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Introduction

Microbial, fungal and viral communities of bronchial and alveolar surfaces are closely related to microbiota of upper airways and oropharyngeal mucosa. Therefore, their microbiological variability shows sufficient intercorrelations [1]. In healthy persons, the microbial composition in lungs closely matches the upper respiratory tract (URT), especially in periglottic region. The total contents of bacteria are gradually decreasing from upper respiratory ways to the lower bronchoalveolar structures [2].

Meanwhile, in severe pneumonias, the clinically relevant changes of lung microbiota are generally, assessed by analy-sis of bronchoalveolar lavage (BAL) sampled during diagnostic bronchoscopy, thus representing a direct and efficient way to get a reliable etiological diagnosis in suggested infectious complications. Along with bacteriological studies, a number of viral pathogens are routinely detected, mainly, by PCR techniques or immunohistochemistry, whereas fungal infections could be suggested by specific polysaccharide antigens, or direct cultures. The bacterial diversity may be assayed both by classical cultural methods, and by modern DNA deep sequencing methods.

In particular, a range of techniques could be used for the search of opportunistic pathogenic bacteria in bronchoalveolar samples. E.g., Gaibani et al. [3] examined the BAL specimens from 24 patients with post-COVID pneumonia. The samples were cultured on conventional selective agar plates. The species of bacterial isolates were identified by MALDI-TOF mass-spectrometry, and in vitro antimicrobial susceptibility was tested by routine methods. Moreover, V3 to V4 region of the standard 16S rRNA gene was subjected to PCR, the resulting amplicon libraries were sequenced using MySec platform by means of next-generation sequencing (NGS). In summary, the lung microbiome of these patients showed predominance of Pseudomonas spp. (25%), Enterobacteriaceae (19%), Streptococcaceae (12%), Staphylococcaceae (11%). In particular, the DNA sequences of Klebsiella spp. (7%), Enterococci (5%), and Prevotella (4%) were also detected.

A number of patients with systemic malignant disorders present with polymicrobial airway colonization caused by preceding cytostatic therapy resulting into severe immune deficiency. Bronchoscopic examination of 436 consecutive adult patients with hematological malignancies and pulmonary infiltrates had revealed infectious agents in BAL of 219 patients of them 45 (20.5%), with microbial colonization, 39 of them with two pathogens, and 6 with three agents [4]. Aspergillus spp. was the most common co-pathogen identified. The authors have confirmed a more severe clinical course and higher hospital mortality in the patients with polymicrobial pulmonary infections.

A sufficient issue concerns relative diagnostic value of classical bacterial cultures and DNA-based NGS diagnostics. Such studies are now underway. E.g., direct comparisons between the diagnostic significance of was performed by a Chinese team who have enrolled a group of severe community-acquired pneumonia (SCAP) patients admitted to intensive care unit (ICU). BAL samples were taken by bronchoscopy within 48 h of ICU admission [5]. The isolated DNA was sequenced in the V3-V4 hypervariable region of the 16S rRNA gene of all PCR-amplified samples by means of Illumina Miseq platform. The multivariate analysis of variance has shown that positive bacteria lab test results had the strongest independent association with lung microbiota (P=0.018), thus confirming permanent diagnostic value of standard clinical culture of bacterial microbiota.

A number of studies concerned total contents and species diversity of lung microbiota in HSCT patients. Currently, the pre-transplant diagnostics of infectious respiratory disorders in the patients planned for HSCT is based on complex examination including pulmonary function tests (PFT), chest high-resolution computed tomography (HRCT), and laboratory examination of available BAL samples [6]. The authors have examined 142 children that should be subjected to HSCT. Different abnormalities were revealed in 74% of patients, mostly, for subnormal PFT tests. Chest HRCT showed clinically significant disturbances in 19% of the cases. BAL microbiota was abnormal in 43% of patients; respiratory viruses (PCR) were found in 35 patients, fungi (antigen or culture) in 21, and bacteria (culture) in 22. Prognostic value of these disorders could influence subsequent treatment approaches.

In the patients undergoing HSCT, severe impairement of lung microbiota is observed, due to transient cytopenia, immunocompromised state and massive antibiotic prophylaxis at early terms posttransplant. Early and late pulmonary infections post-HSCT are well known and described in details as reviewed by Astaschanka et al. [7].

The BAL microbiology, may yield a variety of common bacterial agents S. aureus, E.coli, coagulase-negative staphylococci, Enterococci spp., P.aeruginosa, Klebsiella pneumonia etc. Additional PCR and antigen assays revealed multiple viral and fungal species. E.g., BAL samples taken after hematopoietic transplants may often contain a number of different bacterial, fungal and viral species, sometimes, presenting mixed infection [8]. Fungal species, especially, Aspergillus, is a common finding in BAL samples taken from HSCT patients [9].

Similar study was carried out in 193 children and adolescents who underwent myeloablative conditioning and HSCT has revealed mixed microbiota [10]. Of them, 34% underwent bronchoscopy with a total of 101 BAL samples, mostly after allogeneic HSCT (allo-HSCT). The lung-derived samples were tested for bacterial, fungal and viral infectious pathogens using staining and culture methods. 40% of samples proved to be positive, with a majority showing bacterial pathogen as well as fungal and viral agents. In particular, the diagnostic assays revealed Mycobacteria, S. epidermidis, vancomycin-resistant enterococci, coagulase-negative staphylococci, P.aeruginosa, Legionells, Serratia, Streptococcus spp., Enterococcus faecium, Lactobacilli spp.

Despite recent advent of novel DNA-sequencing approaches, the classical bacteriological evaluation of biological samples retains its diagnostic value, in particular due to its ability to assess antibiotic resistance of microbial isolates. Hence, the aim of this study was a comparative evaluation of aerobic and facultative anaerobic microbiota components in bronchoalveolar lavage samples taken in immunocompromised patients with infectious lung complications which developed after intensive chemotherapy, antibiotic therapy and subsequent hematopoietic stem cell transplantation (HSCT).

Materials and methods

Our study included clinical and laboratory data of 691 patients subjected to hematopoietic stem cell transplantation (HSCT) 2013 through 2020, aged from 1 to 71 years (a mean of 38.5+ 23.9).

Distribution of BAL samples by distinct disorders was as follows: acute lymphoid leukemia (ALL, n=232 samples); acute myeloid leukemia (AML, n=331); aplastic and refractory anemias (AA, n=104); Hodgkin disease (HD, n=163); chronic myeloid leukemia (CML, n=79); non-Hodgkin lymphomas (NHL, n=63), other malignant and inherited disorders (n=58).

Myeloablative and non-myeloablative conditioning regimens for HSCT were carried out in 44% and 56% of cases, respectively. Stem cells were obtained from bone marrow or peripheral blood 497 : 596).

The types of HSCT were as follows: related compatible donors (19.2%); related haploidentical donors (21.6%); unrelated compatible donors (49.1%); autologous transplants (10.2%).

The doses of transfused CD34+ cells widely varied from 0.8 to 18×10⁶ cells /kg body weight.

Prophylaxis of graft-versus-host disease was mostly, performed by the posttransplant cyclophosphamide (PtCy) as well cyclosporin A, tacrolimus, sirolimus and glucocorticosteroids.

For statistical analysis, the groups of patients were also divided by age: 0-5 years (group 1, n=79); 6-14 children (group 2, n=129); 15-21 years old (group 3, n=194); >22 years (group 4, n=720). Moreover, the results of bacteriological examination were classified by terms post-transplant, starting from <100 days before HSCT (point 0); during the 1^st month (point 1); 2^nd month (point 2); 3^rd month (point 3), etc., up to 6 months after HSCT (point 6).

In the course of conditioning treatment and HSCT, the patients obtained antibiotic prophylaxis including administration of fluoroquinolones from D+1 to D+60. Amoxicillin was also administered, especially, to children. In cases of posttransplant febrile neutropenia, empirical therapy with broad-spectrum antibiotics was prescribed. Upon isolation of antibiotic-resistant microbial strains, the treatment was changed to other antibiotics (per os or intravenously) as guided by the in vitro testing of microbial sensitivity.

A total of 1123 samples of bronchoalveolar lavage were collected by means of diagnostic bronchoscopy within D-100 to D+180 post-HSCT. The endoscopy was performed according to appropriate clinical indications as prescribed by the attending doctor and intensive care specialist. Written informed consent for the procedure was obtained from the patients or their guardians.

Inoculation of laboratory cultures and isolation of bacteria from the BAL samples were made to differential culture media by classical bacteriological techniques. The isolated microorganisms were identified by means of commercial biochemical test systems (BBL Crystal), as well as with MALDI-TOF mass spectrometry using VITEK MS instrument. The sensitivity of clinical isolates to antibiotics was determined by means of disk diffusion test systems. The results of microbial sensitivity tests were interpreted according to the Guidelines of European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria.

Statistical evaluation of results was performed using parametric and nonparametric statistic criteria, to analyze time- and age-dependent course of the bacterial landscape revealed by microbial cultures, and for distinct microbial associations after HSCT using the STATISTICA 10 program.

Results

The detection rates for distinct cultured bacterial species among the total BAL sample massive was as follows: bacteria of Enterobacterales order were revealed in 25% of the samples (280/1123), with Klebsiella pneumoniae (19.1%, 215/1123) being prevailing species, whereas Escherichia coli (2.5%) and Enterobacter spp. (2.3%) were detected at similarly low rates (28/1123 and 26/1123, respectively. The incidence of Citrobacter spp., Proteus mirabilis, Serratia marcescens did not exceed 1%. Among Gram-negative, non-fermenting bacteria, Pseudomonas aeruginosa was detected in 5% of BAL specimens (56/1123). In particular, P. аeruginosa v. non mucosa, and v. mucosa were found at similar rates (29/1123 и 27/1123). Other Pseudomonas species were isolated in 4.5% (51/1123); Acinetobacter spp., 3.7% (41/1123); Stenotrophomonas maltophilia, 2.1% (24/1123). The ratio of coagulase-negative staphylococci was 5.6% (63/1123), of them Staphylococcus epidermidis was found in 4.2% (47/1123). Staphylococcus aureus was isolated in 4.5% of the samples (51/1123). Streptococcus spp. was revealed in 20.7% (233/1123 samples) including Streptococcus viridans group (15.7%, 176/1123); Streptococcus pneumoniae (1.5%, 17/1123). Enterococci encountered in 12.4% of BAL samples (139/1123), of them Enterococcus faecium was identified in 7.0% (79/1123); Enterococcus faecalis, in 5.3% (60/1123). Different Candida species were found in 14% of the BAL specimens (157/1123), as a rule, within microbial associations; the incidence of Haemophilus spp. was 0.9% (10/1123).

Detection rates for the most common bacterial species as classified by the age of patients are shown in Fig. 1. Of note, the seeding rates for S.viridans, a common member of normal mucosal microbiota, tended to decrease with age, reaching a significant decline in adolescents of >15 years old and adult patients (p<0.01). Meanwhile, the rates of Klebsiella detection, in our experience, proved to be relatively high in all studied age groups.

Figure 1. Age dependence of bacterial seeding rates for the dominant bacterial species in bronchoalveolar lavage of oncohematological patients both before and after HSCT (group 1: 0-5 years; group 2: 6-14 years; group 3: 15-21 years; group 4: >22 years. A, S.epidermidis; B, S.viridans; C, Klebsiella spp. Abscissa, age groups (group 1, 0-5 y.o.; group 2, 6-14 y.o.; group 3, 15-21 y.o.; group 4, >22 y.o. Ordinate, ratio of positive microbial findings.

To prove the trends of posttransplant microbial colonization, we have assessed time dynamics for the dominant bacterial species within 6 months after HSCT (Fig. 2).

As seen from Fig. 2A, the S.epidermidis seeding frequency did not sufficiently change over time posttransplant (a mean of 10-18%). By contrary, S.viridans detection rates dropped ca. 2-fold during 1^st month after HSCT (approx. from 30% to 10%), probably, due to intensive antibiotic prophylaxis over the period of transient cytopenia (p<0.02). Meanwhile, the most interesting finding concerned posttransplant changes in Klebsiella spp. detection. Its low seeding rates before HSCT and over 1^st month posttransplant (3 to 5%) were followed by sharply increased emergence of this commensal bacteria at later terms after HSCT (2 to 6 months), as seen from Fig. 2C (p<0.001). Interestingly, its detection was not affected by antibiotic treatment during early posttransplant period and additional antibacterial treatment due to presumed infectious complications requiring bronchoscopy and BAL sampling.

Figure 2. Frequency of S.epidermidis (A); S.viridans (B), and Klebsiella spp. (C) detection in bronchoalveolar lavage of oncohematololgical patients collected at various times after HSCT. Abscissa, terms post-HSCT (months); ordinate, ratio of positive microbial findings.

Antibiotic resistance was tested for all bacterial isolates derived from the BAL samples. Figures 3 to 8 depict the resistance patterns of the leading BAL microbiota members obtained from the subjected to HSCT between 2013 and 2020. Antibiotic resistance of Klebsiella pneumoniae ssp pneumoniae, was equally high during the entire tine period. It comprised over 80% for III generation cephalosporins, aztreonam, fluoroquinolones and protected aminopenicillins. Carbapenem resistance varied from 33% to imipenem to 54% for meropenem. 96% of the tested isolates were colistin-sensitive. Colistin sensitivity was determined by serial dilutions technique in liquid nutrient medium.

Common detection of K.pneumoniae accomplished by increased resistance rate presume high relevance of this pathogen for development of nosocomial infections in various clinical settings, especially in immunocompromised patients. Within mentioned time period, the meticillin-resistant S.aureus (MRSA) was isolated in 6% of BAL samples, whereas the rate of MRCoNS was 71%. All isolates of Staphylococci proved to be tigecycline-sensitive. Sensitivity of staphylococci to vancomycin was assessed by means of gradient diffusion (Е test). S.aureus showed 100% sensitivity to vancomycin and linezolid. Among the CoNS strains, 2% were resistant for vancomycin, and 5%, for linezolid. The isolates sensitive to linezolid were also considered tedizolid-sensitive. Erythromycin was used to determine sensitivity to azithromycin, clarithromycin, and roxythromycin. Fluorochinolone sensitivity of staphylococci was evaluated by their sensitivity to norfloxacine. The norfloxacin-sensitive strains were considered to be sensitive to moxyfloxacin and, at higher exposure, to ciprofloxacin and levofloxacin. Fluorochinolone sensitivity of S.aureus proved to be 97%, appropriate rate for CoNS was 35%.

Figure 3. Resistance of Klebsiella pneumoniae ssp pneumonia to various antibiotics (biological samples: bronchoalveolar lavage, 2013 to 2020)

The members of Gram-negative non-fermenting bacteria exhibited high resistance levels to carbapenems, i.e., >70% of resistant isolates among Acinetobacter spp., over 50% resistant strains were documented for P.aeruginosa. Colistin sensitivity was as high as 96% for Pseudomonas spp. (two resistant strains from 52 isolates) and 93% for Acinetobacter spp. (one case of resistance of 15).

The Enterococcus isolates from BAL samples have shown 100% resistance rates for linezolid and tigecycline; resistance rate was 3% for vancomycin (4 isolates of 137). 50% of E.faecium isolates proved to be ampicillin-resistant, whereas 92% of E.faecalis isolates remained sensitive to this drug.

Discussion

The significance of bacterial findings in BAL was considered in different transplantological aspects. E.g., a review article by Gudiol et al. [11] was dedicated to Hospital-acquired pneumonia (HAP) which present serious complications in transplant patients. Bacteria are the leading cause of nosocomial pneumonia for both immunocompetent and transplant recipients caused by Gram-negative organisms, and, especially, highly prevalent Pseudomonas aeruginosa. In addition to the usual colonizing microorganisms of the respiratory tract, such as Streptococcus pneumoniae, Branhamella catharralis and Staphylococcus aureus, and various Gram-negative bacilli are an important cause of HAP/VAP in both populations. The most relevant opportunistic pathogens are Aspergillus fumigatus, Pneumocystis jirovecii and cytomegalovirus.

Streptococcus viridians is nearly absent from normal lungs, but it proved to be a common commensal microbe cultured from many BAL samples in the patients with chronic obstructive pulmonary disease, bronchial carcinoma, as well as following tracheostomy [12], thus presuming massive colonization with this species in various chronic respiratory disorders. Rapid bacterial colonization, especially, with S.viridans, S.aureus, P. aeruginosa was observed after bronchial valve implantation in lung emphysema patients [13]. Therefore, predominance of S.viridans in BAL samples both before and after HSCT seems to be a useful marker of chronic lung damage due to massive cytotoxic therapies in oncohematological patients. Increased frequency of S.viridans in younger patients (<15 years old) revealed in our study could be also explained by higher susceptibility of respiratory mucosa in children to previous anticancer treatment.

To our knowledge, there are no published data on the time-dependent changes of Klebsiella spp. in bronchoalveolar lavage following hematopoietic stem cell transplantation. Rather high prevalence of this bacteria was found among the HSCT patients with sinusitis and other disorders of upper respiratory ways at our BMT Center. Interestingly, higher rates of Klebsiella detection were found in the maxillary cavities which represent a common reservoir of pathogenic agents in immunocompromised persons [14].

One may presume that the late activation of Klebsiella on respiratory mucosa may be caused by antibiotic-resistant strains colonizing these areas.

To suggest possible origin of these strains, one may refer a study of 91 BAL specimens obtained from critically ill patients with acute respiratory disorder (ARDS). Next-generation sequencing of bacterial DNA fragments was performed by means of Illumina MiSeq platform [15]. The ARDS-associated sequencing reads were similar to Enterobacteriaceae, including Escherichia coli, Enterobacter spp., and Klebsiella pneumoniae. The authors conclude that lung microbiota in ARDS patients is characterized by relative enrichment with gut-associated species of the Enterobacteriaceae family. Our findings concerning Klebsiella colonization of lower airways confirm these observations and provide evidence for higher risk of gut bacteria migration to other anatomic sites, due to extended septic process. This suggestion was made in our previous review [16].

A complex study of general cytokine responses and NGS-based evaluation of BAL bacterial microbiota in HSCT patients with pneumonias has shown reactive and non-reactive microbiota phenotypes [17, 18]. In the reactive phenotype, Pseudomonas Aeruginosa was the most abundant species, while in the nonreactive phenotype, cytomegalovirus (CMV) predominated. Moreover, other bacteria, S.pneumoniae, S.aureus, Acinetobacter spp., Klebsiella spp., Stenotrophomonas spp. were found in different quantities.

The new sequencing methods are recently applied for analy-sis of BAL microbiota. When comparing relative diagnostic efficiency of conventional bacterial cultures and novel metagenomic next-generation sequencing (mNGS) of BAL samples, a much higher sensitivity was revealed by analysis of different biological samples from pediatric HSCT patients by means of NGS approach, due to versatility of DNA reading technique and larger number of potentially pathogenic agents found by the multiple DNA sequencing [19]. The sensitivity of mNGS for diagnosing pulmonary infections post-transplant was 91.7 vs 22.9% by conventional testing. However, mNGS proved to be less specific (78.5%) than traditional methods (92.9%).

Later recolonization of pathogenic microorganisms post-HSCT is possible, including Klebsiella spp., S. aureus, S.pneumoniae, at a high risk of resistant strain selection, which was confirmed by us in the present work. One should note, however, that these 3 types of pathogenic bacteria were detected in a total of 13% of patients with sinusitis, i.e. the pathogen remained unknown in most cases. For additional diagnostics, along with search for pathogenic fungi and viruses, the extended diagnostics, e.g., of strictly anaerobic microbiota, are needed. In this aspect, implementation of advanced sequencing (NGS technique) will be of great importance, thus making it possible to assess biological diversity and the ratio of main microbiota classes in complex clinical samples, e.g., from mucosal surfaces.

Conclusion

1. In summary, the patients with oncohematological disease subjected to massive cytostatic therapy and allogeneic HSCT exhibit sufficient evolution of bronchoalveolar microbiota over the first 6 months posttransplant.

2. Follow-up of the BAL bacterial microbiota has revealed early exhaustion of S.viridans pool post-transplant, more likely, due to intensive anti-infectious treatment over the cytopenic period.

3. Decreased seeding levels are shown for S.viridans and S.epidermidis in adolescents over 15 years and adult patients.

4. Sharp increase of Klebsiella spp. detection rates at later terms (>2 months) after HSCT suggests airway colonization by the antibiotic-resistant microorganisms.

5. Future studies of BAL microbiota require combined diagnostic approaches, including mass spectrometry, PCR techniques for detection of strictly anaerobic bacteria, viral and fungal agents, as well as novel DNA-based technologies (e.g., next-generation DNA sequencing).

Conflict of interest

None declared.

Acknowledgement

This study was partially funded from Russian Ministry of Health and by Russian Science Foundation, grant No. №22-15-00149 of 18.05.2022.

References

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    doi: 10.3389/fmicb.2022.868160

" ["~DETAIL_TEXT"]=> string(33117) "

Introduction

Microbial, fungal and viral communities of bronchial and alveolar surfaces are closely related to microbiota of upper airways and oropharyngeal mucosa. Therefore, their microbiological variability shows sufficient intercorrelations [1]. In healthy persons, the microbial composition in lungs closely matches the upper respiratory tract (URT), especially in periglottic region. The total contents of bacteria are gradually decreasing from upper respiratory ways to the lower bronchoalveolar structures [2].

Meanwhile, in severe pneumonias, the clinically relevant changes of lung microbiota are generally, assessed by analy-sis of bronchoalveolar lavage (BAL) sampled during diagnostic bronchoscopy, thus representing a direct and efficient way to get a reliable etiological diagnosis in suggested infectious complications. Along with bacteriological studies, a number of viral pathogens are routinely detected, mainly, by PCR techniques or immunohistochemistry, whereas fungal infections could be suggested by specific polysaccharide antigens, or direct cultures. The bacterial diversity may be assayed both by classical cultural methods, and by modern DNA deep sequencing methods.

In particular, a range of techniques could be used for the search of opportunistic pathogenic bacteria in bronchoalveolar samples. E.g., Gaibani et al. [3] examined the BAL specimens from 24 patients with post-COVID pneumonia. The samples were cultured on conventional selective agar plates. The species of bacterial isolates were identified by MALDI-TOF mass-spectrometry, and in vitro antimicrobial susceptibility was tested by routine methods. Moreover, V3 to V4 region of the standard 16S rRNA gene was subjected to PCR, the resulting amplicon libraries were sequenced using MySec platform by means of next-generation sequencing (NGS). In summary, the lung microbiome of these patients showed predominance of Pseudomonas spp. (25%), Enterobacteriaceae (19%), Streptococcaceae (12%), Staphylococcaceae (11%). In particular, the DNA sequences of Klebsiella spp. (7%), Enterococci (5%), and Prevotella (4%) were also detected.

A number of patients with systemic malignant disorders present with polymicrobial airway colonization caused by preceding cytostatic therapy resulting into severe immune deficiency. Bronchoscopic examination of 436 consecutive adult patients with hematological malignancies and pulmonary infiltrates had revealed infectious agents in BAL of 219 patients of them 45 (20.5%), with microbial colonization, 39 of them with two pathogens, and 6 with three agents [4]. Aspergillus spp. was the most common co-pathogen identified. The authors have confirmed a more severe clinical course and higher hospital mortality in the patients with polymicrobial pulmonary infections.

A sufficient issue concerns relative diagnostic value of classical bacterial cultures and DNA-based NGS diagnostics. Such studies are now underway. E.g., direct comparisons between the diagnostic significance of was performed by a Chinese team who have enrolled a group of severe community-acquired pneumonia (SCAP) patients admitted to intensive care unit (ICU). BAL samples were taken by bronchoscopy within 48 h of ICU admission [5]. The isolated DNA was sequenced in the V3-V4 hypervariable region of the 16S rRNA gene of all PCR-amplified samples by means of Illumina Miseq platform. The multivariate analysis of variance has shown that positive bacteria lab test results had the strongest independent association with lung microbiota (P=0.018), thus confirming permanent diagnostic value of standard clinical culture of bacterial microbiota.

A number of studies concerned total contents and species diversity of lung microbiota in HSCT patients. Currently, the pre-transplant diagnostics of infectious respiratory disorders in the patients planned for HSCT is based on complex examination including pulmonary function tests (PFT), chest high-resolution computed tomography (HRCT), and laboratory examination of available BAL samples [6]. The authors have examined 142 children that should be subjected to HSCT. Different abnormalities were revealed in 74% of patients, mostly, for subnormal PFT tests. Chest HRCT showed clinically significant disturbances in 19% of the cases. BAL microbiota was abnormal in 43% of patients; respiratory viruses (PCR) were found in 35 patients, fungi (antigen or culture) in 21, and bacteria (culture) in 22. Prognostic value of these disorders could influence subsequent treatment approaches.

In the patients undergoing HSCT, severe impairement of lung microbiota is observed, due to transient cytopenia, immunocompromised state and massive antibiotic prophylaxis at early terms posttransplant. Early and late pulmonary infections post-HSCT are well known and described in details as reviewed by Astaschanka et al. [7].

The BAL microbiology, may yield a variety of common bacterial agents S. aureus, E.coli, coagulase-negative staphylococci, Enterococci spp., P.aeruginosa, Klebsiella pneumonia etc. Additional PCR and antigen assays revealed multiple viral and fungal species. E.g., BAL samples taken after hematopoietic transplants may often contain a number of different bacterial, fungal and viral species, sometimes, presenting mixed infection [8]. Fungal species, especially, Aspergillus, is a common finding in BAL samples taken from HSCT patients [9].

Similar study was carried out in 193 children and adolescents who underwent myeloablative conditioning and HSCT has revealed mixed microbiota [10]. Of them, 34% underwent bronchoscopy with a total of 101 BAL samples, mostly after allogeneic HSCT (allo-HSCT). The lung-derived samples were tested for bacterial, fungal and viral infectious pathogens using staining and culture methods. 40% of samples proved to be positive, with a majority showing bacterial pathogen as well as fungal and viral agents. In particular, the diagnostic assays revealed Mycobacteria, S. epidermidis, vancomycin-resistant enterococci, coagulase-negative staphylococci, P.aeruginosa, Legionells, Serratia, Streptococcus spp., Enterococcus faecium, Lactobacilli spp.

Despite recent advent of novel DNA-sequencing approaches, the classical bacteriological evaluation of biological samples retains its diagnostic value, in particular due to its ability to assess antibiotic resistance of microbial isolates. Hence, the aim of this study was a comparative evaluation of aerobic and facultative anaerobic microbiota components in bronchoalveolar lavage samples taken in immunocompromised patients with infectious lung complications which developed after intensive chemotherapy, antibiotic therapy and subsequent hematopoietic stem cell transplantation (HSCT).

Materials and methods

Our study included clinical and laboratory data of 691 patients subjected to hematopoietic stem cell transplantation (HSCT) 2013 through 2020, aged from 1 to 71 years (a mean of 38.5+ 23.9).

Distribution of BAL samples by distinct disorders was as follows: acute lymphoid leukemia (ALL, n=232 samples); acute myeloid leukemia (AML, n=331); aplastic and refractory anemias (AA, n=104); Hodgkin disease (HD, n=163); chronic myeloid leukemia (CML, n=79); non-Hodgkin lymphomas (NHL, n=63), other malignant and inherited disorders (n=58).

Myeloablative and non-myeloablative conditioning regimens for HSCT were carried out in 44% and 56% of cases, respectively. Stem cells were obtained from bone marrow or peripheral blood 497 : 596).

The types of HSCT were as follows: related compatible donors (19.2%); related haploidentical donors (21.6%); unrelated compatible donors (49.1%); autologous transplants (10.2%).

The doses of transfused CD34+ cells widely varied from 0.8 to 18×10⁶ cells /kg body weight.

Prophylaxis of graft-versus-host disease was mostly, performed by the posttransplant cyclophosphamide (PtCy) as well cyclosporin A, tacrolimus, sirolimus and glucocorticosteroids.

For statistical analysis, the groups of patients were also divided by age: 0-5 years (group 1, n=79); 6-14 children (group 2, n=129); 15-21 years old (group 3, n=194); >22 years (group 4, n=720). Moreover, the results of bacteriological examination were classified by terms post-transplant, starting from <100 days before HSCT (point 0); during the 1^st month (point 1); 2^nd month (point 2); 3^rd month (point 3), etc., up to 6 months after HSCT (point 6).

In the course of conditioning treatment and HSCT, the patients obtained antibiotic prophylaxis including administration of fluoroquinolones from D+1 to D+60. Amoxicillin was also administered, especially, to children. In cases of posttransplant febrile neutropenia, empirical therapy with broad-spectrum antibiotics was prescribed. Upon isolation of antibiotic-resistant microbial strains, the treatment was changed to other antibiotics (per os or intravenously) as guided by the in vitro testing of microbial sensitivity.

A total of 1123 samples of bronchoalveolar lavage were collected by means of diagnostic bronchoscopy within D-100 to D+180 post-HSCT. The endoscopy was performed according to appropriate clinical indications as prescribed by the attending doctor and intensive care specialist. Written informed consent for the procedure was obtained from the patients or their guardians.

Inoculation of laboratory cultures and isolation of bacteria from the BAL samples were made to differential culture media by classical bacteriological techniques. The isolated microorganisms were identified by means of commercial biochemical test systems (BBL Crystal), as well as with MALDI-TOF mass spectrometry using VITEK MS instrument. The sensitivity of clinical isolates to antibiotics was determined by means of disk diffusion test systems. The results of microbial sensitivity tests were interpreted according to the Guidelines of European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria.

Statistical evaluation of results was performed using parametric and nonparametric statistic criteria, to analyze time- and age-dependent course of the bacterial landscape revealed by microbial cultures, and for distinct microbial associations after HSCT using the STATISTICA 10 program.

Results

The detection rates for distinct cultured bacterial species among the total BAL sample massive was as follows: bacteria of Enterobacterales order were revealed in 25% of the samples (280/1123), with Klebsiella pneumoniae (19.1%, 215/1123) being prevailing species, whereas Escherichia coli (2.5%) and Enterobacter spp. (2.3%) were detected at similarly low rates (28/1123 and 26/1123, respectively. The incidence of Citrobacter spp., Proteus mirabilis, Serratia marcescens did not exceed 1%. Among Gram-negative, non-fermenting bacteria, Pseudomonas aeruginosa was detected in 5% of BAL specimens (56/1123). In particular, P. аeruginosa v. non mucosa, and v. mucosa were found at similar rates (29/1123 и 27/1123). Other Pseudomonas species were isolated in 4.5% (51/1123); Acinetobacter spp., 3.7% (41/1123); Stenotrophomonas maltophilia, 2.1% (24/1123). The ratio of coagulase-negative staphylococci was 5.6% (63/1123), of them Staphylococcus epidermidis was found in 4.2% (47/1123). Staphylococcus aureus was isolated in 4.5% of the samples (51/1123). Streptococcus spp. was revealed in 20.7% (233/1123 samples) including Streptococcus viridans group (15.7%, 176/1123); Streptococcus pneumoniae (1.5%, 17/1123). Enterococci encountered in 12.4% of BAL samples (139/1123), of them Enterococcus faecium was identified in 7.0% (79/1123); Enterococcus faecalis, in 5.3% (60/1123). Different Candida species were found in 14% of the BAL specimens (157/1123), as a rule, within microbial associations; the incidence of Haemophilus spp. was 0.9% (10/1123).

Detection rates for the most common bacterial species as classified by the age of patients are shown in Fig. 1. Of note, the seeding rates for S.viridans, a common member of normal mucosal microbiota, tended to decrease with age, reaching a significant decline in adolescents of >15 years old and adult patients (p<0.01). Meanwhile, the rates of Klebsiella detection, in our experience, proved to be relatively high in all studied age groups.

Figure 1. Age dependence of bacterial seeding rates for the dominant bacterial species in bronchoalveolar lavage of oncohematological patients both before and after HSCT (group 1: 0-5 years; group 2: 6-14 years; group 3: 15-21 years; group 4: >22 years. A, S.epidermidis; B, S.viridans; C, Klebsiella spp. Abscissa, age groups (group 1, 0-5 y.o.; group 2, 6-14 y.o.; group 3, 15-21 y.o.; group 4, >22 y.o. Ordinate, ratio of positive microbial findings.

To prove the trends of posttransplant microbial colonization, we have assessed time dynamics for the dominant bacterial species within 6 months after HSCT (Fig. 2).

As seen from Fig. 2A, the S.epidermidis seeding frequency did not sufficiently change over time posttransplant (a mean of 10-18%). By contrary, S.viridans detection rates dropped ca. 2-fold during 1^st month after HSCT (approx. from 30% to 10%), probably, due to intensive antibiotic prophylaxis over the period of transient cytopenia (p<0.02). Meanwhile, the most interesting finding concerned posttransplant changes in Klebsiella spp. detection. Its low seeding rates before HSCT and over 1^st month posttransplant (3 to 5%) were followed by sharply increased emergence of this commensal bacteria at later terms after HSCT (2 to 6 months), as seen from Fig. 2C (p<0.001). Interestingly, its detection was not affected by antibiotic treatment during early posttransplant period and additional antibacterial treatment due to presumed infectious complications requiring bronchoscopy and BAL sampling.

Figure 2. Frequency of S.epidermidis (A); S.viridans (B), and Klebsiella spp. (C) detection in bronchoalveolar lavage of oncohematololgical patients collected at various times after HSCT. Abscissa, terms post-HSCT (months); ordinate, ratio of positive microbial findings.

Antibiotic resistance was tested for all bacterial isolates derived from the BAL samples. Figures 3 to 8 depict the resistance patterns of the leading BAL microbiota members obtained from the subjected to HSCT between 2013 and 2020. Antibiotic resistance of Klebsiella pneumoniae ssp pneumoniae, was equally high during the entire tine period. It comprised over 80% for III generation cephalosporins, aztreonam, fluoroquinolones and protected aminopenicillins. Carbapenem resistance varied from 33% to imipenem to 54% for meropenem. 96% of the tested isolates were colistin-sensitive. Colistin sensitivity was determined by serial dilutions technique in liquid nutrient medium.

Common detection of K.pneumoniae accomplished by increased resistance rate presume high relevance of this pathogen for development of nosocomial infections in various clinical settings, especially in immunocompromised patients. Within mentioned time period, the meticillin-resistant S.aureus (MRSA) was isolated in 6% of BAL samples, whereas the rate of MRCoNS was 71%. All isolates of Staphylococci proved to be tigecycline-sensitive. Sensitivity of staphylococci to vancomycin was assessed by means of gradient diffusion (Е test). S.aureus showed 100% sensitivity to vancomycin and linezolid. Among the CoNS strains, 2% were resistant for vancomycin, and 5%, for linezolid. The isolates sensitive to linezolid were also considered tedizolid-sensitive. Erythromycin was used to determine sensitivity to azithromycin, clarithromycin, and roxythromycin. Fluorochinolone sensitivity of staphylococci was evaluated by their sensitivity to norfloxacine. The norfloxacin-sensitive strains were considered to be sensitive to moxyfloxacin and, at higher exposure, to ciprofloxacin and levofloxacin. Fluorochinolone sensitivity of S.aureus proved to be 97%, appropriate rate for CoNS was 35%.

Figure 3. Resistance of Klebsiella pneumoniae ssp pneumonia to various antibiotics (biological samples: bronchoalveolar lavage, 2013 to 2020)

The members of Gram-negative non-fermenting bacteria exhibited high resistance levels to carbapenems, i.e., >70% of resistant isolates among Acinetobacter spp., over 50% resistant strains were documented for P.aeruginosa. Colistin sensitivity was as high as 96% for Pseudomonas spp. (two resistant strains from 52 isolates) and 93% for Acinetobacter spp. (one case of resistance of 15).

The Enterococcus isolates from BAL samples have shown 100% resistance rates for linezolid and tigecycline; resistance rate was 3% for vancomycin (4 isolates of 137). 50% of E.faecium isolates proved to be ampicillin-resistant, whereas 92% of E.faecalis isolates remained sensitive to this drug.

Discussion

The significance of bacterial findings in BAL was considered in different transplantological aspects. E.g., a review article by Gudiol et al. [11] was dedicated to Hospital-acquired pneumonia (HAP) which present serious complications in transplant patients. Bacteria are the leading cause of nosocomial pneumonia for both immunocompetent and transplant recipients caused by Gram-negative organisms, and, especially, highly prevalent Pseudomonas aeruginosa. In addition to the usual colonizing microorganisms of the respiratory tract, such as Streptococcus pneumoniae, Branhamella catharralis and Staphylococcus aureus, and various Gram-negative bacilli are an important cause of HAP/VAP in both populations. The most relevant opportunistic pathogens are Aspergillus fumigatus, Pneumocystis jirovecii and cytomegalovirus.

Streptococcus viridians is nearly absent from normal lungs, but it proved to be a common commensal microbe cultured from many BAL samples in the patients with chronic obstructive pulmonary disease, bronchial carcinoma, as well as following tracheostomy [12], thus presuming massive colonization with this species in various chronic respiratory disorders. Rapid bacterial colonization, especially, with S.viridans, S.aureus, P. aeruginosa was observed after bronchial valve implantation in lung emphysema patients [13]. Therefore, predominance of S.viridans in BAL samples both before and after HSCT seems to be a useful marker of chronic lung damage due to massive cytotoxic therapies in oncohematological patients. Increased frequency of S.viridans in younger patients (<15 years old) revealed in our study could be also explained by higher susceptibility of respiratory mucosa in children to previous anticancer treatment.

To our knowledge, there are no published data on the time-dependent changes of Klebsiella spp. in bronchoalveolar lavage following hematopoietic stem cell transplantation. Rather high prevalence of this bacteria was found among the HSCT patients with sinusitis and other disorders of upper respiratory ways at our BMT Center. Interestingly, higher rates of Klebsiella detection were found in the maxillary cavities which represent a common reservoir of pathogenic agents in immunocompromised persons [14].

One may presume that the late activation of Klebsiella on respiratory mucosa may be caused by antibiotic-resistant strains colonizing these areas.

To suggest possible origin of these strains, one may refer a study of 91 BAL specimens obtained from critically ill patients with acute respiratory disorder (ARDS). Next-generation sequencing of bacterial DNA fragments was performed by means of Illumina MiSeq platform [15]. The ARDS-associated sequencing reads were similar to Enterobacteriaceae, including Escherichia coli, Enterobacter spp., and Klebsiella pneumoniae. The authors conclude that lung microbiota in ARDS patients is characterized by relative enrichment with gut-associated species of the Enterobacteriaceae family. Our findings concerning Klebsiella colonization of lower airways confirm these observations and provide evidence for higher risk of gut bacteria migration to other anatomic sites, due to extended septic process. This suggestion was made in our previous review [16].

A complex study of general cytokine responses and NGS-based evaluation of BAL bacterial microbiota in HSCT patients with pneumonias has shown reactive and non-reactive microbiota phenotypes [17, 18]. In the reactive phenotype, Pseudomonas Aeruginosa was the most abundant species, while in the nonreactive phenotype, cytomegalovirus (CMV) predominated. Moreover, other bacteria, S.pneumoniae, S.aureus, Acinetobacter spp., Klebsiella spp., Stenotrophomonas spp. were found in different quantities.

The new sequencing methods are recently applied for analy-sis of BAL microbiota. When comparing relative diagnostic efficiency of conventional bacterial cultures and novel metagenomic next-generation sequencing (mNGS) of BAL samples, a much higher sensitivity was revealed by analysis of different biological samples from pediatric HSCT patients by means of NGS approach, due to versatility of DNA reading technique and larger number of potentially pathogenic agents found by the multiple DNA sequencing [19]. The sensitivity of mNGS for diagnosing pulmonary infections post-transplant was 91.7 vs 22.9% by conventional testing. However, mNGS proved to be less specific (78.5%) than traditional methods (92.9%).

Later recolonization of pathogenic microorganisms post-HSCT is possible, including Klebsiella spp., S. aureus, S.pneumoniae, at a high risk of resistant strain selection, which was confirmed by us in the present work. One should note, however, that these 3 types of pathogenic bacteria were detected in a total of 13% of patients with sinusitis, i.e. the pathogen remained unknown in most cases. For additional diagnostics, along with search for pathogenic fungi and viruses, the extended diagnostics, e.g., of strictly anaerobic microbiota, are needed. In this aspect, implementation of advanced sequencing (NGS technique) will be of great importance, thus making it possible to assess biological diversity and the ratio of main microbiota classes in complex clinical samples, e.g., from mucosal surfaces.

Conclusion

1. In summary, the patients with oncohematological disease subjected to massive cytostatic therapy and allogeneic HSCT exhibit sufficient evolution of bronchoalveolar microbiota over the first 6 months posttransplant.

2. Follow-up of the BAL bacterial microbiota has revealed early exhaustion of S.viridans pool post-transplant, more likely, due to intensive anti-infectious treatment over the cytopenic period.

3. Decreased seeding levels are shown for S.viridans and S.epidermidis in adolescents over 15 years and adult patients.

4. Sharp increase of Klebsiella spp. detection rates at later terms (>2 months) after HSCT suggests airway colonization by the antibiotic-resistant microorganisms.

5. Future studies of BAL microbiota require combined diagnostic approaches, including mass spectrometry, PCR techniques for detection of strictly anaerobic bacteria, viral and fungal agents, as well as novel DNA-based technologies (e.g., next-generation DNA sequencing).

Conflict of interest

None declared.

Acknowledgement

This study was partially funded from Russian Ministry of Health and by Russian Science Foundation, grant No. №22-15-00149 of 18.05.2022.

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Однако при развитии тяжелых пневмоний, особенно у пациентов с иммунодефицитами, отмечается существенное нарастание количества, частоты выявления и биоразнообразия бактерий в бронхоальвеолярных смывах (БАЛ), наряду с колонизацией бронхов условно патогенными микроорганизмами из других инфицированных сайтов. Так, у многих пациентов с онкологическими заболеваниями на фоне цитостатической терапии развиваются тяжелые пневмонии с полимикробной колонизаций нижних дыхательных путей. Целью нашей работы была сравнительная оценка аэробной и факультативно-анаэробной микробиоты в образцах БАЛ от детей и взрослых пациентов после трансплантации гемопоэтических клеток (ТГСК). </p> <h3>Пациенты и методы</h3> <p style="text-align: justify;"> Проведено обследование 691 пациента, главным образом – с онкогематологическими заболеваниями, леченными цитостатической терапией и ТГСК (алло-ТГСК в 90% случаев). Возраст пациентов составлял от 1 до 71 г. (медиана – 38,5 л.). Применяли миело- или немиелоаблативную кондиционирующую терапию (44% и 56% случаев). Для исследования проводили забор 1123 образцов биоматериала (БАЛ) при диагностической бронхоскопии по соответствующим клиническим показаниями в период от D-100 до D+180 после ТГСК. Культивирование бактерий на селективных средах проводили в аэробных условиях по стандартным методикам, виды бактерий в изолятах идентифицировали с помощью биохимических тестов (BBL Crystal), масс-спектрометрии (MALDI-TOF), чувствительность к антибиотикам – диск-диффузионными тестами. </p> <h3>Результаты</h3> <p style="text-align: justify;"> В целом, частота выявления отдельных бактериальных видов в образцах БАЛ была следующей: <i>K.pneumoniae</i> – 19,1%, <i>P.aeruginosa</i> – 5%, <i>S. epidermidis</i> – 4,2%, <i>S. aureus</i> – 4,5%, <i>Acinetobacter spp.</i> – 3,7%, <i>E.faecium</i> – 7,0%, <i>E.faecalis</i> – 5,3%, <i>E.coli</i> – 2,5%, <i>Enterobacter spp.</i> – 2,3%, <i>Streptococcus pneumoniae</i> – 1,5%, <i>Haemophilus spp.</i> – 0,9% и т.д. Другие микробы <i>Corynebacteria spp., Neisseria spp.</i> и др. встречались реже. Отмечены значительная возрастная динамика состава и частоты различных видов микробиоты в БАЛ после ТГСК. В частности частота высеваемости <i>S.viridans</i> была максимальной у детей младшего возраста (0-5 лет), снижаясь у подростков &gt;15 лет. Та же закономерность, но менее выраженная, отмечена для <i>S.epidermidis</i>. Оба этих микробных вида часто выявляются в нормальной микробиоте. Напротив, частота выявления <i>Klebsiella spp., Pseudomonas spp.</i> и <i>S.aureus</i> в пробах БАЛ после интенсивной терапии и ТГСК повышается с возрастом пациентов, что говорит о большем риске жизнеопасных легочных инфекций после ТГСК, в том числе – резистентными к антибиотикам штаммами из кишечника у взрослых пациентов в период до 180 дней. </p> <h3>Выводы</h3> <p style="text-align: justify;"> У больных с онкогематологическими заболеваниями в течение 6 мес. после ТГСК отмечаются существенные сдвиги бронхоальвеолярной микробиоты. Показана сниженная высеваемость <i>S.viridans</i> и <i> S.epidermidis</i> у детей старше 15 лет и взрослых. Выявлено подавление микробиоты БАЛ в течение 1-го месяца после ТГСК. В более поздние сроки отмечен высокий риск колонизации <i>Klebsiella spp.</i> в связи с селекцией антибиотикорезистентных штаммов. Частота встречаемости <i>K.pneumoniae</i> и ее высокий уровень резистентности показывают актуальность данного патогена в развитии нозокомиальных инфекций у иммунокомпрометированных пациентов. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Трансплантация гемопоэтических клеток, бактериальная микробиота, бронхоальвеолярные смывы, возраст, временной фактор. </p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(288) "Спектр бронхоальвеолярной бактериальной микробиоты после трансплантации гемопоэтических стволовых клеток: возрастная зависимость и нарушения микробиоты" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(288) "Спектр бронхоальвеолярной бактериальной микробиоты после трансплантации гемопоэтических стволовых клеток: возрастная зависимость и нарушения микробиоты" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(288) "Спектр бронхоальвеолярной бактериальной микробиоты после трансплантации гемопоэтических стволовых клеток: возрастная зависимость и нарушения микробиоты" ["SECTION_META_TITLE"]=> string(288) "Спектр бронхоальвеолярной бактериальной микробиоты после трансплантации гемопоэтических стволовых клеток: возрастная зависимость и нарушения микробиоты" ["SECTION_META_KEYWORDS"]=> string(288) "Спектр бронхоальвеолярной бактериальной микробиоты после трансплантации гемопоэтических стволовых клеток: возрастная зависимость и нарушения микробиоты" ["SECTION_META_DESCRIPTION"]=> string(288) "Спектр бронхоальвеолярной бактериальной микробиоты после трансплантации гемопоэтических стволовых клеток: возрастная зависимость и нарушения микробиоты" ["SECTION_PICTURE_FILE_ALT"]=> string(288) "Спектр бронхоальвеолярной бактериальной микробиоты после трансплантации гемопоэтических стволовых клеток: возрастная зависимость и нарушения микробиоты" ["SECTION_PICTURE_FILE_TITLE"]=> string(288) "Спектр бронхоальвеолярной бактериальной микробиоты после трансплантации гемопоэтических стволовых клеток: возрастная зависимость и нарушения микробиоты" 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["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_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"]=> string(2) "25" ["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) "28640" ["VALUE"]=> array(2) { ["TEXT"]=> string(381) "<p>Анна А. Спиридонова^1,3, Алиса Г. Волкова¹, Алексей Б. Чухловин^1,2, Иван С. Моисеев¹, Людмила С. Зубаровская¹, Александр Д. Кулагин¹</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(297) "

Анна А. Спиридонова^1,3, Алиса Г. Волкова¹, Алексей Б. Чухловин^1,2, Иван С. Моисеев¹, Людмила С. Зубаровская¹, Александр Д. Кулагин¹

" ["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"]=> string(2) "26" ["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) "28641" ["VALUE"]=> array(2) { ["TEXT"]=> string(649) "<p>¹ Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия<br> ² Детский научно-клинический центр инфекционных болезней, Санкт-Петербург, Россия<br> ³ Санкт-Петербургский НИИ эпидемиологии и микробиологии им. Пастера, 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(589) "

¹ Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
² Детский научно-клинический центр инфекционных болезней, Санкт-Петербург, Россия
³ Санкт-Петербургский НИИ эпидемиологии и микробиологии им. Пастера, Санкт-Петербург, Россия

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Однако при развитии тяжелых пневмоний, особенно у пациентов с иммунодефицитами, отмечается существенное нарастание количества, частоты выявления и биоразнообразия бактерий в бронхоальвеолярных смывах (БАЛ), наряду с колонизацией бронхов условно патогенными микроорганизмами из других инфицированных сайтов. Так, у многих пациентов с онкологическими заболеваниями на фоне цитостатической терапии развиваются тяжелые пневмонии с полимикробной колонизаций нижних дыхательных путей. Целью нашей работы была сравнительная оценка аэробной и факультативно-анаэробной микробиоты в образцах БАЛ от детей и взрослых пациентов после трансплантации гемопоэтических клеток (ТГСК). </p> <h3>Пациенты и методы</h3> <p style="text-align: justify;"> Проведено обследование 691 пациента, главным образом – с онкогематологическими заболеваниями, леченными цитостатической терапией и ТГСК (алло-ТГСК в 90% случаев). Возраст пациентов составлял от 1 до 71 г. (медиана – 38,5 л.). Применяли миело- или немиелоаблативную кондиционирующую терапию (44% и 56% случаев). Для исследования проводили забор 1123 образцов биоматериала (БАЛ) при диагностической бронхоскопии по соответствующим клиническим показаниями в период от D-100 до D+180 после ТГСК. Культивирование бактерий на селективных средах проводили в аэробных условиях по стандартным методикам, виды бактерий в изолятах идентифицировали с помощью биохимических тестов (BBL Crystal), масс-спектрометрии (MALDI-TOF), чувствительность к антибиотикам – диск-диффузионными тестами. </p> <h3>Результаты</h3> <p style="text-align: justify;"> В целом, частота выявления отдельных бактериальных видов в образцах БАЛ была следующей: <i>K.pneumoniae</i> – 19,1%, <i>P.aeruginosa</i> – 5%, <i>S. epidermidis</i> – 4,2%, <i>S. aureus</i> – 4,5%, <i>Acinetobacter spp.</i> – 3,7%, <i>E.faecium</i> – 7,0%, <i>E.faecalis</i> – 5,3%, <i>E.coli</i> – 2,5%, <i>Enterobacter spp.</i> – 2,3%, <i>Streptococcus pneumoniae</i> – 1,5%, <i>Haemophilus spp.</i> – 0,9% и т.д. Другие микробы <i>Corynebacteria spp., Neisseria spp.</i> и др. встречались реже. Отмечены значительная возрастная динамика состава и частоты различных видов микробиоты в БАЛ после ТГСК. В частности частота высеваемости <i>S.viridans</i> была максимальной у детей младшего возраста (0-5 лет), снижаясь у подростков &gt;15 лет. Та же закономерность, но менее выраженная, отмечена для <i>S.epidermidis</i>. Оба этих микробных вида часто выявляются в нормальной микробиоте. Напротив, частота выявления <i>Klebsiella spp., Pseudomonas spp.</i> и <i>S.aureus</i> в пробах БАЛ после интенсивной терапии и ТГСК повышается с возрастом пациентов, что говорит о большем риске жизнеопасных легочных инфекций после ТГСК, в том числе – резистентными к антибиотикам штаммами из кишечника у взрослых пациентов в период до 180 дней. </p> <h3>Выводы</h3> <p style="text-align: justify;"> У больных с онкогематологическими заболеваниями в течение 6 мес. после ТГСК отмечаются существенные сдвиги бронхоальвеолярной микробиоты. Показана сниженная высеваемость <i>S.viridans</i> и <i> S.epidermidis</i> у детей старше 15 лет и взрослых. Выявлено подавление микробиоты БАЛ в течение 1-го месяца после ТГСК. В более поздние сроки отмечен высокий риск колонизации <i>Klebsiella spp.</i> в связи с селекцией антибиотикорезистентных штаммов. Частота встречаемости <i>K.pneumoniae</i> и ее высокий уровень резистентности показывают актуальность данного патогена в развитии нозокомиальных инфекций у иммунокомпрометированных пациентов. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Трансплантация гемопоэтических клеток, бактериальная микробиота, бронхоальвеолярные смывы, возраст, временной фактор. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(6454) "

Состав микробиоты бронхоальвеолярных отделов у здоровых детей и взрослых в целом коррелирует с составом популяций верхних дыхательных путей. Однако при развитии тяжелых пневмоний, особенно у пациентов с иммунодефицитами, отмечается существенное нарастание количества, частоты выявления и биоразнообразия бактерий в бронхоальвеолярных смывах (БАЛ), наряду с колонизацией бронхов условно патогенными микроорганизмами из других инфицированных сайтов. Так, у многих пациентов с онкологическими заболеваниями на фоне цитостатической терапии развиваются тяжелые пневмонии с полимикробной колонизаций нижних дыхательных путей. Целью нашей работы была сравнительная оценка аэробной и факультативно-анаэробной микробиоты в образцах БАЛ от детей и взрослых пациентов после трансплантации гемопоэтических клеток (ТГСК).

Пациенты и методы

Проведено обследование 691 пациента, главным образом – с онкогематологическими заболеваниями, леченными цитостатической терапией и ТГСК (алло-ТГСК в 90% случаев). Возраст пациентов составлял от 1 до 71 г. (медиана – 38,5 л.). Применяли миело- или немиелоаблативную кондиционирующую терапию (44% и 56% случаев). Для исследования проводили забор 1123 образцов биоматериала (БАЛ) при диагностической бронхоскопии по соответствующим клиническим показаниями в период от D-100 до D+180 после ТГСК. Культивирование бактерий на селективных средах проводили в аэробных условиях по стандартным методикам, виды бактерий в изолятах идентифицировали с помощью биохимических тестов (BBL Crystal), масс-спектрометрии (MALDI-TOF), чувствительность к антибиотикам – диск-диффузионными тестами.

Результаты

В целом, частота выявления отдельных бактериальных видов в образцах БАЛ была следующей: K.pneumoniae – 19,1%, P.aeruginosa – 5%, S. epidermidis – 4,2%, S. aureus – 4,5%, Acinetobacter spp. – 3,7%, E.faecium – 7,0%, E.faecalis – 5,3%, E.coli – 2,5%, Enterobacter spp. – 2,3%, Streptococcus pneumoniae – 1,5%, Haemophilus spp. – 0,9% и т.д. Другие микробы Corynebacteria spp., Neisseria spp. и др. встречались реже. Отмечены значительная возрастная динамика состава и частоты различных видов микробиоты в БАЛ после ТГСК. В частности частота высеваемости S.viridans была максимальной у детей младшего возраста (0-5 лет), снижаясь у подростков >15 лет. Та же закономерность, но менее выраженная, отмечена для S.epidermidis. Оба этих микробных вида часто выявляются в нормальной микробиоте. Напротив, частота выявления Klebsiella spp., Pseudomonas spp. и S.aureus в пробах БАЛ после интенсивной терапии и ТГСК повышается с возрастом пациентов, что говорит о большем риске жизнеопасных легочных инфекций после ТГСК, в том числе – резистентными к антибиотикам штаммами из кишечника у взрослых пациентов в период до 180 дней.

Выводы

У больных с онкогематологическими заболеваниями в течение 6 мес. после ТГСК отмечаются существенные сдвиги бронхоальвеолярной микробиоты. Показана сниженная высеваемость S.viridans и S.epidermidis у детей старше 15 лет и взрослых. Выявлено подавление микробиоты БАЛ в течение 1-го месяца после ТГСК. В более поздние сроки отмечен высокий риск колонизации Klebsiella spp. в связи с селекцией антибиотикорезистентных штаммов. Частота встречаемости K.pneumoniae и ее высокий уровень резистентности показывают актуальность данного патогена в развитии нозокомиальных инфекций у иммунокомпрометированных пациентов.

Ключевые слова

Трансплантация гемопоэтических клеток, бактериальная микробиота, бронхоальвеолярные смывы, возраст, временной фактор.

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Anna A. Spiridonova^1,3, Alisa G. Volkova¹, Alexei B. Chukhlovin^1,2, Ivan S. Moiseev¹, Ludmila S. Zubarovskaya¹, Alexander D. Kulagin¹

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¹ Pavlov University, St. Petersburg, Russia
² Pediatric Research Clinical Center of Infectious Diseases, St. Petersburg, Russia
³ St. Petersburg Pasteur Institute, St. Petersburg, Russia

Correspondence:
Dr. Anna A. Spiridonova, Head, Department of Clinical Microbiology, Pavlov University, 6-8 L.Tolstoy St., 197022, St. Petersburg, Russia
Phone: +7 (921) 920-76-40
E-mail: annaasbac@mail.ru

Citation: Spiridonova AA, Volkova AG, Chukhlovin AB, et al. Spectrum of bronchoalveolar bacterial microbiota following hematopoietic stem cell transplantation: age dependence and microbiota shifts. Cell Ther Transplant 2022; 11(2): 45-53.

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However, pronounced changes of lung microbiota are revealed by analysis of bronchoalveolar lavage (BAL) in severe pneumonias and other pulmonary complications, especially, in immunocompromised patients. E.g., following intensive cytostatic therapy and hematopoietic stem cell transplantation (HSCT), severe impairement of lung microbiota is observed, due to transient cytopenia, immunocompromised state and massive antibiotic prophylaxis. BAL microbiology shows a number of commensal bacteria including potential pathogens from other infectious sites. Hence, the aim of our study was to evaluate the diversity of aerobic and facultative anaerobic microorganisms in BAL samples from the HSCT patients. </p> <h3>Patients and methods</h3> <p style="text-align: justify;"> Our study included 1123 BAL samples from 691 patients subjected to HSCT (1 to 71 years old). The patients were diagnosed, mainly, with myelo- and lymphoproliferative disorders. Myeloablative was carried out in 44% of cases. Stem cells were obtained from bone marrow or peripheral blood (497 <i>vs </i>596 transplants). </p> <p style="text-align: justify;"> The donor types were as follows: related compatible donors (19.2%); related haploidentical donors (21.6%); unrelated compatible donors (49.1%); autologous transplants (10.2%). </p> <p style="text-align: justify;"> Prophylaxis of graft-versus-host disease (GVHD) was mainly performed by the posttransplant cyclophosphamide (PtCy). BAL samples were collected at diagnostic bronchoscopy within D-100 to D+180 post-HSCT, according to appropriate clinical indications. Microbiological cultures and isolation of aerobes and facultative anaerobic bacteria from BAL samples were made by classical bacteriological techniques. Clinical isolates were identified by commercial biochemical test systems, as well as with MALDI-TOF mass spectrometry. The sensitivity of clinical isolates to antibiotics was determined by means of disk diffusion test systems. </p> <h3>Results</h3> <p style="text-align: justify;"> Detection rates of the most common bacteria in BAL were as follows: <i>K.pneumoniae</i>, 19.1%; <i>P.aeruginosa</i>, 5%; <i>S. epidermidis</i>, 4.2%; <i>S. aureus</i>, 4.5%; <i>Acinetobacter spp.</i>, 3.7%; <i>E.faecium</i>, 7.0%; <i>E.faecalis</i>, 5.3%; <i>E.coli</i>, 2.5%; <i>Enterobacter spp.</i>, 2.3%; <i>Streptococcus pneumonia</i>, 1.5%; <i>Haemophilus spp.</i>, 0.9%, etc. The seeding rates for <i>S.viridans</i> and <i>S.epidermidis</i> tended to decrease with age, whereas the rates of <i>Klebsiella</i> detection, proved to be relatively high in all the studied age groups. Total bacterial numbers decreased during 1^st month after HSCT, including those for <i>S.viridans</i>. Interestingly, the incidence of <i>Klebsiella spp.</i> showed sharp increase at 3-4 months posttransplant, due to selection of antibiotic-resistant strains. </p> <h3>Conclusion</h3> <p style="text-align: justify;"> The patients with oncohematological disease subjected to massive allogeneic HSCT exhibit sufficient changes of bronchoalveolar microbiota over first 6 months posttransplant. Decreased seeding levels are shown for <i>S.viridans</i> and <i>S.epidermidis</i> in adolescents over 15 years and adults. A sufficient suppression of BAL microbiota is revealed within 1st month posttransplant. At later terms after HSCT, high risk of <i>Klebsiella spp.</i> colonization is observed, due to selection of antibiotic-resistant strains. Higher incidence of <i>K.pneumoniae</i> and its high resistance rates suggest relevance of this pathogen for development of nosocomial infections in immunocompromised patients and other clinical settings. </p> <h2>Keywords</h2> <p style="text-align: justify;"> Hematopoietic stem cell transplantation, bacterial microbiota, bronchoalveolar lavage, age dependence, time dependence. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4034) "

In healthy persons, lung microbiota shows close correlations with microbial landscape of upper respiratory tract. However, pronounced changes of lung microbiota are revealed by analysis of bronchoalveolar lavage (BAL) in severe pneumonias and other pulmonary complications, especially, in immunocompromised patients. E.g., following intensive cytostatic therapy and hematopoietic stem cell transplantation (HSCT), severe impairement of lung microbiota is observed, due to transient cytopenia, immunocompromised state and massive antibiotic prophylaxis. BAL microbiology shows a number of commensal bacteria including potential pathogens from other infectious sites. Hence, the aim of our study was to evaluate the diversity of aerobic and facultative anaerobic microorganisms in BAL samples from the HSCT patients.

Patients and methods

Our study included 1123 BAL samples from 691 patients subjected to HSCT (1 to 71 years old). The patients were diagnosed, mainly, with myelo- and lymphoproliferative disorders. Myeloablative was carried out in 44% of cases. Stem cells were obtained from bone marrow or peripheral blood (497 vs 596 transplants).

The donor types were as follows: related compatible donors (19.2%); related haploidentical donors (21.6%); unrelated compatible donors (49.1%); autologous transplants (10.2%).

Prophylaxis of graft-versus-host disease (GVHD) was mainly performed by the posttransplant cyclophosphamide (PtCy). BAL samples were collected at diagnostic bronchoscopy within D-100 to D+180 post-HSCT, according to appropriate clinical indications. Microbiological cultures and isolation of aerobes and facultative anaerobic bacteria from BAL samples were made by classical bacteriological techniques. Clinical isolates were identified by commercial biochemical test systems, as well as with MALDI-TOF mass spectrometry. The sensitivity of clinical isolates to antibiotics was determined by means of disk diffusion test systems.

Results

Detection rates of the most common bacteria in BAL were as follows: K.pneumoniae, 19.1%; P.aeruginosa, 5%; S. epidermidis, 4.2%; S. aureus, 4.5%; Acinetobacter spp., 3.7%; E.faecium, 7.0%; E.faecalis, 5.3%; E.coli, 2.5%; Enterobacter spp., 2.3%; Streptococcus pneumonia, 1.5%; Haemophilus spp., 0.9%, etc. The seeding rates for S.viridans and S.epidermidis tended to decrease with age, whereas the rates of Klebsiella detection, proved to be relatively high in all the studied age groups. Total bacterial numbers decreased during 1^st month after HSCT, including those for S.viridans. Interestingly, the incidence of Klebsiella spp. showed sharp increase at 3-4 months posttransplant, due to selection of antibiotic-resistant strains.

Conclusion

The patients with oncohematological disease subjected to massive allogeneic HSCT exhibit sufficient changes of bronchoalveolar microbiota over first 6 months posttransplant. Decreased seeding levels are shown for S.viridans and S.epidermidis in adolescents over 15 years and adults. A sufficient suppression of BAL microbiota is revealed within 1st month posttransplant. At later terms after HSCT, high risk of Klebsiella spp. colonization is observed, due to selection of antibiotic-resistant strains. Higher incidence of K.pneumoniae and its high resistance rates suggest relevance of this pathogen for development of nosocomial infections in immunocompromised patients and other clinical settings.

Keywords

Hematopoietic stem cell transplantation, bacterial microbiota, bronchoalveolar lavage, age dependence, time dependence.

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Spiridonova^1,3, Alisa G. Volkova¹, Alexei B. Chukhlovin^1,2, Ivan S. Moiseev¹, Ludmila S. Zubarovskaya¹, Alexander D. Kulagin¹</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(206) "

Anna A. Spiridonova^1,3, Alisa G. Volkova¹, Alexei B. Chukhlovin^1,2, Ivan S. Moiseev¹, Ludmila S. Zubarovskaya¹, Alexander D. Kulagin¹

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Anna A. Spiridonova^1,3, Alisa G. Volkova¹, Alexei B. Chukhlovin^1,2, Ivan S. Moiseev¹, Ludmila S. Zubarovskaya¹, Alexander D. Kulagin¹

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However, pronounced changes of lung microbiota are revealed by analysis of bronchoalveolar lavage (BAL) in severe pneumonias and other pulmonary complications, especially, in immunocompromised patients. E.g., following intensive cytostatic therapy and hematopoietic stem cell transplantation (HSCT), severe impairement of lung microbiota is observed, due to transient cytopenia, immunocompromised state and massive antibiotic prophylaxis. BAL microbiology shows a number of commensal bacteria including potential pathogens from other infectious sites. Hence, the aim of our study was to evaluate the diversity of aerobic and facultative anaerobic microorganisms in BAL samples from the HSCT patients. </p> <h3>Patients and methods</h3> <p style="text-align: justify;"> Our study included 1123 BAL samples from 691 patients subjected to HSCT (1 to 71 years old). The patients were diagnosed, mainly, with myelo- and lymphoproliferative disorders. Myeloablative was carried out in 44% of cases. Stem cells were obtained from bone marrow or peripheral blood (497 <i>vs </i>596 transplants). </p> <p style="text-align: justify;"> The donor types were as follows: related compatible donors (19.2%); related haploidentical donors (21.6%); unrelated compatible donors (49.1%); autologous transplants (10.2%). </p> <p style="text-align: justify;"> Prophylaxis of graft-versus-host disease (GVHD) was mainly performed by the posttransplant cyclophosphamide (PtCy). BAL samples were collected at diagnostic bronchoscopy within D-100 to D+180 post-HSCT, according to appropriate clinical indications. Microbiological cultures and isolation of aerobes and facultative anaerobic bacteria from BAL samples were made by classical bacteriological techniques. Clinical isolates were identified by commercial biochemical test systems, as well as with MALDI-TOF mass spectrometry. The sensitivity of clinical isolates to antibiotics was determined by means of disk diffusion test systems. </p> <h3>Results</h3> <p style="text-align: justify;"> Detection rates of the most common bacteria in BAL were as follows: <i>K.pneumoniae</i>, 19.1%; <i>P.aeruginosa</i>, 5%; <i>S. epidermidis</i>, 4.2%; <i>S. aureus</i>, 4.5%; <i>Acinetobacter spp.</i>, 3.7%; <i>E.faecium</i>, 7.0%; <i>E.faecalis</i>, 5.3%; <i>E.coli</i>, 2.5%; <i>Enterobacter spp.</i>, 2.3%; <i>Streptococcus pneumonia</i>, 1.5%; <i>Haemophilus spp.</i>, 0.9%, etc. The seeding rates for <i>S.viridans</i> and <i>S.epidermidis</i> tended to decrease with age, whereas the rates of <i>Klebsiella</i> detection, proved to be relatively high in all the studied age groups. Total bacterial numbers decreased during 1^st month after HSCT, including those for <i>S.viridans</i>. Interestingly, the incidence of <i>Klebsiella spp.</i> showed sharp increase at 3-4 months posttransplant, due to selection of antibiotic-resistant strains. </p> <h3>Conclusion</h3> <p style="text-align: justify;"> The patients with oncohematological disease subjected to massive allogeneic HSCT exhibit sufficient changes of bronchoalveolar microbiota over first 6 months posttransplant. Decreased seeding levels are shown for <i>S.viridans</i> and <i>S.epidermidis</i> in adolescents over 15 years and adults. A sufficient suppression of BAL microbiota is revealed within 1st month posttransplant. At later terms after HSCT, high risk of <i>Klebsiella spp.</i> colonization is observed, due to selection of antibiotic-resistant strains. Higher incidence of <i>K.pneumoniae</i> and its high resistance rates suggest relevance of this pathogen for development of nosocomial infections in immunocompromised patients and other clinical settings. </p> <h2>Keywords</h2> <p style="text-align: justify;"> Hematopoietic stem cell transplantation, bacterial microbiota, bronchoalveolar lavage, age dependence, time dependence. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4034) "

In healthy persons, lung microbiota shows close correlations with microbial landscape of upper respiratory tract. However, pronounced changes of lung microbiota are revealed by analysis of bronchoalveolar lavage (BAL) in severe pneumonias and other pulmonary complications, especially, in immunocompromised patients. E.g., following intensive cytostatic therapy and hematopoietic stem cell transplantation (HSCT), severe impairement of lung microbiota is observed, due to transient cytopenia, immunocompromised state and massive antibiotic prophylaxis. BAL microbiology shows a number of commensal bacteria including potential pathogens from other infectious sites. Hence, the aim of our study was to evaluate the diversity of aerobic and facultative anaerobic microorganisms in BAL samples from the HSCT patients.

Patients and methods

Our study included 1123 BAL samples from 691 patients subjected to HSCT (1 to 71 years old). The patients were diagnosed, mainly, with myelo- and lymphoproliferative disorders. Myeloablative was carried out in 44% of cases. Stem cells were obtained from bone marrow or peripheral blood (497 vs 596 transplants).

The donor types were as follows: related compatible donors (19.2%); related haploidentical donors (21.6%); unrelated compatible donors (49.1%); autologous transplants (10.2%).

Prophylaxis of graft-versus-host disease (GVHD) was mainly performed by the posttransplant cyclophosphamide (PtCy). BAL samples were collected at diagnostic bronchoscopy within D-100 to D+180 post-HSCT, according to appropriate clinical indications. Microbiological cultures and isolation of aerobes and facultative anaerobic bacteria from BAL samples were made by classical bacteriological techniques. Clinical isolates were identified by commercial biochemical test systems, as well as with MALDI-TOF mass spectrometry. The sensitivity of clinical isolates to antibiotics was determined by means of disk diffusion test systems.

Results

Detection rates of the most common bacteria in BAL were as follows: K.pneumoniae, 19.1%; P.aeruginosa, 5%; S. epidermidis, 4.2%; S. aureus, 4.5%; Acinetobacter spp., 3.7%; E.faecium, 7.0%; E.faecalis, 5.3%; E.coli, 2.5%; Enterobacter spp., 2.3%; Streptococcus pneumonia, 1.5%; Haemophilus spp., 0.9%, etc. The seeding rates for S.viridans and S.epidermidis tended to decrease with age, whereas the rates of Klebsiella detection, proved to be relatively high in all the studied age groups. Total bacterial numbers decreased during 1^st month after HSCT, including those for S.viridans. Interestingly, the incidence of Klebsiella spp. showed sharp increase at 3-4 months posttransplant, due to selection of antibiotic-resistant strains.

Conclusion

The patients with oncohematological disease subjected to massive allogeneic HSCT exhibit sufficient changes of bronchoalveolar microbiota over first 6 months posttransplant. Decreased seeding levels are shown for S.viridans and S.epidermidis in adolescents over 15 years and adults. A sufficient suppression of BAL microbiota is revealed within 1st month posttransplant. At later terms after HSCT, high risk of Klebsiella spp. colonization is observed, due to selection of antibiotic-resistant strains. Higher incidence of K.pneumoniae and its high resistance rates suggest relevance of this pathogen for development of nosocomial infections in immunocompromised patients and other clinical settings.

Keywords

Hematopoietic stem cell transplantation, bacterial microbiota, bronchoalveolar lavage, age dependence, time dependence.

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In healthy persons, lung microbiota shows close correlations with microbial landscape of upper respiratory tract. However, pronounced changes of lung microbiota are revealed by analysis of bronchoalveolar lavage (BAL) in severe pneumonias and other pulmonary complications, especially, in immunocompromised patients. E.g., following intensive cytostatic therapy and hematopoietic stem cell transplantation (HSCT), severe impairement of lung microbiota is observed, due to transient cytopenia, immunocompromised state and massive antibiotic prophylaxis. BAL microbiology shows a number of commensal bacteria including potential pathogens from other infectious sites. Hence, the aim of our study was to evaluate the diversity of aerobic and facultative anaerobic microorganisms in BAL samples from the HSCT patients.

Patients and methods

Our study included 1123 BAL samples from 691 patients subjected to HSCT (1 to 71 years old). The patients were diagnosed, mainly, with myelo- and lymphoproliferative disorders. Myeloablative was carried out in 44% of cases. Stem cells were obtained from bone marrow or peripheral blood (497 vs 596 transplants).

The donor types were as follows: related compatible donors (19.2%); related haploidentical donors (21.6%); unrelated compatible donors (49.1%); autologous transplants (10.2%).

Prophylaxis of graft-versus-host disease (GVHD) was mainly performed by the posttransplant cyclophosphamide (PtCy). BAL samples were collected at diagnostic bronchoscopy within D-100 to D+180 post-HSCT, according to appropriate clinical indications. Microbiological cultures and isolation of aerobes and facultative anaerobic bacteria from BAL samples were made by classical bacteriological techniques. Clinical isolates were identified by commercial biochemical test systems, as well as with MALDI-TOF mass spectrometry. The sensitivity of clinical isolates to antibiotics was determined by means of disk diffusion test systems.

Results

Detection rates of the most common bacteria in BAL were as follows: K.pneumoniae, 19.1%; P.aeruginosa, 5%; S. epidermidis, 4.2%; S. aureus, 4.5%; Acinetobacter spp., 3.7%; E.faecium, 7.0%; E.faecalis, 5.3%; E.coli, 2.5%; Enterobacter spp., 2.3%; Streptococcus pneumonia, 1.5%; Haemophilus spp., 0.9%, etc. The seeding rates for S.viridans and S.epidermidis tended to decrease with age, whereas the rates of Klebsiella detection, proved to be relatively high in all the studied age groups. Total bacterial numbers decreased during 1^st month after HSCT, including those for S.viridans. Interestingly, the incidence of Klebsiella spp. showed sharp increase at 3-4 months posttransplant, due to selection of antibiotic-resistant strains.

Conclusion

The patients with oncohematological disease subjected to massive allogeneic HSCT exhibit sufficient changes of bronchoalveolar microbiota over first 6 months posttransplant. Decreased seeding levels are shown for S.viridans and S.epidermidis in adolescents over 15 years and adults. A sufficient suppression of BAL microbiota is revealed within 1st month posttransplant. At later terms after HSCT, high risk of Klebsiella spp. colonization is observed, due to selection of antibiotic-resistant strains. Higher incidence of K.pneumoniae and its high resistance rates suggest relevance of this pathogen for development of nosocomial infections in immunocompromised patients and other clinical settings.

Keywords

Hematopoietic stem cell transplantation, bacterial microbiota, bronchoalveolar lavage, age dependence, time dependence.

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¹ Pavlov University, St. Petersburg, Russia
² Pediatric Research Clinical Center of Infectious Diseases, St. Petersburg, Russia
³ St. Petersburg Pasteur Institute, St. Petersburg, Russia

Correspondence:
Dr. Anna A. Spiridonova, Head, Department of Clinical Microbiology, Pavlov University, 6-8 L.Tolstoy St., 197022, St. Petersburg, Russia
Phone: +7 (921) 920-76-40
E-mail: annaasbac@mail.ru

Citation: Spiridonova AA, Volkova AG, Chukhlovin AB, et al. Spectrum of bronchoalveolar bacterial microbiota following hematopoietic stem cell transplantation: age dependence and microbiota shifts. Cell Ther Transplant 2022; 11(2): 45-53.

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¹ Pavlov University, St. Petersburg, Russia
² Pediatric Research Clinical Center of Infectious Diseases, St. Petersburg, Russia
³ St. Petersburg Pasteur Institute, St. Petersburg, Russia

Correspondence:
Dr. Anna A. Spiridonova, Head, Department of Clinical Microbiology, Pavlov University, 6-8 L.Tolstoy St., 197022, St. Petersburg, Russia
Phone: +7 (921) 920-76-40
E-mail: annaasbac@mail.ru

Citation: Spiridonova AA, Volkova AG, Chukhlovin AB, et al. Spectrum of bronchoalveolar bacterial microbiota following hematopoietic stem cell transplantation: age dependence and microbiota shifts. Cell Ther Transplant 2022; 11(2): 45-53.

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Анна А. Спиридонова^1,3, Алиса Г. Волкова¹, Алексей Б. Чухловин^1,2, Иван С. Моисеев¹, Людмила С. Зубаровская¹, Александр Д. Кулагин¹

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Анна А. Спиридонова^1,3, Алиса Г. Волкова¹, Алексей Б. Чухловин^1,2, Иван С. Моисеев¹, Людмила С. Зубаровская¹, Александр Д. Кулагин¹

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Однако при развитии тяжелых пневмоний, особенно у пациентов с иммунодефицитами, отмечается существенное нарастание количества, частоты выявления и биоразнообразия бактерий в бронхоальвеолярных смывах (БАЛ), наряду с колонизацией бронхов условно патогенными микроорганизмами из других инфицированных сайтов. Так, у многих пациентов с онкологическими заболеваниями на фоне цитостатической терапии развиваются тяжелые пневмонии с полимикробной колонизаций нижних дыхательных путей. Целью нашей работы была сравнительная оценка аэробной и факультативно-анаэробной микробиоты в образцах БАЛ от детей и взрослых пациентов после трансплантации гемопоэтических клеток (ТГСК). </p> <h3>Пациенты и методы</h3> <p style="text-align: justify;"> Проведено обследование 691 пациента, главным образом – с онкогематологическими заболеваниями, леченными цитостатической терапией и ТГСК (алло-ТГСК в 90% случаев). Возраст пациентов составлял от 1 до 71 г. (медиана – 38,5 л.). Применяли миело- или немиелоаблативную кондиционирующую терапию (44% и 56% случаев). Для исследования проводили забор 1123 образцов биоматериала (БАЛ) при диагностической бронхоскопии по соответствующим клиническим показаниями в период от D-100 до D+180 после ТГСК. Культивирование бактерий на селективных средах проводили в аэробных условиях по стандартным методикам, виды бактерий в изолятах идентифицировали с помощью биохимических тестов (BBL Crystal), масс-спектрометрии (MALDI-TOF), чувствительность к антибиотикам – диск-диффузионными тестами. </p> <h3>Результаты</h3> <p style="text-align: justify;"> В целом, частота выявления отдельных бактериальных видов в образцах БАЛ была следующей: <i>K.pneumoniae</i> – 19,1%, <i>P.aeruginosa</i> – 5%, <i>S. epidermidis</i> – 4,2%, <i>S. aureus</i> – 4,5%, <i>Acinetobacter spp.</i> – 3,7%, <i>E.faecium</i> – 7,0%, <i>E.faecalis</i> – 5,3%, <i>E.coli</i> – 2,5%, <i>Enterobacter spp.</i> – 2,3%, <i>Streptococcus pneumoniae</i> – 1,5%, <i>Haemophilus spp.</i> – 0,9% и т.д. Другие микробы <i>Corynebacteria spp., Neisseria spp.</i> и др. встречались реже. Отмечены значительная возрастная динамика состава и частоты различных видов микробиоты в БАЛ после ТГСК. В частности частота высеваемости <i>S.viridans</i> была максимальной у детей младшего возраста (0-5 лет), снижаясь у подростков &gt;15 лет. Та же закономерность, но менее выраженная, отмечена для <i>S.epidermidis</i>. Оба этих микробных вида часто выявляются в нормальной микробиоте. Напротив, частота выявления <i>Klebsiella spp., Pseudomonas spp.</i> и <i>S.aureus</i> в пробах БАЛ после интенсивной терапии и ТГСК повышается с возрастом пациентов, что говорит о большем риске жизнеопасных легочных инфекций после ТГСК, в том числе – резистентными к антибиотикам штаммами из кишечника у взрослых пациентов в период до 180 дней. </p> <h3>Выводы</h3> <p style="text-align: justify;"> У больных с онкогематологическими заболеваниями в течение 6 мес. после ТГСК отмечаются существенные сдвиги бронхоальвеолярной микробиоты. Показана сниженная высеваемость <i>S.viridans</i> и <i> S.epidermidis</i> у детей старше 15 лет и взрослых. Выявлено подавление микробиоты БАЛ в течение 1-го месяца после ТГСК. В более поздние сроки отмечен высокий риск колонизации <i>Klebsiella spp.</i> в связи с селекцией антибиотикорезистентных штаммов. Частота встречаемости <i>K.pneumoniae</i> и ее высокий уровень резистентности показывают актуальность данного патогена в развитии нозокомиальных инфекций у иммунокомпрометированных пациентов. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Трансплантация гемопоэтических клеток, бактериальная микробиота, бронхоальвеолярные смывы, возраст, временной фактор. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(6454) "

Состав микробиоты бронхоальвеолярных отделов у здоровых детей и взрослых в целом коррелирует с составом популяций верхних дыхательных путей. Однако при развитии тяжелых пневмоний, особенно у пациентов с иммунодефицитами, отмечается существенное нарастание количества, частоты выявления и биоразнообразия бактерий в бронхоальвеолярных смывах (БАЛ), наряду с колонизацией бронхов условно патогенными микроорганизмами из других инфицированных сайтов. Так, у многих пациентов с онкологическими заболеваниями на фоне цитостатической терапии развиваются тяжелые пневмонии с полимикробной колонизаций нижних дыхательных путей. Целью нашей работы была сравнительная оценка аэробной и факультативно-анаэробной микробиоты в образцах БАЛ от детей и взрослых пациентов после трансплантации гемопоэтических клеток (ТГСК).

Пациенты и методы

Проведено обследование 691 пациента, главным образом – с онкогематологическими заболеваниями, леченными цитостатической терапией и ТГСК (алло-ТГСК в 90% случаев). Возраст пациентов составлял от 1 до 71 г. (медиана – 38,5 л.). Применяли миело- или немиелоаблативную кондиционирующую терапию (44% и 56% случаев). Для исследования проводили забор 1123 образцов биоматериала (БАЛ) при диагностической бронхоскопии по соответствующим клиническим показаниями в период от D-100 до D+180 после ТГСК. Культивирование бактерий на селективных средах проводили в аэробных условиях по стандартным методикам, виды бактерий в изолятах идентифицировали с помощью биохимических тестов (BBL Crystal), масс-спектрометрии (MALDI-TOF), чувствительность к антибиотикам – диск-диффузионными тестами.

Результаты

В целом, частота выявления отдельных бактериальных видов в образцах БАЛ была следующей: K.pneumoniae – 19,1%, P.aeruginosa – 5%, S. epidermidis – 4,2%, S. aureus – 4,5%, Acinetobacter spp. – 3,7%, E.faecium – 7,0%, E.faecalis – 5,3%, E.coli – 2,5%, Enterobacter spp. – 2,3%, Streptococcus pneumoniae – 1,5%, Haemophilus spp. – 0,9% и т.д. Другие микробы Corynebacteria spp., Neisseria spp. и др. встречались реже. Отмечены значительная возрастная динамика состава и частоты различных видов микробиоты в БАЛ после ТГСК. В частности частота высеваемости S.viridans была максимальной у детей младшего возраста (0-5 лет), снижаясь у подростков >15 лет. Та же закономерность, но менее выраженная, отмечена для S.epidermidis. Оба этих микробных вида часто выявляются в нормальной микробиоте. Напротив, частота выявления Klebsiella spp., Pseudomonas spp. и S.aureus в пробах БАЛ после интенсивной терапии и ТГСК повышается с возрастом пациентов, что говорит о большем риске жизнеопасных легочных инфекций после ТГСК, в том числе – резистентными к антибиотикам штаммами из кишечника у взрослых пациентов в период до 180 дней.

Выводы

У больных с онкогематологическими заболеваниями в течение 6 мес. после ТГСК отмечаются существенные сдвиги бронхоальвеолярной микробиоты. Показана сниженная высеваемость S.viridans и S.epidermidis у детей старше 15 лет и взрослых. Выявлено подавление микробиоты БАЛ в течение 1-го месяца после ТГСК. В более поздние сроки отмечен высокий риск колонизации Klebsiella spp. в связи с селекцией антибиотикорезистентных штаммов. Частота встречаемости K.pneumoniae и ее высокий уровень резистентности показывают актуальность данного патогена в развитии нозокомиальных инфекций у иммунокомпрометированных пациентов.

Ключевые слова

Трансплантация гемопоэтических клеток, бактериальная микробиота, бронхоальвеолярные смывы, возраст, временной фактор.

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Состав микробиоты бронхоальвеолярных отделов у здоровых детей и взрослых в целом коррелирует с составом популяций верхних дыхательных путей. Однако при развитии тяжелых пневмоний, особенно у пациентов с иммунодефицитами, отмечается существенное нарастание количества, частоты выявления и биоразнообразия бактерий в бронхоальвеолярных смывах (БАЛ), наряду с колонизацией бронхов условно патогенными микроорганизмами из других инфицированных сайтов. Так, у многих пациентов с онкологическими заболеваниями на фоне цитостатической терапии развиваются тяжелые пневмонии с полимикробной колонизаций нижних дыхательных путей. Целью нашей работы была сравнительная оценка аэробной и факультативно-анаэробной микробиоты в образцах БАЛ от детей и взрослых пациентов после трансплантации гемопоэтических клеток (ТГСК).

Пациенты и методы

Проведено обследование 691 пациента, главным образом – с онкогематологическими заболеваниями, леченными цитостатической терапией и ТГСК (алло-ТГСК в 90% случаев). Возраст пациентов составлял от 1 до 71 г. (медиана – 38,5 л.). Применяли миело- или немиелоаблативную кондиционирующую терапию (44% и 56% случаев). Для исследования проводили забор 1123 образцов биоматериала (БАЛ) при диагностической бронхоскопии по соответствующим клиническим показаниями в период от D-100 до D+180 после ТГСК. Культивирование бактерий на селективных средах проводили в аэробных условиях по стандартным методикам, виды бактерий в изолятах идентифицировали с помощью биохимических тестов (BBL Crystal), масс-спектрометрии (MALDI-TOF), чувствительность к антибиотикам – диск-диффузионными тестами.

Результаты

В целом, частота выявления отдельных бактериальных видов в образцах БАЛ была следующей: K.pneumoniae – 19,1%, P.aeruginosa – 5%, S. epidermidis – 4,2%, S. aureus – 4,5%, Acinetobacter spp. – 3,7%, E.faecium – 7,0%, E.faecalis – 5,3%, E.coli – 2,5%, Enterobacter spp. – 2,3%, Streptococcus pneumoniae – 1,5%, Haemophilus spp. – 0,9% и т.д. Другие микробы Corynebacteria spp., Neisseria spp. и др. встречались реже. Отмечены значительная возрастная динамика состава и частоты различных видов микробиоты в БАЛ после ТГСК. В частности частота высеваемости S.viridans была максимальной у детей младшего возраста (0-5 лет), снижаясь у подростков >15 лет. Та же закономерность, но менее выраженная, отмечена для S.epidermidis. Оба этих микробных вида часто выявляются в нормальной микробиоте. Напротив, частота выявления Klebsiella spp., Pseudomonas spp. и S.aureus в пробах БАЛ после интенсивной терапии и ТГСК повышается с возрастом пациентов, что говорит о большем риске жизнеопасных легочных инфекций после ТГСК, в том числе – резистентными к антибиотикам штаммами из кишечника у взрослых пациентов в период до 180 дней.

Выводы

У больных с онкогематологическими заболеваниями в течение 6 мес. после ТГСК отмечаются существенные сдвиги бронхоальвеолярной микробиоты. Показана сниженная высеваемость S.viridans и S.epidermidis у детей старше 15 лет и взрослых. Выявлено подавление микробиоты БАЛ в течение 1-го месяца после ТГСК. В более поздние сроки отмечен высокий риск колонизации Klebsiella spp. в связи с селекцией антибиотикорезистентных штаммов. Частота встречаемости K.pneumoniae и ее высокий уровень резистентности показывают актуальность данного патогена в развитии нозокомиальных инфекций у иммунокомпрометированных пациентов.

Ключевые слова

Трансплантация гемопоэтических клеток, бактериальная микробиота, бронхоальвеолярные смывы, возраст, временной фактор.

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¹ Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
² Детский научно-клинический центр инфекционных болезней, Санкт-Петербург, Россия
³ Санкт-Петербургский НИИ эпидемиологии и микробиологии им. Пастера, Санкт-Петербург, Россия

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¹ Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
² Детский научно-клинический центр инфекционных болезней, Санкт-Петербург, Россия
³ Санкт-Петербургский НИИ эпидемиологии и микробиологии им. Пастера, Санкт-Петербург, Россия

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Introduction

Since introduction of Milan criteria, an excellent outcomes of liver transplantation (LT) for hepatocellular carcinoma (HCC) were validated [1-3]. Unfortunately, this favorable outcome is not always achievable. The risk for recurrent HCC (rHCC) is still reported in approximately one-fifth of patients transplanted for presence of HCC. The occurrence of rHCC is a significant setback in the clinical course of affected patients with dismal prognosis reported in most instances [4-9].

Furthermore, the incidence of rHCC poses significant ethical concerns about current allocation system which favors transplantation of more HCC patients. The number of transplanted HCC patients has been reported to be steadily increasing over last two decades. The transplantation activity causes increased burden of already limited deceased donor pool, or provokes a debate over the living donation outcomes [10, 11].

It is therefore crucial to report the cases of rHCC following liver transplantation, to identify their clinical patterns, and to promote development of screening protocols for their early detection and treatment. Moreover, a comprehensive analysis should be made for identifying the risk factors associated with HCC recurrence.

This study aims primarily at reporting of the incidence of recurrent HCC following liver transplantation, to describe their clinical patterns, current therapeutic modalities at our center. It also addresses potential risk factors of HCC recurrence, by comparing them to the data reported elsewhere.

Materials and methods

A total of 178 patients diagnosed for having HCC approved the research consent and were subsequently included in the study. The clinical charts for those patients considered for liver transplant at our center were retrospectively reviewed. HCC at our center is diagnosed by contrast-enhanced computed tomography (CT) and/or abdominal magnetic resonance imaging (MRI). Staging was based on chest CT, cranial CT, and technetium-99m bone scintigraphy, to exclude extra-hepatic disease.

Current study was approved by our institutional Research Ethical Committee under the 8/11/09/02/2020 code. The ethical approval was obtained before conduction of this study. Patients were consented to use medical charts to obtain pertinent medical information for research purposes only. Extensive efforts to protect patients’ identity were also ensured. In accordance with Declaration of Helsinki, all the patients were consented about their clinical management and were also informed that their decision to approve or disapprove the research consent will not influence their clinical management.

Our center currently adopts Milan Criteria (MC) as the standard criteria for LT for HCC. Any patient who is beyond MC is usually considered for a downstaging protocol using one or more locoregional therapies to downstage the tumor to within MC. LT for the down-staged patients is considered after further confirmation of the absence of extrahepatic disease. Pretransplant locoregional therapies included radiofrequency ablation (RFA), trans-arterial chemotherapy (TACE) and/or trans-arterial radiotherapy (TARE). Cases which were found unfit for liver transplantation were excluded from the study.

LT was performed using either deceased donor liver transplants (DDLT), or liver transplantation from a living donor (LDLT). The LDLT donors were first- and second-degree relatives of respective patients. Cases of pediatric LT or liver re-transplantation were excluded from this study.

The liver explants were studied for presence of HCC lesions. Size, number, tumor grade, and lymph vascular invasion were reported by an experienced liver transplant pathologist. Triple immunosuppression protocol was utilized for LT recipients including calcineurin inhibitors (CNI) corticosteroids and mycophenolate mofetil.

İn addition to routine liver transplant follow-up protocol, the patients transplanted for HCC were followed up by liver ultrasound, α-fetoprotein (AFP), and liver function tests at six-month intervals for the rest of their lives. The cases with new focal liver lesion were further diagnosed by contrast-enhanced dynamic study to characterize this lesions, and liver biopsy was also taken to diagnose uncertain cases. The recurrent HCC (rHCC) cases were identified, and their clinical data were comprehensively collected.

Demographic data, pretransplant variables, transplant-related variables as well as characteristics of malignancies (number of lesions, tumor size and grade, lymph vascular invasion) were retrieved from the patient charts. Additionally, risk estimation of tumor recurrence after transplant (RETREAT score) was calculated [12], and these data were correlated with HCC recurrence. The data were analyzed by means of t-test and chi-square test. P-value of <0.05 was considered statistically significant. Kaplan-Meier curves were used to express survival outcomes and its significance was determined by log-rank test.

Results

A total of 178 patients presenting with HCC agreed to participate in the study. Fig. 1 shows their distribution as regards liver transplant, downstaging locoregional therapy (LRT) and incidence of recurrent HCC.

Figure 1. Distribution of HCC patients according to LT, LRT, and incidence of rHCC

148 adult patients underwent LT due to presence of HCC at our institution between August 2006 and December 2020. They included 93 males (62.8%) and 55 females (37.2%), ninety-six of them were within Milan criteria. The mean post-transplant follow-up for the studied patients was 53±34.8 months, range from 24.3 to 160.1 months. The overall 5-year survival of patients, grafts, and tumor-free survival were 72.7%, 90.8% and 87.7%, respectively (Fig. 2).

Figure 2. Overall patient, graft and tumor-free survival following LT for HCC patients

A total of 16 patients had HCC recurrence during the follow-up period (8.9% of transplanted HCC patients). Of them, eleven rHCC cases were registered in males. Nevertheless, gender factor did not differ significantly between patients with HCC recurrence compared to those with no rHCC (P=0.6). The mean age at HCC recurrence was 60.8±4.1 years. The current study demonstrated that most HCC recurrencies (68.8%) were observed within two years from liver transplant. Moreover, elevated AFP and distant metastases (mainly, lung lesions) dominated in clinical pattern in 87.5% and 56.3% of rHCC patients, respectively (Table 1).

Vascular invasion, poor tumor differentiation and RETREAT score differed significantly between the patients with rHCC and patients with no HCC recurrence. On the other hand, transplant criteria, type of transplant and total tumor volume (TTV)>115 cm³ showed no significant difference (Table 2). Correlation between RETREAT score, transplant criteria, and HCC recurrence is shown in Table 3.

Unfortunately, all rHCC cases in the current study were beyond surgical or locoregional therapy. Sorafenib was administered to these patients as a supportive measure. None of these patients were alive at the time of current report, their median survival following rHCC diagnosis was 135±11.5 days.

Table 2. Transplant and tumor-related variables for rHCC following liver transplantation

Table 3. Correlation between RETREAT score, transplant criteria and HCC recurrence

Discussion

The results of current study compare well with medical literature as regards the overall excellent outcome for transplanted HCC patients and the overall rate of rHCC [2, 3]. Filgueira et al., reported rHCC in 15-20% of transplanted HCC patients within a median of 12-16 months form liver transplant with around 75% occurring in the first two years. Timing of HCC recurrence in the current study was within two years following liver transplant in 68.8% of patients.

Filgueira et al. reported a poor prognosis for rHCC patients with median survival of 7-16 months from diagnosis of recurrence. They also claimed that HCC recurrence should be considered a systemic disease as only 30% of patients show isolated hepatic recurrence [4]. Chagas et al., reported 8% HCC recurrence rate and isolated hepatic recurrence in more than one-quarter of patients. Post-recurrence survival rates were 34% at 1 year compared to 0% in the current study [5].

Filgueira et al., reported that curative therapeutic modalities including reaction and ablative techniques are of value specially in cases where a smaller number and size of lesions is detected provided the disease is strictly confined to the liver. They quoted significantly longer median survival (22 months compared to 9 months in those with palliative treatment only) [5].

In the current study, it was noted that rHCC presentation is of the very late pattern, where there are limited options for therapeutic options and only palliation is possible. This might indicate vulnerability in screening protocol for rHCC and immunosuppression in the current study. It calls for more tailored approach for patients with high risk for HCC recurrence.

The use of rapamycin in patient transplanted for HCC was suggested and practiced in many transplant center [13-15]. It was hypothesized that rapamycin will improve recurrence free survival in these vulnerable patients. Nevertheless; (SiLVER trial) failed to show such effect [16].

Risk factors for HCC recurrence were traditionally reported to include male gender, those beyond Milan criteria, or those with partial response to LRT, AFP >400 ng/dL, those microvascular invasion, poor differentiation, TTV>115 cm³, and LDLT [6-9].

Only vascular invasion and poor tumor differentiation were shown to significantly related to HCC recurrence in the current study. Conversely, transplant criteria, TTV and type of transplant did not show significant relation.

As regards HCC outcome, much emphasis was always credited to the classical volume related tumor criteria e.g., number of HCC lesions, size of the HCC lesions, TTV, etc. the results of current study confirm that volume related criteria are at least insufficient to predict high risk patients for HCC recurrence [17-21]. More factors should be included in this regards namely, the biology-related tumor criteria e.g., poor differentiation, and vascular invasion. It is thus feasible to apply risk stratification scores for HCC recurrence which encompass various radiological, pathological and laboratory variables like RETREAT score [12, 22, 23].

In the current study, HCC recurrence was entirely reported in patients with 3 or more points on the RETREAT score, the incidence of rHCC incidence increased from nil in those of ≤2 points to around one third of those with 3-5 points and up to 70 % of those with more than 5 points. RETREAT score predicted the occurrence of rHCC in our patients and correlated significantly with its occurrence, P=0.00.

Conclusion

HCC recurrence is still a significant medical concern for transplanted HCC patients. Early detection is imperative for the use of more curative options for the management of rHCC.

Volume related criteria are insufficient to predict high risk patients for HCC recurrence. More factors should be included in this regard, namely poor differentiation, and vascular invasion. Risk stratification models for HCC recurrence should be employed to identify high risk patients for HCC recurrence. RETRAET score is a valid and feasible option in this regards.

Screening protocols should be tailored to the risk of HCC recurrence. Closer follow up, and more liberal use of dynamic imaging should be employed in those with high risk for HCC recurrence.

Conflict of interest

This research received no external funding. The authors declare no conflict of interest.

References

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16. Geissler EK, Schnitzbauer AA, Zülke C, Lamby PE, Proneth A, Duvoux C, et al. Sirolimus use in liver transplant recipients with hepatocellular carcinoma: A randomized, multicenter, open-label phase 3 trial. Transplantation. 2016; 100(1):116-125.
    doi: 10.1097/TP.0000000000000965
17. Yao FY, Ferrell L, Bass NM, Watson JJ, Bacchetti P, Venook A, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001; 33(6):1394-1403. doi: 10.1053/jhep.2001.24563
18. Mehta N, Yao FY. Moving past "One size (and number) fits all" in the selection of candidates with hepatocellular carcinoma for liver transplantation. Liver Transpl. 2013; 19(10): 1055-1058. doi: 10.1002/lt.23730
19. Jonas S, Bechstein WO, Steinmüller T, Herrmann M, Radke C, Berg T, et al. Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology. 2001 ;33(5):1080-1086.
    doi: 10.1053/jhep.2001.23561
20. Marsh JW, Finkelstein SD, Demetris AJ, Swalsky PA, Sasatomi E, Bandos A, et al. Genotyping of hepatocellular carcinoma in liver transplant recipients adds predictive power for determining recurrence-free survival. Liver Transpl. 2003; 9(7): 664-671.
    doi: 10.1053/jlts.2003.50144
21. Abdelfattah MR, Elsiesy H, Al-Manea H, Broering DC. Liver transplantation for hepatocellular carcinoma within the Milan criteria versus the University of California San Francisco criteria: a comparative study. Eur J Gastroenterol Hepatol. 2018; 30(4):398-403.
    doi: 10.1097/MEG.0000000000001044
22. Parfitt JR, Marotta P, Alghamdi M, Wall W, Khakhar A, Suskin NG, et al. Recurrent hepatocellular carcinoma after transplantation: use of a pathological score on explanted livers to predict recurrence. Liver Transpl. 2007; 13(4):543-551. doi: 10.1002/lt.21078
23. Agopian VG, Harlander-Locke M, Zarrinpar A, Kaldas FM, Farmer DG, Yersiz H, et al. A novel prognostic nomogram accurately predicts hepatocellular carcinoma recurrence after liver transplantation: analysis of 865 consecutive liver transplant recipients. J Am Coll Surg. 2015; 220(4):416-427. doi: 10.1016/j.jamcollsurg.2014.12.025

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Introduction

Since introduction of Milan criteria, an excellent outcomes of liver transplantation (LT) for hepatocellular carcinoma (HCC) were validated [1-3]. Unfortunately, this favorable outcome is not always achievable. The risk for recurrent HCC (rHCC) is still reported in approximately one-fifth of patients transplanted for presence of HCC. The occurrence of rHCC is a significant setback in the clinical course of affected patients with dismal prognosis reported in most instances [4-9].

Furthermore, the incidence of rHCC poses significant ethical concerns about current allocation system which favors transplantation of more HCC patients. The number of transplanted HCC patients has been reported to be steadily increasing over last two decades. The transplantation activity causes increased burden of already limited deceased donor pool, or provokes a debate over the living donation outcomes [10, 11].

It is therefore crucial to report the cases of rHCC following liver transplantation, to identify their clinical patterns, and to promote development of screening protocols for their early detection and treatment. Moreover, a comprehensive analysis should be made for identifying the risk factors associated with HCC recurrence.

This study aims primarily at reporting of the incidence of recurrent HCC following liver transplantation, to describe their clinical patterns, current therapeutic modalities at our center. It also addresses potential risk factors of HCC recurrence, by comparing them to the data reported elsewhere.

Materials and methods

A total of 178 patients diagnosed for having HCC approved the research consent and were subsequently included in the study. The clinical charts for those patients considered for liver transplant at our center were retrospectively reviewed. HCC at our center is diagnosed by contrast-enhanced computed tomography (CT) and/or abdominal magnetic resonance imaging (MRI). Staging was based on chest CT, cranial CT, and technetium-99m bone scintigraphy, to exclude extra-hepatic disease.

Current study was approved by our institutional Research Ethical Committee under the 8/11/09/02/2020 code. The ethical approval was obtained before conduction of this study. Patients were consented to use medical charts to obtain pertinent medical information for research purposes only. Extensive efforts to protect patients’ identity were also ensured. In accordance with Declaration of Helsinki, all the patients were consented about their clinical management and were also informed that their decision to approve or disapprove the research consent will not influence their clinical management.

Our center currently adopts Milan Criteria (MC) as the standard criteria for LT for HCC. Any patient who is beyond MC is usually considered for a downstaging protocol using one or more locoregional therapies to downstage the tumor to within MC. LT for the down-staged patients is considered after further confirmation of the absence of extrahepatic disease. Pretransplant locoregional therapies included radiofrequency ablation (RFA), trans-arterial chemotherapy (TACE) and/or trans-arterial radiotherapy (TARE). Cases which were found unfit for liver transplantation were excluded from the study.

LT was performed using either deceased donor liver transplants (DDLT), or liver transplantation from a living donor (LDLT). The LDLT donors were first- and second-degree relatives of respective patients. Cases of pediatric LT or liver re-transplantation were excluded from this study.

The liver explants were studied for presence of HCC lesions. Size, number, tumor grade, and lymph vascular invasion were reported by an experienced liver transplant pathologist. Triple immunosuppression protocol was utilized for LT recipients including calcineurin inhibitors (CNI) corticosteroids and mycophenolate mofetil.

İn addition to routine liver transplant follow-up protocol, the patients transplanted for HCC were followed up by liver ultrasound, α-fetoprotein (AFP), and liver function tests at six-month intervals for the rest of their lives. The cases with new focal liver lesion were further diagnosed by contrast-enhanced dynamic study to characterize this lesions, and liver biopsy was also taken to diagnose uncertain cases. The recurrent HCC (rHCC) cases were identified, and their clinical data were comprehensively collected.

Demographic data, pretransplant variables, transplant-related variables as well as characteristics of malignancies (number of lesions, tumor size and grade, lymph vascular invasion) were retrieved from the patient charts. Additionally, risk estimation of tumor recurrence after transplant (RETREAT score) was calculated [12], and these data were correlated with HCC recurrence. The data were analyzed by means of t-test and chi-square test. P-value of <0.05 was considered statistically significant. Kaplan-Meier curves were used to express survival outcomes and its significance was determined by log-rank test.

Results

A total of 178 patients presenting with HCC agreed to participate in the study. Fig. 1 shows their distribution as regards liver transplant, downstaging locoregional therapy (LRT) and incidence of recurrent HCC.

Figure 1. Distribution of HCC patients according to LT, LRT, and incidence of rHCC

148 adult patients underwent LT due to presence of HCC at our institution between August 2006 and December 2020. They included 93 males (62.8%) and 55 females (37.2%), ninety-six of them were within Milan criteria. The mean post-transplant follow-up for the studied patients was 53±34.8 months, range from 24.3 to 160.1 months. The overall 5-year survival of patients, grafts, and tumor-free survival were 72.7%, 90.8% and 87.7%, respectively (Fig. 2).

Figure 2. Overall patient, graft and tumor-free survival following LT for HCC patients

A total of 16 patients had HCC recurrence during the follow-up period (8.9% of transplanted HCC patients). Of them, eleven rHCC cases were registered in males. Nevertheless, gender factor did not differ significantly between patients with HCC recurrence compared to those with no rHCC (P=0.6). The mean age at HCC recurrence was 60.8±4.1 years. The current study demonstrated that most HCC recurrencies (68.8%) were observed within two years from liver transplant. Moreover, elevated AFP and distant metastases (mainly, lung lesions) dominated in clinical pattern in 87.5% and 56.3% of rHCC patients, respectively (Table 1).

Vascular invasion, poor tumor differentiation and RETREAT score differed significantly between the patients with rHCC and patients with no HCC recurrence. On the other hand, transplant criteria, type of transplant and total tumor volume (TTV)>115 cm³ showed no significant difference (Table 2). Correlation between RETREAT score, transplant criteria, and HCC recurrence is shown in Table 3.

Unfortunately, all rHCC cases in the current study were beyond surgical or locoregional therapy. Sorafenib was administered to these patients as a supportive measure. None of these patients were alive at the time of current report, their median survival following rHCC diagnosis was 135±11.5 days.

Table 2. Transplant and tumor-related variables for rHCC following liver transplantation

Table 3. Correlation between RETREAT score, transplant criteria and HCC recurrence

Discussion

The results of current study compare well with medical literature as regards the overall excellent outcome for transplanted HCC patients and the overall rate of rHCC [2, 3]. Filgueira et al., reported rHCC in 15-20% of transplanted HCC patients within a median of 12-16 months form liver transplant with around 75% occurring in the first two years. Timing of HCC recurrence in the current study was within two years following liver transplant in 68.8% of patients.

Filgueira et al. reported a poor prognosis for rHCC patients with median survival of 7-16 months from diagnosis of recurrence. They also claimed that HCC recurrence should be considered a systemic disease as only 30% of patients show isolated hepatic recurrence [4]. Chagas et al., reported 8% HCC recurrence rate and isolated hepatic recurrence in more than one-quarter of patients. Post-recurrence survival rates were 34% at 1 year compared to 0% in the current study [5].

Filgueira et al., reported that curative therapeutic modalities including reaction and ablative techniques are of value specially in cases where a smaller number and size of lesions is detected provided the disease is strictly confined to the liver. They quoted significantly longer median survival (22 months compared to 9 months in those with palliative treatment only) [5].

In the current study, it was noted that rHCC presentation is of the very late pattern, where there are limited options for therapeutic options and only palliation is possible. This might indicate vulnerability in screening protocol for rHCC and immunosuppression in the current study. It calls for more tailored approach for patients with high risk for HCC recurrence.

The use of rapamycin in patient transplanted for HCC was suggested and practiced in many transplant center [13-15]. It was hypothesized that rapamycin will improve recurrence free survival in these vulnerable patients. Nevertheless; (SiLVER trial) failed to show such effect [16].

Risk factors for HCC recurrence were traditionally reported to include male gender, those beyond Milan criteria, or those with partial response to LRT, AFP >400 ng/dL, those microvascular invasion, poor differentiation, TTV>115 cm³, and LDLT [6-9].

Only vascular invasion and poor tumor differentiation were shown to significantly related to HCC recurrence in the current study. Conversely, transplant criteria, TTV and type of transplant did not show significant relation.

As regards HCC outcome, much emphasis was always credited to the classical volume related tumor criteria e.g., number of HCC lesions, size of the HCC lesions, TTV, etc. the results of current study confirm that volume related criteria are at least insufficient to predict high risk patients for HCC recurrence [17-21]. More factors should be included in this regards namely, the biology-related tumor criteria e.g., poor differentiation, and vascular invasion. It is thus feasible to apply risk stratification scores for HCC recurrence which encompass various radiological, pathological and laboratory variables like RETREAT score [12, 22, 23].

In the current study, HCC recurrence was entirely reported in patients with 3 or more points on the RETREAT score, the incidence of rHCC incidence increased from nil in those of ≤2 points to around one third of those with 3-5 points and up to 70 % of those with more than 5 points. RETREAT score predicted the occurrence of rHCC in our patients and correlated significantly with its occurrence, P=0.00.

Conclusion

HCC recurrence is still a significant medical concern for transplanted HCC patients. Early detection is imperative for the use of more curative options for the management of rHCC.

Volume related criteria are insufficient to predict high risk patients for HCC recurrence. More factors should be included in this regard, namely poor differentiation, and vascular invasion. Risk stratification models for HCC recurrence should be employed to identify high risk patients for HCC recurrence. RETRAET score is a valid and feasible option in this regards.

Screening protocols should be tailored to the risk of HCC recurrence. Closer follow up, and more liberal use of dynamic imaging should be employed in those with high risk for HCC recurrence.

Conflict of interest

This research received no external funding. The authors declare no conflict of interest.

References

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2. Pomfret EA, Washburn K, Wald C, Nalesnik MA, Douglas D, Russo M, et al. Report of a national conference on liver allocation in patients with hepatocellular carcinoma in the United States. Liver Transpl. 2010; 16(3):262-278. doi: 10.1002/lt.21999
3. Clavien PA, Lesurtel M, Bossuyt PM, Gores GJ, Langer B, Perrier A; OLT for HCC Consensus Group. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol. 2012; 13(1):e11-22.
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4. Filgueira NA. Hepatocellular carcinoma recurrence after liver transplantation: Risk factors, screening and clinical presentation. World J Hepatol. 2019 Mar 27;11(3):261-272. doi: 10.4254/wjh.v11.i3.261
5. Chagas AL, Felga GEG, Diniz MA, Silva RF, Mattos AA, Silva RCMA, et al. Hepatocellular carcinoma recurrence after liver transplantation in a Brazilian multicenter study: clinical profile and prognostic factors of survival. Eur J Gastroenterol Hepatol. 2019; 31(9):1148-1156. doi: 10.1097/MEG.0000000000001448
6. Nissen NN, Menon V, Bresee C, Tran TT, Annamalai A, Poordad F, Fair JH, Klein AS, Boland B, Colquhoun SD. Recurrent hepatocellular carcinoma after liver transplant: identifying the high-risk patient. HPB (Oxford). 2011;13(9):626-632. doi: 10.1111/j.1477-2574.2011.00342.x
7. Toniutto P, Fornasiere E, Fumolo E, Bitetto D. Risk factors for hepatocellular carcinoma recurrence after liver transplantation. Hepatoma Res 2020; 6:50. doi: 10.20517/2394-5079.2020.40
8. Zimmerman MA, Ghobrial RM, Tong MJ, Hiatt JR, Cameron AM, Hong J. Recurrence of hepatocellular carcinoma following liver transplantation: a review of preoperative and postoperative prognostic indicators. Arch Surg. 2008; 143(2):182-188; discussion 188. doi: 10.1001/archsurg.2007.39
9. Fisher RA, Kulik LM, Freise CE, Lok AS, Shearon TH, Brown RS Jr, et al. Hepatocellular carcinoma recurrence and death following living and deceased donor liver transplantation. Am J Transplant. 2007; 7(6):1601-1608. doi: 10.1111/j.1600-6143.2007.01802.x
10. Ioannou GN, Perkins JD, Carithers RL Jr. Liver transplantation for hepatocellular carcinoma: impact of the MELD allocation system and predictors of survival. Gastroenterology. 2008; 134(5):1342-1351. doi: 10.1053/j.gastro.2008.02.013
11. Massie AB, Caffo B, Gentry SE, Hall EC, Axelrod DA, Lentine KL, et al. MELD Exceptions and Rates of Waiting List Outcomes. Am J Transplant. 2011; 11(11):2362-2371. doi: 10.1111/j.1600-6143.2011.03735.x
12. Mehta N, Heimbach J, Harnois DM, Sapisochin G, Dodge JL, Lee D, et al. Validation of a Risk Estimation of Tumor Recurrence After Transplant (RETREAT) Score for Hepatocellular Carcinoma Recurrence After Liver Transplant. JAMA Oncol. 2017;3(4): 493-500.
    doi: 10.1001/jamaoncol.2016.5116
13. Rodríguez-Perálvarez M, Tsochatzis E, Naveas MC, Pieri G, García-Caparrós C, O'Beirne J, et al. Reduced exposure to calcineurin inhibitors early after liver transplantation prevents recurrence of hepatocellular carcinoma. J Hepatol. 2013; 59(6):1193-1199.
    doi: 10.1016/j.jhep.2013.07.012
14. Chen K, Man K, Metselaar HJ, Janssen HL, Peppelenbosch MP, Pan Q. Rationale of personalized immunosuppressive medication for hepatocellular carcinoma patients after liver transplantation. Liver Transpl. 2014; 20(3):261-269. doi: 10.1002/lt.23806
15. Matter MS, Decaens T, Andersen JB, Thorgeirsson SS. Targeting the mTOR pathway in hepatocellular carcinoma: current state and future trends. J Hepatol. 2014; 60(4):855-65. doi: 10.1016/j.jhep.2013.11.031
16. Geissler EK, Schnitzbauer AA, Zülke C, Lamby PE, Proneth A, Duvoux C, et al. Sirolimus use in liver transplant recipients with hepatocellular carcinoma: A randomized, multicenter, open-label phase 3 trial. Transplantation. 2016; 100(1):116-125.
    doi: 10.1097/TP.0000000000000965
17. Yao FY, Ferrell L, Bass NM, Watson JJ, Bacchetti P, Venook A, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001; 33(6):1394-1403. doi: 10.1053/jhep.2001.24563
18. Mehta N, Yao FY. Moving past "One size (and number) fits all" in the selection of candidates with hepatocellular carcinoma for liver transplantation. Liver Transpl. 2013; 19(10): 1055-1058. doi: 10.1002/lt.23730
19. Jonas S, Bechstein WO, Steinmüller T, Herrmann M, Radke C, Berg T, et al. Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology. 2001 ;33(5):1080-1086.
    doi: 10.1053/jhep.2001.23561
20. Marsh JW, Finkelstein SD, Demetris AJ, Swalsky PA, Sasatomi E, Bandos A, et al. Genotyping of hepatocellular carcinoma in liver transplant recipients adds predictive power for determining recurrence-free survival. Liver Transpl. 2003; 9(7): 664-671.
    doi: 10.1053/jlts.2003.50144
21. Abdelfattah MR, Elsiesy H, Al-Manea H, Broering DC. Liver transplantation for hepatocellular carcinoma within the Milan criteria versus the University of California San Francisco criteria: a comparative study. Eur J Gastroenterol Hepatol. 2018; 30(4):398-403.
    doi: 10.1097/MEG.0000000000001044
22. Parfitt JR, Marotta P, Alghamdi M, Wall W, Khakhar A, Suskin NG, et al. Recurrent hepatocellular carcinoma after transplantation: use of a pathological score on explanted livers to predict recurrence. Liver Transpl. 2007; 13(4):543-551. doi: 10.1002/lt.21078
23. Agopian VG, Harlander-Locke M, Zarrinpar A, Kaldas FM, Farmer DG, Yersiz H, et al. A novel prognostic nomogram accurately predicts hepatocellular carcinoma recurrence after liver transplantation: analysis of 865 consecutive liver transplant recipients. J Am Coll Surg. 2015; 220(4):416-427. doi: 10.1016/j.jamcollsurg.2014.12.025

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17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["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"]=> string(2) "20" ["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(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "28626" ["VALUE"]=> string(22) "11/12/2021 12:00:00 am" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(22) "11/12/2021 12:00:00 am" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL } ["ACCEPTED"]=> array(36) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["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"]=> string(2) "21" ["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(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "28627" ["VALUE"]=> string(22) "12/15/2021 12:00:00 am" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(22) "12/15/2021 12:00:00 am" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL } ["PUBLISHED"]=> array(36) { ["ID"]=> string(2) "22" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Дата публикации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "PUBLISHED" ["DEFAULT_VALUE"]=> NULL ["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"]=> string(2) "22" ["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(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Дата публикации" ["~DEFAULT_VALUE"]=> NULL } ["CONTACT"]=> array(36) { ["ID"]=> string(2) "23" ["TIMESTAMP_X"]=> string(19) "2015-09-03 14:43:05" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(14) "Контакт" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "CONTACT" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "23" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHORS"]=> array(36) { ["ID"]=> string(2) "24" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:45:07" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "AUTHORS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "24" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_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"]=> string(2) "25" ["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) "28628" ["VALUE"]=> array(2) { ["TEXT"]=> string(149) "<p>Mохамед Рабей Абдельфаттах¹, Хуссейн Эльсиеси²</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(113) "

Mохамед Рабей Абдельфаттах¹, Хуссейн Эльсиеси²

" ["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"]=> string(2) "26" ["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) "28629" ["VALUE"]=> array(2) { ["TEXT"]=> string(424) "<p>¹ Департамент хируриги, Факультет медицины, Университет Александрии, Египет<br> ² Центр органной трансплантации, Госпиталь короля Фейсала и научный центр, Эр-Рияд, Королевство Саудовской Аравии</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(382) "

¹ Департамент хируриги, Факультет медицины, Университет Александрии, Египет
² Центр органной трансплантации, Госпиталь короля Фейсала и научный центр, Эр-Рияд, Королевство Саудовской Аравии

" ["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"]=> string(2) "27" ["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) "28630" ["VALUE"]=> array(2) { ["TEXT"]=> string(2946) "<p style="text-align: justify;">Риск рецидивов гепатоцеллюлярной карциномы (рГЦК) значителен, и их общий прогноз все еще неблагоприятен. Целью исследования является обобщение данных о частоте рецидивов ГЦК после трансплантации печени (ТП), рассмотрение их клинических особенностей и существующих вариантов терапии в нашем центре. Мы также рассматриваем потенциальные факторы риска рецидивирования ГЦК.</p> <h3>Материалы и методы</h3> <p style="text-align: justify;">Трансплантация печени была выполнена 148 пациентам в сроки с августа 2006 по декабрь 2020 г. в нашем центре. Выявлены случаи рецидивов ГЦК и систематизированы их клинические характеристики.</p> <h3>Результаты</h3> <p style="text-align: justify;">Средние сроки наблюдения после ТП составляли 53±34,8 мес. Рецидивы ГЦК были обнаружены у 16 пациентов (8,9%). Большинство этих больных (68,8%) наблюдали в течение первых двух лет после ТП. Инвазия в лимфатические сосуды, низкая степень дифференцировки опухоли и оценки по шкале RETREAT были достоверно связаны с рецидивами ГЦК.</p> <h3>Выводы</h3> <p style="text-align: justify;">Раннее выявление рецидивов необходимо для применения более эффективных способов контроля рГЦК. Критерии, основанные на оценке объема опухоли, не достаточны для прогнозирования случаев рецидивов ГЦК высокого риска. Следует использовать модели стратификации риска для выявления пациентов с плохим прогнозом при рГЦК. Протоколы их обследования должны быть адаптированы с риском рецидивирования ГЦК. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Гепатоцеллюлярная карцинома, трансплантация печени, рецидив опухоли.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2788) "

Риск рецидивов гепатоцеллюлярной карциномы (рГЦК) значителен, и их общий прогноз все еще неблагоприятен. Целью исследования является обобщение данных о частоте рецидивов ГЦК после трансплантации печени (ТП), рассмотрение их клинических особенностей и существующих вариантов терапии в нашем центре. Мы также рассматриваем потенциальные факторы риска рецидивирования ГЦК.

Материалы и методы

Трансплантация печени была выполнена 148 пациентам в сроки с августа 2006 по декабрь 2020 г. в нашем центре. Выявлены случаи рецидивов ГЦК и систематизированы их клинические характеристики.

Результаты

Средние сроки наблюдения после ТП составляли 53±34,8 мес. Рецидивы ГЦК были обнаружены у 16 пациентов (8,9%). Большинство этих больных (68,8%) наблюдали в течение первых двух лет после ТП. Инвазия в лимфатические сосуды, низкая степень дифференцировки опухоли и оценки по шкале RETREAT были достоверно связаны с рецидивами ГЦК.

Выводы

Раннее выявление рецидивов необходимо для применения более эффективных способов контроля рГЦК. Критерии, основанные на оценке объема опухоли, не достаточны для прогнозирования случаев рецидивов ГЦК высокого риска. Следует использовать модели стратификации риска для выявления пациентов с плохим прогнозом при рГЦК. Протоколы их обследования должны быть адаптированы с риском рецидивирования ГЦК.

Ключевые слова

Гепатоцеллюлярная карцинома, трансплантация печени, рецидив опухоли.

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Mohamed Rabei Abdelfattah¹, Hussein Elsiesy²

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¹ Department of Surgery, Faculty of Medicine, University of Alexandria, Egypt
² Organ Transplant Center, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom Saudi Arabia

Correspondence:
Prof. Dr. Mohamed Rabei Abdelfattah. MD, Department of Surgery, Faculty of Medicine, University of Alexandria, AL Khartoum Square, Azzaritta, Alexandria, Egypt, PO BOX 21131
Phone: 0020102 306 1111 (mob.)
E-mail: Mohamad.rabie@gmail.com

Citation: Abdelfattah MR, Elsiesy H. Post-liver transplant HCC recurrence: patterns, treatment, and outcome. Cell Ther Transplant 2022; 11(2): 39-44.

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The risk for recurrent hepatocellular carcinoma is still significant, and its overall prognosis is dismal. This study aims at reporting incidence of recurrent hepatocellular carcinoma (rHCC) cases following liver transplantation (LT), describing their clinical patterns, and current therapeutic modalities at our center. It also concerns potential risk factors related to HCC recurrence.

Materials and methods

A total of 148 patients underwent LT between August 2006 and December 2020 at our Center. Cases with rHCC were identified, and their clinical data were comprehensively collected.

Results

The mean post-transplant follow-up for the studied patients was 53±34.8 months. A total of 16 patients had HCC recurrence (8.9%). Majority of rHCC (68.8%) were observed within the first two years from LT. Vascular lymphatic invasion, poor tumor differentiation and RETREAT score were significantly related to HCC recurrence.

Conclusions

Early detection is an imperative for the use of more curative rHCC-managing options. The tumor volume-based criteria are insufficient to predict high risk patients for HCC recurrence. Risk stratification models for HCC recurrence should be employed to identify high-risk patients for HCC recurrence. Screening protocols should be tailored to the risk of HCC recurrence.

Keywords

Hepatocellular carcinoma, liver transplant, tumor recurrence.

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Mohamed Rabei Abdelfattah¹, Hussein Elsiesy²

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Mohamed Rabei Abdelfattah¹, Hussein Elsiesy²

" } ["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"]=> string(2) "39" ["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) "28636" ["VALUE"]=> array(2) { ["TEXT"]=> string(1758) "<p style="text-align: justify;">The risk for recurrent hepatocellular carcinoma is still significant, and its overall prognosis is dismal. This study aims at reporting incidence of recurrent hepatocellular carcinoma (rHCC) cases following liver transplantation (LT), describing their clinical patterns, and current therapeutic modalities at our center. It also concerns potential risk factors related to HCC recurrence. </p> <h3>Materials and methods</h3> <p style="text-align: justify;">A total of 148 patients underwent LT between August 2006 and December 2020 at our Center. Cases with rHCC were identified, and their clinical data were comprehensively collected.</p> <h3>Results</h3> <p style="text-align: justify;">The mean post-transplant follow-up for the studied patients was 53±34.8 months. A total of 16 patients had HCC recurrence (8.9%). Majority of rHCC (68.8%) were observed within the first two years from LT. Vascular lymphatic invasion, poor tumor differentiation and RETREAT score were significantly related to HCC recurrence.</p> <h3>Conclusions</h3> <p style="text-align: justify;">Early detection is an imperative for the use of more curative rHCC-managing options. The tumor volume-based criteria are insufficient to predict high risk patients for HCC recurrence. Risk stratification models for HCC recurrence should be employed to identify high-risk patients for HCC recurrence. Screening protocols should be tailored to the risk of HCC recurrence.</p> <h2>Keywords</h2> <p style="text-align: justify;">Hepatocellular carcinoma, liver transplant, tumor recurrence.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1600) "

The risk for recurrent hepatocellular carcinoma is still significant, and its overall prognosis is dismal. This study aims at reporting incidence of recurrent hepatocellular carcinoma (rHCC) cases following liver transplantation (LT), describing their clinical patterns, and current therapeutic modalities at our center. It also concerns potential risk factors related to HCC recurrence.

Materials and methods

A total of 148 patients underwent LT between August 2006 and December 2020 at our Center. Cases with rHCC were identified, and their clinical data were comprehensively collected.

Results

The mean post-transplant follow-up for the studied patients was 53±34.8 months. A total of 16 patients had HCC recurrence (8.9%). Majority of rHCC (68.8%) were observed within the first two years from LT. Vascular lymphatic invasion, poor tumor differentiation and RETREAT score were significantly related to HCC recurrence.

Conclusions

Early detection is an imperative for the use of more curative rHCC-managing options. The tumor volume-based criteria are insufficient to predict high risk patients for HCC recurrence. Risk stratification models for HCC recurrence should be employed to identify high-risk patients for HCC recurrence. Screening protocols should be tailored to the risk of HCC recurrence.

Keywords

Hepatocellular carcinoma, liver transplant, tumor recurrence.

" ["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(1600) "

The risk for recurrent hepatocellular carcinoma is still significant, and its overall prognosis is dismal. This study aims at reporting incidence of recurrent hepatocellular carcinoma (rHCC) cases following liver transplantation (LT), describing their clinical patterns, and current therapeutic modalities at our center. It also concerns potential risk factors related to HCC recurrence.

Materials and methods

A total of 148 patients underwent LT between August 2006 and December 2020 at our Center. Cases with rHCC were identified, and their clinical data were comprehensively collected.

Results

The mean post-transplant follow-up for the studied patients was 53±34.8 months. A total of 16 patients had HCC recurrence (8.9%). Majority of rHCC (68.8%) were observed within the first two years from LT. Vascular lymphatic invasion, poor tumor differentiation and RETREAT score were significantly related to HCC recurrence.

Conclusions

Early detection is an imperative for the use of more curative rHCC-managing options. The tumor volume-based criteria are insufficient to predict high risk patients for HCC recurrence. Risk stratification models for HCC recurrence should be employed to identify high-risk patients for HCC recurrence. Screening protocols should be tailored to the risk of HCC recurrence.

Keywords

Hepatocellular carcinoma, liver transplant, tumor recurrence.

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¹ Department of Surgery, Faculty of Medicine, University of Alexandria, Egypt
² Organ Transplant Center, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom Saudi Arabia

Correspondence:
Prof. Dr. Mohamed Rabei Abdelfattah. MD, Department of Surgery, Faculty of Medicine, University of Alexandria, AL Khartoum Square, Azzaritta, Alexandria, Egypt, PO BOX 21131
Phone: 0020102 306 1111 (mob.)
E-mail: Mohamad.rabie@gmail.com

Citation: Abdelfattah MR, Elsiesy H. Post-liver transplant HCC recurrence: patterns, treatment, and outcome. Cell Ther Transplant 2022; 11(2): 39-44.

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¹ Department of Surgery, Faculty of Medicine, University of Alexandria, Egypt
² Organ Transplant Center, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom Saudi Arabia

Correspondence:
Prof. Dr. Mohamed Rabei Abdelfattah. MD, Department of Surgery, Faculty of Medicine, University of Alexandria, AL Khartoum Square, Azzaritta, Alexandria, Egypt, PO BOX 21131
Phone: 0020102 306 1111 (mob.)
E-mail: Mohamad.rabie@gmail.com

Citation: Abdelfattah MR, Elsiesy H. Post-liver transplant HCC recurrence: patterns, treatment, and outcome. Cell Ther Transplant 2022; 11(2): 39-44.

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Mохамед Рабей Абдельфаттах¹, Хуссейн Эльсиеси²

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Mохамед Рабей Абдельфаттах¹, Хуссейн Эльсиеси²

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Целью исследования является обобщение данных о частоте рецидивов ГЦК после трансплантации печени (ТП), рассмотрение их клинических особенностей и существующих вариантов терапии в нашем центре. Мы также рассматриваем потенциальные факторы риска рецидивирования ГЦК.</p> <h3>Материалы и методы</h3> <p style="text-align: justify;">Трансплантация печени была выполнена 148 пациентам в сроки с августа 2006 по декабрь 2020 г. в нашем центре. Выявлены случаи рецидивов ГЦК и систематизированы их клинические характеристики.</p> <h3>Результаты</h3> <p style="text-align: justify;">Средние сроки наблюдения после ТП составляли 53±34,8 мес. Рецидивы ГЦК были обнаружены у 16 пациентов (8,9%). Большинство этих больных (68,8%) наблюдали в течение первых двух лет после ТП. Инвазия в лимфатические сосуды, низкая степень дифференцировки опухоли и оценки по шкале RETREAT были достоверно связаны с рецидивами ГЦК.</p> <h3>Выводы</h3> <p style="text-align: justify;">Раннее выявление рецидивов необходимо для применения более эффективных способов контроля рГЦК. Критерии, основанные на оценке объема опухоли, не достаточны для прогнозирования случаев рецидивов ГЦК высокого риска. Следует использовать модели стратификации риска для выявления пациентов с плохим прогнозом при рГЦК. Протоколы их обследования должны быть адаптированы с риском рецидивирования ГЦК. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Гепатоцеллюлярная карцинома, трансплантация печени, рецидив опухоли.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2788) "

Риск рецидивов гепатоцеллюлярной карциномы (рГЦК) значителен, и их общий прогноз все еще неблагоприятен. Целью исследования является обобщение данных о частоте рецидивов ГЦК после трансплантации печени (ТП), рассмотрение их клинических особенностей и существующих вариантов терапии в нашем центре. Мы также рассматриваем потенциальные факторы риска рецидивирования ГЦК.

Материалы и методы

Трансплантация печени была выполнена 148 пациентам в сроки с августа 2006 по декабрь 2020 г. в нашем центре. Выявлены случаи рецидивов ГЦК и систематизированы их клинические характеристики.

Результаты

Средние сроки наблюдения после ТП составляли 53±34,8 мес. Рецидивы ГЦК были обнаружены у 16 пациентов (8,9%). Большинство этих больных (68,8%) наблюдали в течение первых двух лет после ТП. Инвазия в лимфатические сосуды, низкая степень дифференцировки опухоли и оценки по шкале RETREAT были достоверно связаны с рецидивами ГЦК.

Выводы

Раннее выявление рецидивов необходимо для применения более эффективных способов контроля рГЦК. Критерии, основанные на оценке объема опухоли, не достаточны для прогнозирования случаев рецидивов ГЦК высокого риска. Следует использовать модели стратификации риска для выявления пациентов с плохим прогнозом при рГЦК. Протоколы их обследования должны быть адаптированы с риском рецидивирования ГЦК.

Ключевые слова

Гепатоцеллюлярная карцинома, трансплантация печени, рецидив опухоли.

" ["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(2788) "

Риск рецидивов гепатоцеллюлярной карциномы (рГЦК) значителен, и их общий прогноз все еще неблагоприятен. Целью исследования является обобщение данных о частоте рецидивов ГЦК после трансплантации печени (ТП), рассмотрение их клинических особенностей и существующих вариантов терапии в нашем центре. Мы также рассматриваем потенциальные факторы риска рецидивирования ГЦК.

Материалы и методы

Трансплантация печени была выполнена 148 пациентам в сроки с августа 2006 по декабрь 2020 г. в нашем центре. Выявлены случаи рецидивов ГЦК и систематизированы их клинические характеристики.

Результаты

Средние сроки наблюдения после ТП составляли 53±34,8 мес. Рецидивы ГЦК были обнаружены у 16 пациентов (8,9%). Большинство этих больных (68,8%) наблюдали в течение первых двух лет после ТП. Инвазия в лимфатические сосуды, низкая степень дифференцировки опухоли и оценки по шкале RETREAT были достоверно связаны с рецидивами ГЦК.

Выводы

Раннее выявление рецидивов необходимо для применения более эффективных способов контроля рГЦК. Критерии, основанные на оценке объема опухоли, не достаточны для прогнозирования случаев рецидивов ГЦК высокого риска. Следует использовать модели стратификации риска для выявления пациентов с плохим прогнозом при рГЦК. Протоколы их обследования должны быть адаптированы с риском рецидивирования ГЦК.

Ключевые слова

Гепатоцеллюлярная карцинома, трансплантация печени, рецидив опухоли.

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¹ Департамент хируриги, Факультет медицины, Университет Александрии, Египет
² Центр органной трансплантации, Госпиталь короля Фейсала и научный центр, Эр-Рияд, Королевство Саудовской Аравии

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¹ Департамент хируриги, Факультет медицины, Университет Александрии, Египет
² Центр органной трансплантации, Госпиталь короля Фейсала и научный центр, Эр-Рияд, Королевство Саудовской Аравии

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Introduction

Acute lymphoblastic leukemia (ALL) is one of the most spread pediatric cancers. With improvements of protocols for new diagnosed ALL nowadays 5-year survival achieves approximately 80-90% for these children [1]. However, patients with primary chemoresistance disease or relapse have a dismal prognosis with 5-year OS in first relapse of about 50% [2]. Allogeneic hematopoietic stem cells transplantation (allo-HSCT) has become a standard treatment for high-risk pediatric ALL. Many conditions affect the results of allo-HSCT: age, HLA-incompatibility between the donor and recipient, conditioning regimens, status of disease at the moment of allo-HSCT, persistence of minimal residual disease (MRD) and other [3]. Incidence of relapse after allo-HSCT reaches 70% in patients without remission at the moment of allo-HSCT compare with patients having remission (up to 35% of relapses). Patients with clinic of acute or chronic GVHD have a benefit in OS due to proceeding graft-versus-leukemia reaction [4, 5]. Patients with relapsed/refractory (r/r) disease after allo-HSCT have a poor prognosis with 3-year probability OS about 20% using different salvage option [6]. There are no standard recommendations for this group of patients. Clinical approaches include cytoreductive chemotherapy, target drugs, donor lymphocyte infusion (DLI), CAR-T cells, monoclonal antibody or palliative care. Treatment choices are individualized and depend on somatic status of patients, time of relapse, type of relapse and immune response.

Because most ALL cells in relapse have chemoresistance and get ability to escape the immune-suppressive tumor response conventional chemo-drug induce very short remission and not effective in long time survival.

DLI is a form of adoptive immunotherapy, which mechanism of action based on induction of graft-versus-leukemia (GVL) effect. Patients with ALL in general are less sensitive for immunotherapy, than AML patients, and other reasons of weak response to DLI is immune resistance by immune checkpoint expression, tumor microenvironment or loss of recipient-specific HLA genes [7, 8].

However, the study Nicole Liberio et al. [9] showed, that DLIs could promote durable survival after allo-HSCT in childhood ALL cohort. Moreover, the results of DLI as a therapy for relapsed acute leukemia may be shown comparable to second allo-HSCT [10].

Blinatumomab is a bispecific T-cell engager (BiTE) with two different single-chain Fv fragments binding T-cell CD3 and B-cell CD19 antigens. According to previous studies, blinatumomab has been demonstrated high efficacy in pediatric r/r B-ALL with a good tolerable safety profile. Response rate may reach 90% depending on tumor burden with a long median relapse-free survival (RFS) [11]. Low toxicity allows using this drug after allo-HSCT with comparable results [12, 13].

In study Hengwei Wu et al., [14] blinatumomab showed efficacy in patients undergoing HLA loss relapse after haplo-HSCT. Supposed, that blinatumomab may restore GVL effect.

So, we expect blinatumomab may not only reduce tumor cells, but also make stronger immune pressure for action of DLI.

Here we present first single-center experience of using immunotherapy with Blinatumomab and DLI in 17 children with refractory/relapsed (r/r) CD19+ B-ALL after allo-HSCT.

Patients and methods

We enrolled in this prospective study 17 B-ALL patients with the median age 10 years (8 months-18 years), who were treated by immunotherapy with Blinatumomab and DLI after allo- HSCT. Among them 3 patients (18%) had infant ALL with rearrangement KMT2A. All patients underwent allo-HSCT at RM Gorbacheva Research Institute within a period from 2012 to 2021. Eleven patients (65%) had received a myeloablative conditioning regimen (MAC), including 8 (47%) Bu-based (12-16 mg/kg) conditioning regimen, 2 GIAC [busulfan 3 mg/kg, сyclophosphamide 100 mg/kg, lomustine 120 mg/m², cytarabine 6000 mg/m²] protocol (12%) and one Treosulfan+Fludarabin+Thiotepa followed by TCR αβ+/CD19+ cell depletion. Six patients (35%) had received a reduced-intensity conditioning regimen (RIC) Fludarabin 150mg/m² and Melphalan 140 mg/m². Most children (n=13, 76%) had haploidentical donor, three (18%) patients had matched unrelated donor and one patient had matched related donor. Sixteen (94%) were given regimen of prophylaxis GVHD with сyclophosphamide (PtCy) 50 mg/kg on D+3, D+4, one patient was given immunosuppressive therapy with Rituximab, Tocilizumab, Abatacept after transplantation with TCR αβ+/CD19+ cell depletion. Engraftment with full donor chimerism was confirmed in all analyzed patients. History of acute GVHD of skin grade II after allo-HSCT was observed in 1 (6%) child, history of chronic GVHD of skin mild grade – in 2 children (12%). Disease status before starting of blinatumomab was post-transplant bone marrow relapse in 11 (65%) patients, MRD in 6 (35%) patients. Extramedullary lesions before blinatumomab therapy were observed in 4 patients (24%): 3 patients with involvement of central neural system (CNS) and 1 patient with testicular involvement. Early bone marrow relapse/MRD >10^-4 leukemic blasts of leukemia (up to one year after allo-HSCT) developed in 9 patients (53%). BM relapse occurred up to D+100 in 6 (35%) patients. Five patients (29%) with relapse of the disease had received salvage fludarabine-containing chemotherapy before treatment with blinatumomab. Four patients (24%) had response as blast cell reduction after salvage chemotherapy. Patients with MRD had full donor chimerism before starting blinatumomab and DLI, among patients with relapse 10/11 had chimerism more 50%.

Primary endpoints of the study were overall response rate, relapse-free survival (RFS), overall survival (OS). Overall response included morphologic CR (<5% blasts) and MRD response (<10^-4 leukemic blasts by flow cytometry or polymerase chain reaction) within the first 2 cycles of treatment with blinatumomab and DLI. RFS and OS was calculated from the start of blinatumomab treatment to time of relapse, death, consequently.

Relapse was determined as bone marrow recurrence of disease or extramedullary lesions. Secondary endpoints included frequency of induced acute and chronic GVHD after immunotherapy, grade 3 or higher treatment-related adverse events by NCI CTCAE 5.0, duration of bone marrow response (DOR). DOR was defined as time from initial response to bone marrow relapse, death. Patients alive were censored on the last documented visit date or last contact date.

Relapse-free survival and overall survival are described with Kaplan-Meier with 95% CI estimates. Statistical analysis was performed using IBM SPSS Statistics v 26 and Free statistical software: EZR (Easy R).

Table 1. Demographic Data and Baseline Disease Characteristics (n=17)

Results

Median time from allo-HSCT to blinatumomab therapy was 12 months (range, 2 months – 43 months). Blinatumomab (5-15 µg/m² per day) was administered as a 4-week induction cycle. Patients received up to 3 courses of blinatumomab with the median 1 course. First DLI was mostly given after starting blinatumomab course 1 (ranged from course 1 to course 2) on median day 32 therapy (1-123). Seven patients got first dose of DLI at the moment blinatumomab administration, 3 patients – in several days after finishing blinatumomab administration and seven patients – in 1-3 months after finishing blinatumomab at CR. Total, from 1 to 4 DLI were performed at follow up, doses varied between 1×10⁵ and 6×10⁷ CD3+/kg. Summary median dose of DLI during the combined therapy was 1.7×10⁶ CD3+/kg (range, 1×10⁵-6×10⁷).

Efficacy

The median overall survival for all patients was not reached at a median follow-up of 13.3 months (95% CI, 8.8 to 27.4 months); four (24%) died from progression of leukemia. The Kaplan-Meier estimate overall survival was 76.5% (95% CI, 44%-92%) at a median follow-up time (Fig. 1).

Fifteen (88%) of patients achieved a CR within the first 2 cycles of treatment with blinatumomab +DLI, among them 14 (82%) had MRD negative CR. Median duration of bone marrow response was 7 months (range, 1 to 55.0 months). The median relapse-free survival was 9.1 months (95% CI, 3.0 to 37.2 months) in patients who achieved CR, with the median duration follow up 13,3 months (95% CI, 10.0 to 30.3 months); 10 (67%) patients relapsed, including bone marrow relapse in 4 patients (27%), combined (BM+CNS/bones/parenchymal organs) in 3 (18%) and isolated extramedullary relapse (СNS in 2 and soft tissues in 1) in three (18%) patients (Fig. 2). One patient underwent successful subsequent allo-HSCT after relapse and still alive in MRD negative CR.

Safety

Three children (18%) experienced drug-related adverse events grade 3. One patient had seizure and required transient blinatumomab discontinuation, 1 patient had generalized cytomegalovirus (CMV) infection with involvement of blood, lung and urinary tract, 2 patients had infectious enterocolitis grade 3 (Clostridia, Serratia spp., CMV). There were no observed cytokine release events, grade 4 or fatal reactions.

There were no fatal acute and chronic GVHD after therapy by blinatumomab and DLI. But, one patient (6%) experienced induced acute GVHD of skin and gastrointestinal tract grade 3 after combined immunotherapy. Three children (18%) had chronic GVHD. One patient had classical severe GVHD of skin, gastrointestinal tract and liver after acute GVHD grade 3. One patient had classical mild GVHD of skin and oral mucosa. One patient had "overlap" moderate GVHD of skin and eyes. One patient with history of mild chronic GVHD developed mild chronic GVHD during combined immunotherapy. GVHD was induced in one month after DLI administration in all children. Two patients with chronic GVHD (moderate and severe form) received immunosuppressive therapy (steroids, tacrolimus/sirolimus and ruxolitinib) with success control of symptoms. DLI were discontinued after development of moderate and severe chronic GVHD. Two of 3 patients with chronic GVHD remain in long term CR during 12 and 35 months with good quality of life. Clinical outcomes are shown in Table 2 and Table 3.

Table 3. Treatment details in the distinct clinical B-ALL cases

Discussion

Allo-HSCT may be a curative treatment option for high-risk ALL, however, a portion of patients become refractory or relapse after allo-HSCT with the rate between 30% and 70%. Progressive leukemia remains the main cause of mortality after allo-HSCT.

In our study we have demonstrated results of adoptive immunotherapy based on combination bispecific T cell engager (BiTE) blinatumomab and DLI for salvage group of 17 pediatric B-ALL, including 3 infant ALL with rearrangement KMT2A. This combination is promising with overall rate response (88%) both in patients with persistence MRD and bone marrow relapse. Incidence complete response was higher, than that observed in patients who receive mono-DLI (43%) [9]. It is known that tumor burden has great importance before immunotherapy, so cytoreductive chemotherapy was administered previous in 5 (29%) relapsed patients [12]. One patient with early 4^th relapse and large tumor burden didn’t receive cytoreductive therapy and progressed during immunotherapy.

We have found good short-term toxicity profile of this therapy without the necessary for complete withdrawal of therapy due to adverse events. Infectious complications grade 3, observed in 3 children, could be associated also with pretreatment and absent of full immunological reconstitution after allo-HSCT.

The most common complication after DLI is the induction of acute and chronic GVHD, which develops general in 40-50% of patients. However, the use of PtCy may reduce the risk of developing induced GVHD [15]. The occurrence of chronic GVHD after DLI is considered to be a favorable factor associated with a reduced risk of recurrence and long-term disease-free survival [16, 17, 18, 19, 20, 21].

While the most lymphocyte infusions were haploidentical, the incidence of GVHD was low (24%), that similar with early published study, where haplo-DLI was used for relapse treatment after T cell replete bone marrow transplantation with post-transplantation cyclophosphamide. [15]. Two of 3 patients with GVHD remains in long CR during 12 and 35 months.

Systematic review reported summarized data about concomitant use of blinatumomab and DLI for post-transplant relapsed CD19 positive ALL on 15 adult patients according 2 studies. Before starting blinatumomab therapy, 12 patients had post-transplant bone marrow relapse, 1 patient had an extramedullary relapse, and 2 patients had a MRD without marrow relapse. DLI was mostly given with blinatumomab during cycle 3 (ranged from cycle 2 to cycle 4). Complete remission (CR) with MRD negative status was achieved after 2 cycles of blinatumomab in 3 patients, 2 of them remained in CR for 7 and 13 months. Ten patients showed RR of 70%. One patient developed grade II aGVHD after the combination therapy, Grade 3 late-onset acute skin and gut GVHD were reported in one patient. One patient continued progression of extramedullary disease, 1 patient died to extramedullary and hematologic relapse 12 months after blinatumomab initiation [22, 23].

In our study totally 6 (35%) patients developed relapse with extramedullary involvement, 2 of them had extramedullary before immunotherapy. Five patients with extramedullary involvement are still alive after relapse, 3 of them continue the treatment.

Unfortunately, despite high response rate and a durable remission in our work relapse of disease occurred in 67% of patients. These patients need in continuation of escalated DLI with/without courses of blinatumomab should be considered to control the disease, if there are no signs of clinically significant GVHD.

Further alternative approaches to overcome immune resistance may include chimeric antigen receptor T-cell therapies, checkpoint inhibitors or undergo second allo-HSCT [24, 25, 26, 27].

In the era of immunotherapy, future challenges and goals will be based on understanding the mechanisms of immune evasion by leukemia cells for developing novel therapeutic strategies.

Conclusion

Combination adoptive immunotherapy of blinatumomab and DLI is effective and can induce long-term bone marrow remissions in some relapsed pediatric CD19+ B-ALL after allo-HSCT.

1. Blinatumomab+DLI has a low toxicity profile, low incidence of GVHD and is well tolerated even by young children after haplo-HSCT.

2. The use of immunotherapy after cytoreductive chemotherapy is preferable in patients with extensive bone marrow relapse.

3. For maintaining of durable remission responded patients are needed further treatment.

Conflict of interest

None declared.

Acknowledgments

The study was funded by a grant from Russian Science Foundation № 22-15-00491, https://rscf.ru/project/22-15-00491/

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23. Ueda M, de Lima M, Caimi P, Tomlinson B, Little J, Creger R, et al. Concurrent blinatumomab and donor lymphocyte infusions for treatment of relapsed pre-B-cell ALL after allogeneic hematopoietic cell transplant, Bone Marrow Transplant. 2016; 51(9): 1253-1255. doi: 10.1038/bmt.2016.104
24. Kozhokar PV, Paina OV, Frolova AS, Rakhmanova ZZ, Borovkova AS , Semenova EV, et al. Efficiency of second allogeneic HSCT in the children with acute leukemias with relapses after first transplantation. Cell Ther Ttransplant. 2019; 8(4): 33-40.
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27. Wunderlich M, Manning N, Sexton C, O’Brien E, Byerly L, Stillwell C, et al. PD-1 inhibition enhances blinatumomab response in a UCB/PDX model of relapsed pediatric B-cell acute lymphoblastic leukemia. Front Oncol. 2021; 11. doi: 10.3389/fonc.2021.642466

" ["~DETAIL_TEXT"]=> string(27544) "

Introduction

Acute lymphoblastic leukemia (ALL) is one of the most spread pediatric cancers. With improvements of protocols for new diagnosed ALL nowadays 5-year survival achieves approximately 80-90% for these children [1]. However, patients with primary chemoresistance disease or relapse have a dismal prognosis with 5-year OS in first relapse of about 50% [2]. Allogeneic hematopoietic stem cells transplantation (allo-HSCT) has become a standard treatment for high-risk pediatric ALL. Many conditions affect the results of allo-HSCT: age, HLA-incompatibility between the donor and recipient, conditioning regimens, status of disease at the moment of allo-HSCT, persistence of minimal residual disease (MRD) and other [3]. Incidence of relapse after allo-HSCT reaches 70% in patients without remission at the moment of allo-HSCT compare with patients having remission (up to 35% of relapses). Patients with clinic of acute or chronic GVHD have a benefit in OS due to proceeding graft-versus-leukemia reaction [4, 5]. Patients with relapsed/refractory (r/r) disease after allo-HSCT have a poor prognosis with 3-year probability OS about 20% using different salvage option [6]. There are no standard recommendations for this group of patients. Clinical approaches include cytoreductive chemotherapy, target drugs, donor lymphocyte infusion (DLI), CAR-T cells, monoclonal antibody or palliative care. Treatment choices are individualized and depend on somatic status of patients, time of relapse, type of relapse and immune response.

Because most ALL cells in relapse have chemoresistance and get ability to escape the immune-suppressive tumor response conventional chemo-drug induce very short remission and not effective in long time survival.

DLI is a form of adoptive immunotherapy, which mechanism of action based on induction of graft-versus-leukemia (GVL) effect. Patients with ALL in general are less sensitive for immunotherapy, than AML patients, and other reasons of weak response to DLI is immune resistance by immune checkpoint expression, tumor microenvironment or loss of recipient-specific HLA genes [7, 8].

However, the study Nicole Liberio et al. [9] showed, that DLIs could promote durable survival after allo-HSCT in childhood ALL cohort. Moreover, the results of DLI as a therapy for relapsed acute leukemia may be shown comparable to second allo-HSCT [10].

Blinatumomab is a bispecific T-cell engager (BiTE) with two different single-chain Fv fragments binding T-cell CD3 and B-cell CD19 antigens. According to previous studies, blinatumomab has been demonstrated high efficacy in pediatric r/r B-ALL with a good tolerable safety profile. Response rate may reach 90% depending on tumor burden with a long median relapse-free survival (RFS) [11]. Low toxicity allows using this drug after allo-HSCT with comparable results [12, 13].

In study Hengwei Wu et al., [14] blinatumomab showed efficacy in patients undergoing HLA loss relapse after haplo-HSCT. Supposed, that blinatumomab may restore GVL effect.

So, we expect blinatumomab may not only reduce tumor cells, but also make stronger immune pressure for action of DLI.

Here we present first single-center experience of using immunotherapy with Blinatumomab and DLI in 17 children with refractory/relapsed (r/r) CD19+ B-ALL after allo-HSCT.

Patients and methods

We enrolled in this prospective study 17 B-ALL patients with the median age 10 years (8 months-18 years), who were treated by immunotherapy with Blinatumomab and DLI after allo- HSCT. Among them 3 patients (18%) had infant ALL with rearrangement KMT2A. All patients underwent allo-HSCT at RM Gorbacheva Research Institute within a period from 2012 to 2021. Eleven patients (65%) had received a myeloablative conditioning regimen (MAC), including 8 (47%) Bu-based (12-16 mg/kg) conditioning regimen, 2 GIAC [busulfan 3 mg/kg, сyclophosphamide 100 mg/kg, lomustine 120 mg/m², cytarabine 6000 mg/m²] protocol (12%) and one Treosulfan+Fludarabin+Thiotepa followed by TCR αβ+/CD19+ cell depletion. Six patients (35%) had received a reduced-intensity conditioning regimen (RIC) Fludarabin 150mg/m² and Melphalan 140 mg/m². Most children (n=13, 76%) had haploidentical donor, three (18%) patients had matched unrelated donor and one patient had matched related donor. Sixteen (94%) were given regimen of prophylaxis GVHD with сyclophosphamide (PtCy) 50 mg/kg on D+3, D+4, one patient was given immunosuppressive therapy with Rituximab, Tocilizumab, Abatacept after transplantation with TCR αβ+/CD19+ cell depletion. Engraftment with full donor chimerism was confirmed in all analyzed patients. History of acute GVHD of skin grade II after allo-HSCT was observed in 1 (6%) child, history of chronic GVHD of skin mild grade – in 2 children (12%). Disease status before starting of blinatumomab was post-transplant bone marrow relapse in 11 (65%) patients, MRD in 6 (35%) patients. Extramedullary lesions before blinatumomab therapy were observed in 4 patients (24%): 3 patients with involvement of central neural system (CNS) and 1 patient with testicular involvement. Early bone marrow relapse/MRD >10^-4 leukemic blasts of leukemia (up to one year after allo-HSCT) developed in 9 patients (53%). BM relapse occurred up to D+100 in 6 (35%) patients. Five patients (29%) with relapse of the disease had received salvage fludarabine-containing chemotherapy before treatment with blinatumomab. Four patients (24%) had response as blast cell reduction after salvage chemotherapy. Patients with MRD had full donor chimerism before starting blinatumomab and DLI, among patients with relapse 10/11 had chimerism more 50%.

Primary endpoints of the study were overall response rate, relapse-free survival (RFS), overall survival (OS). Overall response included morphologic CR (<5% blasts) and MRD response (<10^-4 leukemic blasts by flow cytometry or polymerase chain reaction) within the first 2 cycles of treatment with blinatumomab and DLI. RFS and OS was calculated from the start of blinatumomab treatment to time of relapse, death, consequently.

Relapse was determined as bone marrow recurrence of disease or extramedullary lesions. Secondary endpoints included frequency of induced acute and chronic GVHD after immunotherapy, grade 3 or higher treatment-related adverse events by NCI CTCAE 5.0, duration of bone marrow response (DOR). DOR was defined as time from initial response to bone marrow relapse, death. Patients alive were censored on the last documented visit date or last contact date.

Relapse-free survival and overall survival are described with Kaplan-Meier with 95% CI estimates. Statistical analysis was performed using IBM SPSS Statistics v 26 and Free statistical software: EZR (Easy R).

Table 1. Demographic Data and Baseline Disease Characteristics (n=17)

Results

Median time from allo-HSCT to blinatumomab therapy was 12 months (range, 2 months – 43 months). Blinatumomab (5-15 µg/m² per day) was administered as a 4-week induction cycle. Patients received up to 3 courses of blinatumomab with the median 1 course. First DLI was mostly given after starting blinatumomab course 1 (ranged from course 1 to course 2) on median day 32 therapy (1-123). Seven patients got first dose of DLI at the moment blinatumomab administration, 3 patients – in several days after finishing blinatumomab administration and seven patients – in 1-3 months after finishing blinatumomab at CR. Total, from 1 to 4 DLI were performed at follow up, doses varied between 1×10⁵ and 6×10⁷ CD3+/kg. Summary median dose of DLI during the combined therapy was 1.7×10⁶ CD3+/kg (range, 1×10⁵-6×10⁷).

Efficacy

The median overall survival for all patients was not reached at a median follow-up of 13.3 months (95% CI, 8.8 to 27.4 months); four (24%) died from progression of leukemia. The Kaplan-Meier estimate overall survival was 76.5% (95% CI, 44%-92%) at a median follow-up time (Fig. 1).

Fifteen (88%) of patients achieved a CR within the first 2 cycles of treatment with blinatumomab +DLI, among them 14 (82%) had MRD negative CR. Median duration of bone marrow response was 7 months (range, 1 to 55.0 months). The median relapse-free survival was 9.1 months (95% CI, 3.0 to 37.2 months) in patients who achieved CR, with the median duration follow up 13,3 months (95% CI, 10.0 to 30.3 months); 10 (67%) patients relapsed, including bone marrow relapse in 4 patients (27%), combined (BM+CNS/bones/parenchymal organs) in 3 (18%) and isolated extramedullary relapse (СNS in 2 and soft tissues in 1) in three (18%) patients (Fig. 2). One patient underwent successful subsequent allo-HSCT after relapse and still alive in MRD negative CR.

Safety

Three children (18%) experienced drug-related adverse events grade 3. One patient had seizure and required transient blinatumomab discontinuation, 1 patient had generalized cytomegalovirus (CMV) infection with involvement of blood, lung and urinary tract, 2 patients had infectious enterocolitis grade 3 (Clostridia, Serratia spp., CMV). There were no observed cytokine release events, grade 4 or fatal reactions.

There were no fatal acute and chronic GVHD after therapy by blinatumomab and DLI. But, one patient (6%) experienced induced acute GVHD of skin and gastrointestinal tract grade 3 after combined immunotherapy. Three children (18%) had chronic GVHD. One patient had classical severe GVHD of skin, gastrointestinal tract and liver after acute GVHD grade 3. One patient had classical mild GVHD of skin and oral mucosa. One patient had "overlap" moderate GVHD of skin and eyes. One patient with history of mild chronic GVHD developed mild chronic GVHD during combined immunotherapy. GVHD was induced in one month after DLI administration in all children. Two patients with chronic GVHD (moderate and severe form) received immunosuppressive therapy (steroids, tacrolimus/sirolimus and ruxolitinib) with success control of symptoms. DLI were discontinued after development of moderate and severe chronic GVHD. Two of 3 patients with chronic GVHD remain in long term CR during 12 and 35 months with good quality of life. Clinical outcomes are shown in Table 2 and Table 3.

Table 3. Treatment details in the distinct clinical B-ALL cases

Discussion

Allo-HSCT may be a curative treatment option for high-risk ALL, however, a portion of patients become refractory or relapse after allo-HSCT with the rate between 30% and 70%. Progressive leukemia remains the main cause of mortality after allo-HSCT.

In our study we have demonstrated results of adoptive immunotherapy based on combination bispecific T cell engager (BiTE) blinatumomab and DLI for salvage group of 17 pediatric B-ALL, including 3 infant ALL with rearrangement KMT2A. This combination is promising with overall rate response (88%) both in patients with persistence MRD and bone marrow relapse. Incidence complete response was higher, than that observed in patients who receive mono-DLI (43%) [9]. It is known that tumor burden has great importance before immunotherapy, so cytoreductive chemotherapy was administered previous in 5 (29%) relapsed patients [12]. One patient with early 4^th relapse and large tumor burden didn’t receive cytoreductive therapy and progressed during immunotherapy.

We have found good short-term toxicity profile of this therapy without the necessary for complete withdrawal of therapy due to adverse events. Infectious complications grade 3, observed in 3 children, could be associated also with pretreatment and absent of full immunological reconstitution after allo-HSCT.

The most common complication after DLI is the induction of acute and chronic GVHD, which develops general in 40-50% of patients. However, the use of PtCy may reduce the risk of developing induced GVHD [15]. The occurrence of chronic GVHD after DLI is considered to be a favorable factor associated with a reduced risk of recurrence and long-term disease-free survival [16, 17, 18, 19, 20, 21].

While the most lymphocyte infusions were haploidentical, the incidence of GVHD was low (24%), that similar with early published study, where haplo-DLI was used for relapse treatment after T cell replete bone marrow transplantation with post-transplantation cyclophosphamide. [15]. Two of 3 patients with GVHD remains in long CR during 12 and 35 months.

Systematic review reported summarized data about concomitant use of blinatumomab and DLI for post-transplant relapsed CD19 positive ALL on 15 adult patients according 2 studies. Before starting blinatumomab therapy, 12 patients had post-transplant bone marrow relapse, 1 patient had an extramedullary relapse, and 2 patients had a MRD without marrow relapse. DLI was mostly given with blinatumomab during cycle 3 (ranged from cycle 2 to cycle 4). Complete remission (CR) with MRD negative status was achieved after 2 cycles of blinatumomab in 3 patients, 2 of them remained in CR for 7 and 13 months. Ten patients showed RR of 70%. One patient developed grade II aGVHD after the combination therapy, Grade 3 late-onset acute skin and gut GVHD were reported in one patient. One patient continued progression of extramedullary disease, 1 patient died to extramedullary and hematologic relapse 12 months after blinatumomab initiation [22, 23].

In our study totally 6 (35%) patients developed relapse with extramedullary involvement, 2 of them had extramedullary before immunotherapy. Five patients with extramedullary involvement are still alive after relapse, 3 of them continue the treatment.

Unfortunately, despite high response rate and a durable remission in our work relapse of disease occurred in 67% of patients. These patients need in continuation of escalated DLI with/without courses of blinatumomab should be considered to control the disease, if there are no signs of clinically significant GVHD.

Further alternative approaches to overcome immune resistance may include chimeric antigen receptor T-cell therapies, checkpoint inhibitors or undergo second allo-HSCT [24, 25, 26, 27].

In the era of immunotherapy, future challenges and goals will be based on understanding the mechanisms of immune evasion by leukemia cells for developing novel therapeutic strategies.

Conclusion

Combination adoptive immunotherapy of blinatumomab and DLI is effective and can induce long-term bone marrow remissions in some relapsed pediatric CD19+ B-ALL after allo-HSCT.

1. Blinatumomab+DLI has a low toxicity profile, low incidence of GVHD and is well tolerated even by young children after haplo-HSCT.

2. The use of immunotherapy after cytoreductive chemotherapy is preferable in patients with extensive bone marrow relapse.

3. For maintaining of durable remission responded patients are needed further treatment.

Conflict of interest

None declared.

Acknowledgments

The study was funded by a grant from Russian Science Foundation № 22-15-00491, https://rscf.ru/project/22-15-00491/

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В-ОЛЛ после алло-ТГСК" ["SECTION_PICTURE_FILE_TITLE"]=> string(317) "Комбинированная адоптивная иммунотерапия с применением блинатумомаба и инфузий донорских лимфоцитов у детей с рецидивирующим/ рефрактерным течением В-ОЛЛ после алло-ТГСК" ["SECTION_PICTURE_FILE_NAME"]=> string(100) "kombinirovannaya-adoptivnaya-immunoterapiya-s-primeneniem-blinatumomaba-i-infuziy-donorskikh-limfots" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(317) "Комбинированная адоптивная иммунотерапия с применением блинатумомаба и инфузий донорских лимфоцитов у детей с рецидивирующим/ рефрактерным течением В-ОЛЛ после алло-ТГСК" ["SECTION_DETAIL_PICTURE_FILE_TITLE"]=> string(317) "Комбинированная адоптивная иммунотерапия с применением блинатумомаба и инфузий донорских лимфоцитов у детей с рецидивирующим/ рефрактерным течением В-ОЛЛ после алло-ТГСК" ["SECTION_DETAIL_PICTURE_FILE_NAME"]=> string(100) "kombinirovannaya-adoptivnaya-immunoterapiya-s-primeneniem-blinatumomaba-i-infuziy-donorskikh-limfots" 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"Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_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"]=> string(2) "25" ["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) "28616" ["VALUE"]=> array(2) { ["TEXT"]=> string(335) "<p>Любовь А. Цветкова, Олеся В. Паина, Полина В. Кожокарь, Анастасия С. Фролова, Жемал З. Рахманова, Елена В. Бабенко, Елена В. Семенова, Александр Д. Кулагин, Людмила С. Зубаровская</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(323) "

Любовь А. Цветкова, Олеся В. Паина, Полина В. Кожокарь, Анастасия С. Фролова, Жемал З. Рахманова, Елена В. Бабенко, Елена В. Семенова, Александр Д. Кулагин, Людмила С. Зубаровская

" ["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"]=> string(2) "26" ["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) "28617" ["VALUE"]=> array(2) { ["TEXT"]=> string(373) "<p>НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, 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(361) "

НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

" ["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"]=> string(2) "27" ["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) "28618" ["VALUE"]=> array(2) { ["TEXT"]=> string(3409) "<p style="text-align: justify;">Алло-ТГСК является потенциально излечивающим методом терапии детей с В лимфобластным лейкозом (В-ОЛЛ) группы высокого риска. Тем не менее, примерно у 30-70% пациентов возникает рецидив после алло-ТГСК. Пациенты с рецидивирующим/ рефрактерным течением В-ОЛЛ имеют неблагоприятный прогноз с 3-летней общей выживаемостью (ОВ) около 20%. В этом исследовании мы впервые оценили эффективность и безопасность комбинированной адоптивной иммунотерапии биспецифическим активатором Т-клеток блинатумомабом и инфузиями донорских лимфоцитов (ИДЛ) у 17 детей, перенесших алло-ТГСК и имевших после этого рецидив или персистенцию минимальной остаточной болезни. Пятнадцать (88%) пациентов достигли ремиссии в течение первых 2 циклов лечения блинатумомабом +ИДЛ. Медиана безрецидивной выживаемости составила 9,1 мес (95% ДИ, от 3,0 до 37,2 мес.) у пациентов, достигших ответа, с медианой наблюдения 13,3 мес. (95% ДИ, 10,0-30,3 мес.). Медиана OB для всех пациентов не была достигнута при медиане наблюдения 13,3 месяца (95% ДИ, от 8,8 до 27,4 месяцев). ОВ по Каплану-Мейеру составила 76,5% (95% ДИ, 44-92%) при медиане наблюдения 13,3 месяца. Трое детей (18%) развили нежелательные явления 3-й степени тяжести, связанные с введением препарата, и двое детей (12%) имели клинически значимую индуцированную реакцию «трансплантат против хозяина» (РТПХ). Летальных случаев, связанных с терапией, отмечено не было. Дальнейшие варианты иммунотерапии детей с рецидивирующим течением В-ОЛЛ могут включать продолжение курсов комбинированной адоптивной иммунотерапии, монотерапию ИДЛ в эскалированных дозах, терапию Т-клетками с антигенным химерным рецептором, ингибиторами контрольных точек, а также проведение повторной алло-ТГСК.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">В-клеточный острый лимфобластный лейкоз, дети, рецидив, алло-ТГСК, блинатумомаб, инфузии донорских лимфоцитов.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3353) "

Алло-ТГСК является потенциально излечивающим методом терапии детей с В лимфобластным лейкозом (В-ОЛЛ) группы высокого риска. Тем не менее, примерно у 30-70% пациентов возникает рецидив после алло-ТГСК. Пациенты с рецидивирующим/ рефрактерным течением В-ОЛЛ имеют неблагоприятный прогноз с 3-летней общей выживаемостью (ОВ) около 20%. В этом исследовании мы впервые оценили эффективность и безопасность комбинированной адоптивной иммунотерапии биспецифическим активатором Т-клеток блинатумомабом и инфузиями донорских лимфоцитов (ИДЛ) у 17 детей, перенесших алло-ТГСК и имевших после этого рецидив или персистенцию минимальной остаточной болезни. Пятнадцать (88%) пациентов достигли ремиссии в течение первых 2 циклов лечения блинатумомабом +ИДЛ. Медиана безрецидивной выживаемости составила 9,1 мес (95% ДИ, от 3,0 до 37,2 мес.) у пациентов, достигших ответа, с медианой наблюдения 13,3 мес. (95% ДИ, 10,0-30,3 мес.). Медиана OB для всех пациентов не была достигнута при медиане наблюдения 13,3 месяца (95% ДИ, от 8,8 до 27,4 месяцев). ОВ по Каплану-Мейеру составила 76,5% (95% ДИ, 44-92%) при медиане наблюдения 13,3 месяца. Трое детей (18%) развили нежелательные явления 3-й степени тяжести, связанные с введением препарата, и двое детей (12%) имели клинически значимую индуцированную реакцию «трансплантат против хозяина» (РТПХ). Летальных случаев, связанных с терапией, отмечено не было. Дальнейшие варианты иммунотерапии детей с рецидивирующим течением В-ОЛЛ могут включать продолжение курсов комбинированной адоптивной иммунотерапии, монотерапию ИДЛ в эскалированных дозах, терапию Т-клетками с антигенным химерным рецептором, ингибиторами контрольных точек, а также проведение повторной алло-ТГСК.

Ключевые слова

В-клеточный острый лимфобластный лейкоз, дети, рецидив, алло-ТГСК, блинатумомаб, инфузии донорских лимфоцитов.

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Liubov A. Tsvetkova, Olesya V. Paina, Polina V. Kozhokar’, Аnastasia S. Frolova, Zhemal Z. Rakhmanova, Elena V. Babenko, Elena V. Semenova, Alexander D. Kulagin, Ludmila S. Zubarovskaya

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia

Correspondence:
Dr. Liubov A. Tsvetkova, RM Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (921) 643-39-05
E-mail: tsvetluibov@mail.ru

Citation: Tsvetkova LA, Paina OV, Kozhokar' PV, et al. Combined adoptive immunotherapy with Blinatumomab and donor lymphocyte infusions in children with relapsed/refractory B-ALL after allogeneic stem cells transplantation. Cell Ther Transplant 2022; 11(2): 31-38.

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Allo-HSCT is potential curative option for high-risk pediatric B-cell acute leukemia (B-ALL), nevertheless about 30-70% of patients relapsed after allo-HSCT. Patients with relapsed/refractory (r/r) B-ALL have a dismal prognosis with 3-year probability overall survival (OS) about 20%. In this study we firstly appreciated efficacy and safety of combined adoptive immunotherapy with bispecific T-cell engager Blinatumomab and donor lymphocyte infusions (DLI) for 17 children underwent allo-HSCT and having relapse or minimal residual disease (MRD) after that. Fifteen (88%) of patients achieved a complete remission within the first 2 cycles of treatment with blinatumomab and DLI. The median relapse-free survival was 9.1 months (95% CI, 3.0 to 37.2 months) in patients who achieved CR, with the median duration follow up 13,3 months (95% CI, 10.0 to 30.3 months). The median overall survival for all patients was not reached at a median follow-up of 13.3 months (95% CI, 8.8 to 27.4 months). The Kaplan-Meier estimate overall survival was 76.5% (95% CI, 44%-92%) at a median follow-up time 13,3 months. Three children (18%) experienced drug-related adverse events grade 3 and two children (12%) had clinically significant induced "graft- versus-host disease" (GVHD). There were no fatal cases due to the therapy. Further immunotherapy options for r/r pediatric ALL may include repeated courses of combined adoptive immunotherapy, monotherapy of escalated DLI, chimeric antigen receptor T-cell therapies, checkpoint inhibitors or undergo second allo-HSCT.

Keywords

B-cell acute leukemia, children, relapse, allo-HSCT, blinatumomab, donor lymphocyte infusions.

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"HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(80) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(72) "Название (для очень длинных заголовков)" ["~DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } } } ["DISPLAY_PROPERTIES"]=> array(10) { ["AUTHOR_EN"]=> array(37) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_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"]=> 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Tsvetkova, Olesya V. Paina, Polina V. Kozhokar’, Аnastasia S. Frolova, Zhemal Z. Rakhmanova, Elena V. Babenko, Elena V. Semenova, Alexander D. Kulagin, Ludmila S. Zubarovskaya</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(196) "

Liubov A. Tsvetkova, Olesya V. Paina, Polina V. Kozhokar’, Аnastasia S. Frolova, Zhemal Z. Rakhmanova, Elena V. Babenko, Elena V. Semenova, Alexander D. Kulagin, Ludmila S. Zubarovskaya

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Liubov A. Tsvetkova, Olesya V. Paina, Polina V. Kozhokar’, Аnastasia S. Frolova, Zhemal Z. Rakhmanova, Elena V. Babenko, Elena V. Semenova, Alexander D. Kulagin, Ludmila S. Zubarovskaya

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Allo-HSCT is potential curative option for high-risk pediatric B-cell acute leukemia (B-ALL), nevertheless about 30-70% of patients relapsed after allo-HSCT. Patients with relapsed/refractory (r/r) B-ALL have a dismal prognosis with 3-year probability overall survival (OS) about 20%. In this study we firstly appreciated efficacy and safety of combined adoptive immunotherapy with bispecific T-cell engager Blinatumomab and donor lymphocyte infusions (DLI) for 17 children underwent allo-HSCT and having relapse or minimal residual disease (MRD) after that. Fifteen (88%) of patients achieved a complete remission within the first 2 cycles of treatment with blinatumomab and DLI. The median relapse-free survival was 9.1 months (95% CI, 3.0 to 37.2 months) in patients who achieved CR, with the median duration follow up 13,3 months (95% CI, 10.0 to 30.3 months). The median overall survival for all patients was not reached at a median follow-up of 13.3 months (95% CI, 8.8 to 27.4 months). The Kaplan-Meier estimate overall survival was 76.5% (95% CI, 44%-92%) at a median follow-up time 13,3 months. Three children (18%) experienced drug-related adverse events grade 3 and two children (12%) had clinically significant induced "graft- versus-host disease" (GVHD). There were no fatal cases due to the therapy. Further immunotherapy options for r/r pediatric ALL may include repeated courses of combined adoptive immunotherapy, monotherapy of escalated DLI, chimeric antigen receptor T-cell therapies, checkpoint inhibitors or undergo second allo-HSCT.

Keywords

B-cell acute leukemia, children, relapse, allo-HSCT, blinatumomab, donor lymphocyte infusions.

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Allo-HSCT is potential curative option for high-risk pediatric B-cell acute leukemia (B-ALL), nevertheless about 30-70% of patients relapsed after allo-HSCT. Patients with relapsed/refractory (r/r) B-ALL have a dismal prognosis with 3-year probability overall survival (OS) about 20%. In this study we firstly appreciated efficacy and safety of combined adoptive immunotherapy with bispecific T-cell engager Blinatumomab and donor lymphocyte infusions (DLI) for 17 children underwent allo-HSCT and having relapse or minimal residual disease (MRD) after that. Fifteen (88%) of patients achieved a complete remission within the first 2 cycles of treatment with blinatumomab and DLI. The median relapse-free survival was 9.1 months (95% CI, 3.0 to 37.2 months) in patients who achieved CR, with the median duration follow up 13,3 months (95% CI, 10.0 to 30.3 months). The median overall survival for all patients was not reached at a median follow-up of 13.3 months (95% CI, 8.8 to 27.4 months). The Kaplan-Meier estimate overall survival was 76.5% (95% CI, 44%-92%) at a median follow-up time 13,3 months. Three children (18%) experienced drug-related adverse events grade 3 and two children (12%) had clinically significant induced "graft- versus-host disease" (GVHD). There were no fatal cases due to the therapy. Further immunotherapy options for r/r pediatric ALL may include repeated courses of combined adoptive immunotherapy, monotherapy of escalated DLI, chimeric antigen receptor T-cell therapies, checkpoint inhibitors or undergo second allo-HSCT.

Keywords

B-cell acute leukemia, children, relapse, allo-HSCT, blinatumomab, donor lymphocyte infusions.

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia

Correspondence:
Dr. Liubov A. Tsvetkova, RM Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (921) 643-39-05
E-mail: tsvetluibov@mail.ru

Citation: Tsvetkova LA, Paina OV, Kozhokar' PV, et al. Combined adoptive immunotherapy with Blinatumomab and donor lymphocyte infusions in children with relapsed/refractory B-ALL after allogeneic stem cells transplantation. Cell Ther Transplant 2022; 11(2): 31-38.

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia

Correspondence:
Dr. Liubov A. Tsvetkova, RM Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (921) 643-39-05
E-mail: tsvetluibov@mail.ru

Citation: Tsvetkova LA, Paina OV, Kozhokar' PV, et al. Combined adoptive immunotherapy with Blinatumomab and donor lymphocyte infusions in children with relapsed/refractory B-ALL after allogeneic stem cells transplantation. Cell Ther Transplant 2022; 11(2): 31-38.

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Любовь А. Цветкова, Олеся В. Паина, Полина В. Кожокарь, Анастасия С. Фролова, Жемал З. Рахманова, Елена В. Бабенко, Елена В. Семенова, Александр Д. Кулагин, Людмила С. Зубаровская

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Любовь А. Цветкова, Олеся В. Паина, Полина В. Кожокарь, Анастасия С. Фролова, Жемал З. Рахманова, Елена В. Бабенко, Елена В. Семенова, Александр Д. Кулагин, Людмила С. Зубаровская

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ОВ по Каплану-Мейеру составила 76,5% (95% ДИ, 44-92%) при медиане наблюдения 13,3 месяца. Трое детей (18%) развили нежелательные явления 3-й степени тяжести, связанные с введением препарата, и двое детей (12%) имели клинически значимую индуцированную реакцию «трансплантат против хозяина» (РТПХ). Летальных случаев, связанных с терапией, отмечено не было. 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Алло-ТГСК является потенциально излечивающим методом терапии детей с В лимфобластным лейкозом (В-ОЛЛ) группы высокого риска. Тем не менее, примерно у 30-70% пациентов возникает рецидив после алло-ТГСК. Пациенты с рецидивирующим/ рефрактерным течением В-ОЛЛ имеют неблагоприятный прогноз с 3-летней общей выживаемостью (ОВ) около 20%. В этом исследовании мы впервые оценили эффективность и безопасность комбинированной адоптивной иммунотерапии биспецифическим активатором Т-клеток блинатумомабом и инфузиями донорских лимфоцитов (ИДЛ) у 17 детей, перенесших алло-ТГСК и имевших после этого рецидив или персистенцию минимальной остаточной болезни. Пятнадцать (88%) пациентов достигли ремиссии в течение первых 2 циклов лечения блинатумомабом +ИДЛ. Медиана безрецидивной выживаемости составила 9,1 мес (95% ДИ, от 3,0 до 37,2 мес.) у пациентов, достигших ответа, с медианой наблюдения 13,3 мес. (95% ДИ, 10,0-30,3 мес.). Медиана OB для всех пациентов не была достигнута при медиане наблюдения 13,3 месяца (95% ДИ, от 8,8 до 27,4 месяцев). ОВ по Каплану-Мейеру составила 76,5% (95% ДИ, 44-92%) при медиане наблюдения 13,3 месяца. Трое детей (18%) развили нежелательные явления 3-й степени тяжести, связанные с введением препарата, и двое детей (12%) имели клинически значимую индуцированную реакцию «трансплантат против хозяина» (РТПХ). Летальных случаев, связанных с терапией, отмечено не было. Дальнейшие варианты иммунотерапии детей с рецидивирующим течением В-ОЛЛ могут включать продолжение курсов комбинированной адоптивной иммунотерапии, монотерапию ИДЛ в эскалированных дозах, терапию Т-клетками с антигенным химерным рецептором, ингибиторами контрольных точек, а также проведение повторной алло-ТГСК.

Ключевые слова

В-клеточный острый лимфобластный лейкоз, дети, рецидив, алло-ТГСК, блинатумомаб, инфузии донорских лимфоцитов.

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Алло-ТГСК является потенциально излечивающим методом терапии детей с В лимфобластным лейкозом (В-ОЛЛ) группы высокого риска. Тем не менее, примерно у 30-70% пациентов возникает рецидив после алло-ТГСК. Пациенты с рецидивирующим/ рефрактерным течением В-ОЛЛ имеют неблагоприятный прогноз с 3-летней общей выживаемостью (ОВ) около 20%. В этом исследовании мы впервые оценили эффективность и безопасность комбинированной адоптивной иммунотерапии биспецифическим активатором Т-клеток блинатумомабом и инфузиями донорских лимфоцитов (ИДЛ) у 17 детей, перенесших алло-ТГСК и имевших после этого рецидив или персистенцию минимальной остаточной болезни. Пятнадцать (88%) пациентов достигли ремиссии в течение первых 2 циклов лечения блинатумомабом +ИДЛ. Медиана безрецидивной выживаемости составила 9,1 мес (95% ДИ, от 3,0 до 37,2 мес.) у пациентов, достигших ответа, с медианой наблюдения 13,3 мес. (95% ДИ, 10,0-30,3 мес.). Медиана OB для всех пациентов не была достигнута при медиане наблюдения 13,3 месяца (95% ДИ, от 8,8 до 27,4 месяцев). ОВ по Каплану-Мейеру составила 76,5% (95% ДИ, 44-92%) при медиане наблюдения 13,3 месяца. Трое детей (18%) развили нежелательные явления 3-й степени тяжести, связанные с введением препарата, и двое детей (12%) имели клинически значимую индуцированную реакцию «трансплантат против хозяина» (РТПХ). Летальных случаев, связанных с терапией, отмечено не было. Дальнейшие варианты иммунотерапии детей с рецидивирующим течением В-ОЛЛ могут включать продолжение курсов комбинированной адоптивной иммунотерапии, монотерапию ИДЛ в эскалированных дозах, терапию Т-клетками с антигенным химерным рецептором, ингибиторами контрольных точек, а также проведение повторной алло-ТГСК.

Ключевые слова

В-клеточный острый лимфобластный лейкоз, дети, рецидив, алло-ТГСК, блинатумомаб, инфузии донорских лимфоцитов.

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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

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                    [TEXT] => <p><sup>1</sup> Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия<br>
<sup>2</sup> Детский научно-клинический центр инфекционных болезней, Санкт-Петербург, Россия<br>
<sup>3</sup> Санкт-Петербургский НИИ эпидемиологии и микробиологии им. Пастера, Санкт-Петербург, Россия </p>
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1 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

2 Детский научно-клинический центр инфекционных болезней, Санкт-Петербург, Россия

3 Санкт-Петербургский НИИ эпидемиологии и микробиологии им. Пастера, Санкт-Петербург, Россия 
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	Состав микробиоты бронхоальвеолярных отделов у здоровых детей и взрослых в целом коррелирует с составом популяций верхних дыхательных путей. Однако при развитии тяжелых пневмоний, особенно у пациентов с иммунодефицитами, отмечается существенное нарастание количества, частоты выявления и биоразнообразия бактерий в бронхоальвеолярных смывах (БАЛ), наряду с колонизацией бронхов условно патогенными микроорганизмами из других инфицированных сайтов. Так, у многих пациентов с онкологическими заболеваниями на фоне цитостатической терапии развиваются тяжелые пневмонии с полимикробной колонизаций нижних дыхательных путей. Целью нашей работы была сравнительная оценка аэробной и факультативно-анаэробной микробиоты в образцах БАЛ от детей и взрослых пациентов после трансплантации гемопоэтических клеток (ТГСК).
</p>
<h3>Пациенты и методы</h3>
<p style="text-align: justify;">
	Проведено обследование 691 пациента, главным образом – с онкогематологическими заболеваниями, леченными цитостатической терапией и ТГСК (алло-ТГСК в 90% случаев). Возраст пациентов составлял от 1 до 71 г. (медиана – 38,5 л.). Применяли миело- или немиелоаблативную кондиционирующую терапию (44% и 56% случаев). Для исследования проводили забор 1123 образцов биоматериала (БАЛ) при диагностической бронхоскопии по соответствующим клиническим показаниями в период от D-100 до D+180 после ТГСК. Культивирование бактерий на селективных средах проводили в аэробных условиях по стандартным методикам, виды бактерий в изолятах идентифицировали с помощью биохимических тестов (BBL Crystal), масс-спектрометрии (MALDI-TOF), чувствительность к антибиотикам – диск-диффузионными тестами.
</p>
<h3>Результаты</h3>
<p style="text-align: justify;">
	В целом, частота выявления отдельных бактериальных видов в образцах БАЛ была следующей: <i>K.pneumoniae</i> – 19,1%, <i>P.aeruginosa</i> – 5%, <i>S. epidermidis</i> – 4,2%, <i>S. aureus</i> – 4,5%, <i>Acinetobacter spp.</i> – 3,7%, <i>E.faecium</i> – 7,0%, <i>E.faecalis</i> – 5,3%, <i>E.coli</i> – 2,5%, <i>Enterobacter spp.</i> – 2,3%, <i>Streptococcus pneumoniae</i> – 1,5%, <i>Haemophilus spp.</i> – 0,9% и т.д. Другие микробы <i>Corynebacteria spp., Neisseria spp.</i> и др. встречались реже. Отмечены значительная возрастная динамика состава и частоты различных видов микробиоты в БАЛ после ТГСК. В частности частота высеваемости <i>S.viridans</i> была максимальной у детей младшего возраста (0-5 лет), снижаясь у подростков &gt;15 лет. Та же закономерность, но менее выраженная, отмечена для <i>S.epidermidis</i>. Оба этих микробных вида часто выявляются в нормальной микробиоте. Напротив, частота выявления <i>Klebsiella spp., Pseudomonas spp.</i> и <i>S.aureus</i> в пробах БАЛ после интенсивной терапии и ТГСК повышается с возрастом пациентов, что говорит о большем риске жизнеопасных легочных инфекций после ТГСК, в том числе – резистентными к антибиотикам штаммами из кишечника у взрослых пациентов в период до 180 дней.
</p>
<h3>Выводы</h3>
<p style="text-align: justify;">
	У больных с онкогематологическими заболеваниями в течение 6 мес. после ТГСК отмечаются существенные сдвиги бронхоальвеолярной микробиоты. Показана сниженная высеваемость <i>S.viridans</i> и <i> S.epidermidis</i> у детей старше 15 лет и взрослых. Выявлено подавление микробиоты БАЛ в течение 1-го месяца после ТГСК. В более поздние сроки отмечен высокий риск колонизации <i>Klebsiella spp.</i> в связи с селекцией антибиотикорезистентных штаммов. Частота встречаемости <i>K.pneumoniae</i> и ее высокий уровень резистентности показывают актуальность данного патогена в развитии нозокомиальных инфекций у иммунокомпрометированных пациентов.
</p>
<h2>Ключевые слова</h2>
<p style="text-align: justify;">
	Трансплантация гемопоэтических клеток, бактериальная микробиота, бронхоальвеолярные смывы, возраст, временной фактор.
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	Состав микробиоты бронхоальвеолярных отделов у здоровых детей и взрослых в целом коррелирует с составом популяций верхних дыхательных путей. Однако при развитии тяжелых пневмоний, особенно у пациентов с иммунодефицитами, отмечается существенное нарастание количества, частоты выявления и биоразнообразия бактерий в бронхоальвеолярных смывах (БАЛ), наряду с колонизацией бронхов условно патогенными микроорганизмами из других инфицированных сайтов. Так, у многих пациентов с онкологическими заболеваниями на фоне цитостатической терапии развиваются тяжелые пневмонии с полимикробной колонизаций нижних дыхательных путей. Целью нашей работы была сравнительная оценка аэробной и факультативно-анаэробной микробиоты в образцах БАЛ от детей и взрослых пациентов после трансплантации гемопоэтических клеток (ТГСК).

Пациенты и методы

	Проведено обследование 691 пациента, главным образом – с онкогематологическими заболеваниями, леченными цитостатической терапией и ТГСК (алло-ТГСК в 90% случаев). Возраст пациентов составлял от 1 до 71 г. (медиана – 38,5 л.). Применяли миело- или немиелоаблативную кондиционирующую терапию (44% и 56% случаев). Для исследования проводили забор 1123 образцов биоматериала (БАЛ) при диагностической бронхоскопии по соответствующим клиническим показаниями в период от D-100 до D+180 после ТГСК. Культивирование бактерий на селективных средах проводили в аэробных условиях по стандартным методикам, виды бактерий в изолятах идентифицировали с помощью биохимических тестов (BBL Crystal), масс-спектрометрии (MALDI-TOF), чувствительность к антибиотикам – диск-диффузионными тестами.

Результаты

	В целом, частота выявления отдельных бактериальных видов в образцах БАЛ была следующей: K.pneumoniae – 19,1%, P.aeruginosa – 5%, S. epidermidis – 4,2%, S. aureus – 4,5%, Acinetobacter spp. – 3,7%, E.faecium – 7,0%, E.faecalis – 5,3%, E.coli – 2,5%, Enterobacter spp. – 2,3%, Streptococcus pneumoniae – 1,5%, Haemophilus spp. – 0,9% и т.д. Другие микробы Corynebacteria spp., Neisseria spp. и др. встречались реже. Отмечены значительная возрастная динамика состава и частоты различных видов микробиоты в БАЛ после ТГСК. В частности частота высеваемости S.viridans была максимальной у детей младшего возраста (0-5 лет), снижаясь у подростков >15 лет. Та же закономерность, но менее выраженная, отмечена для S.epidermidis. Оба этих микробных вида часто выявляются в нормальной микробиоте. Напротив, частота выявления Klebsiella spp., Pseudomonas spp. и S.aureus в пробах БАЛ после интенсивной терапии и ТГСК повышается с возрастом пациентов, что говорит о большем риске жизнеопасных легочных инфекций после ТГСК, в том числе – резистентными к антибиотикам штаммами из кишечника у взрослых пациентов в период до 180 дней.

Выводы

	У больных с онкогематологическими заболеваниями в течение 6 мес. после ТГСК отмечаются существенные сдвиги бронхоальвеолярной микробиоты. Показана сниженная высеваемость S.viridans и  S.epidermidis у детей старше 15 лет и взрослых. Выявлено подавление микробиоты БАЛ в течение 1-го месяца после ТГСК. В более поздние сроки отмечен высокий риск колонизации Klebsiella spp. в связи с селекцией антибиотикорезистентных штаммов. Частота встречаемости K.pneumoniae и ее высокий уровень резистентности показывают актуальность данного патогена в развитии нозокомиальных инфекций у иммунокомпрометированных пациентов.

Ключевые слова

	Трансплантация гемопоэтических клеток, бактериальная микробиота, бронхоальвеолярные смывы, возраст, временной фактор.

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                    [TEXT] => <p><sup>1</sup> Pavlov University, St. Petersburg, Russia<br>
<sup>2</sup> Pediatric Research Clinical Center of Infectious Diseases, St. Petersburg, Russia<br>
<sup>3</sup> St. Petersburg Pasteur Institute, St. Petersburg, Russia</p><br>
<p><b>Correspondence:</b><br>
Dr. Anna A. Spiridonova, Head, Department of Clinical Microbiology, Pavlov University, 6-8 L.Tolstoy St., 197022, St. Petersburg, Russia<br>
Phone: +7 (921) 920-76-40<br>
E-mail: annaasbac@mail.ru</p><br>
<p><b>Citation:</b> Spiridonova AA, Volkova AG, Chukhlovin AB, et al. Spectrum of bronchoalveolar bacterial microbiota following
hematopoietic stem cell transplantation: age dependence and microbiota shifts. Cell Ther Transplant 2022; 11(2): 45-53.</p>
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1 Pavlov University, St. Petersburg, Russia

2 Pediatric Research Clinical Center of Infectious Diseases, St. Petersburg, Russia

3 St. Petersburg Pasteur Institute, St. Petersburg, Russia


Correspondence:

Dr. Anna A. Spiridonova, Head, Department of Clinical Microbiology, Pavlov University, 6-8 L.Tolstoy St., 197022, St. Petersburg, Russia

Phone: +7 (921) 920-76-40

E-mail: annaasbac@mail.ru


Citation: Spiridonova AA, Volkova AG, Chukhlovin AB, et al. Spectrum of bronchoalveolar bacterial microbiota following
hematopoietic stem cell transplantation: age dependence and microbiota shifts. Cell Ther Transplant 2022; 11(2): 45-53.
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	 In healthy persons, lung microbiota shows close correlations with microbial landscape of upper respiratory tract. However, pronounced changes of lung microbiota are revealed by analysis of bronchoalveolar lavage (BAL) in severe pneumonias and other pulmonary complications, especially, in immunocompromised patients. E.g., following intensive cytostatic therapy and hematopoietic stem cell transplantation (HSCT), severe impairement of lung microbiota is observed, due to transient cytopenia, immunocompromised state and massive antibiotic prophylaxis. BAL microbiology shows a number of commensal bacteria including potential pathogens from other infectious sites. Hence, the aim of our study was to evaluate the diversity of aerobic and facultative anaerobic microorganisms in BAL samples from the HSCT patients.
</p>
<h3>Patients and methods</h3>
<p style="text-align: justify;">
	 Our study included 1123 BAL samples from 691 patients subjected to HSCT (1 to 71 years old). The patients were diagnosed, mainly, with myelo- and lymphoproliferative disorders. Myeloablative was carried out in 44% of cases. Stem cells were obtained from bone marrow or peripheral blood (497 <i>vs </i>596 transplants).
</p>
<p style="text-align: justify;">
	 The donor types were as follows: related compatible donors (19.2%); related haploidentical donors (21.6%); unrelated compatible donors (49.1%); autologous transplants (10.2%).
</p>
<p style="text-align: justify;">
	 Prophylaxis of graft-versus-host disease (GVHD) was mainly performed by the posttransplant cyclophosphamide (PtCy). BAL samples were collected at diagnostic bronchoscopy within D-100 to D+180 post-HSCT, according to appropriate clinical indications. Microbiological cultures and isolation of aerobes and facultative anaerobic bacteria from BAL samples were made by classical bacteriological techniques. Clinical isolates were identified by commercial biochemical test systems, as well as with MALDI-TOF mass spectrometry. The sensitivity of clinical isolates to antibiotics was determined by means of disk diffusion test systems.
</p>
<h3>Results</h3>
<p style="text-align: justify;">
	 Detection rates of the most common bacteria in BAL were as follows: <i>K.pneumoniae</i>, 19.1%; <i>P.aeruginosa</i>, 5%; <i>S. epidermidis</i>, 4.2%; <i>S. aureus</i>, 4.5%; <i>Acinetobacter spp.</i>, 3.7%; <i>E.faecium</i>, 7.0%; <i>E.faecalis</i>, 5.3%; <i>E.coli</i>, 2.5%; <i>Enterobacter spp.</i>, 2.3%; <i>Streptococcus pneumonia</i>, 1.5%; <i>Haemophilus spp.</i>, 0.9%, etc. The seeding rates for <i>S.viridans</i> and <i>S.epidermidis</i> tended to decrease with age, whereas the rates of <i>Klebsiella</i> detection, proved to be relatively high in all the studied age groups. Total bacterial numbers decreased during 1<sup>st</sup> month after HSCT, including those for <i>S.viridans</i>. Interestingly, the incidence of <i>Klebsiella spp.</i> showed sharp increase at 3-4 months posttransplant, due to selection of antibiotic-resistant strains.
</p>
<h3>Conclusion</h3>
<p style="text-align: justify;">
	 The patients with oncohematological disease subjected to massive allogeneic HSCT exhibit sufficient changes of bronchoalveolar microbiota over first 6 months posttransplant. Decreased seeding levels are shown for <i>S.viridans</i> and <i>S.epidermidis</i> in adolescents over 15 years and adults. A sufficient suppression of BAL microbiota is revealed within 1st month posttransplant. At later terms after HSCT, high risk of <i>Klebsiella spp.</i> colonization is observed, due to selection of antibiotic-resistant strains. Higher incidence of <i>K.pneumoniae</i> and its high resistance rates suggest relevance of this pathogen for development of nosocomial infections in immunocompromised patients and other clinical settings.
</p>
<h2>Keywords</h2>
<p style="text-align: justify;">
	 Hematopoietic stem cell transplantation, bacterial microbiota, bronchoalveolar lavage, age dependence, time dependence.
</p>
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	 In healthy persons, lung microbiota shows close correlations with microbial landscape of upper respiratory tract. However, pronounced changes of lung microbiota are revealed by analysis of bronchoalveolar lavage (BAL) in severe pneumonias and other pulmonary complications, especially, in immunocompromised patients. E.g., following intensive cytostatic therapy and hematopoietic stem cell transplantation (HSCT), severe impairement of lung microbiota is observed, due to transient cytopenia, immunocompromised state and massive antibiotic prophylaxis. BAL microbiology shows a number of commensal bacteria including potential pathogens from other infectious sites. Hence, the aim of our study was to evaluate the diversity of aerobic and facultative anaerobic microorganisms in BAL samples from the HSCT patients.

Patients and methods

	 Our study included 1123 BAL samples from 691 patients subjected to HSCT (1 to 71 years old). The patients were diagnosed, mainly, with myelo- and lymphoproliferative disorders. Myeloablative was carried out in 44% of cases. Stem cells were obtained from bone marrow or peripheral blood (497 vs 596 transplants).


	 The donor types were as follows: related compatible donors (19.2%); related haploidentical donors (21.6%); unrelated compatible donors (49.1%); autologous transplants (10.2%).


	 Prophylaxis of graft-versus-host disease (GVHD) was mainly performed by the posttransplant cyclophosphamide (PtCy). BAL samples were collected at diagnostic bronchoscopy within D-100 to D+180 post-HSCT, according to appropriate clinical indications. Microbiological cultures and isolation of aerobes and facultative anaerobic bacteria from BAL samples were made by classical bacteriological techniques. Clinical isolates were identified by commercial biochemical test systems, as well as with MALDI-TOF mass spectrometry. The sensitivity of clinical isolates to antibiotics was determined by means of disk diffusion test systems.

Results

	 Detection rates of the most common bacteria in BAL were as follows: K.pneumoniae, 19.1%; P.aeruginosa, 5%; S. epidermidis, 4.2%; S. aureus, 4.5%; Acinetobacter spp., 3.7%; E.faecium, 7.0%; E.faecalis, 5.3%; E.coli, 2.5%; Enterobacter spp., 2.3%; Streptococcus pneumonia, 1.5%; Haemophilus spp., 0.9%, etc. The seeding rates for S.viridans and S.epidermidis tended to decrease with age, whereas the rates of Klebsiella detection, proved to be relatively high in all the studied age groups. Total bacterial numbers decreased during 1st month after HSCT, including those for S.viridans. Interestingly, the incidence of Klebsiella spp. showed sharp increase at 3-4 months posttransplant, due to selection of antibiotic-resistant strains.

Conclusion

	 The patients with oncohematological disease subjected to massive allogeneic HSCT exhibit sufficient changes of bronchoalveolar microbiota over first 6 months posttransplant. Decreased seeding levels are shown for S.viridans and S.epidermidis in adolescents over 15 years and adults. A sufficient suppression of BAL microbiota is revealed within 1st month posttransplant. At later terms after HSCT, high risk of Klebsiella spp. colonization is observed, due to selection of antibiotic-resistant strains. Higher incidence of K.pneumoniae and its high resistance rates suggest relevance of this pathogen for development of nosocomial infections in immunocompromised patients and other clinical settings.

Keywords

	 Hematopoietic stem cell transplantation, bacterial microbiota, bronchoalveolar lavage, age dependence, time dependence.

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                    [TEXT] => <p><sup>1</sup> Департамент хируриги, Факультет медицины, Университет Александрии, Египет<br>
<sup>2</sup> Центр органной трансплантации, Госпиталь короля Фейсала и научный центр, Эр-Рияд, Королевство Саудовской Аравии</p>
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1 Департамент хируриги, Факультет медицины, Университет Александрии, Египет

2 Центр органной трансплантации, Госпиталь короля Фейсала и научный центр, Эр-Рияд, Королевство Саудовской Аравии
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                    [TEXT] => <p style="text-align: justify;">Риск рецидивов гепатоцеллюлярной карциномы (рГЦК) значителен, и их общий прогноз все еще неблагоприятен. Целью исследования является обобщение данных о частоте рецидивов ГЦК после трансплантации печени (ТП), рассмотрение их клинических особенностей и существующих вариантов терапии в нашем центре. Мы также рассматриваем потенциальные факторы риска рецидивирования ГЦК.</p>
<h3>Материалы и методы</h3>
<p style="text-align: justify;">Трансплантация печени была выполнена 148 пациентам в сроки с августа 2006 по декабрь 2020 г. в нашем центре. Выявлены случаи рецидивов ГЦК и систематизированы их клинические характеристики.</p>
<h3>Результаты</h3>
<p style="text-align: justify;">Средние сроки наблюдения после ТП составляли 53±34,8 мес. Рецидивы ГЦК были обнаружены у 16 пациентов (8,9%). Большинство этих больных (68,8%) наблюдали в течение первых двух лет после ТП. Инвазия в лимфатические сосуды, низкая степень дифференцировки опухоли и оценки по шкале RETREAT были достоверно связаны с рецидивами ГЦК.</p>
<h3>Выводы</h3>
<p style="text-align: justify;">Раннее выявление рецидивов необходимо для применения более эффективных способов контроля рГЦК. Критерии, основанные на оценке объема опухоли, не достаточны для прогнозирования случаев рецидивов ГЦК высокого риска. Следует использовать модели стратификации риска для выявления пациентов с плохим прогнозом при рГЦК. Протоколы их обследования должны быть адаптированы с риском рецидивирования ГЦК. </p>
<h2>Ключевые слова</h2>
<p style="text-align: justify;">Гепатоцеллюлярная карцинома, трансплантация печени, рецидив опухоли.</p>
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Риск рецидивов гепатоцеллюлярной карциномы (рГЦК) значителен, и их общий прогноз все еще неблагоприятен. Целью исследования является обобщение данных о частоте рецидивов ГЦК после трансплантации печени (ТП), рассмотрение их клинических особенностей и существующих вариантов терапии в нашем центре. Мы также рассматриваем потенциальные факторы риска рецидивирования ГЦК.
Материалы и методы
Трансплантация печени была выполнена 148 пациентам в сроки с августа 2006 по декабрь 2020 г. в нашем центре. Выявлены случаи рецидивов ГЦК и систематизированы их клинические характеристики.
Результаты
Средние сроки наблюдения после ТП составляли 53±34,8 мес. Рецидивы ГЦК были обнаружены у 16 пациентов (8,9%). Большинство этих больных (68,8%) наблюдали в течение первых двух лет после ТП. Инвазия в лимфатические сосуды, низкая степень дифференцировки опухоли и оценки по шкале RETREAT были достоверно связаны с рецидивами ГЦК.
Выводы
Раннее выявление рецидивов необходимо для применения более эффективных способов контроля рГЦК. Критерии, основанные на оценке объема опухоли, не достаточны для прогнозирования случаев рецидивов ГЦК высокого риска. Следует использовать модели стратификации риска для выявления пациентов с плохим прогнозом при рГЦК. Протоколы их обследования должны быть адаптированы с риском рецидивирования ГЦК. 
Ключевые слова
Гепатоцеллюлярная карцинома, трансплантация печени, рецидив опухоли.
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Mohamed Rabei Abdelfattah1, Hussein Elsiesy2
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                    [TEXT] => <p><sup>1</sup> Department of Surgery, Faculty of Medicine, University of Alexandria, Egypt<br>
<sup>2</sup> Organ Transplant Center, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom Saudi Arabia</p><br>
<p><b>Correspondence:</b><br>
Prof. Dr. Mohamed Rabei Abdelfattah. MD, Department
of Surgery, Faculty of Medicine, University of Alexandria,
AL Khartoum Square, Azzaritta, Alexandria, Egypt,
PO BOX 21131<br>
Phone: 0020102 306 1111 (mob.)<br>
E-mail: Mohamad.rabie@gmail.com</p><br>
<p><b>Citation:</b> Abdelfattah MR, Elsiesy H. Post-liver transplant HCC recurrence: patterns, treatment, and outcome. Cell Ther Transplant 2022; 11(2): 39-44.</p>
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1 Department of Surgery, Faculty of Medicine, University of Alexandria, Egypt

2 Organ Transplant Center, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom Saudi Arabia


Correspondence:

Prof. Dr. Mohamed Rabei Abdelfattah. MD, Department
of Surgery, Faculty of Medicine, University of Alexandria,
AL Khartoum Square, Azzaritta, Alexandria, Egypt,
PO BOX 21131

Phone: 0020102 306 1111 (mob.)

E-mail: Mohamad.rabie@gmail.com


Citation: Abdelfattah MR, Elsiesy H. Post-liver transplant HCC recurrence: patterns, treatment, and outcome. Cell Ther Transplant 2022; 11(2): 39-44.
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                    [TEXT] => <p style="text-align: justify;">The risk for recurrent hepatocellular carcinoma is still significant, and its overall prognosis is dismal. This study aims at reporting incidence of recurrent hepatocellular carcinoma (rHCC) cases following liver transplantation (LT), describing their clinical patterns, and current therapeutic modalities at our center. It also concerns potential risk factors related to HCC recurrence. </p>
<h3>Materials and methods</h3>
<p style="text-align: justify;">A total of 148 patients underwent LT between August 2006 and December 2020 at our Center. Cases with rHCC were identified, and their clinical data were comprehensively collected.</p>
<h3>Results</h3>
<p style="text-align: justify;">The mean post-transplant follow-up for the studied patients was 53±34.8 months. A total of 16 patients had HCC recurrence (8.9%). Majority of rHCC (68.8%) were observed within the first two years from LT. Vascular lymphatic invasion, poor tumor differentiation and RETREAT score were significantly related to HCC recurrence.</p>
<h3>Conclusions</h3>
<p style="text-align: justify;">Early detection is an imperative for the use of more curative rHCC-managing options. The tumor volume-based criteria are insufficient to predict high risk patients for HCC recurrence. Risk stratification models for HCC recurrence should be employed to identify high-risk patients for HCC recurrence. Screening protocols should be tailored to the risk of HCC recurrence.</p>
<h2>Keywords</h2>
<p style="text-align: justify;">Hepatocellular carcinoma, liver transplant, tumor recurrence.</p>
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The risk for recurrent hepatocellular carcinoma is still significant, and its overall prognosis is dismal. This study aims at reporting incidence of recurrent hepatocellular carcinoma (rHCC) cases following liver transplantation (LT), describing their clinical patterns, and current therapeutic modalities at our center. It also concerns potential risk factors related to HCC recurrence. 
Materials and methods
A total of 148 patients underwent LT between August 2006 and December 2020 at our Center. Cases with rHCC were identified, and their clinical data were comprehensively collected.
Results
The mean post-transplant follow-up for the studied patients was 53±34.8 months. A total of 16 patients had HCC recurrence (8.9%). Majority of rHCC (68.8%) were observed within the first two years from LT. Vascular lymphatic invasion, poor tumor differentiation and RETREAT score were significantly related to HCC recurrence.
Conclusions
Early detection is an imperative for the use of more curative rHCC-managing options. The tumor volume-based criteria are insufficient to predict high risk patients for HCC recurrence. Risk stratification models for HCC recurrence should be employed to identify high-risk patients for HCC recurrence. Screening protocols should be tailored to the risk of HCC recurrence.
Keywords
Hepatocellular carcinoma, liver transplant, tumor recurrence.
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<h2>Ключевые слова</h2>
<p style="text-align: justify;">В-клеточный острый лимфобластный лейкоз, дети, рецидив, алло-ТГСК, блинатумомаб, инфузии донорских лимфоцитов.</p>
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Ключевые слова
В-клеточный острый лимфобластный лейкоз, дети, рецидив, алло-ТГСК, блинатумомаб, инфузии донорских лимфоцитов.
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                    [TEXT] => <p>RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia</p><br>
<p><b>Correspondence:</b><br>
Dr. Liubov A. Tsvetkova, RM Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia<br>
Phone: +7 (921) 643-39-05<br>
E-mail: tsvetluibov@mail.ru</p><br>
<p><b>Citation:</b> Tsvetkova LA, Paina OV, Kozhokar' PV, et al. Combined adoptive immunotherapy with Blinatumomab and donor lymphocyte infusions in children with relapsed/refractory B-ALL after allogeneic stem cells transplantation. Cell Ther Transplant 2022; 11(2): 31-38. </p>
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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:

Dr. Liubov A. Tsvetkova, RM Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia

Phone: +7 (921) 643-39-05

E-mail: tsvetluibov@mail.ru


Citation: Tsvetkova LA, Paina OV, Kozhokar' PV, et al. Combined adoptive immunotherapy with Blinatumomab and donor lymphocyte infusions in children with relapsed/refractory B-ALL after allogeneic stem cells transplantation. Cell Ther Transplant 2022; 11(2): 31-38. 
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                    [TEXT] => <p style="text-align: justify;">Allo-HSCT is potential curative option for high-risk pediatric B-cell acute leukemia (B-ALL), nevertheless about 30-70% of patients relapsed after allo-HSCT. Patients with relapsed/refractory (r/r) B-ALL have a dismal prognosis with 3-year probability overall survival (OS) about 20%. In this study we firstly appreciated efficacy and safety of combined adoptive immunotherapy with bispecific T-cell engager Blinatumomab and donor lymphocyte infusions (DLI) for 17 children underwent allo-HSCT and having relapse or minimal residual disease (MRD) after that. Fifteen (88%) of patients achieved a complete remission within the first 2 cycles of treatment with blinatumomab and DLI. The median relapse-free survival was 9.1 months (95% CI, 3.0 to 37.2 months) in patients who achieved CR, with the median duration follow up 13,3 months (95% CI, 10.0 to 30.3 months). The median overall survival for all patients was not reached at a median follow-up of 13.3 months (95% CI, 8.8 to 27.4 months). The Kaplan-Meier estimate overall survival was 76.5% (95% CI, 44%-92%) at a median follow-up time 13,3 months. Three children (18%) experienced drug-related adverse events grade 3 and two children (12%) had clinically significant induced "graft-
versus-host disease" (GVHD). There were no fatal cases due to the therapy. Further immunotherapy options for r/r pediatric ALL may include repeated courses of combined adoptive immunotherapy, monotherapy of escalated DLI, chimeric antigen receptor T-cell therapies, checkpoint inhibitors or undergo second allo-HSCT. </p>
<h2>Keywords</h2>
<p style="text-align: justify;">B-cell acute leukemia, children, relapse, allo-HSCT, blinatumomab, donor lymphocyte infusions.</p>
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Allo-HSCT is potential curative option for high-risk pediatric B-cell acute leukemia (B-ALL), nevertheless about 30-70% of patients relapsed after allo-HSCT. Patients with relapsed/refractory (r/r) B-ALL have a dismal prognosis with 3-year probability overall survival (OS) about 20%. In this study we firstly appreciated efficacy and safety of combined adoptive immunotherapy with bispecific T-cell engager Blinatumomab and donor lymphocyte infusions (DLI) for 17 children underwent allo-HSCT and having relapse or minimal residual disease (MRD) after that. Fifteen (88%) of patients achieved a complete remission within the first 2 cycles of treatment with blinatumomab and DLI. The median relapse-free survival was 9.1 months (95% CI, 3.0 to 37.2 months) in patients who achieved CR, with the median duration follow up 13,3 months (95% CI, 10.0 to 30.3 months). The median overall survival for all patients was not reached at a median follow-up of 13.3 months (95% CI, 8.8 to 27.4 months). The Kaplan-Meier estimate overall survival was 76.5% (95% CI, 44%-92%) at a median follow-up time 13,3 months. Three children (18%) experienced drug-related adverse events grade 3 and two children (12%) had clinically significant induced "graft-
versus-host disease" (GVHD). There were no fatal cases due to the therapy. Further immunotherapy options for r/r pediatric ALL may include repeated courses of combined adoptive immunotherapy, monotherapy of escalated DLI, chimeric antigen receptor T-cell therapies, checkpoint inhibitors or undergo second allo-HSCT. 
Keywords
B-cell acute leukemia, children, relapse, allo-HSCT, blinatumomab, donor lymphocyte infusions.
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