ISSN 1866-8836
Клеточная терапия и трансплантация

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N. Solid tumors

High-dose chemotherapy and autologous stem cell transplantation in children with Ewing’s sarcoma/PNET

Ilya V. Kazantsev1, Tatjana V. Youhta2, Elena V. Morozova1, Svetlana A. Safonova2, Yury A. Punanov2, Liudmila S. Zubarovskaya1, Boris V. Afanasyev1

The outcome of treatment in patients with high-risk (HR) retinoblastoma

Igor S. Dolgopolov1, Tatiana L. Ushakova1, Olga N. Gorovtzova1, Alevtina I. Pavlovskaya2, Roman I. Pimenov1, Vasilii K. Boyarshinov1, Natalia S. Subbotina1, Igor V. Glekov1, Vladimir G. Poliakov1, George L. Mentkevich1

Restoration of ovarian function after cryopreserved ovarian tissue transplantation in women exposed to complex treatment for gynecological cancer: feasibility of this option in pediatric cancer patients

Alla S. Lisyanskya1,2, Natalia I. Tapilskaya1,3, Margarita B. Belogurova3,4, Yulia V. Dinikina3, Ekaterina V. Tsibatova4, Georgy M. Manikhas1

Treatment of patients with high-risk axial and pelvic Ewing’s sarcoma (ES). A single-institution experience

Roman I. Pimenov1, Igor S. Dolgopolov1, Vasilii K. Boyarshinov1, Natalia S. Subbotina1, Igor V. Visochin1, Stuart Siegiel2, George L. Mentkevich1

Aggressiveness of tumor resection improves survival in pediatric malignant gliomas

Ludmila I. Shats1, Margarita B. Belogurova1, Olga G. Zheludkova 2

First experience of treatment of high-risk neuroblastoma patients using autologous peripheral blood stem cells transplantation

Igor N. Vyatkin1,2,  Egor V. Shorikov1,2, Andrey A. Igumenshev1,2, Larisa V. Vakhonina1,2, Natalya G. Maisheva1,2, Yulia A. Yakovleva1,2, Grigory A. Tsaur1,2, Alexander M. Popov1,2,3, Elizaveta R. Semenikhina1, Leonid I. Savelyev1,2,3, Larisa G. Fechina1,2

N. Solid tumors

High-dose chemotherapy and autologous stem cell transplantation in children with Ewing’s sarcoma/PNET

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Ilya V. Kazantsev1, Tatjana V. Youhta2, Elena V. Morozova1, Svetlana A. Safonova2, Yury A. Punanov2, Liudmila S. Zubarovskaya1, Boris V. Afanasyev1

1Memorial R. M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University,
St. Petersburg, Russia; 2Federal State Institution N.N. Petrov Research Institute of Oncology, Saint Petersburg

Correspondence
Ilya V. Kazantsev, Comissara Smirnova str., 10a, 32, St. Petersburg, 194044, Russia, Phone: +7 (921) 317-47-49
E-mail: Ilya_Kazantsev@spam is badinbox.ru

The clinical course of Ewing’s sarcoma/PNET in children is characterized by a rapid increase of tumor mass and early metastases. In this context a substantial part of the affected pediatric population – children with clinically detectable metastatic disease or heavy tumor burden – has a poor prognosis. Although contemporary therapy programs – those that combine systemic chemotherapy with local control measures – achieve  5-year event-free survival (EFS) in 70–80% of children with localized disease, the results in high-risk groups are still to be improved with a 5-year EFS rate of 20–30%. Some research data provides evidence of high-dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplantation (auto-HSCT) being a promising option for treatment of these high-risk patients.

Patients and methods

From 2003 to December 2008 a total of 17 pediatric patients with Ewing’s sarcoma/PNET received HDCD with auto-HSCT. There were 11 males and 6 females (male-female ratio of 1.8:1) with a median age at diagnosis of 13.4 yrs (range 3–18 yrs). In all the cases, diagnosis was histologically proved. Of the 17 patients, 13 had metastatic disease and 4 had localized disease. In all the patients with localized disease the initial tumor volume exceeded 200 sm3. In all the cases the therapy program included 6 courses of polychemotherapy (ifosfamide, vincristine, doxorubicin and etoposide), surgical treatment or local irradiation of primary disease sight (48–56 Gy). There were 8 patients who received 8 courses of maintenance chemotherapy (vincristine, dactinomycin, ifosfamide). In 9 cases the maintenance therapy was substituted for HDCT with auto-HSCT. We used the following conditioning regimens: oral busulfan 16 mg/kg and melphalan 140 mg/m2 in 7 patients and melphalan 140–200 mg/m2 in 2 patients. We used different stem cell sources: bone marrow (BM) in 5 patients, peripheral blood stem cells (PBSC) in 2 patients, and BM and PBSC – due to the poor yield of SC – in 2 patients. A mean dose of CD34+ cells in the graft amounted to 3.26 x 106 (range 1.0–8.9 x 106).

Results

In the maintenance therapy group (n=8) 5 patients had a relapse of metastatic disease and died of tumor progression, 2 patients had a local relapse and received salvage therapy – in one case, HDCT with auto-HSCT – and both are presently disease–free, while 1 patient died of overwhelming sepsis.

In the HDCT group (n=9) 8 of the patients are alive – 1 died of disease progression – 4 patients remain in remission, 2 patients failed to achieve remission and received allogeneic HSCT, and 2 patients relapsed 2–8 months after HDCT with auto-HSCT. All children transplanted in partial remission or disease progression later relapsed. All of the children that are at the moment disease-free were diagnosed stage IV Ewing’s sarcoma– distant metastases at the time of diagnosis – but achieved complete remission (CR) at the end of the induction chemotherapy course. The toxicity of HDCT regimens was moderate: all of the patients had grade II–III mucositis, 6 patients had febrile neutropenia, and 2 patients had toxic hepatitis.

Conclusions

HDCT with auto-HSCT in high-risk group children with Ewing’s sarcoma/PNET has acceptable toxicity and allows improved PFS for patients in CR after standard therapy regimens.

Keywords

Ewing's sarcoma, PNET, autologous hematopoietic stem cell transplantation, maintenance therapy

N. Solid tumors

The outcome of treatment in patients with high-risk (HR) retinoblastoma

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Igor S. Dolgopolov1, Tatiana L. Ushakova1, Olga N. Gorovtzova1, Alevtina I. Pavlovskaya2, Roman I. Pimenov1, Vasilii K. Boyarshinov1, Natalia S. Subbotina1, Igor V. Glekov1, Vladimir G. Poliakov1, George L. Mentkevich1

1Institute of Pediatric Oncology and Hematology, Bone Marrow Transplantation Department, Moscow, Russia; 2Institute of Clinical Oncology

From 2001 to 2008 16 patients (8 female, 8 male) with high-risk retinoblastoma (RB) were treated in our center. HR was defined as microscopic residual tumor after enucleation (stage II, n=8); regional extension (stage III, n=4): a) overt orbital disease (n=3) b) involvement of regional or cervical lymph nodes (n=1); metastatic disease (stage IV): a) metastasis (multiple lesions (n=1)), b) CNS extension: prechiasmatic lesion (n=3). The median age was 32 (8–115) years and the median body weight was 13.8 (9.8–32) kg. Two patients (pts) had bilateral RB (1st case: operated on left eye and relapsed in the right eye with orbital involvement 3 months after surgery; second: metastatic disease with prechiasmatic lesion). The induction phase included 4 courses of CT including cyclophosphamide, VP-16 and carboplatin, surgery and external beam RT at a dose of 50 Gy. PBSCs were harvested after the first course of CT. Conditioning included busulfan 16 mg/kg and melphalan 140 mg/m2, followed by autologous SCT. Twelve pts received a median number of 3.5 (2.2–4.8)x106 CD34+ cells/kg. Toxicity was moderate in all but one pt (stage III), who died on d+8 from sepsis caused by Klebsiella pneumonia. The median number of days to WBC >1.0x109/l, Plt >20, and 50x109/l was 10 (9–11), 14 (10–20), and 17 (14–35) days respectively. Three pts died due to relapse: in CNS (n=2), and one with metastatic disease experienced a progression of disease in bone, BM, testis and lymph nodes 8 months after HDCT. Eight patients are alive and well at follow-up of 55 months. EFS and DFS were 64% and 68% respectively. Three patients refused HDCT. Two out of 3 (both with prechiasmatic lesion) relapsed in CNS and died. One with stage II is alive and disease free. One pt with overt orbital disease progressed when on treatment and later died.

Keywords

high-risk retinoblastoma, high-dose chemotherapy, autologous stem cell transplantation

N. Solid tumors

Restoration of ovarian function after cryopreserved ovarian tissue transplantation in women exposed to complex treatment for gynecological cancer: feasibility of this option in pediatric cancer patients

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Alla S. Lisyanskya1,2, Natalia I. Tapilskaya1,3, Margarita B. Belogurova3,4, Yulia V. Dinikina3, Ekaterina V. Tsibatova4, Georgy M. Manikhas1

1City Clinical Oncology Dispensary; 2AVA-Peter Clinic; 3St. Petersburg State Pediatric Medical Academy, Department of Oncology, Radiodiagnostics and Radiotherapy Section; 4City Clinical Hospital №31, Department of Pediatric Oncology and Hematology Saint Petersburg, Russia

Correspondence
Alla S. Lisyanskya, City Clinical Oncology Dispensary, pr. Veteranov 56, 198255 St. Petersburg, Russia
Phone: +7 (812) 3768917, E-mail: deton.hospital31@inbox.ru

Objective

To appreciate the possibilities for preserving ovarian function and improving quality of life in women of a reproductive age exposed to complex treatment for gynecological cancer.   

Due to increasing pediatric cancer survival rates attention has turned to the long-term sequelae of treatment.  Possibilities to preserve fertility in these pts are widely discussed.

Materials and methods

Sixteen pts with gynecological cancer participated in our research. Before undergoing gonadotoxic treatment, a laparoscopic collection of ovarian cortical tissue – which was then cryopreserved – was carried out in all pts. After the completion of a patient-specific treatment, hormonal blood tests confirmed premature ovarian failure. After heterotopic transplantation was performed, ovarian function was continuously monitored by hormonal blood tests; follicular development was assessed by ultrasonography.

Results

Normal hormonal status was recovered in 15 pts due to transplantation procedure, while in 10 pts regular cyclic follicular development was observed. In 1 patient received a mature ovule after a follicle puncture. According to the psychological tests taken in all pts exposed to ovarian tissue transplantation, an increase in their life quality was registered.   

Conclusions

Autotransplantation of ovarian tissue in reproductive-aged women with oncogynecological disease can preserve fertility and “stop” the menopause. Cryopreserved ovarian tissue – transplanted into a heterotopic site – may lead to the production of mature ovules that admit the possibility to conceive a child. These methods are reasonable in oncopediatric pts who have a realistic chance of long-term survival and whose scheduled treatment carries a high risk of gonadal damage.

Keywords

oncogynecology, children, chemotherapy, fertility, cryopreservation

N. Solid tumors

Treatment of patients with high-risk axial and pelvic Ewing’s sarcoma (ES). A single-institution experience

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Roman I. Pimenov1, Igor S. Dolgopolov1, Vasilii K. Boyarshinov1, Natalia S. Subbotina1, Igor V. Visochin1, Stuart Siegiel2, George L. Mentkevich1

1Institute of Pediatric Oncology and Hematology, Bone Marrow Transplantation Department, Moscow, Russia; 2CHLA, Los-Angeles, USA

Correspondence
Roman I. Pimenov, 24, Kashirskoye shosse, 115476, Moscow, Russia, Phone: +7 (903) 1991909
E-mail: onco@spam is badlist.ru

This study was initiated in an attempt to improve DFS rates in patients (pts) with high-risk axial and pelvic ES by using autoPBSCT. From January 1997 to December 2007 35 pts (M/F–15/21) with high-risk ES (localized 25 pts; metastatic 10 pts (lungs-only: 2, combined or other sites: 8) received HDCT with autologous transplantation. The median primary tumor volume was 739 cm3. CT consisted of 5 courses: numbers 1, 3, and 5 included cyclophosphamide 2100 mg/m2 day on days 1 and 2, doxorubicin 37.5 mg/m2 as a 24-hour infusion on days 1 and 2, and vincristine 1.5 mg/m2 on days 1, 8, and 15. Cycles 2 and 4 consisted of ifosfamide 2400 mg/m2/day on days 1–5 and VP-16 100 mg/m2/day on days 1–5. No G-CSF was given routinely between cycles. RT was given after the fifth cycle of CT at a median dose of 52 Gy (range, 50–56). Patients with lung involvement received lung irradiation after the second cycle of CT at a dose of 10.8-12 Gy. All pts received busulfan 16 mg/kg, melphalan 140 mg/m2-based HDCT (n=9); with the addition of thiotepa (TT) 600-900 mg/m2 (n=11) or VP16 1400 mg/m2 (n=15), followed by autologous stem cell recovery (6.4 (1.9–25.3) x 106 CD34+ cells/kg). The median number of days to WBC>1.0x109/l, Plt>20, and 50x109/l was 10 (8–14), 16 (0–52) and 28 (11–66) days, respectively. TRM was 6% (2 pts out of 35). Six pts relapsed. DFS at 5 yrs was 50% in metastatic pts vs 88% in pts with localized tumor (p>0.05). EFS and DFS were 69% and 75% with a median follow-up of 103 and 112 months, respectively. DFS in the TT, VP16, and BuMel groups was 83%, 67%, and 79%, respectively (p<0.05).

We conclude that pts with high-risk ES may benefit from BuMel-based regimens, and that an addition of any drug to BuMel regimen increases toxicity with no influence on DFS.

Keywords

Ewing’s sarcoma, high-dose chemotherapy, autologous bone marrow transplantation

N. Solid tumors

Aggressiveness of tumor resection improves survival in pediatric malignant gliomas

Ludmila I. Shats1, Margarita B. Belogurova1, Olga G. Zheludkova 2

1City Hospital № 31, St. Petersburg, Russia; 2Clinic Research Center of Hematology, Oncology, and Immunology, Moscow, Russia

Correspondence
City Hospital № 31, pr. Dinamo, 3, St. Petersburg, Russia
Phone/Fax: +7 (812) 235 07 21, E-mail: deton.hospital31@inbox.ru

Over a 13-year period (1994–2007) 48 children between 3 and 18 years of age with anaplastic astrocytoma (26 pts) and glioblastoma multiforme
(22 pts) were treated with surgery, local radiation therapy, and different regimens of chemotherapy. The retrospective analysis of survival was provided.  In our study there was a statistically significant difference in overall survival (OS) between patients with malignant gliomas who underwent a greater-than-90% resection of the tumor and those who underwent a less-than-90% tumor’s resection (5-year OS 42% vs 20% P=0.013). This difference held up stronger for patients with anaplastic astrocytoma who underwent total and subtotal resection (5-year OS 88.8% vs 43% of P=0.0036). A greater-than-90% surgical resection of newly-diagnosed malignant gliomas in children confers a statistical survival advantage when followed by local field irradiation and any kind of chemotherapy.

Figure 1.

2009-5-en-Shats-et-al-Figure-1.JPG

Keywords

anaplastic astrocytoma, glioblastoma multiforme, pediatric malignant glioma, neurosurgery, children

N. Solid tumors

First experience of treatment of high-risk neuroblastoma patients using autologous peripheral blood stem cells transplantation

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Igor N. Vyatkin1,2,  Egor V. Shorikov1,2, Andrey A. Igumenshev1,2, Larisa V. Vakhonina1,2, Natalya G. Maisheva1,2, Yulia A. Yakovleva1,2, Grigory A. Tsaur1,2, Alexander M. Popov1,2,3, Elizaveta R. Semenikhina1, Leonid I. Savelyev1,2,3, Larisa G. Fechina1,2

1Regional Children Hospital 1, Ekaterinburg, Russia; 2Research Institute of Medical Cell Technologies, Ekaterinburg, Russia; 3Ural State Medical Academy, Ekaterinburg, Russia

Correspondence
Egor Shorikov, S. Deryabina Street 32, 620149 Ekaterinburg, Russia, Regional Children Hospital 1, Pediatric Oncology & Hematology Center, Phone: +7 (343) 216-6881, Fax: +7 (343) 216-6887
E-mail: cohc@spam is badbk.ru

Objective

To investigate the efficacy of auto-PBSCT in patients (pts) with high-risk (HR) neuroblastoma.

Methods

From June 2007 to August 2008 five pts with HR neuroblastoma were recruited. There were 3 boys and 2 girls aged from 11 to 113 months (median 52). Three pts with stage 4 and 2 pts with relapsed neuroblastoma (4 in CR and 1 in PR) received auto-PBSCT with a regimen of Melphalan 135 mg/m2+etoposide 40 mg/kg+carboplatin 1500 mg/m2. In all patients PBSCs were mobilized with G-CSF 10 µg/kg/day for 6 days and leukapheresis was performed on days 5 and 6 of G-CSF administration by cell separator. In 3 out of 5 cases positive immunomagnetic selection of CD34+ harvested cells was carried out. The median purity and viability of selected CD34+ cells was 97.1% (range 88.2%–97.4%) and 91.8% (range 71.6%–99.6%), respectively. The median number of administered CD34+ cells was 11.3×106/kg (range 5.1 to 41.4×106/kg).

Results

All children demonstrated engraftment. The median time for take of neutrophils and platelets after auto-PBSCT was 11 days (range 9–40) and 40 days (range 13–79), respectively. No patients experienced organ toxicities greater than WHO grade II or life-threatening infections. Progression disease was documented in 1 patient and 2 relapses were registered at the median time of 223 days (range 188–390); 2 patients remained in CR for 295 and 534 days. Both relapsed patients died; the other 3 are alive.

Conclusion

These preliminary results suggest that auto-PBSCT can be considered a curative therapeutic approach in patients with HR neuroblastoma.

Keywords

neuroblastoma, PBSCT, children, CD34+ cell selection