairment, disease history and treatment, patient satisfaction, disease information availability; for physicians – physician demographics and caseload, patient disease burden, patient management and treatment decisions, physician perceptions [11]. This was an exploratory survey; no any special standardized questionnaires were applied during the survey.
Before completing the survey, patients and physicians consented to participate in the project. Both patients and physicians participated in the online survey independently of each other. To keep confidentiality, all physicians and patients were assigned identification numbers. Before the start of the survey, all the participants were given instructions on the procedure and principles of electronic questionnaire completion. The survey took 25-30 minutes.
The results survey are presented as descriptive statistics with estimation of mean values, standard deviations, and percentages for each position tested. Analyses were conducted in Stata statistical software version 16.0 or later (StataCorp, 2015. Stata statistical software: Release 16 (College Station, TX, StataCorp LP)). Where missing values were found in a particular variable, any participant with missing values was removed from all pieces of analysis where that variable was used. However, patients and physicians removed from one piece of analysis were still eligible for inclusion in other analyses. It was expected that the base of patients and physicians would vary from variable to variable for this reason.
Results
Characteristics of the patients and attending physicians
Overall, 40 patients with Ph(-) MPNs and 30 physicians completed the online survey. The characteristics of the patients included in the survey are summarized in Table 1. The distribution by diagnosis was as follows: PV, 42.5%; MF, 37.5%, and ET, 20% of patients. Twelve (80%) of the 15 MF patients were diagnosed with primary MF. Mean age of the patients at the time of diagnosis was 54.9 ± 9.7 years, duration of the disorder was 3.0 ± 2.2 years. Hence, their mean age at the survey was 57.9 ± 10.4 years. Diabetes mellitus (38% of ET patients), congestive heart failure (20% of MF patients), peptic ulcer (18% of PV patients), deep vein thrombosis (18% of PV patients) and liver disease (18% of PV patients) were the most common comorbidities in this group.
It is worth of note that over a half of the patients (55%) exhibited symptoms for a year prior to diagnosis, 17.5% during two years, and almost 1/3 of patients (27.5%) felt them over two years prior to the clinical diagnosis.
Of 30 physicians participating in the survey, 24 (80%) were hematologists, and 6 (20%) were hematologists-oncologists. Approximately half of the physicians (47%) had 3 to 15 years of professional experience, 40% had 15 to 25 years, and 13% had experience of 25 to 33 years. Over the period of 12 months preceding the survey, each of the physicians treated, on average, 10 MF cases, 16 PV patients, and 14 ET cases. 63% of physicians worked in regional clinic hospitals, 30% in specialized referral centers, and 7%, at the University clinics.
Table 1. Clinical and demographic characteristics of the patients
Symptoms in Ph(-) MPN patients
Figure 1. Most commonly reported symptoms across all Ph(-) MPNs during last 12 months: A – myelofibrosis, B – polycythemia vera, and С – essential thrombocythemia
At diagnosis, the patients reported fatigue (63%) and weakness (53%) as the most common Ph(-) MPN symptoms. Other symptoms post-diagnosis included pruritus (33%) and night sweats (30%). On average, Ph(-) MPN patients mentioned seven symptoms ever experienced during their illness. The MF patients complained about eight symptoms, compared with six symptoms usually reported by PV and ET patients.
The five most common symptoms reported by MF, PV and ET patients over the past 12 months are listed in Figure 1. Over half of the MF patients reported fatigue (80%), weakness (67%), and night sweats (60%). Worth of note, not all patients believed these symptoms were related to the disease. In particular, the patients did not associate fatigue, weakness, and night sweats with the disease in 33%, 40% and 56% cases, respectively. As for PV symptoms, 59% of patients felt weakness, and 41% experienced fatigue and pruritus. Hence, 20% and 14% of the patients did not relate weakness and fatigue, respectively, to specific symptoms of their disease. Meanwhile, all the patients believed that pruritus was associated with the disease. 50% of ET patients experienced fatigue and numbness/tingling. Of note, all the patients associated fatigue with the disease; as for numbness/tingling, 12.5% of patients did not associate this symptom with the disease. At the same time, most physicians (69%) believed that the vast majority of the patients associated their symptoms with myeloproliferative disease.
The patients also evaluated severity of their symptoms in the past 12 months using a 10-point numerical rating scale (NRS). Some symptoms were severe: ≥7 points on the NRS scale. Patients with Ph(-) MPN reported the following severe symptoms: fatigue (n=18), weakness (n=15), headache (n=9), night sweats (n=8), abdominal pain (n=7), fever (n=5), dizziness (n=5), bone pain (n=2), nose bleeding (n=2) and facial flushing (n=2).
Attending physicians also answered some questions about symptoms in their patients. They were asked to list five most significant symptoms for the patients with each type of Ph(-) MPNs. For MF, the physicians mentioned fatigue (72%), unintentional weight loss (59%), weakness (45%), abdominal discomfort (34%), and night sweats (31%). Of note, only half of the physicians, when compared to their patients, reported night sweats in these cases. In PV, physicians pointed to itching (59%), headaches (45%), hypertension (41%), facial flushing and numbness/tingling in hands and feet (38%). Moreover, as opposed to patients, none of the physicians mentioned weakness or fatigue. For ET, the physicians noted fatigue (59%), nasal bleeding and thrombotic events clot (48%), headaches (37%), and weakness (33%). Unlike patients, physicians did not mention numbness/tingling. As evidenced by the above data, there are discrepancies in the patient and physician perception of the most significant symptoms experienced by Ph(-) MPN patients, while 77% of physicians believed that they have correctly assessed the symptom burden.
As a separate task, both physicians and patients were asked to choose from the list of symptoms experienced by patients those traits that, according to the patient, were most likely to be resolved (1 to 3). The MF patients mentioned fatigue (47%) and pruritus (33%); physicians chose weakness (45%) and fatigue (31%). Patients with PV pointed to pruritus (41%), whereas, in opinion of physicians, pruritus (52%) and hypertension (48%) were most likely to be resolved. As for ET, the patients chose fatigue (38%), while physicians highlighted fatigue, tingling in the hands/feet, and predisposal for thrombosis (44%).
These discrepancies in the physician and patient description of the symptoms that are most significant to patients can be partially explained using the survey data, with regard of the physician’s strategies when discussing symptoms and general well-being during the patients’ clinical visit. The majority of patients mentioned in the survey that the physicians were interested in their symptoms and overall well-being. Patients noticed the following: during the clinic visit, attending physician was actively interested in their well-being and symptoms (55% of patients); the doctor asked them about specific, most important symptoms (25%); the physician expected patients to report their concerns (15%); the physician asked them to fill out questionnaires and discussed existing problems with them on the basis of their answers (5%). All the patients stated that the physician was interested in their well-being and existing symptoms.
In addition, significant differences between physicians and patients were revealed, regarding the time that physicians spent discussing blood test results and well-being with the patients. The vast majority of patients (93%) believed that during the visit the physician spent most of the time discussing blood test results with them. At the same time, only 43% of physicians believed that they spent more time discussing blood test results with the patient rather than their well-being.
According to the survey of physicians, they received information about the patient’s symptoms and overall well-being in the following way: 43% of physicians were actively interested in the patient’s problems during the visit; 37% discussed the most important symptoms with the patient, and 13% expected reporting of any alarming symptoms from patients. Only 7% of physicians told that they asked patients to fill out questionnaires to record their symptoms. At the same time, 83% of physicians stated that they assessed patient's symptoms at each visit. When evaluating the severity of symptoms, 43% of physicians considered the impact of disease on the daily life of the patient, and 27% of physicians based it on their own assessment. Only 20% of physicians used questionnaires for standard assessment of the symptoms.
Disease impact on the quality of life in Ph(-) MPN patients
The list of questions in the patient’s and physician’s survey checklists focused on the impact of symptoms on patient’s quality of life and daily activities [9, 11]. Most Ph(-) MPN patients (81%) believed that the symptoms reduced their quality of life (Table 2). All the MF patients, 65% of PV patients, and 75% of ET patients agreed with this statement. Physicians also shared the view that the disease symptoms lead to worsening of quality of life of patients. Furthermore, 77% of physicians believed that even mild or moderate symptoms in patients could be associated with reduced quality of life.
Table 2. Symptom interference with quality of life in Ph(-) MPN patients
As a special point, the effect of symptoms on daily life activities was evaluated by the survey. Figure 2 shows the distribution of the patient’s and physician’s answers about impact of the symptoms upon daily activities of patients, their family and social life, relationships with caregivers, as well as limitations of activities caused by pain/discomfort. As evidenced in the Figure 2, most patients and physicians believed that disease symptoms affect the mentioned daily activities of patients. Most patients and physicians also indicated that pain/discomfort limits patient's daily activities, especially in MF patients, compared to PV and ET. In MF, the reported symptoms had a higher impact on their daily activities, family and social life. Pain/discomfort also significantly limited their daily activities. In general, the discrepancy between physicians and patients in assessing the impact of disease symptoms on daily life was not significant.
Figure 2. Patient and physician perceptions of the disease symptom burden on daily activities in Ph(-) MPN patients; A, myelofibrosis; B polycythemia vera; C, essential thrombocythemia
The patients were also asked in what way the disease affected various aspects of their quality of life (Figure 3). For the vast majority of Ph(-) MPN patients, the disease had a significant impact on physical (95%) and emotional (87%) functioning. Almost all of the patients (95%) experienced anxiety, because of their condition and were worried that their condition would worsen. It is noteworthy that 80% of patients believed that their health was worse, if compared to their condition evaluated by treating physician, and 77% felt helpless.
Figure 3. Disease impact on various aspects of quality of life as assessed by Ph(-) MPN patients
As for different forms of Ph(-) MPNs, all the patients with MF and ET, as well as 88% of patients with PV, experienced some degree of physical problems caused by their condition. All the ET patients, 87% of MF patients, and 82% of PV patients reported emotional burden associated with the disease. All the MF patients, 94% of PV patients and 87% of ET patients experienced anxiety related to their condition. At the same time, 93%, 71% and 75% of patients with MF, PV and ET, respectively, believed that they felt worse than perceived by their treating physician. Moreover, 93%, 71% and 62% of patients with MF, IP and ET, respectively, indicated that they felt helpless.
All surveyed physicians believed that MF and PV patients had physical and emotional limitations; 7% of physicians believed that ET patients did not experience such restrictions.
Disease impact on work productivity in Ph(-) MPN patients
The patient survey contained questions about employment, disability, limitations in overall activity and support from caregivers. From the proposed list of employment options, over one-third of patients (35%) stated that they worked full time, 13% were in part-time employment, and 5% were on sick leave. Other patients claimed they were pensioners (43%) or unemployed (6%). Overall, 53% of patients reported that they continued to work at the time of the survey. Over past 7 days, the patients had to miss, on average, 2.8 hours of working time, due to their disease. To assess the impact of the disease on productivity at work and overall activity, patients were asked to choose a number on a scale from 0 to 10, where 0 means "no effect of the disease on work/overall activity" and 10 means "completely unable to work/illness completely interferes with overall activity". According to the survey results, 32% of patients indicated that their disease significantly (score 7-10) limited their productivity at work; the disease significantly affected overall activity in 48% of patients.
Overall, 48% of Ph(-) MPN patients reported requiring assistance from a caregiver, with 46% of MF patients, 36% of PV patients and 13% of ET patients needed for support often or sometimes. Half of these patients were supported by their children. In 47% of cases, a support for the patients was provided by the people who continued to work. Assistance with housework (79%) and transportation (74%) were the main forms of support.
Treatment of Ph(-) MPNs and physician’s and patient’s perspectives on treatment goals
The surveys for physicians contained the following questions regarding treatment: 1) treatment strategy at the time of diagnosis; 2) therapy prescribed anytime in the past; 3) treatment that physicians currently prescribed for their patients. Physicians had to choose the answers from the proposed list of treatment options separately for patients with MF, PV and ET. According to their answers, the physicians chose a strategy of waiting and observation in 12% of MF patients, in 15% of PV cases, and in 18% of ET patients at the time of diagnosis. Details of previous treatment for patients with MF, PV and ET, and currently prescribed therapies, as well as reasons for changing therapy are summarized in Table 3. In general, there is no much difference between the past and current therapies prescribed by physicians to treat specific MF, PV and ET patients. Some differences between the past and current therapies were observed for MF treatment with epoetin-α, androgens and glucocorticosteroids, for PV treatment with epoetin-α, for ET treatment with glucocorticosteroids and BMT/HSCT.
Table 3. Treatment prescribed in the past, currently prescribed therapy, and the reasons for changing therapy in patients with MF, IP and ET
Worth of note, half of the physicians reported an increase in symptoms of a specific Ph(-) MPN as the reason for the change of treatment.
The questionnaire for physicians also included questions concerning prognostic risk assessment in patients with Ph(-) MPN, and criteria for assessing the disease progression. According to the survey, 70% of physicians used different tools to calculate prognostic risk scores in their practice. IPSS was the most commonly used scale for assessing prognostic risk (43%). Among those physicians who did not use the available risk assessment tools, 33% considered these methods useful, but did not have enough time to use them in clinical practice; the same number of physicians (33%) were familiar with these assessment tools, but did not consider them practically useful; 11% of physicians stated that they were not familiar with these tools. The physicians pointed to the following main criteria for the disease progression: in MF, deterioration of the patient's condition (86%), increasing splenomegaly (86%), and continued weight loss (79%); in PV, changes of hemoglobin levels (83%), changing severity of symptoms (79%), evolving new symptom(s) (72%); in ET, changes in platelet levels (85%), development of new symptom(s) (78%), and deterioration of the patient's condition (70%).
Both physicians and patients were given a separate block of questions related to the main treatment goals. Physicians and patients were asked to select the main treatment goals (except for a curation) from a list of statements. The physician and patient survey results regarding goals for MF, PV and ET treatment are shown in Figure 4. Information is shown as the percentages of patients and physicians who have chosen the definite treatment goals. As seen in Figure 4, the MF, PV and ET patients have selected the following main treatment goals: better quality of life (60%, 76%, and 75%, respectively), reduction of symptoms (60%, 47%, and 50%, respectively), normal blood counts (53%, 53%, and 50%, respectively), and slower progression of the disease (47%, 41%, 50%, respectively). Physicians indicated the following main treatment goals (except for a cure) in Ph(-) MPN patients: in MF, improved quality of life (66%), slower disease progression (55%) and reduction in spleen size (52%); in PV and ET, better quality of life (69% and 59%, respectively), prevention of thrombotic events (48% and 67%), retarded disease progression (48% and 48%), and reduced frequency of phlebotomies in the PV patients (48%).
Figure 4. Ph(-) MPN treatment goals (other than cure), as reported by physicians and patients
In addition, the patients filled a list of supplementary statements on how successful or unsuccessful the treatment could be. When evaluating the success of treatment, patients used the following criteria: quality of life improvement or relief of symptoms (68%), reduced number of the symptoms (48%), physician’s conclusion (48%), and blood testing results (43%).
Moreover, the physicians were also given a list of statements describing challenges in Ph(-) MPN treatment. With regard to the treatment of MF, PV and ET patients, physicians selected the following unresolved issues: chances for cure (41%, 31% and 41%, respectively), and ability to delay progression of the disease (21%, 21% and 19%, respectively). Furthermore, 22% of physicians stated that a search for new effective drugs is an important aspect of ET treatment.
Perception of the physician-patient relationship by physicians and Ph(-) MPN patients
Both physician’s and patient’s surveys contained questions about patient satisfaction with the treatment, effectiveness of the physician in management of the disease, as well as the physician-patient relationship. In terms of treatment satisfaction, 98% of Ph(-) MPN patients were generally satisfied with the treatment (65% were completely satisfied and 33% were somewhat satisfied). Overall, 85% of patients were satisfied with efficiency of the disease control achieved by their physician (75% were completely satisfied and 10% were somewhat satisfied). As for physicians, 90% of them were satisfied with their management of the disease. Similarly, 90% of physicians reported that their priority goals concerning treatment agreed with the patients' perspectives: 37% believed that they completely agreed, 53% agreed to some extent. In general, all the patients were satisfied with the communication with their physician. When asked about the physician-patient relationship, 84% of physicians stated that they were satisfied with their communication with patients. Whereas 95% of patients indicated that they were generally satisfied with the awareness of various aspects of the disease, 5% were not satisfied. When asked about patient awareness of the disease, 87% of physicians believed that patients were well informed.
The majority of patients (95%) reported that they received information about their disease directly from their physician; 20% of patients indicated that they had difficulties with finding information about their disease.
Discussion
This paper presents data on survey of Russian patients and physicians evaluating the impact of chronic Ph(-) MPNs on various aspects of patients' well-being, conducted as a part of the international Landmark Survey. One of the main aims of the Landmark Survey is to study the symptoms experienced by Ph(-) MPN patients and their impact on daily activities as assessed by patients and physicians. The survey was also designed to investigate how the disease affects the patient’s quality of life and work productivity, both from the patient’s and physician's perspective. The analysis was based on the survey completed by 40 patients with Ph(-) MPN and 30 attending physicians.
The results of the survey revealed a significant impact of Ph(-) MPNs on quality of life of the patients. Accordingly, the disease symptoms in majority of Ph(-) MPN patients (100% of MF cases, 65% of PV cases, and 75% of ET patients), led to impairment of their quality of life. In general, these data are consistent with results of the original Landmark study conducted in the USA, where 81% of MF patients, 66% of PV patients and 56% of ET patients reported worsening of their quality of life due to the disease [8]. However, compared with the original study, a higher number of MF (100% versus 81%) and ET (75% versus 56%) patients in the Russian sample reported the negative effect of the disease symptoms on their quality of life.
In terms of the most common symptoms after diagnosis, Ph(-), the MPN patients noted fatigue (63%) and weakness (53%), thus being consistent with the data from the Landmark Survey in other countries [8-11]. It is worth of note that over a half of the patients (54%) experienced symptoms for a year prior to diagnosis, and the remaining patients had symptoms for two or more years before receiving the diagnosis, which is significantly more than in other countries [8-10].
When analyzing the symptoms exhibited by Ph(-) MPN patients over the past 12 months, it was shown that most patients, regardless of the disease, noted weakness or fatigue. Other common symptoms were different, depending on the specific Ph(-) MPN subtype. It is important to note that not all patients believed these symptoms were related to the disease.
This data is in line with the published results of Landmark survey in the countries with development markets according to which many patients also did not recognize that their symptoms could be MPN-related. For example, in this study 18% MF and 25% PV did not think their fatigue/tiredness resulted from MPNs [10]. According to our data, 33% and 14% of MF and PV patients, respectively, did not recognize fatigue as a symptom of the disease. It should also be noted that the analysis of the physician’s and patient’s responses regarding the most important patient’s symptoms revealed a discrepancy in their assessments. To some extent, these differences can be explained by the fact that only a half of the physicians actively discussed well-being and symptoms with patients during clinic visits. Moreover, the results show that only 20% of asked physicians use standardized questionnaires to assess the severity of symptoms, i.e., a significantly smaller proportion compared to their colleagues in other countries [8-10].
The analyzed results of the patient’s and physician’s surveys evaluating the effect of disease symptoms on daily lives of patients, including their everyday activities, family or social life, relationships with caregivers, and pain/discomfort that limits activity, revealed that, in the opinion of most patients and physicians, the disease burden affects daily lives of patients. It is worth of note that, in general, the discrepancy between physicians and patients in assessing the impact of disease symptoms on daily life was not significant. These results are consistent with previous reports that included non-US patients [12-14], as well as the recent US Landmark survey [6].
In a separate subset of questions, patients and physicians evaluated how the disease affected various aspects of their physical and emotional functioning. In the overwhelming majority of cases both patients and physicians reported that the disease caused significant physical and emotional hardship for Ph(-) MPN patients. The following data requires a special consideration: almost all the patients experienced anxiety because of their condition and were worried that their condition would worsen; moreover, 80% believed that their health was worse than what their treating physician perceived.
It was also shown that Ph(-) MPNs affect working ability and overall activity of patients. Thus, 32% of patients indicated that their disease significantly (score 7-10) limited their productivity at work; the disease had a significant impact on the overall activity of 48% of patients. Similar data was collected by the Landmark Survey in other countries [11].
Overall, almost a half of Ph(-) MPN patients reported requiring assistance from a caregiver, with 46% of MF patients, 36% of PV patients and 13% of ET patients needing support often or sometimes. These results are consistent with data obtained in other countries [11].
A separate analysis was conducted on the responses of physicians regarding treatment strategies at the time of diagnosis, treatments that were prescribed in the past, and treatments currently prescribed for their patients. It is interesting to note that half of the physicians reported an increase in symptoms as the reason for changing treatment, which emphasizes the importance of improving approaches to symptom management in Ph(-) MPN patients.
Responses of physicians on the approaches of Ph(-) MPN prognostic risk assessment were also analyzed. It should be noted that 70% of physicians used different tools to assess prognostic risk in their practice, but a third of physicians did not resort to their use due to lack of time, doubts about the usefulness of these tools or simply due to insufficient information about them.
Patient’s and physician’s responses regarding the MF, PV and ET therapy goals are of particular interest. It is important to note that both patients and physicians chose the improvement of the quality of life and symptom relief, as well as slowing the progression of the disease as the main treatment goals. In terms of evaluating treatment success, most patients (68%) mentioned the improvement in quality of life and symptom relief. This fact highlights the relevance of patient quality of life assessments as one of the important treatment outcomes. Besides, the international guidelines on assessing clinical response of Ph(-) MPN patients to treatment suggest the use of information on patient’s quality of life and symptoms [15, 16].
Satisfaction with the treatment as well as with the physician-patient relationship was also analyzed. With regard to the physician-patient relationship, 84% of physicians and 100% of patients were satisfied with it. According to the majority of the physicians (87%), patient awareness of the disease was rather high. Overall, 95% of patients were satisfied with their knowledge of the various aspects of the disease. At the same time, the issues identified in the survey of physicians and patients in relation to significant discrepancies between physician’s and patient’s assessment of burdensome symptoms, and specific perception of certain symptoms as not related to their disease by the patients highlight the importance of further improvement of symptom assessment strategies in Ph(-) MPN patients and raising awareness about the disease among the medical community, Ph(-) MPN patients and their relatives.
Despite the fact that the results were obtained in a limited sample of respondents (40 patients with Ph(-) MPN and 30 physicians), it is the first comprehensive analysis of the problems associated with the disease and treatment of Ph(-) MPN obtained in the Russian population of these patients, and the information is presented from the viewpoint of both patients and physicians. In general, the results of our survey demonstrate that patients with Ph(-) MPN feel a significant negative impact of the disease on various aspects of their life, have impaired quality of life and reduced work productivity. This data confirm the previously published results of the Landmark Survey conducted in other countries [6-11]. At the same time, this analysis enabled us to identify features of the disease impact and treatment upon various aspects of daily life of Ph(-) MPN patients in Russia, to describe their perceptions of the treatment goals, to assess the degree of satisfaction with treatment and disease control, and also to gain an insight into the physician-patient relationship and the strategies that physicians use in real clinical practice to obtain information about the impact of the disease and treatment on various aspects of the patient’s life. Overall, the results obtained support the value of patient’s perspective about the disease and its treatment for Ph(-) MPN to improve quality of care of this patients’ population [17-19].
Conclusion
Evaluation and synthesis of the survey data collected among Russian Ph(-)MPN patients and their attending physicians as part of the Landmark Survey constitute an important contribution to this project conducted in different countries. This data revealed that the patients with different Ph(-) MPNs have serious disease-related restrictions in everyday life, altered quality of life and reduced work productivity. In addition, the survey has revealed discordance in physician’s and patient’s assessment of the problems that patients face in relation to the disease and treatment. These differences indicate a need for new approaches, in order to improve of quality of care for this patients’ population, as well as for raising knowledge on the Ph(-) MPNs among the medical community and patients. Further clinical research is required to substantiate the development of patient-centered treatment programs for chronic Ph-negative myeloproliferative neoplasms in Russian Federation, as well as to provide detailed information for the patients and their relatives about the disease and its treatment.
Acknowledgements
No conflict of interest declared.
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" ["DETAIL_TEXT_TYPE"]=> string(4) "html" ["~DETAIL_TEXT_TYPE"]=> string(4) "html" ["PREVIEW_TEXT"]=> string(0) "" ["~PREVIEW_TEXT"]=> string(0) "" ["PREVIEW_TEXT_TYPE"]=> string(4) "text" ["~PREVIEW_TEXT_TYPE"]=> string(4) "text" ["PREVIEW_PICTURE"]=> NULL ["~PREVIEW_PICTURE"]=> NULL ["LANG_DIR"]=> string(4) "/ru/" ["~LANG_DIR"]=> string(4) "/ru/" ["SORT"]=> string(3) "500" ["~SORT"]=> string(3) "500" ["CODE"]=> string(100) "otnoshenie-k-zabolevaniyu-i-lecheniyu-u-patsientov-s-khronicheskimi-ph-negativnymi-neoplaziyami-rezu" ["~CODE"]=> string(100) "otnoshenie-k-zabolevaniyu-i-lecheniyu-u-patsientov-s-khronicheskimi-ph-negativnymi-neoplaziyami-rezu" ["EXTERNAL_ID"]=> string(4) "1855" ["~EXTERNAL_ID"]=> string(4) "1855" ["IBLOCK_TYPE_ID"]=> string(7) "journal" ["~IBLOCK_TYPE_ID"]=> string(7) "journal" ["IBLOCK_CODE"]=> string(7) "volumes" ["~IBLOCK_CODE"]=> string(7) "volumes" ["IBLOCK_EXTERNAL_ID"]=> NULL ["~IBLOCK_EXTERNAL_ID"]=> NULL ["LID"]=> string(2) "s2" ["~LID"]=> string(2) "s2" ["EDIT_LINK"]=> NULL ["DELETE_LINK"]=> NULL ["DISPLAY_ACTIVE_FROM"]=> string(0) "" ["IPROPERTY_VALUES"]=> array(18) { ["ELEMENT_META_TITLE"]=> string(336) "Отношение к заболеванию и лечению у пациентов с хроническими Ph-негативными неоплазиями: результаты опросов врачей и их пациентов в России, как часть международного исследования Landmark" ["ELEMENT_META_KEYWORDS"]=> string(0) "" ["ELEMENT_META_DESCRIPTION"]=> string(536) "Отношение к заболеванию и лечению у пациентов с хроническими Ph-негативными неоплазиями: результаты опросов врачей и их пациентов в России, как часть международного исследования LandmarkAttitudes to the disease and therapy in patients with chronic Ph-negative myeloproliferative neoplasms: results of the physician and patient surveys in Russia as a part of International Landmark Study" ["ELEMENT_PREVIEW_PICTURE_FILE_ALT"]=> string(3388) "<p style="text-align: justify;">Целью данной статьи была оценка и обобщение данных, полученных при опросах российских больных и их лечащих врачей, проведенных в рамках международного исследования Landmark для стран с развивающимся рынком, направленного на выяснение проблем и вопросов ведения пациентов с хроническими Ph-негативными миелопролиферативными новообразованиями (МПН).</p> <p style="text-align: justify;">Разосланные онлайн-формы заполняли 40 взрослых пациентов с Ph(-) МПН (истинная полицитемия – 42,5%; миелофиброз – 37,5%; эссенциальная тромбоцитемия – 20%), а также 30 врачей с достаточным опытом лечения Ph(-) МПН. В рамках этого исследования, лечащие врачи и пациенты отвечали на вопросы, касающиеся восприятия симптомов заболевания и их воздействия на качество жизни, повседневную активность и продуктивность работы пациентов, а также их отношения к основным целям терапии и различным аспектам общения больного и врача. Результаты: выявлен ряд различий между восприятием заболевания и лечения больными и врачами, что дополняет данные исследования Landmark, полученные в других странах. Было показано, что больные с различными вариантами Ph(-) МПН сталкиваются со значительными проблемами в повседневной жизни, нарушениями качества жизни и снижением работоспособности, обусловленными заболеванием. Отсутствие совпадения в оценке тяжести и лечения болезни врачом и больным указывает на необходимость новых подходов к улучшению качества клинического обслуживания для этой категории больных. Дальнейшие исследования в этой области были бы важным шагом к внедрению в Российской Федерации программ лечения Ph(-) МПН, ориентированных на больных.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Миелопролиферативные неоплазии, хронические, Ph-негативные, опрос пациентов и врачей, симптомы, качество жизни, пациент-ориентированные программы. </p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(336) "Отношение к заболеванию и лечению у пациентов с хроническими Ph-негативными неоплазиями: результаты опросов врачей и их пациентов в России, как часть международного исследования Landmark" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(336) "Отношение к заболеванию и лечению у пациентов с хроническими Ph-негативными неоплазиями: результаты опросов врачей и их пациентов в России, как часть международного исследования Landmark" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(336) "Отношение к заболеванию и лечению у пациентов с хроническими Ph-негативными неоплазиями: результаты 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Морозова<sup>1</sup>, Мария В. Барабанщикова<sup>1</sup>, Татьяна И. Ионова<sup>2</sup>, <span style="border: 1px solid black; margin: 0; padding: 2px 2px;">Борис В. Афанасьев<sup>1</sup></span></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(272) "
Елена В. Морозова1, Мария В. Барабанщикова1, Татьяна И. Ионова2, Борис В. Афанасьев1
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "26471" ["VALUE"]=> array(2) { ["TEXT"]=> string(592) "<p><sup>1</sup> НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия<br> <sup>2</sup> Санкт-Петербургский государственный университетский госпиталь, Санкт-Петербург, Россия</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(550) "1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Санкт-Петербургский государственный университетский госпиталь, Санкт-Петербург, Россия
Целью данной статьи была оценка и обобщение данных, полученных при опросах российских больных и их лечащих врачей, проведенных в рамках международного исследования Landmark для стран с развивающимся рынком, направленного на выяснение проблем и вопросов ведения пациентов с хроническими Ph-негативными миелопролиферативными новообразованиями (МПН).
Разосланные онлайн-формы заполняли 40 взрослых пациентов с Ph(-) МПН (истинная полицитемия – 42,5%; миелофиброз – 37,5%; эссенциальная тромбоцитемия – 20%), а также 30 врачей с достаточным опытом лечения Ph(-) МПН. В рамках этого исследования, лечащие врачи и пациенты отвечали на вопросы, касающиеся восприятия симптомов заболевания и их воздействия на качество жизни, повседневную активность и продуктивность работы пациентов, а также их отношения к основным целям терапии и различным аспектам общения больного и врача. Результаты: выявлен ряд различий между восприятием заболевания и лечения больными и врачами, что дополняет данные исследования Landmark, полученные в других странах. Было показано, что больные с различными вариантами Ph(-) МПН сталкиваются со значительными проблемами в повседневной жизни, нарушениями качества жизни и снижением работоспособности, обусловленными заболеванием. Отсутствие совпадения в оценке тяжести и лечения болезни врачом и больным указывает на необходимость новых подходов к улучшению качества клинического обслуживания для этой категории больных. Дальнейшие исследования в этой области были бы важным шагом к внедрению в Российской Федерации программ лечения Ph(-) МПН, ориентированных на больных.
Ключевые слова
Миелопролиферативные неоплазии, хронические, Ph-негативные, опрос пациентов и врачей, симптомы, качество жизни, пациент-ориентированные программы.
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2 Saint Petersburg State University Hospital, St. Petersburg, Russia
Correspondence
Prof. Dr Sci Tatyana I. Ionova, Saint Petersburg State University Hospital, Fontanka Emb 154, 198103, St. Petersburg, Russia
Phone: +7 (962) 710 1711
E-mail: tation16@gmail.com
The aim of this paper was to present evaluation and synthesis of data derived from a survey of Russian patients and physicians, performed as a part of the international Landmark study for the emerging market countries designed to specify problems and areas of concern in management of patients with chronic Ph-negative myeloproliferative neoplasms (MPN). The online survey forms were filled by 40 adult patients with Ph(-) MPNs (PV, 42.5%; MF, 37.5%; ET, 20%) and 30 physicians with sufficient experience in the Ph(-) MPNs treatment. As a part of this survey, patients and physicians answered questions related to perception of the disease symptoms and their impact on quality of life, daily activities and work productivity of patients, as well as their attitude to main treatment goals and various aspects of the patient-physician communication. The results revealed a number of differences between patient and physician perception of the disease and treatment, thus complementing the data of the Landmark Survey in other countries. It was shown that the patients with different variants of Ph(-) MPNs encounter sufficient disease-related difficulties in everyday life, impaired quality of life and reduced work productivity. Lack of coincidence revealed between the physician and patient assessment of the disease burden and treatment indicates the need for new ways of improving quality of clinical care provided to this category of patients. Further research in this area would be an important step towards implementation of patient-centered Ph(-) MPN treatment programs in Russian Federation.
Keywords
Myeloproliferative neoplasms, chronic, Ph-negative, physician and patient survey, symptoms, quality of life, patient-centered treatment programs.
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Keywords
Myeloproliferative neoplasms, chronic, Ph-negative, physician and patient survey, symptoms, quality of life, patient-centered treatment programs.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1838) "The aim of this paper was to present evaluation and synthesis of data derived from a survey of Russian patients and physicians, performed as a part of the international Landmark study for the emerging market countries designed to specify problems and areas of concern in management of patients with chronic Ph-negative myeloproliferative neoplasms (MPN). The online survey forms were filled by 40 adult patients with Ph(-) MPNs (PV, 42.5%; MF, 37.5%; ET, 20%) and 30 physicians with sufficient experience in the Ph(-) MPNs treatment. As a part of this survey, patients and physicians answered questions related to perception of the disease symptoms and their impact on quality of life, daily activities and work productivity of patients, as well as their attitude to main treatment goals and various aspects of the patient-physician communication. The results revealed a number of differences between patient and physician perception of the disease and treatment, thus complementing the data of the Landmark Survey in other countries. It was shown that the patients with different variants of Ph(-) MPNs encounter sufficient disease-related difficulties in everyday life, impaired quality of life and reduced work productivity. Lack of coincidence revealed between the physician and patient assessment of the disease burden and treatment indicates the need for new ways of improving quality of clinical care provided to this category of patients. Further research in this area would be an important step towards implementation of patient-centered Ph(-) MPN treatment programs in Russian Federation.
Keywords
Myeloproliferative neoplasms, chronic, Ph-negative, physician and patient survey, symptoms, quality of life, patient-centered treatment programs.
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2 Saint Petersburg State University Hospital, St. Petersburg, Russia
Correspondence
Prof. Dr Sci Tatyana I. Ionova, Saint Petersburg State University Hospital, Fontanka Emb 154, 198103, St. Petersburg, Russia
Phone: +7 (962) 710 1711
E-mail: tation16@gmail.com
1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia
2 Saint Petersburg State University Hospital, St. Petersburg, Russia
Correspondence
Prof. Dr Sci Tatyana I. Ionova, Saint Petersburg State University Hospital, Fontanka Emb 154, 198103, St. Petersburg, Russia
Phone: +7 (962) 710 1711
E-mail: tation16@gmail.com
Елена В. Морозова1, Мария В. Барабанщикова1, Татьяна И. Ионова2, Борис В. Афанасьев1
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В рамках этого исследования, лечащие врачи и пациенты отвечали на вопросы, касающиеся восприятия симптомов заболевания и их воздействия на качество жизни, повседневную активность и продуктивность работы пациентов, а также их отношения к основным целям терапии и различным аспектам общения больного и врача. Результаты: выявлен ряд различий между восприятием заболевания и лечения больными и врачами, что дополняет данные исследования Landmark, полученные в других странах. Было показано, что больные с различными вариантами Ph(-) МПН сталкиваются со значительными проблемами в повседневной жизни, нарушениями качества жизни и снижением работоспособности, обусловленными заболеванием. Отсутствие совпадения в оценке тяжести и лечения болезни врачом и больным указывает на необходимость новых подходов к улучшению качества клинического обслуживания для этой категории больных. Дальнейшие исследования в этой области были бы важным шагом к внедрению в Российской Федерации программ лечения Ph(-) МПН, ориентированных на больных.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Миелопролиферативные неоплазии, хронические, Ph-негативные, опрос пациентов и врачей, симптомы, качество жизни, пациент-ориентированные программы. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3310) "Целью данной статьи была оценка и обобщение данных, полученных при опросах российских больных и их лечащих врачей, проведенных в рамках международного исследования Landmark для стран с развивающимся рынком, направленного на выяснение проблем и вопросов ведения пациентов с хроническими Ph-негативными миелопролиферативными новообразованиями (МПН).
Разосланные онлайн-формы заполняли 40 взрослых пациентов с Ph(-) МПН (истинная полицитемия – 42,5%; миелофиброз – 37,5%; эссенциальная тромбоцитемия – 20%), а также 30 врачей с достаточным опытом лечения Ph(-) МПН. В рамках этого исследования, лечащие врачи и пациенты отвечали на вопросы, касающиеся восприятия симптомов заболевания и их воздействия на качество жизни, повседневную активность и продуктивность работы пациентов, а также их отношения к основным целям терапии и различным аспектам общения больного и врача. Результаты: выявлен ряд различий между восприятием заболевания и лечения больными и врачами, что дополняет данные исследования Landmark, полученные в других странах. Было показано, что больные с различными вариантами Ph(-) МПН сталкиваются со значительными проблемами в повседневной жизни, нарушениями качества жизни и снижением работоспособности, обусловленными заболеванием. Отсутствие совпадения в оценке тяжести и лечения болезни врачом и больным указывает на необходимость новых подходов к улучшению качества клинического обслуживания для этой категории больных. Дальнейшие исследования в этой области были бы важным шагом к внедрению в Российской Федерации программ лечения Ph(-) МПН, ориентированных на больных.
Ключевые слова
Миелопролиферативные неоплазии, хронические, Ph-негативные, опрос пациентов и врачей, симптомы, качество жизни, пациент-ориентированные программы.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(3310) "Целью данной статьи была оценка и обобщение данных, полученных при опросах российских больных и их лечащих врачей, проведенных в рамках международного исследования Landmark для стран с развивающимся рынком, направленного на выяснение проблем и вопросов ведения пациентов с хроническими Ph-негативными миелопролиферативными новообразованиями (МПН).
Разосланные онлайн-формы заполняли 40 взрослых пациентов с Ph(-) МПН (истинная полицитемия – 42,5%; миелофиброз – 37,5%; эссенциальная тромбоцитемия – 20%), а также 30 врачей с достаточным опытом лечения Ph(-) МПН. В рамках этого исследования, лечащие врачи и пациенты отвечали на вопросы, касающиеся восприятия симптомов заболевания и их воздействия на качество жизни, повседневную активность и продуктивность работы пациентов, а также их отношения к основным целям терапии и различным аспектам общения больного и врача. Результаты: выявлен ряд различий между восприятием заболевания и лечения больными и врачами, что дополняет данные исследования Landmark, полученные в других странах. Было показано, что больные с различными вариантами Ph(-) МПН сталкиваются со значительными проблемами в повседневной жизни, нарушениями качества жизни и снижением работоспособности, обусловленными заболеванием. Отсутствие совпадения в оценке тяжести и лечения болезни врачом и больным указывает на необходимость новых подходов к улучшению качества клинического обслуживания для этой категории больных. Дальнейшие исследования в этой области были бы важным шагом к внедрению в Российской Федерации программ лечения Ph(-) МПН, ориентированных на больных.
Ключевые слова
Миелопролиферативные неоплазии, хронические, Ph-негативные, опрос пациентов и врачей, симптомы, качество жизни, пациент-ориентированные программы.
" } ["ORGANIZATION_RU"]=> array(37) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "26471" ["VALUE"]=> array(2) { ["TEXT"]=> string(592) "<p><sup>1</sup> НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия<br> <sup>2</sup> Санкт-Петербургский государственный университетский госпиталь, Санкт-Петербург, Россия</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(550) "1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Санкт-Петербургский государственный университетский госпиталь, Санкт-Петербург, Россия
1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Санкт-Петербургский государственный университетский госпиталь, Санкт-Петербург, Россия
Introduction
Survival rates of children and adolescents with oncological diseases significantly improved due to development of novel chemotherapy (ChT) protocols. In large part, this could be explained by more aggressive treatment, thus requiring a more careful selection of supportive and symptomatic therapy. Pain is among the most common symptoms which trouble both sick children themselves, and their parents [1].
Hematopoietic stem cell transplantation (HSCT) is a high-risk treatment aimed for therapy of both oncological, non-malignant hematological and some orphan diseases. Early post-transplant period is accompanied by such common conditions, e.g., weakness, pains and insomnia. These complaints are presented in 8 to 55% of autologous HSCTs [2], and 60 до 80% of allogeneic HSCT recipients [3]. Oral and gastrointestinal mucositis is among common painful complications occurring in 20 to 40% of chemotherapy (ChT) courses, and in up to 80% cases of conditioning treatment preceding HSCT, dependent on the drug combination applied [4].
Cytotoxic drugs used for conditioning therapy before allo-HSCT could damage endothelium of liver with subsequent development of veno-occlusive disease which could manifest with hepatomegaly accompanied by right upper quadrant pain due to extensive distension of Glisson capsule. This complication may encounter in 13.7% cases of HCST, as well as after ChT course [5]. In our experience, pain syndromes may be also connected with development of acute hemorrhagic cystitis, infections, fast engraftment, bone marrow necrosis, bone pain associated with corticosteroid withdrawal etc.
Thrombocytopenia, agranulocytosis, and, sometimes, renal dysfunction comprise special features in the patients after HSCT and some ChT regimens, thus limiting the opportunities for usage of nonsteroid anti-inflammatory drugs (NSAID), as first step of WHO analgetic ladder. Administration of these medicines as analgetics, could also hide fever of infectious origin. One should also note limited routes for administration of painkillers, i.e., per oral uptake could be difficult due to evolving mucositis. Rectal administration is not recommended, because of high-risk translocation of gut microflora in neutropenic conditions, whereas intramuscular injections are contraindicated, due to thrombocytopenia and painful manipulation [6, 7]. In this view, management of weak and moderate pain with NSAID may be difficult, and one should change the therapy for second-line treatment at early stages. Previously, WHO has excluded the second stage of pain relief ladder using weak opioids, e.g., codeine [7]. From 2009 to 2012, several cases of breath depression were registered in children under 5 years old after codeine postoperative analgesia after tonsillectomy. Most likely, this side effect was associated with individual genetic feature of cytochrome enzymes e.g., ultra-fast codeine activation by CYP2D6 with excessive production of morphine which, under normal excretion rates, could be accumulated at toxic concentrations.
In particular, tramadol is mostly inactivated by two enzymes, CYP2D6 and CYP3A4, whereas unchanged М1 metabolite, is, in turn, is excreted with urine. The analgetic effects of the drug are explained by, at least, two mechanisms, i.e., interaction between tramadol/M1 metabolite and μ-opiate receptors (OPRM1), as well as inhibition of serotonin and norepinephrine reuptake by tramadol, thus suppressing pain impulse transmission at the level of spinal cord [8, 9]. Undoubtedly, the patients with ultra-fast tramadol metabolism are in high-risk group, especially, in cases of high-dose treatment and appropriate comorbidities of respiratory system, sleep apnea in tonsillar hyperplasia, or obesity conditions [10]. Therefore, some authors recommend to admit the patients to inpatient unit as early as 24 hours before treatment, in cases of acute nociceptive pain in patients administered tramadol and uncertain CYP2D6 activity levels [11]. Concerning the analgetic capacity, tramadol takes an intermediate position between NSAID and potent opioids, but at the same time, some publications report on less common frequency of sedation, respiratory depression, constipation and other side effects typical to strong opioids [12]. At the present time, tramadol is widely used for treatment of nociceptive pain in traumas and after surgical interventions in children [13, 14, 15, 16, 17, 18]. For moderate pain, the WHO analgesia ladder presumes low doses of strong opioids (oxycodone or morphine) to be the main alternative for weak opioids.
High individual variability of efficient dose is a specific feature of morphine administration. This characteristic could be explained by differences in its bioavailability, metabolism and excretion. The main morphine metabolites are as follows: morphine-6-glucuronide, which exhibits higher analgetic ability, but can elicit nausea, vomiting, excessive sedation, as well as morphime-3-glucuronide with probable antianalgetic and neurotoxic effects [19]. Several studies report about efficiency and safety of low-dose-morphine when managing moderate pain, e.g., in pediatric practice [20, 21, 22, 23]. In turn, the adverse effects of morphine derivatives are not shown at the present time (19).
Worth of note, however, both morphine and tramadol, may also display some side effects, including nausea, vomiting, respiratory depression, urinary retention, constipation, skin itching etc., thus causing discomfort to the patient [24, 25]. Therefore, the aim of our study was to evaluate efficiency and safety of tramadol and low-dose morphine in the treatment of moderate pain in children.
Patients and methods
Figure 1. Patients age distribution
Figure 2. Distribution of main causes of pain
The study was conducted in the Anesthesiology Department of R. M. Gorbacheva Memorial Institute for Pediatric Hematology, Oncology and Transplantation. The study included 159 primary admittances of the patients 1 to 17 years old (a median of 8 years) with complaints of moderate pain. Their age distribution is shown in Fig. 1.
The diagnoses were as follows: solid malignancies, 55.4% (n=88); hemoblastoses, 35.2% (n=56); non-malignant hematological disorders, 5% (n=8) and orphan diseases 4.4% (n=7).
Of them, 13.8% (n=22) were subjected to ChT, 68.8% (n=109) underwent allo- or auto-HSCT with myeloablative treatment regimen; 17.6% (n=28) received HSCT with non-myeloablative conditioning. The main reasons for pain syndrome were: mucositis, 85.5% (n=136), bone pain associated with hematopoiesis recovery, 5% (n=8); progression of primary disease, 5% (n=8); intestinal graft-versus-host disease (GvHD) 1.3%, (n=2), mucositis combined with acute cystitis 2.5% (n=4); paraproctitis, 0.7% (n=1), as seen in Fig. 2.
The intensity if pain was evaluated 3 times a day throughout the observation period to age-matched scale adapted to abilities of the patient (FLACC, verbal scale, Wong-Baker Faces Pain Rating Scale, or visual analogue scale). The total time of observation, including, changing lines of analgesic therapy, if necessary, ranged from 1 to 20 days (median 6 days). The response to therapy was assessed integrally by such parameters as: pain intensity (permanent and activity-evoked), quality of night sleep, ability of food and drink intake without an pain related failure, the possibility of non-pharmacological treatment and patient satisfaction. All the patients were classified into 2 groups in a ratio 3:1. The drugs were injected by continuous infusion at the inpatient clinic. In the first group (n=118), standard tramadol doses were administered as the 1st-line therapy (0.2 to 0.3 mg/kg/h). The patients in the 2nd group (n=41) were administered low-dose morphine (0.01 to 0.019 mg/kg/h). The initially prescribed analgetic was the first line of therapy, if there was a change of therapy, then the new analgetic was considered the second line of therapy. Drug infusion was performed permanently, via central venous catheter under hospital conditions. Pain intensity and drug acceptability were evaluated 2-3 times a day. In cases of insufficient analgesia, i.e., non-reduced or enhanced pain, lack of food and fluid intake because of pain etc., the drug was changed, or morphine dosage was increased. The analgetics were also changed in case of bad tolerance of current therapy. The choice of drug was made individually, depending on clinical situation.
Statistical evaluation was performed by means of SPSS software, using Chi-square test. When checking statistical hypotheses, the difference was presumed significant by p<0.05.
Results
The results of our study have revealed that the therapy was effective in 40.7% (n=48) and 58.5% (n=24) for tramadol and low-dose morphine treatment respectively, whereas in 0.8% of the cases, tramadol administration was prolonged to the end of staying in the unit/transfer to hospice, with good therapy acceptability. Enhanced analgetic treatment was required in 53.4% (n=63) for the 1st group versus 39.0% (n=16) for the patients in the 2nd group (Table 1).
Table 1. First line therapy results
Adverse effects in the first (tramadol-treated) group were observed in 5.1% (n=6). In particular, we observed one case of somnolescence with subsequent excitation in a girl of 4 years old; one case of dizziness with tremor in a girl of 11 years old. Two cases of involuntary contractions of striated muscles were detected: a 6 years old girl had twitching of right hand by 2 days after tramadol injections, and a 10 years old boy developed involuntary contractions of mimic muscles after 3 days of treatment, probably, due to serotoninergic effect of the drug. We have also seen one case of vomiting and nausea in the 17 years old female, as well as a case of nausea and anxiety in the 16 years old female. At the next treatment courses, this pain management was based on strong opioids. Their injection was accompanied by similar side effects. However, the mentioned side effects were no health-threatening. Subsequently 6 years old girl required the change of therapy to fentanyl. In other cases after cancellation of tramadol infusion, weak pain persisted, but further analgesia was not necessary. In the second group, only one female patient (2.4% of total) treated with low-dose morphine developed intestinal paralysis that was resolved after the therapy change.
Upon statistical analysis with Chi-square method, no significant differences were found between the tramadol group and low-dose morphine-treated groups in effectiveness and frequency of side effects (p=0.237).
In case of inefficiency of tramadol or low doses of morphine the second line of therapy included morphine in a low dose (after tramadol administration) was used in 29.1% (n=23), morphine in a standard dose (from 0.02 mg/kg/hr) in 17.7% (n=14) or fentanyl at a dose of 0.05 mcg/kg/hr in 53.2% (n=42) (Table 2).
Table 2. Distribution of the 2nd line therapy medicines
We also evaluated the safety of low and standard doses of morphine in the second line of pain management therapy (Table 3). As result, we observed that side effects appeared in two cases: one because of nausea and vomiting and one due to complaints of blurred focus of vision, which was possibly associated with myosis. In group of standard doses of morphine one case of postrenal urinary retention. All three cases required a revision of treatment.
Table 3. Results of second line therapy with morphine in low and standard doses
Upon statistical analysis with Chi-square method, no significant differences were found between the standard and low-dose morphine-treated patients in effectiveness and frequency of side effects (p=0.271).
Discussion
Currently, some authors state that the respiratory depression is rarely encountered when tramadol dosage is carefully maintained [26, 27]. Frequency of nausea and vomiting are compatible (10-40%) when administering tramadol or opioids [28]. In our experience, a case of intestinal paralysis should be noted in a female patient from 2nd group with mucositis. She had also side effects in the course of immune suppressors (nephro- and neurotoxicity), as well as pancytopenia and hemorrhagic syndrome that could be risk factors of this condition. Concerning adverse effects associated with tramadol prescription, the literature presents only single cases of generalized cramps due to excessive dosage and drug administration to a child under 1 year old [29]. One may also suggest an evolving serotonin syndrome connected to high dosage of serotoninergic drugs (selective serotonin reuptake inhibitors, some monoamine oxidase inhibitors), which includes excitation, ataxia, increased sweating, diarrhea, fever, hyperreflexia, and tremor. In our study, similar symptoms were seen in 4 patients, however, at less significant. This is, probably, connected with non-opioid effects of the drug (inhibition of serotonin and norepinephrin reuptake) [30, 31]. However, one cannot exclude ultra-fast CYP2D6 activity. That is the key aspects influencing tramadol efficiency and, potentially, genetic studies could serve as a predictor of efficacy and safety of the drug. Meanwhile, the CYP2D6 gene polymorphism is quite variable and requires time-consuming molecular genetic studies, thus reducing value of this technique in case of acute pain. One should also understand that the genotype will correspond to phenotype, with regard to variable clearance and body weight [8]. Therefore, we observe the children at the hospital within first 24 hours after starting tramadol infusion. For the patients requiring longer analgesia period, than in our study, tramadol shows lesser potential risk of dependence compared to classical opioids [32]. It’s also important to note that administration of tramadol has a less strict legal regulation [33, 34]. Due to social prejustice, its administration causes lesser anxiety on the part of parents and adolescent patients with respect to adverse effects, ex., addiction. Similarly, in cases with inefficiency of this therapy, the parents take easier administration of strong opioids [35, 36]. In future, tapentadol and local morphine applications could be promising therapeutic options [37]. However, there are only modest data on the studies of these medications in children and adolescents.
Conclusions
Based on the study data, we may suggest that tramadol exerts analgetic effects which are comparable to low-dose morphine. However, administration of these drugs needs dynamic observation of pediatric patients in the hospital at initial steps of therapy, due to some features of individual response and probable side effects. These issues also require further studies in larger groups of patients.
Authors are grateful to Elena V. Verbitskaya, assistant professor of the department of clinical pharmacology and evidence-based medicine, for her help in statistical data processing.
Conflict of interests
The authors declare no conflicts of interest.
References
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Introduction
Survival rates of children and adolescents with oncological diseases significantly improved due to development of novel chemotherapy (ChT) protocols. In large part, this could be explained by more aggressive treatment, thus requiring a more careful selection of supportive and symptomatic therapy. Pain is among the most common symptoms which trouble both sick children themselves, and their parents [1].
Hematopoietic stem cell transplantation (HSCT) is a high-risk treatment aimed for therapy of both oncological, non-malignant hematological and some orphan diseases. Early post-transplant period is accompanied by such common conditions, e.g., weakness, pains and insomnia. These complaints are presented in 8 to 55% of autologous HSCTs [2], and 60 до 80% of allogeneic HSCT recipients [3]. Oral and gastrointestinal mucositis is among common painful complications occurring in 20 to 40% of chemotherapy (ChT) courses, and in up to 80% cases of conditioning treatment preceding HSCT, dependent on the drug combination applied [4].
Cytotoxic drugs used for conditioning therapy before allo-HSCT could damage endothelium of liver with subsequent development of veno-occlusive disease which could manifest with hepatomegaly accompanied by right upper quadrant pain due to extensive distension of Glisson capsule. This complication may encounter in 13.7% cases of HCST, as well as after ChT course [5]. In our experience, pain syndromes may be also connected with development of acute hemorrhagic cystitis, infections, fast engraftment, bone marrow necrosis, bone pain associated with corticosteroid withdrawal etc.
Thrombocytopenia, agranulocytosis, and, sometimes, renal dysfunction comprise special features in the patients after HSCT and some ChT regimens, thus limiting the opportunities for usage of nonsteroid anti-inflammatory drugs (NSAID), as first step of WHO analgetic ladder. Administration of these medicines as analgetics, could also hide fever of infectious origin. One should also note limited routes for administration of painkillers, i.e., per oral uptake could be difficult due to evolving mucositis. Rectal administration is not recommended, because of high-risk translocation of gut microflora in neutropenic conditions, whereas intramuscular injections are contraindicated, due to thrombocytopenia and painful manipulation [6, 7]. In this view, management of weak and moderate pain with NSAID may be difficult, and one should change the therapy for second-line treatment at early stages. Previously, WHO has excluded the second stage of pain relief ladder using weak opioids, e.g., codeine [7]. From 2009 to 2012, several cases of breath depression were registered in children under 5 years old after codeine postoperative analgesia after tonsillectomy. Most likely, this side effect was associated with individual genetic feature of cytochrome enzymes e.g., ultra-fast codeine activation by CYP2D6 with excessive production of morphine which, under normal excretion rates, could be accumulated at toxic concentrations.
In particular, tramadol is mostly inactivated by two enzymes, CYP2D6 and CYP3A4, whereas unchanged М1 metabolite, is, in turn, is excreted with urine. The analgetic effects of the drug are explained by, at least, two mechanisms, i.e., interaction between tramadol/M1 metabolite and μ-opiate receptors (OPRM1), as well as inhibition of serotonin and norepinephrine reuptake by tramadol, thus suppressing pain impulse transmission at the level of spinal cord [8, 9]. Undoubtedly, the patients with ultra-fast tramadol metabolism are in high-risk group, especially, in cases of high-dose treatment and appropriate comorbidities of respiratory system, sleep apnea in tonsillar hyperplasia, or obesity conditions [10]. Therefore, some authors recommend to admit the patients to inpatient unit as early as 24 hours before treatment, in cases of acute nociceptive pain in patients administered tramadol and uncertain CYP2D6 activity levels [11]. Concerning the analgetic capacity, tramadol takes an intermediate position between NSAID and potent opioids, but at the same time, some publications report on less common frequency of sedation, respiratory depression, constipation and other side effects typical to strong opioids [12]. At the present time, tramadol is widely used for treatment of nociceptive pain in traumas and after surgical interventions in children [13, 14, 15, 16, 17, 18]. For moderate pain, the WHO analgesia ladder presumes low doses of strong opioids (oxycodone or morphine) to be the main alternative for weak opioids.
High individual variability of efficient dose is a specific feature of morphine administration. This characteristic could be explained by differences in its bioavailability, metabolism and excretion. The main morphine metabolites are as follows: morphine-6-glucuronide, which exhibits higher analgetic ability, but can elicit nausea, vomiting, excessive sedation, as well as morphime-3-glucuronide with probable antianalgetic and neurotoxic effects [19]. Several studies report about efficiency and safety of low-dose-morphine when managing moderate pain, e.g., in pediatric practice [20, 21, 22, 23]. In turn, the adverse effects of morphine derivatives are not shown at the present time (19).
Worth of note, however, both morphine and tramadol, may also display some side effects, including nausea, vomiting, respiratory depression, urinary retention, constipation, skin itching etc., thus causing discomfort to the patient [24, 25]. Therefore, the aim of our study was to evaluate efficiency and safety of tramadol and low-dose morphine in the treatment of moderate pain in children.
Patients and methods
Figure 1. Patients age distribution
Figure 2. Distribution of main causes of pain
The study was conducted in the Anesthesiology Department of R. M. Gorbacheva Memorial Institute for Pediatric Hematology, Oncology and Transplantation. The study included 159 primary admittances of the patients 1 to 17 years old (a median of 8 years) with complaints of moderate pain. Their age distribution is shown in Fig. 1.
The diagnoses were as follows: solid malignancies, 55.4% (n=88); hemoblastoses, 35.2% (n=56); non-malignant hematological disorders, 5% (n=8) and orphan diseases 4.4% (n=7).
Of them, 13.8% (n=22) were subjected to ChT, 68.8% (n=109) underwent allo- or auto-HSCT with myeloablative treatment regimen; 17.6% (n=28) received HSCT with non-myeloablative conditioning. The main reasons for pain syndrome were: mucositis, 85.5% (n=136), bone pain associated with hematopoiesis recovery, 5% (n=8); progression of primary disease, 5% (n=8); intestinal graft-versus-host disease (GvHD) 1.3%, (n=2), mucositis combined with acute cystitis 2.5% (n=4); paraproctitis, 0.7% (n=1), as seen in Fig. 2.
The intensity if pain was evaluated 3 times a day throughout the observation period to age-matched scale adapted to abilities of the patient (FLACC, verbal scale, Wong-Baker Faces Pain Rating Scale, or visual analogue scale). The total time of observation, including, changing lines of analgesic therapy, if necessary, ranged from 1 to 20 days (median 6 days). The response to therapy was assessed integrally by such parameters as: pain intensity (permanent and activity-evoked), quality of night sleep, ability of food and drink intake without an pain related failure, the possibility of non-pharmacological treatment and patient satisfaction. All the patients were classified into 2 groups in a ratio 3:1. The drugs were injected by continuous infusion at the inpatient clinic. In the first group (n=118), standard tramadol doses were administered as the 1st-line therapy (0.2 to 0.3 mg/kg/h). The patients in the 2nd group (n=41) were administered low-dose morphine (0.01 to 0.019 mg/kg/h). The initially prescribed analgetic was the first line of therapy, if there was a change of therapy, then the new analgetic was considered the second line of therapy. Drug infusion was performed permanently, via central venous catheter under hospital conditions. Pain intensity and drug acceptability were evaluated 2-3 times a day. In cases of insufficient analgesia, i.e., non-reduced or enhanced pain, lack of food and fluid intake because of pain etc., the drug was changed, or morphine dosage was increased. The analgetics were also changed in case of bad tolerance of current therapy. The choice of drug was made individually, depending on clinical situation.
Statistical evaluation was performed by means of SPSS software, using Chi-square test. When checking statistical hypotheses, the difference was presumed significant by p<0.05.
Results
The results of our study have revealed that the therapy was effective in 40.7% (n=48) and 58.5% (n=24) for tramadol and low-dose morphine treatment respectively, whereas in 0.8% of the cases, tramadol administration was prolonged to the end of staying in the unit/transfer to hospice, with good therapy acceptability. Enhanced analgetic treatment was required in 53.4% (n=63) for the 1st group versus 39.0% (n=16) for the patients in the 2nd group (Table 1).
Table 1. First line therapy results
Adverse effects in the first (tramadol-treated) group were observed in 5.1% (n=6). In particular, we observed one case of somnolescence with subsequent excitation in a girl of 4 years old; one case of dizziness with tremor in a girl of 11 years old. Two cases of involuntary contractions of striated muscles were detected: a 6 years old girl had twitching of right hand by 2 days after tramadol injections, and a 10 years old boy developed involuntary contractions of mimic muscles after 3 days of treatment, probably, due to serotoninergic effect of the drug. We have also seen one case of vomiting and nausea in the 17 years old female, as well as a case of nausea and anxiety in the 16 years old female. At the next treatment courses, this pain management was based on strong opioids. Their injection was accompanied by similar side effects. However, the mentioned side effects were no health-threatening. Subsequently 6 years old girl required the change of therapy to fentanyl. In other cases after cancellation of tramadol infusion, weak pain persisted, but further analgesia was not necessary. In the second group, only one female patient (2.4% of total) treated with low-dose morphine developed intestinal paralysis that was resolved after the therapy change.
Upon statistical analysis with Chi-square method, no significant differences were found between the tramadol group and low-dose morphine-treated groups in effectiveness and frequency of side effects (p=0.237).
In case of inefficiency of tramadol or low doses of morphine the second line of therapy included morphine in a low dose (after tramadol administration) was used in 29.1% (n=23), morphine in a standard dose (from 0.02 mg/kg/hr) in 17.7% (n=14) or fentanyl at a dose of 0.05 mcg/kg/hr in 53.2% (n=42) (Table 2).
Table 2. Distribution of the 2nd line therapy medicines
We also evaluated the safety of low and standard doses of morphine in the second line of pain management therapy (Table 3). As result, we observed that side effects appeared in two cases: one because of nausea and vomiting and one due to complaints of blurred focus of vision, which was possibly associated with myosis. In group of standard doses of morphine one case of postrenal urinary retention. All three cases required a revision of treatment.
Table 3. Results of second line therapy with morphine in low and standard doses
Upon statistical analysis with Chi-square method, no significant differences were found between the standard and low-dose morphine-treated patients in effectiveness and frequency of side effects (p=0.271).
Discussion
Currently, some authors state that the respiratory depression is rarely encountered when tramadol dosage is carefully maintained [26, 27]. Frequency of nausea and vomiting are compatible (10-40%) when administering tramadol or opioids [28]. In our experience, a case of intestinal paralysis should be noted in a female patient from 2nd group with mucositis. She had also side effects in the course of immune suppressors (nephro- and neurotoxicity), as well as pancytopenia and hemorrhagic syndrome that could be risk factors of this condition. Concerning adverse effects associated with tramadol prescription, the literature presents only single cases of generalized cramps due to excessive dosage and drug administration to a child under 1 year old [29]. One may also suggest an evolving serotonin syndrome connected to high dosage of serotoninergic drugs (selective serotonin reuptake inhibitors, some monoamine oxidase inhibitors), which includes excitation, ataxia, increased sweating, diarrhea, fever, hyperreflexia, and tremor. In our study, similar symptoms were seen in 4 patients, however, at less significant. This is, probably, connected with non-opioid effects of the drug (inhibition of serotonin and norepinephrin reuptake) [30, 31]. However, one cannot exclude ultra-fast CYP2D6 activity. That is the key aspects influencing tramadol efficiency and, potentially, genetic studies could serve as a predictor of efficacy and safety of the drug. Meanwhile, the CYP2D6 gene polymorphism is quite variable and requires time-consuming molecular genetic studies, thus reducing value of this technique in case of acute pain. One should also understand that the genotype will correspond to phenotype, with regard to variable clearance and body weight [8]. Therefore, we observe the children at the hospital within first 24 hours after starting tramadol infusion. For the patients requiring longer analgesia period, than in our study, tramadol shows lesser potential risk of dependence compared to classical opioids [32]. It’s also important to note that administration of tramadol has a less strict legal regulation [33, 34]. Due to social prejustice, its administration causes lesser anxiety on the part of parents and adolescent patients with respect to adverse effects, ex., addiction. Similarly, in cases with inefficiency of this therapy, the parents take easier administration of strong opioids [35, 36]. In future, tapentadol and local morphine applications could be promising therapeutic options [37]. However, there are only modest data on the studies of these medications in children and adolescents.
Conclusions
Based on the study data, we may suggest that tramadol exerts analgetic effects which are comparable to low-dose morphine. However, administration of these drugs needs dynamic observation of pediatric patients in the hospital at initial steps of therapy, due to some features of individual response and probable side effects. These issues also require further studies in larger groups of patients.
Authors are grateful to Elena V. Verbitskaya, assistant professor of the department of clinical pharmacology and evidence-based medicine, for her help in statistical data processing.
Conflict of interests
The authors declare no conflicts of interest.
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Екатерина В. Гончарова1,2, Инга Е. Заводова1, Никита П. Волков1, Ольга А. Иванова1, Максим А. Кучер1,
Алексей Ю. Соколов2,3, Максим П. Богомольный1, Глеб Э. Ульрих4, Людмила С. Зубаровская1, Борис В. Афанасьев1
1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Отдел нейрофармакологии Института фармакологии им. А. В. Вальдмана ПСПбГМУ им. акад. И. П. Павлова, Санкт-Петербург, Россия
3 Институт физиологии им. И. П. Павлова Российской академии наук, Санкт-Петербург, Россия
4 Кафедра анестезиологии, реаниматологии и неотложной педиатрии Санкт-Петербургского государственного педиатрического медицинского университета, Санкт-Петербург, Россия
Во время и после проведения полихимиотерапии (ПХТ) с последующей трансплантацией гемопоэтических стволовых клеток (ТГСК) или без нее значительная часть пациентов сталкивается с развитием болевого синдрома различных интенсивности и этиологии. В этот период у пациента может отмечаться тромбоцитопения и лейкопения, вплоть до агранулоцитоза, что ограничивает назначение нестероидных противовоспалительных препаратов (НПВП). В соответствии с рекомендациями ВОЗ при развитии боли умеренной интенсивности и неэффективности НПВП в педиатрической практике возможно назначение опиоидов. При этом не исключается использование трамадола, который в настоящее время, благодаря облегченному правовому регулированию, широко применяется клинической практике. Цель – оценить безопасность и эффективность трамадола и морфина в низких дозах при купировании умеренной ноцицептивной боли различной этиологии у детей после ТГСК и ПХТ.
Материалы и методы
В исследование включено 159 пациентов с жалобами на боль различной локализации интенсивностью от 3 до 6 баллов по шкале оценки, соответствующей возрасту и возможностям ребенка. Возраст детей составлял от 1 до 17 лет (медиана 8 лет). Все пациенты не получали опиоиды за 30 суток до включения в исследование (opioid naïve). Препараты вводили внутривенно посредством круглосуточной микроструйной инфузии в условиях стационара. В первой группе (n=118), в качестве терапии 1 линии назначался трамадол в стандартных дозах (от 0,2 до 0,3 мг/кг/час). Участники второй группы (n=41), получали морфин в низких дозах (от 0,01 до 0,019 мг/кг/час). Эффективность терапии оценивалась по совокупности факторов: снижение интенсивности боли до удовлетворительной для пациента, отсутствие ночных пробуждений, связанных с болью, отсутствие препятствий к приему пищи и/или жидкости в виде болевых ощущений и др. Безопасность оценивалась по наличию или отсутствию побочных эффектов, связанных с назначенными препаратами. Статистическая обработка проводилась в программе SPSS, для определения значимости различий использовался критерий согласия X2.
Результаты
Трамадол был эффективен в 40,7% случаев (n=48), низкие дозы морфина – в 58,5% (n=24).
Назначение 2-й линии терапии, связанное с неэффективностью или плохой переносимостью препаратов первой линии, потребовалось в 1 группе у 53,4% пациентов (n=63), и у 39% (n=16) – во 2 группе. Побочные эффекты, связанные с назначением трамадола, возникли в 5.1% случаев (n=6). В группе морфина у 1 пациентки (2,4%) развился парез кишечника, разрешившийся после смены терапии. При статистическом анализе значимых межгрупповых различий с точки зрения эффективности и безопасности лечения выявлено не было.
Выводы
Оба препарата в сравниваемых дозах показали схожие эффективность и безопасность при купировании умеренной боли у детей после проведения ПХТ и ТГСК.
Ключевые слова
Химиотерапия, противоопухолевая, болевой синдром, мукозиты, трамадол, морфин, эффективность, безопасность.
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2 Department of Neuropharmacology, Valdman Institute of Pharmacology, Pavlov University, St. Petersburg, Russia
3 Pavlov Institute of Physiology of the Russian Academy of Sciences, St. Petersburg, Russia
4 Department of Anesthesiology and Pediatric Intensive Care, Saint Petersburg State Pediatric Medical University, St. Petersburg, Russia
Correspondence
Dr. Ekaterina V. Goncharova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L.Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (911) 087 8976
E-mail: ek.v.goncharova@gmail.com
A sufficient subgroup of patients encounters pain syndrome in the course of cytostatic chemotherapy (ChT), either with or without hematopoietic stem cell transplantation (HSCT). Over this time period, severe thrombocytopenia and leucopenia may develop, thus limiting the opportunities for non-steroidal anti-inflammatory drugs (NSAID). As recommended by WHO, administration of strong opioids to children is possible in moderate pain and inefficiency of NSAIDs. In this case, second step of the pain relief ladder is absent, i.e., codeine application. However, the recommendations do not exclude usage of tramadol, which is widely applied in pediatrics. Our aim was to evaluate relative safety and efficiency of tramadol and morphine in managment of moderate pain in children after HSCT and ChT.
Patients and methods
The study included analysis of 159 children admitted to the ICU pain management team with complaints for weak or moderate pain (form 3 to 6 points on an age-matched scale). The age of patients was from 1 to 17 years, with a median of 8 years old. All the patients did not receive opioids (were opioid naïve) within 30 days before inclusion to the study. The drugs were injected by continuous infusion at the inpatient clinic. In the first group (n=118), standard tramadol doses were administered as the 1st-line therapy (0.2 to 0.3 mg/kg/h). The patients form 2nd group (n=41) were administered low-dose morphine (0.01 to 0.019 mg/kg/h). Treatment efficiency was assessed by FLACC verbal scores, Wong-Baker Faces Pain Rating Scale, or visual analogue scale and quality of life. Statistical evaluation was performed by means of SPSS software, using a nonparametric Chi-square criterion.
Results
When administered tramadol as a first-line therapy, it was efficient in ca. 40.7% of cases (n=48). With low-dose morphine, the response rate proved to be 58.5% (n=24). One patient (0.8%) received tramadol when transferred to other institution. The second-line therapy (strong opioids) was administered due to lack of efficiency, or poor drug acceptability during the first-line treatment. It was observed in 53.4% of group 1 (n=63), and in 39% (n=16) of morphine-treated patients (group 2). Side effects due to tramadol administration were observed in 5.1% of cases (n=6). When administered low-dose morphine, only 1 female patient (2.4%) developed intestinal paresis which resolved after the therapy cancellation. Upon statistical evaluation, no significant differences were revealed between the groups.
Conclusion
Both medical drugs have shown similar efficiency and safety when applied for jugulating weak or moderate nociceptive pain after cytostatic chemotherapy and HSCT in pediatric patients.
Keywords
Chemotherapy, anticancer, pain syndrome, mucositis, tramadol, morphine, efficiency, safety.
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Goncharova<sup>1,2</sup>, Inga E. Zavodova<sup>1</sup>, Nikita P. Volkov<sup>1</sup>, Olga A. Ivanova<sup>1</sup>, Maxim A. Kucher<sup>1</sup>, Alexey Y. Sokolov<sup>2,3</sup>, Maxim P. Bogomolny<sup>1</sup>, Gleb E. Ulrikh<sup>4</sup>, Ludmila S. Zubarovskaya<sup>1</sup>, <span style="border: 1px solid black; margin: 0; padding: 2px 2px;">Boris V. Afanasyev<sup>1</sup> </span></p> " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(402) "Ekaterina V. Goncharova1,2, Inga E. Zavodova1, Nikita P. Volkov1, Olga A. Ivanova1, Maxim A. Kucher1, Alexey Y. Sokolov2,3, Maxim P. Bogomolny1, Gleb E. Ulrikh4, Ludmila S. Zubarovskaya1, Boris V. Afanasyev1
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(402) "Ekaterina V. Goncharova1,2, Inga E. Zavodova1, Nikita P. Volkov1, Olga A. Ivanova1, Maxim A. Kucher1, Alexey Y. Sokolov2,3, Maxim P. Bogomolny1, Gleb E. Ulrikh4, Ludmila S. Zubarovskaya1, Boris V. Afanasyev1
" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "26466" ["VALUE"]=> array(2) { ["TEXT"]=> string(3241) "<p style="text-align: justify;">A sufficient subgroup of patients encounters pain syndrome in the course of cytostatic chemotherapy (ChT), either with or without hematopoietic stem cell transplantation (HSCT). Over this time period, severe thrombocytopenia and leucopenia may develop, thus limiting the opportunities for non-steroidal anti-inflammatory drugs (NSAID). As recommended by WHO, administration of strong opioids to children is possible in moderate pain and inefficiency of NSAIDs. In this case, second step of the pain relief ladder is absent, i.e., codeine application. However, the recommendations do not exclude usage of tramadol, which is widely applied in pediatrics. Our aim was to evaluate relative safety and efficiency of tramadol and morphine in managment of moderate pain in children after HSCT and ChT.</p> <h3>Patients and methods</h3> <p style="text-align: justify;">The study included analysis of 159 children admitted to the ICU pain management team with complaints for weak or moderate pain (form 3 to 6 points on an age-matched scale). The age of patients was from 1 to 17 years, with a median of 8 years old. All the patients did not receive opioids (were opioid naïve) within 30 days before inclusion to the study. The drugs were injected by continuous infusion at the inpatient clinic. In the first group (n=118), standard tramadol doses were administered as the 1<sup>st</sup>-line therapy (0.2 to 0.3 mg/kg/h). The patients form 2<sup>nd</sup> group (n=41) were administered low-dose morphine (0.01 to 0.019 mg/kg/h). Treatment efficiency was assessed by FLACC verbal scores, Wong-Baker Faces Pain Rating Scale, or visual analogue scale and quality of life. Statistical evaluation was performed by means of SPSS software, using a nonparametric Chi-square criterion.</p> <h3>Results</h3> <p style="text-align: justify;">When administered tramadol as a first-line therapy, it was efficient in ca. 40.7% of cases (n=48). With low-dose morphine, the response rate proved to be 58.5% (n=24). One patient (0.8%) received tramadol when transferred to other institution. The second-line therapy (strong opioids) was administered due to lack of efficiency, or poor drug acceptability during the first-line treatment. It was observed in 53.4% of group 1 (n=63), and in 39% (n=16) of morphine-treated patients (group 2). Side effects due to tramadol administration were observed in 5.1% of cases (n=6). When administered low-dose morphine, only 1 female patient (2.4%) developed intestinal paresis which resolved after the therapy cancellation. Upon statistical evaluation, no significant differences were revealed between the groups. </p> <h3>Conclusion</h3> <p style="text-align: justify;">Both medical drugs have shown similar efficiency and safety when applied for jugulating weak or moderate nociceptive pain after cytostatic chemotherapy and HSCT in pediatric patients. </p> <h2>Keywords</h2> <p style="text-align: justify;">Chemotherapy, anticancer, pain syndrome, mucositis, tramadol, morphine, efficiency, safety.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3059) "A sufficient subgroup of patients encounters pain syndrome in the course of cytostatic chemotherapy (ChT), either with or without hematopoietic stem cell transplantation (HSCT). Over this time period, severe thrombocytopenia and leucopenia may develop, thus limiting the opportunities for non-steroidal anti-inflammatory drugs (NSAID). As recommended by WHO, administration of strong opioids to children is possible in moderate pain and inefficiency of NSAIDs. In this case, second step of the pain relief ladder is absent, i.e., codeine application. However, the recommendations do not exclude usage of tramadol, which is widely applied in pediatrics. Our aim was to evaluate relative safety and efficiency of tramadol and morphine in managment of moderate pain in children after HSCT and ChT.
Patients and methods
The study included analysis of 159 children admitted to the ICU pain management team with complaints for weak or moderate pain (form 3 to 6 points on an age-matched scale). The age of patients was from 1 to 17 years, with a median of 8 years old. All the patients did not receive opioids (were opioid naïve) within 30 days before inclusion to the study. The drugs were injected by continuous infusion at the inpatient clinic. In the first group (n=118), standard tramadol doses were administered as the 1st-line therapy (0.2 to 0.3 mg/kg/h). The patients form 2nd group (n=41) were administered low-dose morphine (0.01 to 0.019 mg/kg/h). Treatment efficiency was assessed by FLACC verbal scores, Wong-Baker Faces Pain Rating Scale, or visual analogue scale and quality of life. Statistical evaluation was performed by means of SPSS software, using a nonparametric Chi-square criterion.
Results
When administered tramadol as a first-line therapy, it was efficient in ca. 40.7% of cases (n=48). With low-dose morphine, the response rate proved to be 58.5% (n=24). One patient (0.8%) received tramadol when transferred to other institution. The second-line therapy (strong opioids) was administered due to lack of efficiency, or poor drug acceptability during the first-line treatment. It was observed in 53.4% of group 1 (n=63), and in 39% (n=16) of morphine-treated patients (group 2). Side effects due to tramadol administration were observed in 5.1% of cases (n=6). When administered low-dose morphine, only 1 female patient (2.4%) developed intestinal paresis which resolved after the therapy cancellation. Upon statistical evaluation, no significant differences were revealed between the groups.
Conclusion
Both medical drugs have shown similar efficiency and safety when applied for jugulating weak or moderate nociceptive pain after cytostatic chemotherapy and HSCT in pediatric patients.
Keywords
Chemotherapy, anticancer, pain syndrome, mucositis, tramadol, morphine, efficiency, safety.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(3059) "A sufficient subgroup of patients encounters pain syndrome in the course of cytostatic chemotherapy (ChT), either with or without hematopoietic stem cell transplantation (HSCT). Over this time period, severe thrombocytopenia and leucopenia may develop, thus limiting the opportunities for non-steroidal anti-inflammatory drugs (NSAID). As recommended by WHO, administration of strong opioids to children is possible in moderate pain and inefficiency of NSAIDs. In this case, second step of the pain relief ladder is absent, i.e., codeine application. However, the recommendations do not exclude usage of tramadol, which is widely applied in pediatrics. Our aim was to evaluate relative safety and efficiency of tramadol and morphine in managment of moderate pain in children after HSCT and ChT.
Patients and methods
The study included analysis of 159 children admitted to the ICU pain management team with complaints for weak or moderate pain (form 3 to 6 points on an age-matched scale). The age of patients was from 1 to 17 years, with a median of 8 years old. All the patients did not receive opioids (were opioid naïve) within 30 days before inclusion to the study. The drugs were injected by continuous infusion at the inpatient clinic. In the first group (n=118), standard tramadol doses were administered as the 1st-line therapy (0.2 to 0.3 mg/kg/h). The patients form 2nd group (n=41) were administered low-dose morphine (0.01 to 0.019 mg/kg/h). Treatment efficiency was assessed by FLACC verbal scores, Wong-Baker Faces Pain Rating Scale, or visual analogue scale and quality of life. Statistical evaluation was performed by means of SPSS software, using a nonparametric Chi-square criterion.
Results
When administered tramadol as a first-line therapy, it was efficient in ca. 40.7% of cases (n=48). With low-dose morphine, the response rate proved to be 58.5% (n=24). One patient (0.8%) received tramadol when transferred to other institution. The second-line therapy (strong opioids) was administered due to lack of efficiency, or poor drug acceptability during the first-line treatment. It was observed in 53.4% of group 1 (n=63), and in 39% (n=16) of morphine-treated patients (group 2). Side effects due to tramadol administration were observed in 5.1% of cases (n=6). When administered low-dose morphine, only 1 female patient (2.4%) developed intestinal paresis which resolved after the therapy cancellation. Upon statistical evaluation, no significant differences were revealed between the groups.
Conclusion
Both medical drugs have shown similar efficiency and safety when applied for jugulating weak or moderate nociceptive pain after cytostatic chemotherapy and HSCT in pediatric patients.
Keywords
Chemotherapy, anticancer, pain syndrome, mucositis, tramadol, morphine, efficiency, safety.
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2 Department of Neuropharmacology, Valdman Institute of Pharmacology, Pavlov University, St. Petersburg, Russia
3 Pavlov Institute of Physiology of the Russian Academy of Sciences, St. Petersburg, Russia
4 Department of Anesthesiology and Pediatric Intensive Care, Saint Petersburg State Pediatric Medical University, St. Petersburg, Russia
Correspondence
Dr. Ekaterina V. Goncharova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L.Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (911) 087 8976
E-mail: ek.v.goncharova@gmail.com
1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia
2 Department of Neuropharmacology, Valdman Institute of Pharmacology, Pavlov University, St. Petersburg, Russia
3 Pavlov Institute of Physiology of the Russian Academy of Sciences, St. Petersburg, Russia
4 Department of Anesthesiology and Pediatric Intensive Care, Saint Petersburg State Pediatric Medical University, St. Petersburg, Russia
Correspondence
Dr. Ekaterina V. Goncharova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L.Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (911) 087 8976
E-mail: ek.v.goncharova@gmail.com
Екатерина В. Гончарова1,2, Инга Е. Заводова1, Никита П. Волков1, Ольга А. Иванова1, Максим А. Кучер1,
Алексей Ю. Соколов2,3, Максим П. Богомольный1, Глеб Э. Ульрих4, Людмила С. Зубаровская1, Борис В. Афанасьев1
Екатерина В. Гончарова1,2, Инга Е. Заводова1, Никита П. Волков1, Ольга А. Иванова1, Максим А. Кучер1,
Алексей Ю. Соколов2,3, Максим П. Богомольный1, Глеб Э. Ульрих4, Людмила С. Зубаровская1, Борис В. Афанасьев1
Во время и после проведения полихимиотерапии (ПХТ) с последующей трансплантацией гемопоэтических стволовых клеток (ТГСК) или без нее значительная часть пациентов сталкивается с развитием болевого синдрома различных интенсивности и этиологии. В этот период у пациента может отмечаться тромбоцитопения и лейкопения, вплоть до агранулоцитоза, что ограничивает назначение нестероидных противовоспалительных препаратов (НПВП). В соответствии с рекомендациями ВОЗ при развитии боли умеренной интенсивности и неэффективности НПВП в педиатрической практике возможно назначение опиоидов. При этом не исключается использование трамадола, который в настоящее время, благодаря облегченному правовому регулированию, широко применяется клинической практике. Цель – оценить безопасность и эффективность трамадола и морфина в низких дозах при купировании умеренной ноцицептивной боли различной этиологии у детей после ТГСК и ПХТ.
Материалы и методы
В исследование включено 159 пациентов с жалобами на боль различной локализации интенсивностью от 3 до 6 баллов по шкале оценки, соответствующей возрасту и возможностям ребенка. Возраст детей составлял от 1 до 17 лет (медиана 8 лет). Все пациенты не получали опиоиды за 30 суток до включения в исследование (opioid naïve). Препараты вводили внутривенно посредством круглосуточной микроструйной инфузии в условиях стационара. В первой группе (n=118), в качестве терапии 1 линии назначался трамадол в стандартных дозах (от 0,2 до 0,3 мг/кг/час). Участники второй группы (n=41), получали морфин в низких дозах (от 0,01 до 0,019 мг/кг/час). Эффективность терапии оценивалась по совокупности факторов: снижение интенсивности боли до удовлетворительной для пациента, отсутствие ночных пробуждений, связанных с болью, отсутствие препятствий к приему пищи и/или жидкости в виде болевых ощущений и др. Безопасность оценивалась по наличию или отсутствию побочных эффектов, связанных с назначенными препаратами. Статистическая обработка проводилась в программе SPSS, для определения значимости различий использовался критерий согласия X2.
Результаты
Трамадол был эффективен в 40,7% случаев (n=48), низкие дозы морфина – в 58,5% (n=24).
Назначение 2-й линии терапии, связанное с неэффективностью или плохой переносимостью препаратов первой линии, потребовалось в 1 группе у 53,4% пациентов (n=63), и у 39% (n=16) – во 2 группе. Побочные эффекты, связанные с назначением трамадола, возникли в 5.1% случаев (n=6). В группе морфина у 1 пациентки (2,4%) развился парез кишечника, разрешившийся после смены терапии. При статистическом анализе значимых межгрупповых различий с точки зрения эффективности и безопасности лечения выявлено не было.
Выводы
Оба препарата в сравниваемых дозах показали схожие эффективность и безопасность при купировании умеренной боли у детей после проведения ПХТ и ТГСК.
Ключевые слова
Химиотерапия, противоопухолевая, болевой синдром, мукозиты, трамадол, морфин, эффективность, безопасность.
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Материалы и методы
В исследование включено 159 пациентов с жалобами на боль различной локализации интенсивностью от 3 до 6 баллов по шкале оценки, соответствующей возрасту и возможностям ребенка. Возраст детей составлял от 1 до 17 лет (медиана 8 лет). Все пациенты не получали опиоиды за 30 суток до включения в исследование (opioid naïve). Препараты вводили внутривенно посредством круглосуточной микроструйной инфузии в условиях стационара. В первой группе (n=118), в качестве терапии 1 линии назначался трамадол в стандартных дозах (от 0,2 до 0,3 мг/кг/час). Участники второй группы (n=41), получали морфин в низких дозах (от 0,01 до 0,019 мг/кг/час). Эффективность терапии оценивалась по совокупности факторов: снижение интенсивности боли до удовлетворительной для пациента, отсутствие ночных пробуждений, связанных с болью, отсутствие препятствий к приему пищи и/или жидкости в виде болевых ощущений и др. Безопасность оценивалась по наличию или отсутствию побочных эффектов, связанных с назначенными препаратами. Статистическая обработка проводилась в программе SPSS, для определения значимости различий использовался критерий согласия X2.
Результаты
Трамадол был эффективен в 40,7% случаев (n=48), низкие дозы морфина – в 58,5% (n=24).
Назначение 2-й линии терапии, связанное с неэффективностью или плохой переносимостью препаратов первой линии, потребовалось в 1 группе у 53,4% пациентов (n=63), и у 39% (n=16) – во 2 группе. Побочные эффекты, связанные с назначением трамадола, возникли в 5.1% случаев (n=6). В группе морфина у 1 пациентки (2,4%) развился парез кишечника, разрешившийся после смены терапии. При статистическом анализе значимых межгрупповых различий с точки зрения эффективности и безопасности лечения выявлено не было.
Выводы
Оба препарата в сравниваемых дозах показали схожие эффективность и безопасность при купировании умеренной боли у детей после проведения ПХТ и ТГСК.
Ключевые слова
Химиотерапия, противоопухолевая, болевой синдром, мукозиты, трамадол, морфин, эффективность, безопасность.
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2 Отдел нейрофармакологии Института фармакологии им. А. В. Вальдмана ПСПбГМУ им. акад. И. П. Павлова, Санкт-Петербург, Россия
3 Институт физиологии им. И. П. Павлова Российской академии наук, Санкт-Петербург, Россия
4 Кафедра анестезиологии, реаниматологии и неотложной педиатрии Санкт-Петербургского государственного педиатрического медицинского университета, Санкт-Петербург, Россия
1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Отдел нейрофармакологии Института фармакологии им. А. В. Вальдмана ПСПбГМУ им. акад. И. П. Павлова, Санкт-Петербург, Россия
3 Институт физиологии им. И. П. Павлова Российской академии наук, Санкт-Петербург, Россия
4 Кафедра анестезиологии, реаниматологии и неотложной педиатрии Санкт-Петербургского государственного педиатрического медицинского университета, Санкт-Петербург, Россия
Introduction
Engraftment-related fever and engraftment syndrome are well-known phenomenon post autologous HSCT. Engraftment syndrome refers to the constellation of features associated with engraftment including fever, skin rash, fluid retention, weight gain, and non-cardiogenic pulmonary edema. These features constitute the major criteria of the proposed definition of engraftment syndrome [1]. However, some studies have defined this syndrome differently and its reported incidence varies widely from 7% to as high as 59% in some studies [2-7]. The period of onset of engraftment-related fever often coincides with the time when the patients are likely to have fungal and bacterial infections. Hence, antibiotics are often escalated at the time of onset of breakthrough fever. This leads to increased use of antimicrobials and consequently adds significantly to health care costs.
There is no reliable clinical or laboratory parameter which helps to differentiate engraftment related fever from infectious fever. One study has shown that the ratio of Interleukin-12 to Interleukin-6 could reliably distinguish infectious from non-infectious fever following autologous HSCT [8]. However, measurement of interleukin levels is not available in most transplant centres. Our study stemmed from personal observations that the relative increase in total leukocyte count (TLC) is greater than the relative increase in C-reactive protein (CRP) in patients with engraftment fever whereas the reverse is, generally, seen in infectious fever. With this observation, we aimed to study whether the TLC/CRP ratio helps to distinguish infectious fever from engraftment-related fever in the patients undergoing autologous HSCT.
Patients and methods
Patient characteristics
This is a retrospective analysis of all autologous transplants from March 2011 to September 2013 at a single centre. One hundred and nine consecutive autologous transplants were included in the analysis (Table 1). Fifty-three patients had Hodgkin lymphoma, 19 had Non Hodgkin lymphoma, 34 had multiple myeloma and 3 had neuroblastoma. The median age was 32 years (range 2-63 years). Eighty four patients were males. At the time of transplant, 67 (61%) patients were in complete remission and 37 (34%) were in partial remission.
Chemotherapy and granulocyte colony stimulating factor (G-CSF) were used for stem cell mobilization in 100 (92%) patients while only G-CSF was used in 4 (4%) patients. G-CSF with plerixafor was used in 1 patient. Four (4%) patients did not receive any form of mobilizing drug. All these 4 patients received marrow grafts. All patients with multiple myeloma received melphalan based conditioning regimen, either melphalan alone (n=31) or with bortezomib (n=3). Lymphoma patients received conditioning with lomustine + cytarabine + cyclophosphamide + etoposide [LACE (n=69)], lomustine + etoposide + cytarabine + melphalan [LEAM (n=1)] or carmustine + etoposide + cytarabine + melphalan [BEAM (n=2)] regimen. Patients with neuroblastoma received busulfan + melphalan conditioning. Peripheral blood stem cells graft was used in 103 (95%) patients and bone marrow graft was used in 5 (5%) patients. One patient received a combined marrow and PBSC graft. Stem cells were cryopreserved for a median of 43 days (17-301 days). The median dose of CD34 cells infused was 4.6×106 per kg. Neutrophil and platelet engraftment occurred at a median of 11 days and 13 days, respectively.
Table 1. Patient characteristics
TLC and CRP were measured in the frames of routine blood analyses daily in the morning for all patients from the day of admission to the day of discharge and TLC/CRP ratio was calculated. Complete blood counts were done by Beckman HMX coulter. CRP was measured by the particle-enhanced turbidimetric immunoassay (PETIA) technique. Appropriate clinical and laboratory data were retrieved from patients’ files.
Clinical definitions
Engraftment: Myeloid engraftment was defined as TLC >1×109/L for 3 consecutive days or absolute neutrophil count greater than or equal to 0.5×109/L for 2 consecutive days, whichever was earlier. Platelet engraftment was defined as the first day of consecutive 7 days when platelet count remained about 20×109/L without need for platelet transfusion.
Peri-engraftment period: Peri-engraftment period was defined as period of 72 hours prior to myeloid engraftment to 96 hours after engraftment.
Breakthrough fever: Fever >38°C with onset in peri-engraftment period (usually during the 2nd week post-transplant) after being afebrile for at least 48 hours. Episodes of breakthrough fever were classified as either infectious fever, or engraftment-related fever.
Continuous fever: Patients with fever persisting over 2nd week post-transplant without an afebrile period, or with afebrile period of <48 hours were classified as having continuous fever.
Infectious fever: The condition was classified as infectious fever if blood culture (or culture from any other normally sterile site) was positive, or in case of radiological signs of infection or if fever subsided within 48 hours after change of antibiotics.
Engraftment fever: Engraftment fever was defined as fever with onset in the peri-engraftment period, without any evidence of associated infectious cause, and responding to systemic steroid therapy.
Anti-infective prophylaxis
All the patients received prophylaxis with an anti-fungal agent (voriconazole or posaconazole) and acyclovir. Antifungal prophylaxis was started on day -1 and continued till resolution of neutropenia. In patients receiving systemic steroids for engraftment fever, antifungal prophylaxis was continued until the steroids were stopped. Acyclovir was given for up to 6 months post HSCT. Patients receiving systemic steroids for engraftment fever also received cotrimoxazole prophylaxis. No antibacterial prophylaxis was performed for the period of neutropenia.
Use of growth factors
Filgrastim (G-CSF) was used in all autologous transplants. In patients with lymphomas and neuroblastoma, it started on the next day after stem cell infusion (Day +1). In patients with myeloma, it was started on day +5 post-transplant. In all the patients, it continued until myeloid engraftment.
Treatment strategy for breakthrough fever
Treatment-related decisions were made at the discretion of treating physician. In general, antibacterial or antifungal drugs were added at the onset of breakthrough fever. The antibiotics were continued if the patient became afebrile by 48 hours. If the patient remained febrile beyond 48 hours and blood culture had grown an organism, then antibiotics were modified according to the sensitivity reports. If the fever persisted beyond 48 hours, and there was no evidence of any infective cause, then systemic steroids were started. In few patients with high clinical suspicion of engraftment fever, systemic steroids were started at the onset of breakthrough fever. Initially methylprednisolone was started at a dose of 1-2 mg per kg per day and subsequently changed to oral prednisolone. Prednisolone was tapered every 3rd to 7th day as per discretion of the attending clinician.
Statistical analysis
We studied the trends of TLC:CRP ratio during the course of HSCT. We studied the absolute value of this ratio on the day of breakthrough fever to determine if it helps in distinguishing engraftment-related fever from infectious fever. Optimal cut-off value of the ratio on the day of breakthrough was obtained by plotting a receiver operating characteristic (ROC) curve. Sensitivity and specificity indices were calculated from this value. We also calculated the absolute rise of the ratio from its nadir to post-nadir value (i.e the lowest value and the value on the next day) and studied, whether this absolute rise helps to predict the occurrence of engraftment fever. Categorical data were analysed with chi-square test; continuous data with Mann-Whitney test. Analysis was done by SPSS software (version 18).
Results
Among the 109 patients subjected to autologous HSCT, seventy patients (64%) developed breakthrough fever in the 2nd week post-transplant. Fourteen patients (13%) had continuous fever while 22 (20%) patients did not have fever at any time in the 2nd week. Three patients (3%) expired prior to day 7 (all 3 due to pneumonia with sepsis). Of the 70 patients with breakthrough fever, 19 had multiple myeloma, 36 suffered with Hodgkin lymphoma, 14 had non-Hodgkin lymphoma, and one patient had neuroblastoma. The characteristics and engraftment kinetics of the cohort with breakthrough fever were not different from the entire cohort (Table 1).
The median day of the breakthrough fever onset was day +9 (ranges, day +7 to day+15). Sixty-two patients had engraftment-related fever; 15 of these had a full-blown engraftment syndrome. The overall incidence of engraftment fever was 57% (62 of 109 patients). Among the 62 patients with engraftment fever, one patient died due to full-blown engraftment syndrome. All others recovered. Peri-engraftment hepatic and renal dysfunction was seen in 2 patients each. Antibiotics were escalated in 35 of 62 (56%) patients with engraftment fever at the time of onset of breakthrough fever. All the patients with infectious fever got well (Table 2).
Table 2. Breakthrough fever and clinical outcomes
Trend of TLC-to-CRP ratio following HSCT in myeloma patients
Figure 1. Trend of TLC:CRP ratio during the course of HSCT in myeloma transplants
Figure 2. Trend of TLC:CRP ratio during the course of lymphoma transplants
Figure 3. ROC curve for cut-off of absolute value of TLC:CRP ratio on the day of breakthrough fever for detecting engraftment fever
Table 3. Incidence of engraftment fever according to absolute rise in ratio from its nadir value to post nadir value
The ratio of TLC (expressed in 109/ml) to CRP (expressed in mg/dl) followed a parabolic curve. It had a median value of 12.35 (range 2.34-60) at day -3 of HSCT and gradually declined to a median nadir value of 0.02 (range 0 to 0.16) (Fig. 1). The nadir was attained at a median of 9 days post-transplant. A rising trend of the ratio was first evident at a median of 10 days. This was followed by a gradual rise in ratio towards baseline.
Trend of TLC-to-CRP ratio after HSCT in lymphoma patients
The curve of TLC:CRP ratio was also parabolic in the patients with lymphoma. The median value of the ratio when starting the conditioning chemotherapy (on day -8) was 5.35 (range 0.41 to 83). It reached a nadir median value of 0.01 (range 0-7.55) on day +2. It remained at the nadir level till day +5. Rising trend of the radio was first evident on day +6. A rising trend of the ratio preceded neutrophil engraftment by a median term of 5 days (Fig. 2).
Absolute value of the TLC:CRP ratio on the day of breakthrough fever
We also examined, whether the absolute value of the TLC:CRP ratio on the day of breakthrough fever may help in identifying the cause of fever. The median value of this ratio in patients with engraftment fever was significantly higher than among the patients with infectious fever (0.139 vs 0.038, p=0.013). A ROC curve was constructed for TLC:CRP ratio. The area under the ROC curve was 0.78 (95% CI – 0.66 to 0.89, p <0.0001). This indicates that the test has potentially good diagnostic usefulness. The curve provided an optimum cut off value of 0.056 to discriminate between engraftment and infective fever (Fig. 3).
A ratio greater than or equal to 0.056 on the day of breakthrough fever had sensitivity of 63% (95% CI 50 – 75%) and specificity of 100% (95% CI 63 – 100%) for detecting engraftment fever. The positive and negative predictive values of ratio >0.056 for engraftment related fever were 100% (95% CI 89 – 100%) and 26% (95% CI – 13-45%). Thus, a TLC:CRP ratio of >0.056 is absolutely specific for engraftment fever.
Absolute rise in ratio from nadir value to predict risk of engraftment fever
We studied the rise in ratio from its nadir value to the post nadir value (i.e. value on the next day) and attempted to see if a cut-off could be found, thus helping to predict increased risk of developing engraftment related fever. However, at various cut-off values ranging from 0.001 to 0.01, approximately 60% of the patients developed engraftment fever. Thus, no particular cut-off value predicting an increased risk of developing engraftment fever could be determined in our patient cohort (p=NS) (Table 3). The median increase from the nadir to the post-nadir value was not different in patients with and without engraftment related fever (0.008 vs 0.010, p=0.72).
Discussion
Engraftment fever is a well-known entity post autologous HSCT and occurs in the peri-engraftment period [1]. However, this is also the time when transplant patients may develop fungal and bacterial infections. Unfortunately, there is no laboratory marker or test in routine clinical use which helps to distinguish engraftment related fever versus infectious fever. The distinction is largely based on clinical judgement. Antimicrobials are often escalated in patients who develop breakthrough fever during peri-engraftment period, since it is not always possible to discriminate it from infective fever.
Few studies have tried to differentiate engraftment fever from infectious fever. A study from Memorial Sloan-Kettering Institute suggested that ratio of serum interleukin 12 to interleukin 6 at the time of breakthrough fever helps to discriminate between engraftment and infectious fever [8]. This group studied the levels of various cytokines in serum at various time points following autologous HSCT and found that value of ratio >4.1 at the time of breakthrough fever has a sensitivity of 95% and specificity of 75% for detecting engraftment fever. Although several functions of interleukin 12 are known, one of the important functions is to enhance the proliferation of hematopoietic progenitor cells [9-11]. Also, it is well established that interleukin-6 is the major stimulator of C-reactive protein [12, 13]. Hence, from a biological perspective, the ratio of TLC to CRP could be used as a surrogate marker for the ratio of serum IL-12 to IL-6.
A major problem with the use of serum cytokine levels is the lack of availability of these at most centres. On the other hand, measurements of TLC and CRP values are available at most centres and are relatively inexpensive. The cut-off value of TLC/CRP ratio 0.056 identified in our study has a higher specificity, but lower sensitivity than the IL-12 to IL-6 ratio reported in the previous study [8]. In this study, 17% of episodes of breakthrough fever occurring after neutrophil engraftment were associated with infection. This value is similar to that found in our study (8 of 70 episodes, 11%). Similar to our study, the median value of IL-12 to IL-6 ratio was significantly higher in patients with non-infectious fever compared to those with infectious episodes. The study reported a sensitivity and specificity of 95% and 75% at a cut-off of 4.1. The area under the ROC curve was 0.88 for the IL-12 to IL-6 ratio with 95% CI being 0.79-0.97.
To conclude, a rising trend of the ratio of TLC:CRP is detected prior to neutrophil engraftment. An absolute value of the ratio greater than or equal to 0.056 at the time of breakthrough fever is highly specific for engraftment fever. Further prospective studies are warranted to confirm the findings of this small study. If the findings are confirmed, they could help to prevent unnecessary use of anti-bacterials and anti-fungals in post-transplant period.
Conflicts of interest
None declared.
References
- Spitzer TR. Engraftment syndrome following hematopoietic stem cell transplantation. Bone Marrow Transplant 2001; 27: 893-898.
- Lee C, Gingrich RD, Hohl RJ, Ajram KA. Engraftment syndrome in autologous bone marrow and peripheral stem cell transplantation. Bone Marrow Transplant 1995; 16: 175-182.
- Ravoet C, Feremans W, Husson B, Majois F, Kentos A, Lambermont M, Wallef G, Capel P, Beauduin M, Delannoy A. Clinical evidence for an engraftment syndrome associated with early and steep neutrophil recovery after autologous blood stem cell transplantation. Bone Marrow Transplant 1996; 18: 943-947.
- Edenfield W, Moores LK, Goodwin G, Lee N. An engraftment syndrome in autologous stem cell transplantation related to mononuclear cell dose. Bone Marrow Transplant 2000; 25: 405-409.
- Cahill R, Spitzer TR, Mazumder A. Marrow engraftment and clinical manifestations of capillary leak syndrome. Bone Marrow Transplant 1996; 18: 177-184.
- Nurnberger W, Willers R, Burdach S, Gobel U. Risk factors for capillary leakage syndrome after bone marrow transplantation. Ann Hematol 1997; 74: 221-224.
- Moreb JS, Kubilis PS, Mullins DL, Myers L, Youngblood M, Hutcheson C. Increased frequency of autoaggression syndrome associated with autologous stem cell transplantation in breast cancer patients. Bone Marrow Transplant 1997; 19: 101-106.
- Tuma R, Almyroudis N, Sohn S, Panageas K, Rice R, Galinkin D, Blain M, Montefusco M, Pamer E, Nimer Sd, Kewalramani T. The serum IL-12:IL-6 ratio reliably distinguishes infectious from non-infectious causes of fever during autologous stem cell transplantation. Cytotherapy. 2006; 8: 327-334.
- Trinchieri G. Interleukin-12: a cytokine produced by antigen-presenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood 1994; 84: 4008-4027.
- Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol. 2003; 3: 133-146.
- Wolf SF, Sieburth D, Sypek J. Interleukin 12: a key modulator of immune function. Stem Cells 194; 12: 154-168.
- Jones SA, Novick D, Horiuchi S, Yamamoto N, Szalai AJ, Fuller GM. C-reactive protein: a physiological activator of interleukin 6 receptor shedding. J Exp Med. 1999; 189: 599-604.
- Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003; 111: 1805-1812.
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Introduction
Engraftment-related fever and engraftment syndrome are well-known phenomenon post autologous HSCT. Engraftment syndrome refers to the constellation of features associated with engraftment including fever, skin rash, fluid retention, weight gain, and non-cardiogenic pulmonary edema. These features constitute the major criteria of the proposed definition of engraftment syndrome [1]. However, some studies have defined this syndrome differently and its reported incidence varies widely from 7% to as high as 59% in some studies [2-7]. The period of onset of engraftment-related fever often coincides with the time when the patients are likely to have fungal and bacterial infections. Hence, antibiotics are often escalated at the time of onset of breakthrough fever. This leads to increased use of antimicrobials and consequently adds significantly to health care costs.
There is no reliable clinical or laboratory parameter which helps to differentiate engraftment related fever from infectious fever. One study has shown that the ratio of Interleukin-12 to Interleukin-6 could reliably distinguish infectious from non-infectious fever following autologous HSCT [8]. However, measurement of interleukin levels is not available in most transplant centres. Our study stemmed from personal observations that the relative increase in total leukocyte count (TLC) is greater than the relative increase in C-reactive protein (CRP) in patients with engraftment fever whereas the reverse is, generally, seen in infectious fever. With this observation, we aimed to study whether the TLC/CRP ratio helps to distinguish infectious fever from engraftment-related fever in the patients undergoing autologous HSCT.
Patients and methods
Patient characteristics
This is a retrospective analysis of all autologous transplants from March 2011 to September 2013 at a single centre. One hundred and nine consecutive autologous transplants were included in the analysis (Table 1). Fifty-three patients had Hodgkin lymphoma, 19 had Non Hodgkin lymphoma, 34 had multiple myeloma and 3 had neuroblastoma. The median age was 32 years (range 2-63 years). Eighty four patients were males. At the time of transplant, 67 (61%) patients were in complete remission and 37 (34%) were in partial remission.
Chemotherapy and granulocyte colony stimulating factor (G-CSF) were used for stem cell mobilization in 100 (92%) patients while only G-CSF was used in 4 (4%) patients. G-CSF with plerixafor was used in 1 patient. Four (4%) patients did not receive any form of mobilizing drug. All these 4 patients received marrow grafts. All patients with multiple myeloma received melphalan based conditioning regimen, either melphalan alone (n=31) or with bortezomib (n=3). Lymphoma patients received conditioning with lomustine + cytarabine + cyclophosphamide + etoposide [LACE (n=69)], lomustine + etoposide + cytarabine + melphalan [LEAM (n=1)] or carmustine + etoposide + cytarabine + melphalan [BEAM (n=2)] regimen. Patients with neuroblastoma received busulfan + melphalan conditioning. Peripheral blood stem cells graft was used in 103 (95%) patients and bone marrow graft was used in 5 (5%) patients. One patient received a combined marrow and PBSC graft. Stem cells were cryopreserved for a median of 43 days (17-301 days). The median dose of CD34 cells infused was 4.6×106 per kg. Neutrophil and platelet engraftment occurred at a median of 11 days and 13 days, respectively.
Table 1. Patient characteristics
TLC and CRP were measured in the frames of routine blood analyses daily in the morning for all patients from the day of admission to the day of discharge and TLC/CRP ratio was calculated. Complete blood counts were done by Beckman HMX coulter. CRP was measured by the particle-enhanced turbidimetric immunoassay (PETIA) technique. Appropriate clinical and laboratory data were retrieved from patients’ files.
Clinical definitions
Engraftment: Myeloid engraftment was defined as TLC >1×109/L for 3 consecutive days or absolute neutrophil count greater than or equal to 0.5×109/L for 2 consecutive days, whichever was earlier. Platelet engraftment was defined as the first day of consecutive 7 days when platelet count remained about 20×109/L without need for platelet transfusion.
Peri-engraftment period: Peri-engraftment period was defined as period of 72 hours prior to myeloid engraftment to 96 hours after engraftment.
Breakthrough fever: Fever >38°C with onset in peri-engraftment period (usually during the 2nd week post-transplant) after being afebrile for at least 48 hours. Episodes of breakthrough fever were classified as either infectious fever, or engraftment-related fever.
Continuous fever: Patients with fever persisting over 2nd week post-transplant without an afebrile period, or with afebrile period of <48 hours were classified as having continuous fever.
Infectious fever: The condition was classified as infectious fever if blood culture (or culture from any other normally sterile site) was positive, or in case of radiological signs of infection or if fever subsided within 48 hours after change of antibiotics.
Engraftment fever: Engraftment fever was defined as fever with onset in the peri-engraftment period, without any evidence of associated infectious cause, and responding to systemic steroid therapy.
Anti-infective prophylaxis
All the patients received prophylaxis with an anti-fungal agent (voriconazole or posaconazole) and acyclovir. Antifungal prophylaxis was started on day -1 and continued till resolution of neutropenia. In patients receiving systemic steroids for engraftment fever, antifungal prophylaxis was continued until the steroids were stopped. Acyclovir was given for up to 6 months post HSCT. Patients receiving systemic steroids for engraftment fever also received cotrimoxazole prophylaxis. No antibacterial prophylaxis was performed for the period of neutropenia.
Use of growth factors
Filgrastim (G-CSF) was used in all autologous transplants. In patients with lymphomas and neuroblastoma, it started on the next day after stem cell infusion (Day +1). In patients with myeloma, it was started on day +5 post-transplant. In all the patients, it continued until myeloid engraftment.
Treatment strategy for breakthrough fever
Treatment-related decisions were made at the discretion of treating physician. In general, antibacterial or antifungal drugs were added at the onset of breakthrough fever. The antibiotics were continued if the patient became afebrile by 48 hours. If the patient remained febrile beyond 48 hours and blood culture had grown an organism, then antibiotics were modified according to the sensitivity reports. If the fever persisted beyond 48 hours, and there was no evidence of any infective cause, then systemic steroids were started. In few patients with high clinical suspicion of engraftment fever, systemic steroids were started at the onset of breakthrough fever. Initially methylprednisolone was started at a dose of 1-2 mg per kg per day and subsequently changed to oral prednisolone. Prednisolone was tapered every 3rd to 7th day as per discretion of the attending clinician.
Statistical analysis
We studied the trends of TLC:CRP ratio during the course of HSCT. We studied the absolute value of this ratio on the day of breakthrough fever to determine if it helps in distinguishing engraftment-related fever from infectious fever. Optimal cut-off value of the ratio on the day of breakthrough was obtained by plotting a receiver operating characteristic (ROC) curve. Sensitivity and specificity indices were calculated from this value. We also calculated the absolute rise of the ratio from its nadir to post-nadir value (i.e the lowest value and the value on the next day) and studied, whether this absolute rise helps to predict the occurrence of engraftment fever. Categorical data were analysed with chi-square test; continuous data with Mann-Whitney test. Analysis was done by SPSS software (version 18).
Results
Among the 109 patients subjected to autologous HSCT, seventy patients (64%) developed breakthrough fever in the 2nd week post-transplant. Fourteen patients (13%) had continuous fever while 22 (20%) patients did not have fever at any time in the 2nd week. Three patients (3%) expired prior to day 7 (all 3 due to pneumonia with sepsis). Of the 70 patients with breakthrough fever, 19 had multiple myeloma, 36 suffered with Hodgkin lymphoma, 14 had non-Hodgkin lymphoma, and one patient had neuroblastoma. The characteristics and engraftment kinetics of the cohort with breakthrough fever were not different from the entire cohort (Table 1).
The median day of the breakthrough fever onset was day +9 (ranges, day +7 to day+15). Sixty-two patients had engraftment-related fever; 15 of these had a full-blown engraftment syndrome. The overall incidence of engraftment fever was 57% (62 of 109 patients). Among the 62 patients with engraftment fever, one patient died due to full-blown engraftment syndrome. All others recovered. Peri-engraftment hepatic and renal dysfunction was seen in 2 patients each. Antibiotics were escalated in 35 of 62 (56%) patients with engraftment fever at the time of onset of breakthrough fever. All the patients with infectious fever got well (Table 2).
Table 2. Breakthrough fever and clinical outcomes
Trend of TLC-to-CRP ratio following HSCT in myeloma patients
Figure 1. Trend of TLC:CRP ratio during the course of HSCT in myeloma transplants
Figure 2. Trend of TLC:CRP ratio during the course of lymphoma transplants
Figure 3. ROC curve for cut-off of absolute value of TLC:CRP ratio on the day of breakthrough fever for detecting engraftment fever
Table 3. Incidence of engraftment fever according to absolute rise in ratio from its nadir value to post nadir value
The ratio of TLC (expressed in 109/ml) to CRP (expressed in mg/dl) followed a parabolic curve. It had a median value of 12.35 (range 2.34-60) at day -3 of HSCT and gradually declined to a median nadir value of 0.02 (range 0 to 0.16) (Fig. 1). The nadir was attained at a median of 9 days post-transplant. A rising trend of the ratio was first evident at a median of 10 days. This was followed by a gradual rise in ratio towards baseline.
Trend of TLC-to-CRP ratio after HSCT in lymphoma patients
The curve of TLC:CRP ratio was also parabolic in the patients with lymphoma. The median value of the ratio when starting the conditioning chemotherapy (on day -8) was 5.35 (range 0.41 to 83). It reached a nadir median value of 0.01 (range 0-7.55) on day +2. It remained at the nadir level till day +5. Rising trend of the radio was first evident on day +6. A rising trend of the ratio preceded neutrophil engraftment by a median term of 5 days (Fig. 2).
Absolute value of the TLC:CRP ratio on the day of breakthrough fever
We also examined, whether the absolute value of the TLC:CRP ratio on the day of breakthrough fever may help in identifying the cause of fever. The median value of this ratio in patients with engraftment fever was significantly higher than among the patients with infectious fever (0.139 vs 0.038, p=0.013). A ROC curve was constructed for TLC:CRP ratio. The area under the ROC curve was 0.78 (95% CI – 0.66 to 0.89, p <0.0001). This indicates that the test has potentially good diagnostic usefulness. The curve provided an optimum cut off value of 0.056 to discriminate between engraftment and infective fever (Fig. 3).
A ratio greater than or equal to 0.056 on the day of breakthrough fever had sensitivity of 63% (95% CI 50 – 75%) and specificity of 100% (95% CI 63 – 100%) for detecting engraftment fever. The positive and negative predictive values of ratio >0.056 for engraftment related fever were 100% (95% CI 89 – 100%) and 26% (95% CI – 13-45%). Thus, a TLC:CRP ratio of >0.056 is absolutely specific for engraftment fever.
Absolute rise in ratio from nadir value to predict risk of engraftment fever
We studied the rise in ratio from its nadir value to the post nadir value (i.e. value on the next day) and attempted to see if a cut-off could be found, thus helping to predict increased risk of developing engraftment related fever. However, at various cut-off values ranging from 0.001 to 0.01, approximately 60% of the patients developed engraftment fever. Thus, no particular cut-off value predicting an increased risk of developing engraftment fever could be determined in our patient cohort (p=NS) (Table 3). The median increase from the nadir to the post-nadir value was not different in patients with and without engraftment related fever (0.008 vs 0.010, p=0.72).
Discussion
Engraftment fever is a well-known entity post autologous HSCT and occurs in the peri-engraftment period [1]. However, this is also the time when transplant patients may develop fungal and bacterial infections. Unfortunately, there is no laboratory marker or test in routine clinical use which helps to distinguish engraftment related fever versus infectious fever. The distinction is largely based on clinical judgement. Antimicrobials are often escalated in patients who develop breakthrough fever during peri-engraftment period, since it is not always possible to discriminate it from infective fever.
Few studies have tried to differentiate engraftment fever from infectious fever. A study from Memorial Sloan-Kettering Institute suggested that ratio of serum interleukin 12 to interleukin 6 at the time of breakthrough fever helps to discriminate between engraftment and infectious fever [8]. This group studied the levels of various cytokines in serum at various time points following autologous HSCT and found that value of ratio >4.1 at the time of breakthrough fever has a sensitivity of 95% and specificity of 75% for detecting engraftment fever. Although several functions of interleukin 12 are known, one of the important functions is to enhance the proliferation of hematopoietic progenitor cells [9-11]. Also, it is well established that interleukin-6 is the major stimulator of C-reactive protein [12, 13]. Hence, from a biological perspective, the ratio of TLC to CRP could be used as a surrogate marker for the ratio of serum IL-12 to IL-6.
A major problem with the use of serum cytokine levels is the lack of availability of these at most centres. On the other hand, measurements of TLC and CRP values are available at most centres and are relatively inexpensive. The cut-off value of TLC/CRP ratio 0.056 identified in our study has a higher specificity, but lower sensitivity than the IL-12 to IL-6 ratio reported in the previous study [8]. In this study, 17% of episodes of breakthrough fever occurring after neutrophil engraftment were associated with infection. This value is similar to that found in our study (8 of 70 episodes, 11%). Similar to our study, the median value of IL-12 to IL-6 ratio was significantly higher in patients with non-infectious fever compared to those with infectious episodes. The study reported a sensitivity and specificity of 95% and 75% at a cut-off of 4.1. The area under the ROC curve was 0.88 for the IL-12 to IL-6 ratio with 95% CI being 0.79-0.97.
To conclude, a rising trend of the ratio of TLC:CRP is detected prior to neutrophil engraftment. An absolute value of the ratio greater than or equal to 0.056 at the time of breakthrough fever is highly specific for engraftment fever. Further prospective studies are warranted to confirm the findings of this small study. If the findings are confirmed, they could help to prevent unnecessary use of anti-bacterials and anti-fungals in post-transplant period.
Conflicts of interest
None declared.
References
- Spitzer TR. Engraftment syndrome following hematopoietic stem cell transplantation. Bone Marrow Transplant 2001; 27: 893-898.
- Lee C, Gingrich RD, Hohl RJ, Ajram KA. Engraftment syndrome in autologous bone marrow and peripheral stem cell transplantation. Bone Marrow Transplant 1995; 16: 175-182.
- Ravoet C, Feremans W, Husson B, Majois F, Kentos A, Lambermont M, Wallef G, Capel P, Beauduin M, Delannoy A. Clinical evidence for an engraftment syndrome associated with early and steep neutrophil recovery after autologous blood stem cell transplantation. Bone Marrow Transplant 1996; 18: 943-947.
- Edenfield W, Moores LK, Goodwin G, Lee N. An engraftment syndrome in autologous stem cell transplantation related to mononuclear cell dose. Bone Marrow Transplant 2000; 25: 405-409.
- Cahill R, Spitzer TR, Mazumder A. Marrow engraftment and clinical manifestations of capillary leak syndrome. Bone Marrow Transplant 1996; 18: 177-184.
- Nurnberger W, Willers R, Burdach S, Gobel U. Risk factors for capillary leakage syndrome after bone marrow transplantation. Ann Hematol 1997; 74: 221-224.
- Moreb JS, Kubilis PS, Mullins DL, Myers L, Youngblood M, Hutcheson C. Increased frequency of autoaggression syndrome associated with autologous stem cell transplantation in breast cancer patients. Bone Marrow Transplant 1997; 19: 101-106.
- Tuma R, Almyroudis N, Sohn S, Panageas K, Rice R, Galinkin D, Blain M, Montefusco M, Pamer E, Nimer Sd, Kewalramani T. The serum IL-12:IL-6 ratio reliably distinguishes infectious from non-infectious causes of fever during autologous stem cell transplantation. Cytotherapy. 2006; 8: 327-334.
- Trinchieri G. Interleukin-12: a cytokine produced by antigen-presenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood 1994; 84: 4008-4027.
- Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol. 2003; 3: 133-146.
- Wolf SF, Sieburth D, Sypek J. Interleukin 12: a key modulator of immune function. Stem Cells 194; 12: 154-168.
- Jones SA, Novick D, Horiuchi S, Yamamoto N, Szalai AJ, Fuller GM. C-reactive protein: a physiological activator of interleukin 6 receptor shedding. J Exp Med. 1999; 189: 599-604.
- Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003; 111: 1805-1812.
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["ELEMENT_META_KEYWORDS"]=> string(0) "" ["ELEMENT_META_DESCRIPTION"]=> string(621) "Соотношение количества лейкоцитов и С-реактивного белка в крови: поможет ли это дифференциации между инфекционной лихорадкой и синдромом приживления у пациентов после аутологичной трансплантации гемопоэтических стволовых клеток?Ratio of total leukocyte count to C-reactive protein: does it help to differentiate infectious fever from engraftment fever in patients undergoing autologous hematopoietic stem cell transplant?" ["ELEMENT_PREVIEW_PICTURE_FILE_ALT"]=> string(4284) "<p style="text-align: justify;">«Лихорадка приживления» (ЛП) является частым осложнением аутологичной трансплантации гемопоэтических стволовых клеток (ТГСК). Ее сложно отличить от инфекционной лихорадки (ИЛ). Мы исследовали значимость показателя соотношения общего числа лейкоцитов крови к концентрации С-реактивного белка при дифференциальном диагнозе между ЛП и ИЛ. Группа из 109 пациентов после ауто-ТГСК была обследована ретроспективно в период между мартом 2011 г. и августом 2013 г. Лихорадочное состояние (ЛС) определялось как лихорадка, развивающаяся de novo после афебрильного периода более 48 часов. Эпизоды ЛС классифицировали как ЛП или ИЛ. Инфекционную лихорадку диагностировали в случае позитивной гемокультуры, радиологических симптомов инфекции или лихорадки, продолжающейся в течение 48 часов после смены антибиотика. «Лихорадку приживления» определяли в случаях, связанных с повышением лейкоцитоза без очевидного инфекционного очага. ЛП хорошо отвечала на лечение стероидными гормонами. Ежедневные показатели лейкоцитоза и С-реактивного белка фиксировали по историям болезни. Оптимальный показатель отсечения (cut-off value) данного соотношения на день появления лихорадочного состояния определяли методом построения кривых ROC. Чувствительность и специфичность метода вычисляли по этому показателю. По результатам анализа 109 случаев, лихорадочные состояния проявились у 70 пациентов. Медианным сроком развития лихорадочного состояния был день +9 после ТГСК. 62 пациента имели ЛП. Медиана соотношения лейкоцитоза к С-реактивному белку в день развития лихорадочного состояния была значительна повышена у пациентов с ЛП по сравнению с ИЛ (соответственно, 0,139 и 0,038, p=0,013). При ROC-анализе, площадь под кривой (AUC) была 0,78 (95%CI – 0,66-0,89, p<0,0001). Из графика ROC вычислено оптимальное соотношение лейкоцитоза к С-реактивному белку, равное >0.056 для «лихорадки приживления» при чувствительности и специфичности, соответственно, 63% (95%CI 50-75%) и 100% (95%CI 63-100%). Соотношение числа лейкоцитов к С-реактивному белку (>0,056) высоко специфично для лихорадки приживления. Необходимы проспективные исследования для подтверждения этих результатов. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Лейкоцитоз общий, С-реактивный белок, лихорадка приживления, инфекционная лихорадка, трансплантация стволовых кроветворных клеток, аутологичная. </p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(428) "Соотношение количества лейкоцитов и С-реактивного белка в крови: поможет ли это дифференциации между инфекционной лихорадкой и синдромом приживления у пациентов после аутологичной трансплантации гемопоэтических стволовых клеток?" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(428) "Соотношение количества лейкоцитов и С-реактивного белка в крови: поможет ли это дифференциации между инфекционной лихорадкой и синдромом приживления у пациентов после аутологичной трансплантации гемопоэтических стволовых клеток?" 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2 Национальный институт Хоми Бхабха, Анушакти Нагар, Мумбаи, Индия
3 Департамент биостатистики, Мемориальный центр Тата, Пэймастер Шодика, ACTREC, Харгарб Нави Мумбай, Индия
«Лихорадка приживления» (ЛП) является частым осложнением аутологичной трансплантации гемопоэтических стволовых клеток (ТГСК). Ее сложно отличить от инфекционной лихорадки (ИЛ). Мы исследовали значимость показателя соотношения общего числа лейкоцитов крови к концентрации С-реактивного белка при дифференциальном диагнозе между ЛП и ИЛ. Группа из 109 пациентов после ауто-ТГСК была обследована ретроспективно в период между мартом 2011 г. и августом 2013 г. Лихорадочное состояние (ЛС) определялось как лихорадка, развивающаяся de novo после афебрильного периода более 48 часов. Эпизоды ЛС классифицировали как ЛП или ИЛ. Инфекционную лихорадку диагностировали в случае позитивной гемокультуры, радиологических симптомов инфекции или лихорадки, продолжающейся в течение 48 часов после смены антибиотика. «Лихорадку приживления» определяли в случаях, связанных с повышением лейкоцитоза без очевидного инфекционного очага. ЛП хорошо отвечала на лечение стероидными гормонами. Ежедневные показатели лейкоцитоза и С-реактивного белка фиксировали по историям болезни. Оптимальный показатель отсечения (cut-off value) данного соотношения на день появления лихорадочного состояния определяли методом построения кривых ROC. Чувствительность и специфичность метода вычисляли по этому показателю. По результатам анализа 109 случаев, лихорадочные состояния проявились у 70 пациентов. Медианным сроком развития лихорадочного состояния был день +9 после ТГСК. 62 пациента имели ЛП. Медиана соотношения лейкоцитоза к С-реактивному белку в день развития лихорадочного состояния была значительна повышена у пациентов с ЛП по сравнению с ИЛ (соответственно, 0,139 и 0,038, p=0,013). При ROC-анализе, площадь под кривой (AUC) была 0,78 (95%CI – 0,66-0,89, p<0,0001). Из графика ROC вычислено оптимальное соотношение лейкоцитоза к С-реактивному белку, равное >0.056 для «лихорадки приживления» при чувствительности и специфичности, соответственно, 63% (95%CI 50-75%) и 100% (95%CI 63-100%). Соотношение числа лейкоцитов к С-реактивному белку (>0,056) высоко специфично для лихорадки приживления. Необходимы проспективные исследования для подтверждения этих результатов.
Ключевые слова
Лейкоцитоз общий, С-реактивный белок, лихорадка приживления, инфекционная лихорадка, трансплантация стволовых кроветворных клеток, аутологичная.
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2 Homi Bhabha National Institute, Anushakti Nagar, Mumbai, India
3 Department of Biostatistics, Tata Memorial Centre, Paymaster Shodhika, ACTREC, Kharghar, Navi Mumbai, India
Correspondence
Dr. Navin Khattry, Professor and BMT Programme Co-ordinator, HSCT unit, Department of Medical Oncology, Room 211, Paymaster Shodhika, ACTREC, Kharghar, Navi Mumbai 410210, Maharashtra, India
Phone +91 989 2501 884
E mail: nkhattry@gmail.com
Engraftment fever (EF) is a common complication of autologous HSCT (AHSCT). It is difficult to discern it from infectious fever (IF). We studied the significance of total blood leucocyte count (TLC) to C-reactive protein (CRP) ratio in differentiating EF from IF. 109 consecutive AHSCT patients were retrospectively analysed between March 2011 and August 2013. Breakthrough fever (BF) was defined as new-onset fever preceded by an afebrile period of at least 48 hours. The BF episodes were classified as IF or EF. Infectious fever was diagnosed in case of blood culture positivity, radiological signs of infection, or fever subsiding within 48 hours of changing the antibiotics. Engraftment fever was defined in cases associated with rising leucocyte counts without identifiable infective focus. EF responded well to steroid therapy. Daily TLC and CRP values were obtained from patients’ records. Optimal cut-off value of ratio on day of BF was obtained by plotting ROC curve. Sensitivity and specificity were calculated at this value.
Among 109 cases, the breakthrough fever manifested in seventy patients. The median term for BF was day +9. Sixty-two patients had the EF. Median value of TLC/CRP ratio on the day of BF was significantly higher in patients with EF than with IF (0.139 vs 0.038, p=0.013). With ROC analysis, the AUC value was 0.78 (95%CI – 0.66-0.89, p<0.0001). The ROC curve provided the optimal TLC/CRP value of 0.056. Using a ratio >0.056 for EF, the sensitivity and specificity were 63% (95%CI 50-75%) and 100% (95%CI 63-100%) respectively. TLC/CRP ratio >0.056 is highly specific for EF. Prospective studies are warranted to confirm these findings.
Keywords
Total leukocyte count, C-reactive protein, engraftment fever, infectious fever, stem cell transplant, autologous.
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Gokarn<sup>1,2</sup>, Aniket Mohite<sup>1</sup>, Karthik Shanmugam<sup>1</sup>, Deepan Rajamanickam<sup>1</sup>, Alok Gupta<sup>1</sup>, Libin Mathew<sup>1</sup>, Sadhana Kannan<sup>3</sup>, Navin Khattry<sup>1,2</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(320) "Sachin Punatar1,2, Lingaraj Nayak1,2, Avinash Bonda1,2, Anant Gokarn1,2, Aniket Mohite1, Karthik Shanmugam1, Deepan Rajamanickam1, Alok Gupta1, Libin Mathew1, Sadhana Kannan3, Navin Khattry1,2
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(320) "Sachin Punatar1,2, Lingaraj Nayak1,2, Avinash Bonda1,2, Anant Gokarn1,2, Aniket Mohite1, Karthik Shanmugam1, Deepan Rajamanickam1, Alok Gupta1, Libin Mathew1, Sadhana Kannan3, Navin Khattry1,2
" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "26490" ["VALUE"]=> array(2) { ["TEXT"]=> string(2028) "<p style="text-align: justify;">Engraftment fever (EF) is a common complication of autologous HSCT (AHSCT). It is difficult to discern it from infectious fever (IF). We studied the significance of total blood leucocyte count (TLC) to C-reactive protein (CRP) ratio in differentiating EF from IF. 109 consecutive AHSCT patients were retrospectively analysed between March 2011 and August 2013. Breakthrough fever (BF) was defined as new-onset fever preceded by an afebrile period of at least 48 hours. The BF episodes were classified as IF or EF. Infectious fever was diagnosed in case of blood culture positivity, radiological signs of infection, or fever subsiding within 48 hours of changing the antibiotics. Engraftment fever was defined in cases associated with rising leucocyte counts without identifiable infective focus. EF responded well to steroid therapy. Daily TLC and CRP values were obtained from patients’ records. Optimal cut-off value of ratio on day of BF was obtained by plotting ROC curve. Sensitivity and specificity were calculated at this value. </p> <p style="text-align: justify;">Among 109 cases, the breakthrough fever manifested in seventy patients. The median term for BF was day +9. Sixty-two patients had the EF. Median value of TLC/CRP ratio on the day of BF was significantly higher in patients with EF than with IF (0.139 <i>vs</i> 0.038, p=0.013). With ROC analysis, the AUC value was 0.78 (95%CI – 0.66-0.89, p<0.0001). The ROC curve provided the optimal TLC/CRP value of 0.056. Using a ratio >0.056 for EF, the sensitivity and specificity were 63% (95%CI 50-75%) and 100% (95%CI 63-100%) respectively. TLC/CRP ratio >0.056 is highly specific for EF. Prospective studies are warranted to confirm these findings. </p> <h2>Keywords</h2> <p style="text-align: justify;">Total leukocyte count, C-reactive protein, engraftment fever, infectious fever, stem cell transplant, autologous. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1929) "Engraftment fever (EF) is a common complication of autologous HSCT (AHSCT). It is difficult to discern it from infectious fever (IF). We studied the significance of total blood leucocyte count (TLC) to C-reactive protein (CRP) ratio in differentiating EF from IF. 109 consecutive AHSCT patients were retrospectively analysed between March 2011 and August 2013. Breakthrough fever (BF) was defined as new-onset fever preceded by an afebrile period of at least 48 hours. The BF episodes were classified as IF or EF. Infectious fever was diagnosed in case of blood culture positivity, radiological signs of infection, or fever subsiding within 48 hours of changing the antibiotics. Engraftment fever was defined in cases associated with rising leucocyte counts without identifiable infective focus. EF responded well to steroid therapy. Daily TLC and CRP values were obtained from patients’ records. Optimal cut-off value of ratio on day of BF was obtained by plotting ROC curve. Sensitivity and specificity were calculated at this value.
Among 109 cases, the breakthrough fever manifested in seventy patients. The median term for BF was day +9. Sixty-two patients had the EF. Median value of TLC/CRP ratio on the day of BF was significantly higher in patients with EF than with IF (0.139 vs 0.038, p=0.013). With ROC analysis, the AUC value was 0.78 (95%CI – 0.66-0.89, p<0.0001). The ROC curve provided the optimal TLC/CRP value of 0.056. Using a ratio >0.056 for EF, the sensitivity and specificity were 63% (95%CI 50-75%) and 100% (95%CI 63-100%) respectively. TLC/CRP ratio >0.056 is highly specific for EF. Prospective studies are warranted to confirm these findings.
Keywords
Total leukocyte count, C-reactive protein, engraftment fever, infectious fever, stem cell transplant, autologous.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1929) "Engraftment fever (EF) is a common complication of autologous HSCT (AHSCT). It is difficult to discern it from infectious fever (IF). We studied the significance of total blood leucocyte count (TLC) to C-reactive protein (CRP) ratio in differentiating EF from IF. 109 consecutive AHSCT patients were retrospectively analysed between March 2011 and August 2013. Breakthrough fever (BF) was defined as new-onset fever preceded by an afebrile period of at least 48 hours. The BF episodes were classified as IF or EF. Infectious fever was diagnosed in case of blood culture positivity, radiological signs of infection, or fever subsiding within 48 hours of changing the antibiotics. Engraftment fever was defined in cases associated with rising leucocyte counts without identifiable infective focus. EF responded well to steroid therapy. Daily TLC and CRP values were obtained from patients’ records. Optimal cut-off value of ratio on day of BF was obtained by plotting ROC curve. Sensitivity and specificity were calculated at this value.
Among 109 cases, the breakthrough fever manifested in seventy patients. The median term for BF was day +9. Sixty-two patients had the EF. Median value of TLC/CRP ratio on the day of BF was significantly higher in patients with EF than with IF (0.139 vs 0.038, p=0.013). With ROC analysis, the AUC value was 0.78 (95%CI – 0.66-0.89, p<0.0001). The ROC curve provided the optimal TLC/CRP value of 0.056. Using a ratio >0.056 for EF, the sensitivity and specificity were 63% (95%CI 50-75%) and 100% (95%CI 63-100%) respectively. TLC/CRP ratio >0.056 is highly specific for EF. Prospective studies are warranted to confirm these findings.
Keywords
Total leukocyte count, C-reactive protein, engraftment fever, infectious fever, stem cell transplant, autologous.
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2 Homi Bhabha National Institute, Anushakti Nagar, Mumbai, India
3 Department of Biostatistics, Tata Memorial Centre, Paymaster Shodhika, ACTREC, Kharghar, Navi Mumbai, India
Correspondence
Dr. Navin Khattry, Professor and BMT Programme Co-ordinator, HSCT unit, Department of Medical Oncology, Room 211, Paymaster Shodhika, ACTREC, Kharghar, Navi Mumbai 410210, Maharashtra, India
Phone +91 989 2501 884
E mail: nkhattry@gmail.com
1 HSCT unit, Department of Medical Oncology Tata Memorial Centre, HSCT unit, ACTREC, Kharghar, Navi Mumbai, India
2 Homi Bhabha National Institute, Anushakti Nagar, Mumbai, India
3 Department of Biostatistics, Tata Memorial Centre, Paymaster Shodhika, ACTREC, Kharghar, Navi Mumbai, India
Correspondence
Dr. Navin Khattry, Professor and BMT Programme Co-ordinator, HSCT unit, Department of Medical Oncology, Room 211, Paymaster Shodhika, ACTREC, Kharghar, Navi Mumbai 410210, Maharashtra, India
Phone +91 989 2501 884
E mail: nkhattry@gmail.com
Сачин Пунатар1,2, Лингарадж Наяк1,2, Авинаш Бонда1,2, Анант Гокарн1,2, Аникет Мохите1, Картик Шанмугам1, Дипан Раджаманикам1, Алок Гупта1, Либин Мэтью1, Садхана Каннан3, Навин Хаттри1,2
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Ее сложно отличить от инфекционной лихорадки (ИЛ). Мы исследовали значимость показателя соотношения общего числа лейкоцитов крови к концентрации С-реактивного белка при дифференциальном диагнозе между ЛП и ИЛ. Группа из 109 пациентов после ауто-ТГСК была обследована ретроспективно в период между мартом 2011 г. и августом 2013 г. Лихорадочное состояние (ЛС) определялось как лихорадка, развивающаяся de novo после афебрильного периода более 48 часов. Эпизоды ЛС классифицировали как ЛП или ИЛ. Инфекционную лихорадку диагностировали в случае позитивной гемокультуры, радиологических симптомов инфекции или лихорадки, продолжающейся в течение 48 часов после смены антибиотика. «Лихорадку приживления» определяли в случаях, связанных с повышением лейкоцитоза без очевидного инфекционного очага. ЛП хорошо отвечала на лечение стероидными гормонами. Ежедневные показатели лейкоцитоза и С-реактивного белка фиксировали по историям болезни. Оптимальный показатель отсечения (cut-off value) данного соотношения на день появления лихорадочного состояния определяли методом построения кривых ROC. Чувствительность и специфичность метода вычисляли по этому показателю. По результатам анализа 109 случаев, лихорадочные состояния проявились у 70 пациентов. Медианным сроком развития лихорадочного состояния был день +9 после ТГСК. 62 пациента имели ЛП. Медиана соотношения лейкоцитоза к С-реактивному белку в день развития лихорадочного состояния была значительна повышена у пациентов с ЛП по сравнению с ИЛ (соответственно, 0,139 и 0,038, p=0,013). При ROC-анализе, площадь под кривой (AUC) была 0,78 (95%CI – 0,66-0,89, p<0,0001). Из графика ROC вычислено оптимальное соотношение лейкоцитоза к С-реактивному белку, равное >0.056 для «лихорадки приживления» при чувствительности и специфичности, соответственно, 63% (95%CI 50-75%) и 100% (95%CI 63-100%). Соотношение числа лейкоцитов к С-реактивному белку (>0,056) высоко специфично для лихорадки приживления. Необходимы проспективные исследования для подтверждения этих результатов. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Лейкоцитоз общий, С-реактивный белок, лихорадка приживления, инфекционная лихорадка, трансплантация стволовых кроветворных клеток, аутологичная. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4219) "«Лихорадка приживления» (ЛП) является частым осложнением аутологичной трансплантации гемопоэтических стволовых клеток (ТГСК). Ее сложно отличить от инфекционной лихорадки (ИЛ). Мы исследовали значимость показателя соотношения общего числа лейкоцитов крови к концентрации С-реактивного белка при дифференциальном диагнозе между ЛП и ИЛ. Группа из 109 пациентов после ауто-ТГСК была обследована ретроспективно в период между мартом 2011 г. и августом 2013 г. Лихорадочное состояние (ЛС) определялось как лихорадка, развивающаяся de novo после афебрильного периода более 48 часов. Эпизоды ЛС классифицировали как ЛП или ИЛ. Инфекционную лихорадку диагностировали в случае позитивной гемокультуры, радиологических симптомов инфекции или лихорадки, продолжающейся в течение 48 часов после смены антибиотика. «Лихорадку приживления» определяли в случаях, связанных с повышением лейкоцитоза без очевидного инфекционного очага. ЛП хорошо отвечала на лечение стероидными гормонами. Ежедневные показатели лейкоцитоза и С-реактивного белка фиксировали по историям болезни. Оптимальный показатель отсечения (cut-off value) данного соотношения на день появления лихорадочного состояния определяли методом построения кривых ROC. Чувствительность и специфичность метода вычисляли по этому показателю. По результатам анализа 109 случаев, лихорадочные состояния проявились у 70 пациентов. Медианным сроком развития лихорадочного состояния был день +9 после ТГСК. 62 пациента имели ЛП. Медиана соотношения лейкоцитоза к С-реактивному белку в день развития лихорадочного состояния была значительна повышена у пациентов с ЛП по сравнению с ИЛ (соответственно, 0,139 и 0,038, p=0,013). При ROC-анализе, площадь под кривой (AUC) была 0,78 (95%CI – 0,66-0,89, p<0,0001). Из графика ROC вычислено оптимальное соотношение лейкоцитоза к С-реактивному белку, равное >0.056 для «лихорадки приживления» при чувствительности и специфичности, соответственно, 63% (95%CI 50-75%) и 100% (95%CI 63-100%). Соотношение числа лейкоцитов к С-реактивному белку (>0,056) высоко специфично для лихорадки приживления. Необходимы проспективные исследования для подтверждения этих результатов.
Ключевые слова
Лейкоцитоз общий, С-реактивный белок, лихорадка приживления, инфекционная лихорадка, трансплантация стволовых кроветворных клеток, аутологичная.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(4219) "«Лихорадка приживления» (ЛП) является частым осложнением аутологичной трансплантации гемопоэтических стволовых клеток (ТГСК). Ее сложно отличить от инфекционной лихорадки (ИЛ). Мы исследовали значимость показателя соотношения общего числа лейкоцитов крови к концентрации С-реактивного белка при дифференциальном диагнозе между ЛП и ИЛ. Группа из 109 пациентов после ауто-ТГСК была обследована ретроспективно в период между мартом 2011 г. и августом 2013 г. Лихорадочное состояние (ЛС) определялось как лихорадка, развивающаяся de novo после афебрильного периода более 48 часов. Эпизоды ЛС классифицировали как ЛП или ИЛ. Инфекционную лихорадку диагностировали в случае позитивной гемокультуры, радиологических симптомов инфекции или лихорадки, продолжающейся в течение 48 часов после смены антибиотика. «Лихорадку приживления» определяли в случаях, связанных с повышением лейкоцитоза без очевидного инфекционного очага. ЛП хорошо отвечала на лечение стероидными гормонами. Ежедневные показатели лейкоцитоза и С-реактивного белка фиксировали по историям болезни. Оптимальный показатель отсечения (cut-off value) данного соотношения на день появления лихорадочного состояния определяли методом построения кривых ROC. Чувствительность и специфичность метода вычисляли по этому показателю. По результатам анализа 109 случаев, лихорадочные состояния проявились у 70 пациентов. Медианным сроком развития лихорадочного состояния был день +9 после ТГСК. 62 пациента имели ЛП. Медиана соотношения лейкоцитоза к С-реактивному белку в день развития лихорадочного состояния была значительна повышена у пациентов с ЛП по сравнению с ИЛ (соответственно, 0,139 и 0,038, p=0,013). При ROC-анализе, площадь под кривой (AUC) была 0,78 (95%CI – 0,66-0,89, p<0,0001). Из графика ROC вычислено оптимальное соотношение лейкоцитоза к С-реактивному белку, равное >0.056 для «лихорадки приживления» при чувствительности и специфичности, соответственно, 63% (95%CI 50-75%) и 100% (95%CI 63-100%). Соотношение числа лейкоцитов к С-реактивному белку (>0,056) высоко специфично для лихорадки приживления. Необходимы проспективные исследования для подтверждения этих результатов.
Ключевые слова
Лейкоцитоз общий, С-реактивный белок, лихорадка приживления, инфекционная лихорадка, трансплантация стволовых кроветворных клеток, аутологичная.
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2 Национальный институт Хоми Бхабха, Анушакти Нагар, Мумбаи, Индия
3 Департамент биостатистики, Мемориальный центр Тата, Пэймастер Шодика, ACTREC, Харгарб Нави Мумбай, Индия
1 Отделение ТКМ, Департамент медицинский онкологии, ACTREC, Харгар, Нави Мумбай, Индия
2 Национальный институт Хоми Бхабха, Анушакти Нагар, Мумбаи, Индия
3 Департамент биостатистики, Мемориальный центр Тата, Пэймастер Шодика, ACTREC, Харгарб Нави Мумбай, Индия
Introduction
Fecal microbiome contains hundreds types of bacteria, with only minority of, mostly, aerobic gut bacteria having been detectable in bacteriological cultures. However, conventional microbiological cultures are able to detect only a limited number of aerobic and, to lesser degree, anaerobic bacteria in fecal samples. In this respect, a gene-specific DNA diagnostics, e.g., multiplex PCR aimed for detection of potentially pathogenic microbes, is a more sensitive technique for detection and quantification of distinct microbial species and families at different microbiotes of human body [1].
Moreover, major bacterial classes and families became available for studies and comparisons, due to development of the next-generation sequencing (NGS). Bacteroides and Clostridia comprise the majority of normal intestinal flora as suggested by several NGS studies performed in different parts of the world [2, 3]. These microbial types are susceptible to massive antibiotic treatment which is usually applied in immunocompromised patients after bone marrow transplantation [4].
Still there are no generally approved reference biodiversity values, or marker microorganisms for assessment of gut microbiome in immunocompromised patients following severe cytostatic and antimicrobial therapy. Severe intestinal affection after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a useful clinical model for evaluation of gut microbiome shifts and its correction after fecal microbiota transplantation (FMT) [5]. An FMT protocol for clinical trials in severe graft-versus-host disease (GvHD) was applied quite recently [6].
Despite numerous clinical studies on FMT, there are only few bacterial markers for monitoring its efficiency. Appropriate guidelines are limited to bacteriological screening of the third-party donors of fecal transplants [7]. To our knowledge, there are no clear recommendations on screening of fecal microbiota in the patients. Except of time- and labor-consuming NGS analysis, some multiplex PCR-based approaches may be used that detect distinct gut pathogens [8, 9]. A quite recent approach is based on determination of relative proportions for the dominant phyla in human gut microbiome [10].
To evaluate real biodiversity of intestinal microbiome, most recent works are performed by sequencing of 16S rRNA fragments from multiple bacterial species, with subsequent detection of species-specific genes. The results of NGS assays provide a big number of 16S rRNA nucleotide sequences which correspond to relative representation of distinct bacterial classes in the given sample. The best reliable data derived from NGS analysis concern biological diversity for big taxonomic classes of microbiota, down to the family level. More exact species-specific diagnostics is less robust, due to only marginal interspecies differences in nucleotide sequences detectable by the current NGS technique.
Therefore, some more simple and cost-effective microbial markers are required for evaluation and screening of human microbiota after massive antibiotic therapy and in the course of gut recolonization. Hence, the aim of our study was a search for microbial species detectable by molecular biology techniques that could correlate with clinical results of FMT performed in severe resistant GvHD after allo-HSCT.
Patients and methods
The prospective single-center study included 27 patients at the age of 1 to 52 years old (median, 25 years) after allo-HSCT at the Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation over a period of 2017 to 2019 (Table 1). The main group included 19 post-HSCT patients who developed acute intestinal GvHD. All the patients were in remission state for their primary disease. These patients received FMT due to severe GvHD resistant to standard treatment. The inclusion criterion was steroid-refractory acute or chronic GvHD (overlap-syndrome) accompanied by intestinal affection. Intestinal GvHD has been confirmed by pathological examination of colonic mucosa biopsies. FMT was performed at a median of 110 (37-909) days post-HSCT. The comparison group with similar GvHD symptoms included eight patients who received placebo preparations instead of FMT applied on a median of 56 (34-120) days after HSCT.
Table 1. Clinical characteristics of the FMT patients
Antimicrobial prophylaxis was canceled 3 days before and during TFM treatment. Systemic antibacterial drugs were administered by common clinical indications (local infection, septicemia) to 8 patients (37%) before FMT, and in 18 cases (95%), after the procedure. Seven placebo-treated patients out of 8 (88%) were also exposed to systemic antimicrobial therapy. The patients with proven intestinal affection with HHV6 or EBV herpes viruses received gancyclovir: 11 (58%) in FMT-treated, 8 (100%) in the placebo group.
All the patients received immunosuppressive therapy as the first-line GvHD treatment, by means glucocorticosteroids (methylprednisolone, 1 mg/kg/d). The second-line therapy was performed with Ruxolitinib at the dose of 10-15mg/d (for children 0.25mg/kg/d). The patients underwent clinical and laboratory screening at the following terms: before FMT/placebo treatment D -1-3, D+3, D+16, D+30, D+60, and D+120 after FMT. The next day after last FMT was considered D+1. Primary endpoints were determined on the D+30 following FMT or placebo administration.
Routine laboratory studies at the ICU included daily blood cell and differential leukocyte counts, routine serum biochemistry, serum markers of inflammation (procalcitonine, С-reactive protein). In cases of acute intestinal syndrome, the aerobic microbial cultures of stool samples were routinely seeded, and C.difficile toxins A and B were checked by a simple immune chromatography test (VEDALAB, France).
In four cases (21%), the fecal transplant donation was performed from related donors (mother, 1; father, 2; brother, 1). FMT from unrelated donors was carried out in 15 patients.
Fecal transplants were administered by the following methods: via gastroduodenoscope, in 3 patients (16%); via nasointestinal catheter, in 7cases (3 TFM+ and 4 placebo); 13 patients (68%) ingested gelatin capsules with frozen microbiota. Placebo capsules were used in 4 patients (50%).
The single-center prospective study "Treatment of children and adult patients with inflammatory and infectious gut lesions after allogeneic transplantation of hematopoietic stem cells using transplantation of normal human microbiota" was approved by the Local Review Board at the First I. Pavlov Saint-Petersburg State Medical University №192 от 30.01.2017. The trial was performed in accordance with Good Clinical Practice and Declaration of Helsinki, i.e., full awareness of the study purpose, procedures and possible adverse effects from treatment, as stated by appropriate written informed consent signed by each patient or his (her) competent relative.
Fecal microbiota encapsulation procedure
Preparation of fecal transplants and their storage at -80°C was performed at the specialized microbiological laboratory. In brief, the donor material was supplemented with 10% glycerol and 50% sterile dextrose syrup (v/v), then homogenized with a disposable blender. The material, placed on ice, was then packed up in solid Coni-Snap® Size 0 gelatin capsules using the ProFiller 1100 device. The bar-coded capsules were placed into individual sterile containers. The fecal transplants (FT) were transferred to a freezing chamber (-80°C) and stored until use. The capsules were administered at a dose of 10 (3-15) capsules for 2 or 3 subsequent days. The total dose per single TFM course was 22 g (30 capsules) corresponding to 0.41 (0.29-1.67 g/kg body mass), independent on age and weight of the subjects.
The patients from comparison group were treated with 5 mL of 0.9% physiological saline delivered during diagnostic gastroscopy, or frozen capsules with physiological saline.
Laboratory screening of gut microbiota
Semi-quantitative assessment of fecal microbiota profile was performed with real-time PCR technique using commercial Colonoflor-16test system (Alpha-Lab, Saint Petersburg, Russia). Total bacterial mass, as well most represented microbial species, including strictly anaerobic species, could be detected by this DNA-based technique (Table 2). A set of gene-specific primers is used in this test kit, exploiting the differences in 16S rDNA sequences (see Table 3).
The same fecal DNA samples were used for detailed 16S rDNA sequencing by means of NGS technique, as elsewhere described [11]. The serial microbiome sequencing procedure was carried out with Illumina™ HiSeq 2500 system.
Table 2. Reference values for different microbial species detected by multiplex real-time PCR kit (Colonoflor-16)
Table 3. Gene-specific primers for detection of distinct microbes in fecal material (Colonoflor test system)
Clinical evaluation
Clinical examination of the patients along the observation period until D+120 was performed by the well-validated scales: GvHD severity score [12]; evaluation of clinical response of GvHD patients to therapy [13]; Bristol scale of stool [14].
All the patients (or their parents) filled a special diary with notices on their actual daily condition and severity of distinct symptoms by scoring the adverse treatment effects, according to the Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE), version 5.0 of November 27 2017) [15], as follows: anorexia (1-5 points), nausea (1-3 points), lower intestinal bleeding (1-5 points). Pain syndrome (abdominal pains) was evaluated by the 10-point visual analogue scale for adults and children (VAS), according to WHO criteria [16, 17]. Number of defecations, daily volumes of diarrhea and vomiting were registered. The stool properties were evaluated according to the Bristol scale (1 to 7 points).
Aiming for a more objective evaluation of clinical response, the patients from main group were divided in two sub-groups, i.e., patients who showed full clinical response (CR), and those who responded only partially or lacked any positive response (PLR). These and other parameters were introduced into a common database.
The stool consistence was evaluated by the seven-point Bristol scale [14] (Lewis, Heaton, 1997). Volumes of water lost with stool and vomiting was also registered. A validated toxicity scale was used to evaluate bloody and mucous admixtures, loss of appetite, and other side effects (CTCAE Version 5.0 Published: November 27, 2017), using a 4-point scoring of its intensity (0, the symptom absent; 1, mild degree or periodic; 2, intermediate (often); 3, severe (permanent), requiring proper therapy). To evaluate abdominal pain, a 10-point VAS was applied [16, 17].
To specify rates of clinical response a, we classified the patients in 2 groups, i.e., the FMT outcomes were classified as the main group with complete response (CR), partial response (PR), or treatment failure (NR) in the patients. Full response was registered by 2 criteria, i.e., gut GvHD improvement (stool volume <10 mL/kg/day, absence of abdominal pains and bloody stool, no signs of gut paresis), and stool consistence of <4 points at Bristol scale should be registered. Partial response was documented in cases of complete response for intestinal GvHD, and stool consistence of >4 points by Bristol scale (stool volume >10 ml/kg/day). Absence of clinical response was documented if no complete recovery for intestinal GvHD, along with liquid stool (Bristol scale, 6 to 7 points, daily stool volume >10 mL/kg weight).
On the days before FMT/placebo administration, and by the days +3, +16, +30, +60, +120 after FMT, the mean sum values for preceding time period were calculated, beginning from the next day after last control point until the target point of the study. When analyzing clinical results, the last day of TFM treatment was assumed as day 0 for the observation period.
Statistical evaluation
All clinical and laboratory data obtained during the follow-up examinations were analyzed with R programming language v.3.6.2 in Rstudio v. 1.2.5033. Shannon index for 16S sequencing results was calculated as follows:
where n is a number of detected bacterial groups, pi, frequency of i-th group occurrence. Comparison of samples was performed with non-parametric statistical methods: Wilcoxon test for two-sample comparisons, and Kruskal-Wallis test for three-sample comparison. Visualization was performed by means of R packages ggplot2 [18] and ggpubr [19].
Results
In the whole group of patients, some grade of response (disregarding Bristol scale) was achieved in 23 patients (85%), at D+120, including 18 cases after FMT (95%), and 5 placebo-treated patients (63%) (р=0.0646). Whole response was achieved in 16 patients (84%) after FMT, versus in 5 cases (63%) from placebo group (p=0.3191). One patient deceased without response to FMT (5%) versus 3 patients (38%) in the placebo group.
When evaluating clinical response to GvHD therapy, with regard of stool consistence by Bristol scale, we observed whole clinical response 120 days after FMT in 9 cases (47% with Bristol score of ≤4 points), and 9 patients (47%) showed improvement stool consistence (>4 points). In the placebo group, a complete or partial response was revealed, respectively, in 1 (13%) and 4 (50%) of the patients by the day +120.
Multiplex PCR of fecal microbiota has shown a different time course in FMT- and placebo-treated patients, when compared to their initial (pre-FMT) levels. Total bacterial mass and copy numbers of distinct microbial species exhibited sufficient increase in the patients with complete clinical response (Fig. 1). In patients with full clinical response after FMT, or placebo, we have detected increased amounts of some major microbial groups by means of Colonoflor testing, i.e., Bacteroides fragilis group, Bifidobacterium spp., Faecalibacterium prausnitzii, along with decrease in Enterococcus spp. and Lactobacillus spp.
Figure 1. Relative contents of dominant fecal microbial species in the total set of samples from all the study terms (A), and on day +30 of observation (B) in the patients with complete response (red), partial/absent response (blue) including the placebo group. Abscissa, type of response after FMT. Ordinate, number of genocopies, log10 per standard sample (0.1 g)
E.g., such shifts in total group of samples were demonstrable for B.fragilis group (p=2.1×10-7); F.prausnitzii (p=9.8×10-8) during the observation terms (Fig. 1A). Similar increase in B.fragilis group (p=0.028), and F.prausnitzii (p=0.027) was detectable by the D+30 in FMT-treated or placebo patients (Fig. 1B).
Moreover, a stable and significant increase of B.fragilis group and F.prausnitzii was revealed since early terms in FMT-treated patients compared to placebo-treated patients (Table 4).
Meanwhile, the numbers of Enterococcus, Lactobacillus spp., and Bacteroides thetaiotaomicron, generally, were not changed over this time period (Table 4). In the control group (placebo) we have not found significant changes of fecal microbiota against initial levels over 120 days of monitoring.
Table 4. Significance of differences (p values) between initial (pre-TFM/placebo) and post-FMT levels of certain microorganisms in fecal microbiota of total patient group (19 FMT cases and 8 placebo-treated patients)
Note: The differences significant at P<0.05 are shown in bold-face type.
Mean values of Bifidobacterium spp., E.coli, B.fragilis group and F.prausnitzii were significantly different for the studied groups (р<0.003; р<0.012; р<0.016; р<0.12, respectively), as seen in Fig. 2. We have also found some differences of the microbiota dynamics for the subgroups with complete response, partial/no response: Bifidobacterium spp. (р<0.047), E.coli (р<0.00047), B.fragilis gr. (р<5.6×10-5), F.prausnitzii (р<0.0062).
In the placebo group, we did not detect any cases of C.difficile-associated infections. Meanwhile, three cases of C.difficile infection were detected in the FMT group. However, both A and B toxins of C.difficile became negative by day +16, +30 and +45 s after FMT.
Figure 2. Time-dependent changes of total bacterial mass and four selected bacterial classes are presented over 120 days of observation. Abscissa, subgroups of patients; Ordinate, number of genocopies, log10 per standard sample (0.1 g)
Note: the groups with different response include FMT- and placebo-treated patients.
Hence, relative contents of B.fragilis group in fecal microbiota was selected as a bacterial marker increased upon recolonization, due to sufficient difference between complete and no/partial response to the FMT (p=2.1×10-7), and pronounced dynamics of changes (p=5.6×10-5) over 120 days of observation. Therefore, was selected for further studies, i.e. search for correlations with NGS results on Bacteroidia class.
Correlations between the ratios of specific microbial DNA extracted from fecal samples determined by the 16S rRNA NGS technique were assessed at phylogenetic levels of Bacteroidetes (Phylum), Bacteroidia (Class), and Bacteroidales (Order). Among all microbial specificities detectable by quantitative PCR (Colonoflor test set), only Bacteroides fragilis group showed strong correlation with the ratios of Bacteroidetes phylum and Bacteroidia class revealed NGS approach. When applying NGS technique for detection of gut bacteria, we revealed high correlation only between the general types of bacteroides, i.e. phylum (Bacteroidetes); class (Bacteroidia); order (Bacteroidales); family (Bacteroidaceae), genus (Bacteroides) (Table 5).
Table 5. Correlations between the main types of Bacteroidetes and B.fragilis group determined by NGS approach
B.fragilis contents in fecal microbiota from healthy donors proved to be significantly higher than in the patients with GvHD before FMT (Table 6), thus potentially requiring enhancement of these microorganisms in the patients after HSCT with immune complications. After FMT, the median levels of B.fragilis group are sufficiently increasing in parallel to complete clinical response, being, however, at lower levels in cases with partial or zero response.
Table 6. B.fragilis contents in the fecal microbiota samples (log10 of genocopy numbers) in healthy donors and patients with differential response to FMT
Hence, the evaluation of B.fragilis group using real-time PCR, generally correlates with data on broader Bacteroides class obtained by 16SrRNA sequencing performed by much more complex and costly NGS technique. Meanwhile, multiplex PCR allows to get semi-quantitative results which could be used for routine monitoring of gut dysbiosis and its recovery.
In this series, D+30 proved to be the most informative time point for discerning differences between FMT and placebo-treated patients. I.e., on D+30 (a control point of study), we have found an increase over the D0 ratios in Bacteroidetes phylum; Bacteroidia (Class); Bacteroidales (Order) when studied by NGS approach. A strong correlation was found at all the time points with copy numbers of B.fragilis (PCR technique), as shown in Fig. 3.
Figure 3. Parallel changes of B.fragilis copy numbers (multiplex PCR) and Shannon index of genomic bacterial diversity determined by 16S rRNA sequencing for the groups with complete response (CR) versus partial/lacking response after FMT or placebo on D+30
The numbers of fecal B.fragilis genocopies in all the patients (FMT and placebo) with complete response were increased on D+30, and differed from the groups with partial/zero response after FMT procedure, or after placebo treatment (Fig. 3).
Figure 4. Correlations between fecal Bacteroides fragilis contents (abscissa), and Shannon microbial diversity index (ordinate) in the patients following FMT and/or placebo with complete or partial/absent clinical response at different observation terms. Complete clinical response to FMT: red points; partial or absent effect: blue points
We have revealed a statistically significant correlation between the Shannon index (16 S rRNA sequencing) and B.fragilis levels (multiplex) PCR in the patients after FMT and/or placebo, either with complete response (CR), being significant at p=0.028, or partial/absent response (PR/NR), at p=8×10-4 (Fig. 4).
Hence, on the basis of B.fragilis contents in fecal microbiota, its diversity (by Shannon index), and extent of clinical response for differently treated groups, we have obtained sufficient correlations between the subgroups with complete response, suboptimal response to FMT treatment, and placebo-treated patients.
Discussion
In this study we searched for microbiological correlates of clinical effect produced by FMT. We were able to compare the results of multiplex PCR technique and NGS gene analysis that were performed in parallel in the same fecal samples. Both molecular biology approaches proved to be effective when detecting shifts in gross classes of microbiota, e.g., Bacteroides, Clostridia and Enterobacter.
Using NGS approach, the proportions of some major microbiome classes are revealed, as follows: Bacteroidia, Clostridia, Gammaproteobacteria, Bacilli, Actinobacteria (Bifidobacterium spp). The main classes discerned by the NGS approach are represented by distinct microbial species detected by Colonoflor multiplex PCR (Table 7).
Table 7. Phylogenetic assignment of the bacteria revealed by 16S rRNA-based Colonoflor PCR system, and NGS approach (Illumina, MySeq)
As determined by next-generation sequencing and subsequent bioinformatics mining of resulting data bases for gut bacteria, we revealed high correlation only between gross types of bacteroides, i.e. phylum (Bacteroidetes); class (Bacteroidia); order (Bacteroidales); family (Bacteroidaceae), genus (Bacteroides) (Table 5). However, this correlation becomes much lower, when B.fragilis group is concerned, thus suggesting lesser precision of NGS diagnostics at the species level. Higher accuracy of the multiplex PCR for the B.fragilis group quantification could be explained by better specificity of appropriate primers, and due to presence of a reference gene marker for the total bacterial mass, thus allowing semi-quantitative determination.
To evaluate real biodiversity of intestinal microbiome, most recent works are performed by sequencing of 16S rRNA fragments from multiple bacterial species, with subsequent detection of species-specific genes. The results of NGS assays provide a big number of 16S rRNA nucleotide sequences which correspond to relative representation of distinct bacterial classes in the given sample. The best reliable data derived from NGS analysis concern biological diversity for big taxonomic classes of microbiota, down to the family level. More exact species-specific diagnostics is less robust, due to only marginal interspecies differences in nucleotide sequences detectable by the current NGS technique.
Therefore, some more simple and cost-effective microbial markers are required for evaluation and screening of human microbiota after massive antibiotic therapy and in the course of gut recolonization.
16S RNA gene polymorphism is a good method for control of ratios between the major classes of fecal microbiota. Moreover, drastic shifts of gut microbiota are revealed in several gut infections (mostly, C.difficile) and local immune affection, e.g., GvHD [20]. A conventional multiplex PCR approach allows performing a more specific, cheap and fast detection of major fecal microorganisms which is especially informative when using quantitative PCR (qPCR) after FMT, as shown in our study.
As seen from the presented data, one may recommend detection of the main bacterial groups (Bifidobacterium spp., Escherichia coli, B.fragilis group, Faecalibacterium prausnitzii) as potential markers for assessment of fecal microbiota shifts after FMT. It should be, however, noted that this correlation does not extend to other microbial groups (e.g., Lactobacillus spp., Citrobacter with absence of good correlation with 16S rRNA sequencing for Lactobacillus spp. and Citrobacter, probably, due to suboptimal sensitivity of the given test system for Lactobacillus spp. (<105CFU/sample).
According to the qPCR data, the majority of microbial species sufficiently differed from the initial values on D+16 to D+30 after FMT, as seen for Bifidobacterium spp., Escherichia coli, B.fragilis group, F.prausnitzii. Therefore, one should presume engraftment of main fecal microorganisms after FMT over this period. Bacteroides compose 99% of normal microbiota, with quite important functional potential, being among promising probiotics [21].
Meanwhile, qPCR determination of B.fragilis group has shown a strong correlation with clinical response in the patients after FMT, thus allowing to consider this bacterial marker a potential laboratory correlate of efficient clinical response after FMT. An increase in Bacteroides quantities detected with qPCR and higher relative amounts found by means of NGS-based typing of 16S rDNA may, therefore, reflect engraftment of the major gut bacterial population. Decreased B.fragilis contents in the patients with partial or poor clinical response after D+30 post-FMT may be a non-engraftment marker, whereas increasing B.fragilis levels with a maximum about D+30 are revealed in complete clinical response. Meanwhile, other findings presume pronounced changes in Clostridiales (e.g., Blautia) as possible index of microbiota maintenance, thus deserving their further pathogenetic significance [4]. E.g., the qPCR system for Clostridium spp. should be also applied for additional testing of the gut microbiota restoration, along with testing for pathogenic C.difficile toxins, as a negative prognostic marker.
Monitoring of gut bacterial markers to assess gut microbiota recovery may effectively improve clinical assessment in gastroenterology. The currently used clinical criteria are mostly indirect, including stool volume and quality, intestinal motility, fecal blood and calprotectin tests, thus requiring additional microbial markers aimed for quantitative evaluation of the disease state. Certain bacterial families may serve as semi-quantitative markers of the disease-associated shifts and recovery of the microbiota. We have shown that quantitative PCR of distinct gut microorganisms is quite available and cheaper option for routine follow-up of intestinal dysbiosis [22].
However, the 16S rDNA sequencing by means of NGS approach remain indispensable for research in the field, looking for novel markers of human microbiota in health and disease.
Conclusions
1. Quantitative real-time PCR of the major bacteria groups of gut microbiota, e.g., Bifidobacterium spp., Escherichia coli, B.fragilis group, F.prausnitzii could be used as microbiological marker for evaluation of changing fecal microbiota following fecal transplantation as a routine molecular biology technique.
2. The genocopy counts of B.fragilis group correlate with clinical response in the patients with severe GvHD after allo-HSCT.
3. The time course of B.fragilis group contents could be considered an index of fecal microbiota engraftment following FMT.
4. B.fragilis contents in fecal microbiota measured by multiplex PCR show high positive correlation with Shannon index of bacterial diversity, determined by 16S rRNA gene sequencing.
Conflict of interest
The authors state that they have no conflict of interests.
Acknowledgements
The study was in part supported by a research contract with Russian Ministry of Healthcare effective as of January 2018 to December 2020.
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Introduction
Fecal microbiome contains hundreds types of bacteria, with only minority of, mostly, aerobic gut bacteria having been detectable in bacteriological cultures. However, conventional microbiological cultures are able to detect only a limited number of aerobic and, to lesser degree, anaerobic bacteria in fecal samples. In this respect, a gene-specific DNA diagnostics, e.g., multiplex PCR aimed for detection of potentially pathogenic microbes, is a more sensitive technique for detection and quantification of distinct microbial species and families at different microbiotes of human body [1].
Moreover, major bacterial classes and families became available for studies and comparisons, due to development of the next-generation sequencing (NGS). Bacteroides and Clostridia comprise the majority of normal intestinal flora as suggested by several NGS studies performed in different parts of the world [2, 3]. These microbial types are susceptible to massive antibiotic treatment which is usually applied in immunocompromised patients after bone marrow transplantation [4].
Still there are no generally approved reference biodiversity values, or marker microorganisms for assessment of gut microbiome in immunocompromised patients following severe cytostatic and antimicrobial therapy. Severe intestinal affection after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a useful clinical model for evaluation of gut microbiome shifts and its correction after fecal microbiota transplantation (FMT) [5]. An FMT protocol for clinical trials in severe graft-versus-host disease (GvHD) was applied quite recently [6].
Despite numerous clinical studies on FMT, there are only few bacterial markers for monitoring its efficiency. Appropriate guidelines are limited to bacteriological screening of the third-party donors of fecal transplants [7]. To our knowledge, there are no clear recommendations on screening of fecal microbiota in the patients. Except of time- and labor-consuming NGS analysis, some multiplex PCR-based approaches may be used that detect distinct gut pathogens [8, 9]. A quite recent approach is based on determination of relative proportions for the dominant phyla in human gut microbiome [10].
To evaluate real biodiversity of intestinal microbiome, most recent works are performed by sequencing of 16S rRNA fragments from multiple bacterial species, with subsequent detection of species-specific genes. The results of NGS assays provide a big number of 16S rRNA nucleotide sequences which correspond to relative representation of distinct bacterial classes in the given sample. The best reliable data derived from NGS analysis concern biological diversity for big taxonomic classes of microbiota, down to the family level. More exact species-specific diagnostics is less robust, due to only marginal interspecies differences in nucleotide sequences detectable by the current NGS technique.
Therefore, some more simple and cost-effective microbial markers are required for evaluation and screening of human microbiota after massive antibiotic therapy and in the course of gut recolonization. Hence, the aim of our study was a search for microbial species detectable by molecular biology techniques that could correlate with clinical results of FMT performed in severe resistant GvHD after allo-HSCT.
Patients and methods
The prospective single-center study included 27 patients at the age of 1 to 52 years old (median, 25 years) after allo-HSCT at the Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation over a period of 2017 to 2019 (Table 1). The main group included 19 post-HSCT patients who developed acute intestinal GvHD. All the patients were in remission state for their primary disease. These patients received FMT due to severe GvHD resistant to standard treatment. The inclusion criterion was steroid-refractory acute or chronic GvHD (overlap-syndrome) accompanied by intestinal affection. Intestinal GvHD has been confirmed by pathological examination of colonic mucosa biopsies. FMT was performed at a median of 110 (37-909) days post-HSCT. The comparison group with similar GvHD symptoms included eight patients who received placebo preparations instead of FMT applied on a median of 56 (34-120) days after HSCT.
Table 1. Clinical characteristics of the FMT patients
Antimicrobial prophylaxis was canceled 3 days before and during TFM treatment. Systemic antibacterial drugs were administered by common clinical indications (local infection, septicemia) to 8 patients (37%) before FMT, and in 18 cases (95%), after the procedure. Seven placebo-treated patients out of 8 (88%) were also exposed to systemic antimicrobial therapy. The patients with proven intestinal affection with HHV6 or EBV herpes viruses received gancyclovir: 11 (58%) in FMT-treated, 8 (100%) in the placebo group.
All the patients received immunosuppressive therapy as the first-line GvHD treatment, by means glucocorticosteroids (methylprednisolone, 1 mg/kg/d). The second-line therapy was performed with Ruxolitinib at the dose of 10-15mg/d (for children 0.25mg/kg/d). The patients underwent clinical and laboratory screening at the following terms: before FMT/placebo treatment D -1-3, D+3, D+16, D+30, D+60, and D+120 after FMT. The next day after last FMT was considered D+1. Primary endpoints were determined on the D+30 following FMT or placebo administration.
Routine laboratory studies at the ICU included daily blood cell and differential leukocyte counts, routine serum biochemistry, serum markers of inflammation (procalcitonine, С-reactive protein). In cases of acute intestinal syndrome, the aerobic microbial cultures of stool samples were routinely seeded, and C.difficile toxins A and B were checked by a simple immune chromatography test (VEDALAB, France).
In four cases (21%), the fecal transplant donation was performed from related donors (mother, 1; father, 2; brother, 1). FMT from unrelated donors was carried out in 15 patients.
Fecal transplants were administered by the following methods: via gastroduodenoscope, in 3 patients (16%); via nasointestinal catheter, in 7cases (3 TFM+ and 4 placebo); 13 patients (68%) ingested gelatin capsules with frozen microbiota. Placebo capsules were used in 4 patients (50%).
The single-center prospective study "Treatment of children and adult patients with inflammatory and infectious gut lesions after allogeneic transplantation of hematopoietic stem cells using transplantation of normal human microbiota" was approved by the Local Review Board at the First I. Pavlov Saint-Petersburg State Medical University №192 от 30.01.2017. The trial was performed in accordance with Good Clinical Practice and Declaration of Helsinki, i.e., full awareness of the study purpose, procedures and possible adverse effects from treatment, as stated by appropriate written informed consent signed by each patient or his (her) competent relative.
Fecal microbiota encapsulation procedure
Preparation of fecal transplants and their storage at -80°C was performed at the specialized microbiological laboratory. In brief, the donor material was supplemented with 10% glycerol and 50% sterile dextrose syrup (v/v), then homogenized with a disposable blender. The material, placed on ice, was then packed up in solid Coni-Snap® Size 0 gelatin capsules using the ProFiller 1100 device. The bar-coded capsules were placed into individual sterile containers. The fecal transplants (FT) were transferred to a freezing chamber (-80°C) and stored until use. The capsules were administered at a dose of 10 (3-15) capsules for 2 or 3 subsequent days. The total dose per single TFM course was 22 g (30 capsules) corresponding to 0.41 (0.29-1.67 g/kg body mass), independent on age and weight of the subjects.
The patients from comparison group were treated with 5 mL of 0.9% physiological saline delivered during diagnostic gastroscopy, or frozen capsules with physiological saline.
Laboratory screening of gut microbiota
Semi-quantitative assessment of fecal microbiota profile was performed with real-time PCR technique using commercial Colonoflor-16test system (Alpha-Lab, Saint Petersburg, Russia). Total bacterial mass, as well most represented microbial species, including strictly anaerobic species, could be detected by this DNA-based technique (Table 2). A set of gene-specific primers is used in this test kit, exploiting the differences in 16S rDNA sequences (see Table 3).
The same fecal DNA samples were used for detailed 16S rDNA sequencing by means of NGS technique, as elsewhere described [11]. The serial microbiome sequencing procedure was carried out with Illumina™ HiSeq 2500 system.
Table 2. Reference values for different microbial species detected by multiplex real-time PCR kit (Colonoflor-16)
Table 3. Gene-specific primers for detection of distinct microbes in fecal material (Colonoflor test system)
Clinical evaluation
Clinical examination of the patients along the observation period until D+120 was performed by the well-validated scales: GvHD severity score [12]; evaluation of clinical response of GvHD patients to therapy [13]; Bristol scale of stool [14].
All the patients (or their parents) filled a special diary with notices on their actual daily condition and severity of distinct symptoms by scoring the adverse treatment effects, according to the Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE), version 5.0 of November 27 2017) [15], as follows: anorexia (1-5 points), nausea (1-3 points), lower intestinal bleeding (1-5 points). Pain syndrome (abdominal pains) was evaluated by the 10-point visual analogue scale for adults and children (VAS), according to WHO criteria [16, 17]. Number of defecations, daily volumes of diarrhea and vomiting were registered. The stool properties were evaluated according to the Bristol scale (1 to 7 points).
Aiming for a more objective evaluation of clinical response, the patients from main group were divided in two sub-groups, i.e., patients who showed full clinical response (CR), and those who responded only partially or lacked any positive response (PLR). These and other parameters were introduced into a common database.
The stool consistence was evaluated by the seven-point Bristol scale [14] (Lewis, Heaton, 1997). Volumes of water lost with stool and vomiting was also registered. A validated toxicity scale was used to evaluate bloody and mucous admixtures, loss of appetite, and other side effects (CTCAE Version 5.0 Published: November 27, 2017), using a 4-point scoring of its intensity (0, the symptom absent; 1, mild degree or periodic; 2, intermediate (often); 3, severe (permanent), requiring proper therapy). To evaluate abdominal pain, a 10-point VAS was applied [16, 17].
To specify rates of clinical response a, we classified the patients in 2 groups, i.e., the FMT outcomes were classified as the main group with complete response (CR), partial response (PR), or treatment failure (NR) in the patients. Full response was registered by 2 criteria, i.e., gut GvHD improvement (stool volume <10 mL/kg/day, absence of abdominal pains and bloody stool, no signs of gut paresis), and stool consistence of <4 points at Bristol scale should be registered. Partial response was documented in cases of complete response for intestinal GvHD, and stool consistence of >4 points by Bristol scale (stool volume >10 ml/kg/day). Absence of clinical response was documented if no complete recovery for intestinal GvHD, along with liquid stool (Bristol scale, 6 to 7 points, daily stool volume >10 mL/kg weight).
On the days before FMT/placebo administration, and by the days +3, +16, +30, +60, +120 after FMT, the mean sum values for preceding time period were calculated, beginning from the next day after last control point until the target point of the study. When analyzing clinical results, the last day of TFM treatment was assumed as day 0 for the observation period.
Statistical evaluation
All clinical and laboratory data obtained during the follow-up examinations were analyzed with R programming language v.3.6.2 in Rstudio v. 1.2.5033. Shannon index for 16S sequencing results was calculated as follows:
where n is a number of detected bacterial groups, pi, frequency of i-th group occurrence. Comparison of samples was performed with non-parametric statistical methods: Wilcoxon test for two-sample comparisons, and Kruskal-Wallis test for three-sample comparison. Visualization was performed by means of R packages ggplot2 [18] and ggpubr [19].
Results
In the whole group of patients, some grade of response (disregarding Bristol scale) was achieved in 23 patients (85%), at D+120, including 18 cases after FMT (95%), and 5 placebo-treated patients (63%) (р=0.0646). Whole response was achieved in 16 patients (84%) after FMT, versus in 5 cases (63%) from placebo group (p=0.3191). One patient deceased without response to FMT (5%) versus 3 patients (38%) in the placebo group.
When evaluating clinical response to GvHD therapy, with regard of stool consistence by Bristol scale, we observed whole clinical response 120 days after FMT in 9 cases (47% with Bristol score of ≤4 points), and 9 patients (47%) showed improvement stool consistence (>4 points). In the placebo group, a complete or partial response was revealed, respectively, in 1 (13%) and 4 (50%) of the patients by the day +120.
Multiplex PCR of fecal microbiota has shown a different time course in FMT- and placebo-treated patients, when compared to their initial (pre-FMT) levels. Total bacterial mass and copy numbers of distinct microbial species exhibited sufficient increase in the patients with complete clinical response (Fig. 1). In patients with full clinical response after FMT, or placebo, we have detected increased amounts of some major microbial groups by means of Colonoflor testing, i.e., Bacteroides fragilis group, Bifidobacterium spp., Faecalibacterium prausnitzii, along with decrease in Enterococcus spp. and Lactobacillus spp.
Figure 1. Relative contents of dominant fecal microbial species in the total set of samples from all the study terms (A), and on day +30 of observation (B) in the patients with complete response (red), partial/absent response (blue) including the placebo group. Abscissa, type of response after FMT. Ordinate, number of genocopies, log10 per standard sample (0.1 g)
E.g., such shifts in total group of samples were demonstrable for B.fragilis group (p=2.1×10-7); F.prausnitzii (p=9.8×10-8) during the observation terms (Fig. 1A). Similar increase in B.fragilis group (p=0.028), and F.prausnitzii (p=0.027) was detectable by the D+30 in FMT-treated or placebo patients (Fig. 1B).
Moreover, a stable and significant increase of B.fragilis group and F.prausnitzii was revealed since early terms in FMT-treated patients compared to placebo-treated patients (Table 4).
Meanwhile, the numbers of Enterococcus, Lactobacillus spp., and Bacteroides thetaiotaomicron, generally, were not changed over this time period (Table 4). In the control group (placebo) we have not found significant changes of fecal microbiota against initial levels over 120 days of monitoring.
Table 4. Significance of differences (p values) between initial (pre-TFM/placebo) and post-FMT levels of certain microorganisms in fecal microbiota of total patient group (19 FMT cases and 8 placebo-treated patients)
Note: The differences significant at P<0.05 are shown in bold-face type.
Mean values of Bifidobacterium spp., E.coli, B.fragilis group and F.prausnitzii were significantly different for the studied groups (р<0.003; р<0.012; р<0.016; р<0.12, respectively), as seen in Fig. 2. We have also found some differences of the microbiota dynamics for the subgroups with complete response, partial/no response: Bifidobacterium spp. (р<0.047), E.coli (р<0.00047), B.fragilis gr. (р<5.6×10-5), F.prausnitzii (р<0.0062).
In the placebo group, we did not detect any cases of C.difficile-associated infections. Meanwhile, three cases of C.difficile infection were detected in the FMT group. However, both A and B toxins of C.difficile became negative by day +16, +30 and +45 s after FMT.
Figure 2. Time-dependent changes of total bacterial mass and four selected bacterial classes are presented over 120 days of observation. Abscissa, subgroups of patients; Ordinate, number of genocopies, log10 per standard sample (0.1 g)
Note: the groups with different response include FMT- and placebo-treated patients.
Hence, relative contents of B.fragilis group in fecal microbiota was selected as a bacterial marker increased upon recolonization, due to sufficient difference between complete and no/partial response to the FMT (p=2.1×10-7), and pronounced dynamics of changes (p=5.6×10-5) over 120 days of observation. Therefore, was selected for further studies, i.e. search for correlations with NGS results on Bacteroidia class.
Correlations between the ratios of specific microbial DNA extracted from fecal samples determined by the 16S rRNA NGS technique were assessed at phylogenetic levels of Bacteroidetes (Phylum), Bacteroidia (Class), and Bacteroidales (Order). Among all microbial specificities detectable by quantitative PCR (Colonoflor test set), only Bacteroides fragilis group showed strong correlation with the ratios of Bacteroidetes phylum and Bacteroidia class revealed NGS approach. When applying NGS technique for detection of gut bacteria, we revealed high correlation only between the general types of bacteroides, i.e. phylum (Bacteroidetes); class (Bacteroidia); order (Bacteroidales); family (Bacteroidaceae), genus (Bacteroides) (Table 5).
Table 5. Correlations between the main types of Bacteroidetes and B.fragilis group determined by NGS approach
B.fragilis contents in fecal microbiota from healthy donors proved to be significantly higher than in the patients with GvHD before FMT (Table 6), thus potentially requiring enhancement of these microorganisms in the patients after HSCT with immune complications. After FMT, the median levels of B.fragilis group are sufficiently increasing in parallel to complete clinical response, being, however, at lower levels in cases with partial or zero response.
Table 6. B.fragilis contents in the fecal microbiota samples (log10 of genocopy numbers) in healthy donors and patients with differential response to FMT
Hence, the evaluation of B.fragilis group using real-time PCR, generally correlates with data on broader Bacteroides class obtained by 16SrRNA sequencing performed by much more complex and costly NGS technique. Meanwhile, multiplex PCR allows to get semi-quantitative results which could be used for routine monitoring of gut dysbiosis and its recovery.
In this series, D+30 proved to be the most informative time point for discerning differences between FMT and placebo-treated patients. I.e., on D+30 (a control point of study), we have found an increase over the D0 ratios in Bacteroidetes phylum; Bacteroidia (Class); Bacteroidales (Order) when studied by NGS approach. A strong correlation was found at all the time points with copy numbers of B.fragilis (PCR technique), as shown in Fig. 3.
Figure 3. Parallel changes of B.fragilis copy numbers (multiplex PCR) and Shannon index of genomic bacterial diversity determined by 16S rRNA sequencing for the groups with complete response (CR) versus partial/lacking response after FMT or placebo on D+30
The numbers of fecal B.fragilis genocopies in all the patients (FMT and placebo) with complete response were increased on D+30, and differed from the groups with partial/zero response after FMT procedure, or after placebo treatment (Fig. 3).
Figure 4. Correlations between fecal Bacteroides fragilis contents (abscissa), and Shannon microbial diversity index (ordinate) in the patients following FMT and/or placebo with complete or partial/absent clinical response at different observation terms. Complete clinical response to FMT: red points; partial or absent effect: blue points
We have revealed a statistically significant correlation between the Shannon index (16 S rRNA sequencing) and B.fragilis levels (multiplex) PCR in the patients after FMT and/or placebo, either with complete response (CR), being significant at p=0.028, or partial/absent response (PR/NR), at p=8×10-4 (Fig. 4).
Hence, on the basis of B.fragilis contents in fecal microbiota, its diversity (by Shannon index), and extent of clinical response for differently treated groups, we have obtained sufficient correlations between the subgroups with complete response, suboptimal response to FMT treatment, and placebo-treated patients.
Discussion
In this study we searched for microbiological correlates of clinical effect produced by FMT. We were able to compare the results of multiplex PCR technique and NGS gene analysis that were performed in parallel in the same fecal samples. Both molecular biology approaches proved to be effective when detecting shifts in gross classes of microbiota, e.g., Bacteroides, Clostridia and Enterobacter.
Using NGS approach, the proportions of some major microbiome classes are revealed, as follows: Bacteroidia, Clostridia, Gammaproteobacteria, Bacilli, Actinobacteria (Bifidobacterium spp). The main classes discerned by the NGS approach are represented by distinct microbial species detected by Colonoflor multiplex PCR (Table 7).
Table 7. Phylogenetic assignment of the bacteria revealed by 16S rRNA-based Colonoflor PCR system, and NGS approach (Illumina, MySeq)
As determined by next-generation sequencing and subsequent bioinformatics mining of resulting data bases for gut bacteria, we revealed high correlation only between gross types of bacteroides, i.e. phylum (Bacteroidetes); class (Bacteroidia); order (Bacteroidales); family (Bacteroidaceae), genus (Bacteroides) (Table 5). However, this correlation becomes much lower, when B.fragilis group is concerned, thus suggesting lesser precision of NGS diagnostics at the species level. Higher accuracy of the multiplex PCR for the B.fragilis group quantification could be explained by better specificity of appropriate primers, and due to presence of a reference gene marker for the total bacterial mass, thus allowing semi-quantitative determination.
To evaluate real biodiversity of intestinal microbiome, most recent works are performed by sequencing of 16S rRNA fragments from multiple bacterial species, with subsequent detection of species-specific genes. The results of NGS assays provide a big number of 16S rRNA nucleotide sequences which correspond to relative representation of distinct bacterial classes in the given sample. The best reliable data derived from NGS analysis concern biological diversity for big taxonomic classes of microbiota, down to the family level. More exact species-specific diagnostics is less robust, due to only marginal interspecies differences in nucleotide sequences detectable by the current NGS technique.
Therefore, some more simple and cost-effective microbial markers are required for evaluation and screening of human microbiota after massive antibiotic therapy and in the course of gut recolonization.
16S RNA gene polymorphism is a good method for control of ratios between the major classes of fecal microbiota. Moreover, drastic shifts of gut microbiota are revealed in several gut infections (mostly, C.difficile) and local immune affection, e.g., GvHD [20]. A conventional multiplex PCR approach allows performing a more specific, cheap and fast detection of major fecal microorganisms which is especially informative when using quantitative PCR (qPCR) after FMT, as shown in our study.
As seen from the presented data, one may recommend detection of the main bacterial groups (Bifidobacterium spp., Escherichia coli, B.fragilis group, Faecalibacterium prausnitzii) as potential markers for assessment of fecal microbiota shifts after FMT. It should be, however, noted that this correlation does not extend to other microbial groups (e.g., Lactobacillus spp., Citrobacter with absence of good correlation with 16S rRNA sequencing for Lactobacillus spp. and Citrobacter, probably, due to suboptimal sensitivity of the given test system for Lactobacillus spp. (<105CFU/sample).
According to the qPCR data, the majority of microbial species sufficiently differed from the initial values on D+16 to D+30 after FMT, as seen for Bifidobacterium spp., Escherichia coli, B.fragilis group, F.prausnitzii. Therefore, one should presume engraftment of main fecal microorganisms after FMT over this period. Bacteroides compose 99% of normal microbiota, with quite important functional potential, being among promising probiotics [21].
Meanwhile, qPCR determination of B.fragilis group has shown a strong correlation with clinical response in the patients after FMT, thus allowing to consider this bacterial marker a potential laboratory correlate of efficient clinical response after FMT. An increase in Bacteroides quantities detected with qPCR and higher relative amounts found by means of NGS-based typing of 16S rDNA may, therefore, reflect engraftment of the major gut bacterial population. Decreased B.fragilis contents in the patients with partial or poor clinical response after D+30 post-FMT may be a non-engraftment marker, whereas increasing B.fragilis levels with a maximum about D+30 are revealed in complete clinical response. Meanwhile, other findings presume pronounced changes in Clostridiales (e.g., Blautia) as possible index of microbiota maintenance, thus deserving their further pathogenetic significance [4]. E.g., the qPCR system for Clostridium spp. should be also applied for additional testing of the gut microbiota restoration, along with testing for pathogenic C.difficile toxins, as a negative prognostic marker.
Monitoring of gut bacterial markers to assess gut microbiota recovery may effectively improve clinical assessment in gastroenterology. The currently used clinical criteria are mostly indirect, including stool volume and quality, intestinal motility, fecal blood and calprotectin tests, thus requiring additional microbial markers aimed for quantitative evaluation of the disease state. Certain bacterial families may serve as semi-quantitative markers of the disease-associated shifts and recovery of the microbiota. We have shown that quantitative PCR of distinct gut microorganisms is quite available and cheaper option for routine follow-up of intestinal dysbiosis [22].
However, the 16S rDNA sequencing by means of NGS approach remain indispensable for research in the field, looking for novel markers of human microbiota in health and disease.
Conclusions
1. Quantitative real-time PCR of the major bacteria groups of gut microbiota, e.g., Bifidobacterium spp., Escherichia coli, B.fragilis group, F.prausnitzii could be used as microbiological marker for evaluation of changing fecal microbiota following fecal transplantation as a routine molecular biology technique.
2. The genocopy counts of B.fragilis group correlate with clinical response in the patients with severe GvHD after allo-HSCT.
3. The time course of B.fragilis group contents could be considered an index of fecal microbiota engraftment following FMT.
4. B.fragilis contents in fecal microbiota measured by multiplex PCR show high positive correlation with Shannon index of bacterial diversity, determined by 16S rRNA gene sequencing.
Conflict of interest
The authors state that they have no conflict of interests.
Acknowledgements
The study was in part supported by a research contract with Russian Ministry of Healthcare effective as of January 2018 to December 2020.
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Целью работы было сравнение возможностей и результатов полимеразной цепной реакции в режиме реального времени (ПЦР) и методики 16S-секвенирования для контроля динамики состава фекальной микробиоты у пациентов после ТФМ.</p> <h3>Пациенты и методы</h3> <p style="text-align: justify;">В проспективное, одноцентровое исследование включено 27 пациентов с острой и хронической (overlap-синдром) реакцией «трансплантат против хозяина» (РТПХ) желудочно-кишечного тракта после аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). У 19 пациентов проводили ТФМ, преимущественно, с ингестией капсул. В контрольную группу вошли 8 пациентов, получавшие плацебо. Количественные изменения бактериального состава микроорганизмов фекальной микробиоты оценивали методом ПЦР и 16S-секвенирования в сроки от 3 до 120 сут. после ТФМ. Клинический ответ определяли по 4 шкалам оценки кишечного синдрома и РТПХ.</p> <h3>Результаты</h3> <p style="text-align: justify;">При оценке консистенции стула по Бристольской шкале, как показателя эффективности терапии РТПХ, полный клинический ответ к Д+120 после ФМТ отмечен в 9 случаях (47% с оценкой Бристоля ≤4 баллов), у 9 пациентов (47%) – улучшение консистенции стула (>4 балла). В группе плацебо полный или частичный ответ был выявлен, соответственно, у 1 (13%) и 4 (50%) пациентов. Мультиплексная ПЦР фекальной микробиоты в режиме реального времени показала различную динамику у пациентов после ТФМ или плацебо, по сравнению с исходными уровнями до ТФМ. Общая бактериальная масса и число генокопий отдельных микробных видов значительно повышались после ТФМ. Такие изменения были особенно показательными через 30 сут. для общей микробной массы (p=0,002); <i>Escherichia coli</i> (p=0,001); <i>Bacteroides fragilis group</i> (p=0,05); <i>Faecalibacterium prausnitzii</i> (p=0,005). 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["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "26494" ["VALUE"]=> array(2) { ["TEXT"]=> string(1017) "<p>Олег В. Голощапов<sup>1</sup>, Евгений А. Бакин<sup>1</sup>, Максим А. Кучер<sup>1</sup>, Оксана В. Станевич<sup>1</sup>, Мария А. Суворова<sup>2</sup>, Владимир В. Гостев<sup>3</sup>, Олег С. Глотов<sup>4</sup>, Юрий А. Эйсмонт<sup>4</sup>, Дмитрий Е. Полев<sup>5</sup>, Анастасия Ю. Лобенская<sup>5</sup>, Руслана В. Клементьева<sup>1</sup>, Мария О. Голощапова<sup>1</sup>, Людмила С. Зубаровская<sup>1</sup>, Сергей В. Сидоренко<sup>3</sup>, Александр Н. Суворов<sup>4</sup>, Иван С. Моисеев<sup>1</sup>, Алексей Б. Чухловин<sup>1</sup></p> " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(801) "
Олег В. Голощапов1, Евгений А. Бакин1, Максим А. Кучер1, Оксана В. Станевич1, Мария А. Суворова2, Владимир В. Гостев3, Олег С. Глотов4, Юрий А. Эйсмонт4, Дмитрий Е. Полев5, Анастасия Ю. Лобенская5, Руслана В. Клементьева1, Мария О. Голощапова1, Людмила С. Зубаровская1, Сергей В. Сидоренко3, Александр Н. Суворов4, Иван С. Моисеев1, Алексей Б. Чухловин1
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "26495" ["VALUE"]=> array(2) { ["TEXT"]=> string(1097) "<p><sup>1</sup> НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия<br> <sup>2</sup> Научная лаборатория Эксплана, Санкт-Петербург, Россия <br> <sup>3</sup> Детский научно-клинический центр инфекционных болезней, Санкт-Петербург, Россия <br> <sup>4</sup> Городская больница №40, Санкт-Петербург, Россия<br> <sup>5</sup> ООО «Сербалаб», Санкт-Петербург, Россия<br> <sup>6</sup> Институт экспериментальной медицины, Санкт-Петербург, Россия</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(983) "1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Научная лаборатория Эксплана, Санкт-Петербург, Россия
3 Детский научно-клинический центр инфекционных болезней, Санкт-Петербург, Россия
4 Городская больница №40, Санкт-Петербург, Россия
5 ООО «Сербалаб», Санкт-Петербург, Россия
6 Институт экспериментальной медицины, Санкт-Петербург, Россия