Therapy results in pediatric Hodgkin lymphoma - does less mean better? Experience from a single children's oncology center.

Therapy results in pediatric Hodgkin lymphoma reflect remarkable progress in pediatric oncology. In the last decade, relevant development of new therapeutic options for children with refractory or relapsed disease has been made. In this study, we retrospectively analyzed therapy results and risk factors in children treated in a single oncology center according to five therapeutic protocols. Data from 114 children treated by a single institution between 1997 and 2022 were analyzed. Classic Hodgkin lymphoma therapy results were divided into four therapeutic periods: 1997-2009, 2009-2014, 2014-2019, and 2019-2022. For nodular lymphocyte-predominant Hodgkin lymphoma, data from one therapeutic protocol was analyzed. For the entire group, the 5-year probability of overall survival was 93.5%. There were no statistically significant differences between therapeutic periods. The occurrence of B symptoms at diagnosis and incidence of relapse were risk factors for death (p = 0.018 and p < 0.001). Relapse occurred in 5 cases. The 5-year probability of relapse-free survival for the entire group was 95.2%, without significant differences between groups. Patients treated between 1997 and 2009 had over a sixfold higher risk for events, defined as primary progression, relapse, death, or incidence of secondary malignancies (OR = 6.25, p = 0.086). The 5-year probability of event-free survival for all patients was 91.3%. Five patients died, and the most common cause of death was relapse. Modern therapeutic protocols in pediatric Hodgkin lymphoma are marked by excellent outcomes. Patients with disease relapses have a notably high risk of death, and the development of new therapeutic options for this group remains one of the main goals of current trials.

Infection With Saprochaete Clavata in Children After Hematopoietic Cell Transplantation.

Septic shock is a very rare manifestation of invasive fungal disease (IFD) in children after allogeneic hematopoietic cell transplantation (allo-HCT). The objective of this paper is analysis of two cases of pediatric patients with IFD caused by Saprochaete clavata after allo-HCT. Literature data on this infection in children and its outcome were also summarized. Infection with Saprochaete clavate presenting with symptoms of septic shock was being reported in 4 children, and 2 of them survived the infection. In conclusion, with quick diagnosis and quick treatment, the outcome of therapy of infection with Saprochaete clavata was successful.

The Successful Sequential Use of Plerixafor and Eltrombopag For Hematopoietic Cell Transplantation in a Child With High-risk Neuroblastoma.

High-dose chemotherapy with autologous hematopoietic stem cell transplantation improves event-free survival in patients with high-risk neuroblastoma. However, in heavily pretreated patients, poor marrow function can be an obstacle in the successful proceeding of therapy. Priming with plerixafor plus filgrastim is an option for effective mobilization and collection of stem cells. In addition, thrombopoietin agonist eltrombopag can improve the outcome of posttransplantation thrombocytopenia and poor graft function in the posttransplant setting. We describe a case of a child with high-risk neuroblastoma, for whom plerixafor and eltrombopag were used as an effective and safe supportive therapy.

Complex profile of multiple hepatobiliary and gastrointestinal complications after hematopoietic stem cell transplantation in a child with Nijmegen breakage syndrome.

Patients with Nijmegen breakage syndrome (NBS) can develop life-threatening immunodeficiency, which should be treated with hematopoietic stem cell transplantation (HSCT). We report the case of a 14-year-old girl with NBS who due to an increasing number of severe complications was referred for HSCT from a matched unrelated donor. After reduced-intensity conditioning and transplantation of peripheral blood hematopoietic cells, during the early post-transplant period (days 0-30), the girl suffered from severe mucositis, fever episodes, mild acute renal injury and facial vasculitis. All these complications were managed successfully. During the intermediate post-transplant period (days 30-100) a number of hepatic and gastrointestinal complications occurred, including cholecystitis, cholelithiasis with choledocholithiasis, pancreatitis as well as acute bleeding from the lower gastrointestinal tract caused by rectal and recto-sigmoid junction ulcers. All the obstacles were obviously attributable both to the primary congenital disease, its complications, and transplantation itself. We overcame these complications and treated the patient with the best possible and safe methods. The multidisciplinary approach based on combined surgical, endoscopic and conservative management of multiple post-transplant complications was successful for the patient.

Transplant-related mortality and survival in children with malignancies treated with allogeneic hematopoietic stem cell transplantation. A multicenter analysis.

The aim of the study was to assess the risk of TRM in pediatric patients treated for malignant disorders with allogeneic HSCT, according to different risk factors. The treatment outcome was analyzed in 299 pediatric patients treated in pediatric transplant departments from 2006 to 2015. To compare the outcome, patients were analyzed all together and in groups according to the diagnosis, age at transplant, donor type, disease status, stem cell source, and pediatric TRM score. At the end of the observation time, 82 patients were alive, 82 died, of which 40 due to transplant-related reasons. The most frequently observed causes of TRM were toxic complications effecting with organ failure (38%), followed by infections (26%), PTLD (14.3%), and GvHD (16.7%). There was no statistical difference in the incidence of TRM depending on stem cell source (P = .209) and primary diagnosis (P = .301). According to TRM score, TRM was significantly higher in high-risk group (P = .006). High-risk patients had lower survival comparing to low/intermediate group (P = .0001). OS did not differ between ALL, AML, and MDS/JMML groups. The study confirmed the utility of factors included in TRM score stratification in assessing the risk of transplant procedure in pediatric patients transplanted for malignancies.

Does the Harvesting Technique Affect the Properties of Adipose-Derived Stem Cells?-The Comparative Biological Characterization.

The objective of this study was to evaluate complex biological properties of human stem cells isolated from adipose tissue (ASCs) harvested utilizing different methods: surgical resection (R), power-assisted liposuction (PAL), and laser-assisted liposuction (LAL). ASCs were isolated from healthy donors, due to surgical resection, power-, and laser-assisted liposuction. Isolated cells were characterized by their clonogenicity, proliferation rate, doubling time, multilineage differentiation, and senescence potential. The average number of ASCs from 1g/1 ml of solid adipose tissue/lipoaspirate was 2.9 × 105 ± 2.4 × 105 , 1.1 × 105 ± 0.8 × 105 , and 1.2 × 105 ± 0.7 × 105 , respectively, for ASCsR, ASCsPAL, and ASCsLAL. However, number of colonies formed by ASCsR and ASCsPAL was significantly higher compared to the average number of colonies formed by ASCsLAL. Also, in comparison to other analyzed cell groups, ASCsPAL obtained the highest proliferative activity. All analyzed cells were characterized by stable expression of CD90 and CD44 markers during prolonged culture. Expression of CD34 and CD45 markers was decreasing in subsequent passages. Presented study shows that different ASCs collection method affects some basic characteristics of these cells, such as number of isolated cells, clonogeneity, or doubling time. J. Cell. Biochem. 118: 1097-1107, 2017. © 2016 Wiley Periodicals, Inc.

High Quality Independent From a Donor: Human Amniotic Fluid Derived Stem Cells-A Practical Analysis Based on 165 Clinical Cases.

The aim of the study was to extend the potential use of human stem cells isolated from amniotic fluid in medical applications by confirming their high homogeneity and quality. Amniotic fluid samples were collected during amniocentesis from 165 women during pregnancy. The proliferation rate, clonogenicity, karyotype, aging process, pluripotent cell markers, expression of surface markers, and the potential to differentiate into adipose, bone and cartilage cells of hAFSCs were analyzed. Obtained results revealed that mesenchymal stem cells could be derived successfully from amniotic fluid, which exhibit properties comparable with MSCs of other origins. It is the first study, in which such a large group of patients was involved. Comprehensive statistical and biological analysis were conducted some of which clearly being innovative in relation to human amniotic fluid-derived stem cells. J. Cell. Biochem. 118: 116-126, 2017. © 2016 Wiley Periodicals, Inc.

Hair follicle stem cells can be driven into a urothelial-like phenotype: an experimental study.

The aim of this study was to show that conditioned medium might induce transdifferentiation of hair follicle stem cells into urothelial-like cells. Several conditioned media and culture conditions (skeletal muscle cell conditioned medium, smooth muscle cell conditioned medium, fibroblast conditioned medium, transforming growth factor-conditioned medium, urothelial cell conditioned medium, and co-culture of hair follicle stem cells and urothelial cells) were used. The hair follicle stem cells phenotype from rat whisker hair follicles was checked by using flow cytometry and immunofluorescence. Cytokeratins 7, 8, 15 and 18 were used as markers. Urothelial cell conditioned medium increased the expression of urothelial markers (cytokeratin 7, cytokeratin 8, cytokeratin 18), whereas it decreased a hair follicle stem cells marker (cytokeratin 15) after 2 weeks of culture. This process depended on the time of cultivation. This medium was able to sustain the epithelial phenotype of the culture. Other media including a co-culture system failed to induce similar changes. Smooth muscle conditioned medium resulted in a loss of cells in culture. Hair follicle stem cells are capable of differentiating into urothelial-like cells in vitro when exposed to a bladder-specific microenvironment.

Carboplatin and sodium butyrate, separate--yes, but combined--never.

With the object of improving the effectiveness of a malignant melanoma's treatment and a patients' quality of life, there is a serious need to identify new anticancer compounds, for example, among naturally derived compounds such as sodium butyrate. The aim of this study was to assess the combined impact of carboplatin (C) and sodium butyrate on the B16 melanoma viability by in vitro. B16 cell line was exposed to various concentrations of carboplatin (0.001-10 micromol/L) and sodium butyrate (1 to 100 mmol/L) for 24 h. LC10, LC50 and LC90 values were calculated. The influence of carboplatin and sodium butyrate on the cell cycle and apoptosis was assessed. Additionally, magnetic stem cell sorting was performed, positive melanoma CD133 cells were isolated and the effects of carboplatin and sodium butyrate on cell viability with heterogeneous population of melanoma cells (CD133+/CD133-) was compared. For carboplatin LC50 and LC90 were 1.2 micromol/L and 4.58 pmol/L, respectively. For sodium butyrate LC50 and LC90 were 65.73 mmol/L and 275.06 mmol/L. The value for LC10 could not be determined. Sodium butyrate at the highest concentration (100.0 mmol/L) resulted in only 57.36% mortality of cells. A synergistic effect of both compounds was observed in low concentrations of sodium butyrate and carboplatin. That synergism disappeared at concentrations corresponding to LC50. At the concentration corresponding to LC50 C and high concentration of sodium butyrate, a decrease of cell numbers in phase G2/M was observed (r = -0.97). Cells were arrested in phase G1/G0 and S. The presented results exclude the possibility of the combined application of sodium butyrate and carboplatin in cancer therapy.

Isocitrate dehydrogenase 1 R132H mutation is not detected in angiocentric glioma.

Mutations of isocitrate dehydrogenase-1 gene (IDH1), most commonly resulting in replacement of arginine at position 132 by histidine (R132H), have been described in World Health Organization grade II and III diffuse gliomas and secondary glioblastoma. Immunohistochemistry using a mouse monoclonal antibody has a high specificity and sensitivity for detecting IDH1 R132H mutant protein in sections from formalin-fixed, paraffin-embedded tissue. Angiocentric glioma (AG), a unique neoplasm with mixed phenotypic features of diffuse glioma and ependymoma, has recently been codified as a grade I neoplasm in the 2007 World Health Organization classification of central nervous system tumors. The present study was designed to evaluate IDH1 R132H protein in AG. Three cases of AG were collected, and the diagnoses were confirmed. Expression of mutant IDH1 R132H protein was determined by immunohistochemistry on representative formalin-fixed, paraffin-embedded sections using the antihuman mouse monoclonal antibody IDH1 R132H (Dianova, Hamburg, Germany). Known IDH1 mutation-positive and IDH1 wild-type cases of grade II to IV glioma served as positive and negative controls. All 3 patients were male, aged 3, 5, and 15 years, with intra-axial tumors in the right posterior parietal-occipital lobe, right frontal lobe, and left frontal lobe, respectively. All 3 cases showed characteristic morphologic features of AG, including a monomorphous population of slender bipolar cells that diffusely infiltrated cortical parenchyma and ensheathed cortical blood vessels radially and longitudinally. All 3 cases were negative for the presence of IDH1 R132H mutant protein (0/3). All control cases showed appropriate reactivity. IDH1 R132H mutation has been described as a common molecular signature of grade II and III diffuse gliomas and secondary glioblastoma; however, AG, which exhibits some features of diffuse glioma, has not been evaluated. The absence of mutant IDH1 R132H protein expression in AG may help further distinguish this unique neoplasm from diffuse glioma.

Letermovir Prophylaxis for Cytomegalovirus Infection in Children After Hematopoietic Cell Transplantation.

BACKGROUND/AIM: Cytomegalovirus (CMV) infection is one of the major causes of morbidity following hematopoietic cell transplantation (HCT). Allogeneic HCT (allo-HCT) recipients are at the highest risk of clinically significant CMV reactivation. While letermovir has been approved for prophylactic use in CMV seropositive adults, reports on pediatric data are very limited. The objective of the study was to examine the use of letermovir for prophylaxis from CMV infection in children undergoing allo-HCT in a single center. PATIENTS AND METHODS: This retrospective matched-pair analysis study included 39 CMV-seropositive pediatric patients undergoing allo-HCT receiving letermovir as a primary prophylaxis for CMV infection on a compassionate-use basis (LMV group, n=13) or not (control group, n=26). There were no differences in basic characteristics between the analyzed groups. Among patients of the study group, 12 received primary prophylaxis with letermovir from day +1 after HCT. One patient, previously treated with ganciclovir received secondary prophylaxis from day +18. RESULTS: Prophylactic dose of letermovir was adjusted to cyclosporine co-administration, varied in between 120-480 mg, and given orally, once daily. No CMV reactivation was observed during administration of letermovir. Cumulative incidence of CMV reactivation was significantly higher for the control group not receiving prophylaxis. Of the 13 patients of the study group, three died; however, deaths were not attributable to CMV infection. We did not observe any toxicities related to letermovir. CONCLUSION: Our data support letermovir prophylaxis efficacy and safety in pediatric patients after allo-HCT. Compared with the historical group, prophylactic use of letermovir decreased the number of CMV reactivations in children.

Case report: Cellular therapy for hydroa vacciniforme-like lymphoproliferative disorder in pediatric common variable immunodeficiency with chronic active Epstein-Barr virus infection.

Hydroa vacciniforme-like lymphoproliferative disorder (HV-LPD) is a cutaneous form of chronic active Epstein-Barrvirus (EBV) infection, which can develop into the extremely rare systemic lymphoma. Patients with Inborn errors of immunity (IEI), such as common variable immunodeficiency (CVID), are at higher risk of developing a severe course of infections especially viral and malignancies than the general population. The aim of the study was to present complex diagnostic and therapeutic management of HV-LPD. The clinical diagnosis was confirmed at the histological and molecular level with next generation sequencing. HV-LPD was diagnosed in a patient with CVID and chronic active Epstein-Barr virus (CAEBV) infection. The patient was refractory to CHOP chemotherapy and immunosuppressive treatment in combination with antiviral drugs (prednisone, bortezomib, gancyclovir). The third-party donor EBV-specific cytotoxic T cells (EBV-CTL, tabelecleucel) were used, which stabilised the disease course. Finally, matched unrelated donor hematopoietic cell transplantation (MUD-HCT) was performed followed by another cycle of EBV-CTL.

Rhabdomyosarcoma in a Patient With Duchenne Muscular Dystrophy: A Possible Association.

Duchenne muscular dystrophy (DMD), caused by a mutation in the DMD gene, is known to be associated with co-morbidities including cardiomyopathy, respiratory failure, neuromuscular scoliosis and intellectual disability. Animal studies have explored the susceptibility of dystrophin-deficient mice with the development of myogenic tumors. While there is adequate literature describing both DMD and rhabdomyosarcoma (RMS) separately, there has yet to be a comprehensive literature review investigating the possibility that patients with DMD may be at a higher risk of developing RMS and other myogenic tumors. We present the case of a pediatric patient with DMD who developed alveolar RMS and review the literature for susceptibility to development of myogenic tumors in cases of DMD gene mutation.

Factors Modifying Outcome After MIBG Therapy in Children With Neuroblastoma-A National Retrospective Study.

BACKGROUND: Neuroblastoma is the most common pediatric extracranial tumor with varied prognoses, but the survival of treated refractory or relapsing patients remains poor. OBJECTIVE: This analysis presents the outcomes of children with neuroblastoma undergoing MIBG therapy in Poland in 2006-2019. STUDY DESIGN: A retrospective cohort of 55 patients with refractory or relapsed neuroblastoma treated with I-131 MIBG in Poland in 2006-2019 was analyzed. The endpoints were overall survival (OS), event-free survival (EFS), cumulative incidence (CI) of second cancers and CI of hypothyroidism. Survival curves were estimated using the Kaplan-Meier method and compared between the cohorts by the log-rank test. Cox modeling was adopted to estimate hazard ratios for OS and EFS, considering factors with P < 0.2. RESULTS: Fifty-five patients with a median age of 78.4 months (range 18-193) with neuroblastoma underwent one or more (4 patients) courses of MIBG I-131 therapy. Fifteen patients were not administered chemotherapy, 3 children received standard-dose chemotherapy, and 37 patients were administered high-dose chemotherapy (HDCT) (busulfan-melphalan in 24 and treosulfan-based in 12 patients). Forty-six patients underwent stem cell transplantation, with autologous (35 patients), haploidentical (6), allogeneic (4), and syngeneic grafts (1). The median time from first MIBG therapy to SCT was 22 days. Children with relapsing tumors had inferior OS compared to those with primary resistant disease (21.2% vs 58.7%, p=0.0045). Survival was better in patients without MYCN gene amplification. MIBG therapy was never curative, except in patients further treated with HDCT with stem cell rescue irrespective of the donor type. 31 patients were referred for immune therapy after MIBG therapy, and the 5-year OS in this group was superior to the untreated children (55.2% vs 32.7%, p=0.003), but the difference in the 5-year EFS was not significant (25.6% vs 32.9%, p=ns). In 3 patients, a second malignancy was diagnosed. In 19.6% of treated children, hypothyroidism was diagnosed within 5 years after MIBG therapy. CONCLUSION: MIBG therapy can be incorporated into the therapeutic strategy of relapsed or resistant neuroblastoma patients as preconditioning with HDCT rather than stand-alone therapy. Follow-up is required due to the incidence of thyroid failure and risk of second cancers.

Acute Lymphoblastic Leukemia in Children: Better Transplant Outcomes After Total Body Irradiation-based Conditioning.

BACKGROUND/AIM: Comparison of transplant outcomes in long-term follow-up of children after total body irradiation (TBI)- or chemotherapy-based conditioning allogeneic hematopoietic cell transplantation (allo-HCT). PATIENTS AND METHODS: Patients undergoing allo-HCT for Acute lymphoblastic leukemia (ALL) conditioned either with TBI (n=55) or chemotherapy (n=84) were compared. The following transplant outcomes were analyzed: overall survival (OS), event-free survival (EFS), relapse incidence (RI), and graft-versus-host-disease (GVHD)-free-relapse-free survival (GRFS). RESULTS: All analyzed long-term transplant outcomes were significantly better for patients conditioned with TBI at 2 years after transplant. OS at 2 years was 84% after TBI and 60.5% after chemotherapy-conditioning (p=0.005). Risk factor analysis showed that two factors, TBI-based conditioning and transplant in first remission of ALL, significantly improved OS, EFS, GRFS, and decreased RI. CONCLUSION: TBI-based conditioning before allogeneic HCT in children with acute lymphoblastic leukemia provides significantly better transplant outcomes, when compared to chemotherapy-based conditioning.

Health-related quality of life among paediatric survivors of primary brain tumours and acute leukaemia.

PURPOSE: Comparative assessment of the HRQL of paediatric survivors of brain tumours (BT) and of acute leukaemia against a population of their healthy peers. METHODS: The study consisted of patients who had completed treatment for BT (n=36) or acute leukaemia (n=35) and were aged between 8 and 19. Healthy children (n=60) were selected from among pupils of schools. HRQL was evaluated directly and indirectly on the basis of the Polish language version of the PedsQLTM 4.0 Generic Core scales. The influence of selected factors (sex, age, time from the end of treatment and type of treatment) on the HRQL result was analysed. RESULTS: In all the aspects analysed (total, physical, psychosocial, emotional, social and school functioning), the HRQL of BT and leukaemia survivors was significantly lower in comparison to their healthy peers. The HRQL of patients after BT treatment was also significantly lower than that of the survivors of leukaemia. The parent-proxy reported HRQL was consistent with the children's selfassessment. Patients treated with radiotherapy presented a significantly lower evaluation of life quality in the physical sphere. CONCLUSIONS: Evaluation of HRQL should be treated as an additional independent parameter in an assessment of the long-term results of oncological treatment.

[Analysis of the immunological reconstitution, effectiveness and safety of vaccination in children with cancer]. / Ocena rekonstrukcji immunologicznej oraz bezpieczenstwa i skutecznosci szczepien ochronnych u dzieci leczonych z powodu choroby nowotworowej.

UNLABELLED: The aim of this study was an assessment of immunologic reconstitution, efficiency and safety of vaccination performed in course of oncological treatment and after the therapy. PATIENTS: 129 children aged 1 month-19,5 years with diagnosis of leukemia or lymphoma (74,4%) or a solid tumor (25,6%). Immune status was evaluated 6 months after cessation of treatment in order to plan active immunization. Effectiveness of vaccination against hepatitis B was performed too. PATIENTS who did not complete immunization against hepatitis B at the time of diagnosis continued vaccination according to the scheme 0-1-6 months, the others were given one doubled dose. In 90,7% patients complete immune reconstitution was observed and both mandatory and optional immunization was then resumed. In 5,4% of children vaccination with live vaccines was suspended due to moderate immune deficiencies. In 3,9% of patients severe immune deficiencies were diagnosed and vaccination was abandoned. At diagnosis of cancer double vaccine doses against hepatitis B were given to 94,6% of patients, while 5,4% continued standard vaccination scheme. After anticancer therapy anti-HBs titer >100 IU/ml was observed in 55%, 10-100 IU/ml in 26% and <10 IU/ml in 18,6% of patients. One case of HBV infection was noted. Neither adverse reactions after immunization nor life-threatening infections the patients were vaccinated against was noted. Our Immunization protocol adopted in the study seem to be efficient and safe.

Impact of Palifermin on Transplant Outcomes in Children and Adolescents Undergoing Allogeneic Hematopoietic Cell Transplantation.

BACKGROUND: Oral mucositis (OM) is considered to be one of the worst and most debilitating complications of conditioning for hematopoietic cell transplantation (HCT). Prevention and treatment of this complication is one of the utmost priorities of supportive therapy during transplant procedure. The objective of this study was the analysis of the influence of palifermin, keratinocyte growth factor (KGF), on transplant outcomes in patients undergoing allo-HCT. PATIENTS AND METHODS: A total of 253 allo-HCTs performed between 2003-2018 in patients aged 0-19 years at a single center were analyzed. KGF was administered in 161 HCTs. Uni- and multivariate risk factor analyses were performed. RESULTS: In spite of reducing the duration and grade of mucositis, no prognostic impact of KGF was shown for overall survival, event-free survival, relapse incidence, acute and chronic graft-versus-host disease (GVHD), nor GVHD-free relapse-free survival. CONCLUSION: Palifermin had no impact on transplant outcomes in children and adolescents undergoing allo-HCT.

Outcome of Pediatric Acute Lymphoblastic Leukemia: Sixty Years of Progress.

BACKGROUND: A retrospective analysis was performed to investigate the survival outcomes in pediatric acute lymphoblastic leukemia (ALL) based on time period. We hypothesized that improvement has been obtained with the time-dependent therapeutic era and rise in the gross domestic product (GDP) and Human Development Index (HDI). MATERIALS AND METHODS: Data from 710 children who were treated for ALL between 1958 and 2018 at a single pediatric center were analyzed for probability of 5-year overall survival (pOS), event-free survival (pEFS) and relapse risk (pRR). Time periods were defined by the treatment protocols used in seven consecutive therapeutic eras. RESULTS: Over the 60-year period analyzed, pOS increased from 1.2% to 90.7%, pEFS from 1.2% to 86.6%, and pRR decreased from 98.8% to 9.9% for patients treated in the past decade. Risk of mortality for patients who received chemotherapy and hematopoietic cell transplant was reduced to 9.9% in the recent era, however, no statistically significant survival difference was found between patients treated with stem cell transplant and those not. CONCLUSION: The therapeutic era, related to improved GDP and HDI, was a statistically significant predictor of increased OS from ALL.