Revisiting the role of radiotherapy in the treatment of neuroblastoma 4S: 30 years of institutional experience and systematic review.

Background and purpose: Neuroblastoma 4S is a rare subtype of metastatic neuroblastoma found in children younger than 12 months, characterized by liver, skin, or bone marrow metastases. While the prognosis for patients is generally favorable, rapid progression of liver metastases can lead to life-threatening organ insufficiency. In such cases, immediate treatment with chemotherapy or radiotherapy is necessary. Given the recent decline in radiotherapy utilization, this study aims to reassess its role, evaluating its effectiveness and toxicity. Materials and methods: We conducted a systematic review and an institutional retrospective analysis to assess the use of radiotherapy for hepatomegaly in patients with neuroblastoma 4S. The study included data from 164 patients from the literature and 16 patients from our institutional cohort. We extracted and analyzed data on short- and long-term outcomes, as well as reports of radiotherapy-induced toxicity. Results: Our institutional data showed that 81 % of patients responded to low-dose radiotherapy administered at a median dose of 450 cGy in three fractions, resulting in liver shrinkage and symptom resolution. Based on the systematic review, 1-year survival rate was 80 %, while 5-year survival rate was 75 %. No serious toxicity was observed with the current low-dose radiotherapy; however, one case of induced secondary malignancy was reported. Conclusion: Radiation therapy is an effective treatment modality for hepatomegaly in patients with neuroblastoma 4S, with a success rate of about 80 %. Despite being administered to infants, a low dose of 450-600 cGy does not result in toxicity related to the kidneys, liver, or posture defects.

Incidence of bacterial and fungal infections in Polish pediatric patients with acute lymphoblastic leukemia during the pandemic.

The most common complications related to the treatment of childhood acute lymphoblastic leukemia (ALL) are infections. The aim of the study was to analyze the incidence and mortality rates among pediatric patients with ALL who were treated in 17 Polish pediatric hematology centers in 2020-2021 during the pandemic. Additionally, we compared these results with those of our previous study, which we conducted in the years 2012-2017. The retrospective analysis included 460 patients aged 1-18 years with newly diagnosed ALL. In our study, 361/460 (78.5%) children were reported to have microbiologically documented bacterial infections during chemotherapy. Ten patients (2.8%) died due to sepsis. Fungal infections were reported in 99 children (21.5%), of whom five (5.1%) died due to the infection. We especially observed an increase in bacterial infections during the pandemic period compared to the previous study. The directions of our actions should be to consider antibiotic prophylaxis, shorten the duration of hospitalization, and educate parents and medical staff about complications (mainly infections) during anticancer therapy. It is necessary to continue clinical studies evaluating infection prophylaxis to improve outcomes in childhood ALL patients.

Viral Infection Profile in Children Treated for Acute Lymphoblastic Leukemia-Results of Nationwide Study.

Viral infections can be a serious complication of therapy in children with acute lymphoblastic leukemia (ALL). In this study, we focused on the incidence and the profile of viral infection in children with ALL treated in 17 pediatric oncology centers in Poland in the two-year periods of 2018-2019 and 2020-2021. We also compared the frequency of viral infections in 2018-2019 to that in 2020-2021. In 2020-2021, a total of 192 children with ALL had a viral infection during intensive chemotherapy. A total number of 312 episodes of viral infections were diagnosed. The most common infections detected in the samples were: COVID-19 (23%), rhinovirus (18%), and respiratory syncytial virus (14%). COVID-19 and BK virus infections were the reason for the death 1% of all patients. In 2018-2019, a total of 53 ALL patients who had a viral infection were reported and 72 viral events were observed, mainly adenovirus (48.6%), rotavirus (31.9%), and herpes zoster (8.3%). No deaths were reported during this period. The cumulative incidence of viral infections in 2018-2019 was 10.4%, while for 2020-2021, it was 36.7%. In conclusion, a high incidence of COVID-19 infection was observed among pediatric patients with ALL in Poland. The mortality rate in our material was low. The viral profile in ALL children undergoing chemotherapy can be useful for clinicians to improve prophylactic and therapeutic strategies.

Infections With Stenotrophomonas maltophilia in Children Undergoing Anticancer Therapy or Hematopoietic Cell Transplantation: A Multicenter Nationwide Study.

BACKGROUND: Infections caused by Stenotrophomonas maltophilia (SM) have documented high mortality rate in immunocompromised patients. AIM: This nationwide multicenter study was performed to analyze the epidemiology of SM infections in children undergoing anticancer therapy (pediatric hematology and oncology [PHO]) or hematopoietic cell transplantation (HCT) over 2012-2019, including incidence and outcome of SM infections, as well as treatment regimens and multidrug resistance. METHODS: Cumulative incidence of SM infections was calculated using the competing risk analysis from the day of diagnosis (PHO setting) or from the day of transplantation (HCT setting). The Kaplan-Meier method was used to determine survival from infection. RESULTS: During the study period of 8 years, a total number of 1356 HCTs and 7337 children newly diagnosed for malignancy were analyzed. Diagnosis of acute leukemia was a predisposing factor for SM infection. The cumulative incidence of SM infections was comparable in HCT patients in comparison to PHO (0.81% vs. 0.76%). High rate of trimethoprim/sulfamethoxazole susceptibility among SM isolates was observed in both groups of patients (80.8%). Although this was the drug of choice, survival rates from SM infections were significantly lower in HCT than in PHO (45% vs. 85%, P = 0.001, log-rank test). We found the transplant procedure and lack of clinical resolution after 18 days of antibiotic therapy to be independent mortality risk factors. CONCLUSIONS: The risk of SM infections and the occurrence of resistant bacterial strains in allo-HCT patients were comparable to PHO patients. Irrespective of target antibiotic therapy, the outcome of SM infections was better in the PHO setting.

Prevalence, Epidemiology, Etiology, and Sensitivity of Invasive Bacterial Infections in Pediatric Patients Undergoing Oncological Treatment: A Multicenter Nationwide Study.

Background: Infectious complications (IC) caused by bacterial strains often impede anticancer therapy. The study aimed to retrospectively analyze bacterial IC that could help predict the risk and optimize the empirical treatment for bacterial infections in pediatric cancer patients. Patients and Methods: Over a 72-month period, all-in 5,599 children with cancer: 2,441 patients with hematological malignancy (HM including acute leukemias, Hodgkin and non-Hodgkin lymphomas [NHLs], and Langerhans cell histiocytosis) and 3,158 with solid tumors (STs including central nervous system tumors, neuroblastoma, Wilms' tumor, soft tissue sarcoma, germ cell tumors, Ewing sarcoma, osteosarcoma, hepatoblastoma, and others) were enrolled into the study. Episodes of bacterial infectious complications (EBICs) confirmed by microbiological findings were reported by each hospital and analyzed centrally. Results: At least 1 EBIC was diagnosed in 2,155 (36.8%) children (1,281 [59.4%] with HM and 874 [40.6%] with ST; p < 0.001). All-in 4,860 EBICs were diagnosed including 62.2% episodes in children with HM and 37.8% in children with ST (p < 0.001). Having analyzed the source of infections, blood stream infections predominated, apart from NHL patients in whom the most common type was gut infections. The profile of bacteria strains was different in HM and ST groups (p < 0.001). However, in both groups the most common Gram-negative pathogen was Enterobacteriaceae, with the rate being higher in the HM group. Among Gram-negative strains low susceptibility to ceftazidime, whereas among Enterococcus spp. low susceptibility to vancomycin was noticed. The rate of multidrug-resistant (MDR) pathogens was high, especially for Gram negatives (47.7% vs. 23.9%; p < 0.001). The survival after infections was comparable for HM and ST patients (p = 0.215). Conclusions: The risk of bacterial IC in HM patients was higher than in the ST group. The high rate of MDR strains was detected in pediatric cancer patients, especially in those with HM.

Varicella-zoster virus infection in the pediatric population with acute lymphoblastic leukemia in Poland.

Varicella-zoster virus (VZV) infection in pediatric hemato-oncology patients can be a therapeutic problem when children are exposed to immunosuppression. The aim of this study is to evaluate the incidence of VZV infection, antiviral therapy and outcome in children with ALL treated in polish hemato-oncological centers between 2012 and 2019 years. This study included medical records of 1874 patients, aged 1 to 18 years, with newly diagnosed acute lymphoblastic leukemia. During chemotherapy, 406 children out of 1874 (21.6%) experienced viral infections. The incidence of VZV infection in the whole group children with ALL was 1.8%. Among them, 34 (8.4%) patients were diagnosed with VZV infection. Thirty-five episodes of viral infections were identified. The median time of VCV therapy was 12 days. Herpes zoster infection occurred in 24 (70.6%) children, and varicella in 10 (29.4%) ones. The average time from the start of chemotherapy to the appearance of herpes zoster was 7.26 ± 4.05 months. VZV infection occurred mainly during the maintenance therapy, the reinduction and induction phases. There was no correlation between steroid dosage or type and subsequent zoster. The total lymphocyte count of these patients on the first day of zoster was reduced. No serious complications were observed due to this infection. All patients survived. In conclusion, a low incidence of VZV infection was observed among pediatric patients with ALL in Poland. This analysis indicates that currently used therapeutic methods are effective in children with cancer and VZV infection. The main focus should be on the prevention of delayed chemotherapy.

Infectious profile in children with ALL during chemotherapy: A report of study group for infections.

INTRODUCTION: The treatment-related mortality in currently published studies of acute lymphoblastic leukemia (ALL) in children is 2-4%, mainly due to infections. The aim of the study was to analyse the incidence, epidemiology, profile of infection and the death rate in children with ALL. PATIENTS AND METHODS: The retrospective analysis included 1363 patients, aged 1-18 years, with newly diagnosed ALL, who were treated in 17 pediatric hematology centers between 2012 and 2017 in Poland. The patients received therapy according to the ALL IC-BFM 2002 and 2009 (International Berlin-Frankfurt-Munster Study Group) protocols. RESULTS: In our study, 726 out of 1363 (53.2%) children were reported to have a microbiologically documented bacterial infection during chemotherapy. 1511 episodes of these infection were diagnosed. A total number of 251/1363 (18.4%) children experienced a viral infection. 304 episodes were documented by PCR test (polymerase chain reaction). A fungal infection was reported in 278 (20.4%) children, including 10.1% of probable, 6.0% of proven, 83% of possible diagnosis. A higher frequency of fungal infection was noted in the recent years. In our material, the rate of death was 2.4%, mainly due to fungal infection. CONCLUSIONS: Our results present the epidemiology of infectious disease in the Polish ALL patient population. The most frequent were bacterial infections, followed by fungal and viral ones. Similar to the previously published data, the mortality rate in our material was 2.4%.

Infections in children with acute myeloid leukemia: increased mortality in relapsed/refractory patients.

The aim of this nationwide study was to describe the epidemiology and profile of bacterial infections (BI), invasive fungal disease (IFD) and viral infections (VI) in patients with de novo and relapsed/refractory (rel/ref) acute myeloid leukemia (AML). Within the studied group of 250 children with primary AML, at least one infectious complication (IC) was diagnosed in 76.0% (n = 190) children including 85.1% (n = 504) episodes of BI, 8.3% (n = 49) - IFD and 6.6% (n = 39) - VI. Among 61 patients with rel/ref AML, at least one IC was found in 67.2% (n = 41) of children including 78.8% (n = 78) of BI, 14.1% (n = 14) of IFD and 7.1% (n = 7) of VI. In all AML patients, within BI Gram-negative strains were predominant. Half of these strains were multi-drug resistant. Characteristics of IFD and VI were comparable for de novo and rel/ref AML. The infection-related mortality was significantly higher, while survival from infection was significantly lower in patients with rel/ref disease.

Infectious complications in children treated for hodgkin and non-hodgkin lymphomas in polish pediatric leukemia/lymphoma study group: incidence, epidemiology and etiology.

The objective of this nation-wide study was to evaluate the epidemiology and profile of bacterial (BI), viral (VI), and invasive fungal disease (IFD) in patients treated for non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) between the years 2013-2015. In the analyzed period of time, within the studied group of 328 children diagnosed and treated for lymphomas, at least one infectious complication (IC) was diagnosed i.e. 39.3% children. In these patients there were 350 episodes of IC, therein 80.6% episodes of BI, 11.1% episodes of VI, and 8.3% episodes of IFD. In both groups, NHL and HL patients, a stable level of bacterial infections, with an increase in resistance rates, and increased levels of viral and fungal infections were observed. Profile of BI does not depend on lymphoma type, with predominance of Gram-negative bacteria and higher prevalence of MDR pathogens. The overall survival of lymphoma patients with IC was comparable for different types of infections.

Association of 49245A>G (rs868) polymorphism in the 3'UTR of donor TGFBR1 gene with course of hepatitis C following orthotopic liver transplantation.

BACKGROUND: Terminal hepatitis C is one of the leading indications for orthotopic liver transplantation (OLT). However, hepatitis C virus (HCV) reinfection occurs in almost all recipients and usually leads to progressive fibrosis and graft failure. Transforming growth factor-b (TGF-ß) plays a part in transplanted liver cirrhosis, but nothing is known about the possible role of genetic diversity of TGF-ß receptor system. Therefore, the aim of our study was to investigate whether genetic variation in 3' untranslated region (3'UTR) of TGF-ß receptor type I (TGFBR1) gene is associated with recurrence and severity of hepatitis C and liver fibrosis following OLT in HCV-infected patients. MATERIAL AND METHODS: The study group included 95 chronic hepatitis C patients following OLT. The recipients and donors were genotyped for 49245A>G (rs868) and 51976G>A (rs334349) single nucleotide polymorphisms (SNP). RESULTS: Donor rs868 AA genotype was strongly associated with worse clinical course of recurrent hepatitis C. The rs868 AA group displayed more severe symptoms of hepatitis C during the follow-up and the fibrosis score in this group was significantly higher 3 years after OLT. CONCLUSIONS: Clinical course of hepatitis C after OLT may depend on donor rs868 SNP located in TGFBR1 3'UTR.

The BAG3 gene variants in Polish patients with dilated cardiomyopathy: four novel mutations and a genotype-phenotype correlation.

BACKGROUND: BAG3 gene mutations have been recently implicated as a novel cause of dilated cardiomyopathy (DCM). Our aim was to evaluate the prevalence of BAG3 mutations in Polish patients with DCM and to search for genotype-phenotype correlations. METHODS: We studied 90 unrelated probands by direct sequencing of BAG3 exons and splice sites. Large deletions/insertions were screened for by quantitative real time polymerase chain reaction (qPCR). RESULTS: We found 5 different mutations in 6 probands and a total of 21 mutations among their relatives: the known p.Glu455Lys mutation (2 families), 4 novel mutations: p.Gln353ArgfsX10 (c.1055delC), p.Gly379AlafsX45 (c.1135delG), p.Tyr451X (c.1353C>A) and a large deletion of 17,990 bp removing BAG3 exons 3-4. Analysis of mutation positive relatives of the probands from this study pooled with those previously reported showed higher DCM prevalence among those with missense vs. truncating mutations (OR = 8.33, P = 0.0058) as well as a difference in age at disease onset between the former and the latter in Kaplan-Meier survival analysis (P = 0.006). Clinical data from our study suggested that in BAG3 mutation carriers acute onset DCM with hemodynamic compromise may be triggered by infection. CONCLUSIONS: BAG3 point mutations and large deletions are relatively frequent cause of DCM. Delayed DCM onset associated with truncating vs. non-truncating mutations may be important for genetic counseling.

mTOR is frequently active in GH-secreting pituitary adenomas without influencing their morphopathological features.

Initiating factors and mechanisms of tumor formation are poorly understood in nonfamilial pituitary adenomas. Alteration of intracellular pathways is an underlying event in numerous neoplasms. Among them, excessive activation of mammalian target of rapamycin (mTOR) pathway and its two main regulators, Akt and Erk, has been detected frequently in solid tumors. This study tests the activation of mTOR pathway in pituitary adenomas and its influence on their morphopathological features. Fifty-three pituitary adenomas were fresh frozen after surgery and analyzed by western blotting using phospho-specific antibodies. The impact of Akt and Erk activation on mTOR pathway was assessed in five primary cultures derived from the excised adenomas using selective kinase inhibitors. Statistical correlations of size, volume, Ki-67 %, Knosp's grading, and somatostatin receptor (SSTR) expression with the activation of mentioned kinases was performed. GHomas showed the highest frequency (71 %) and level of mTOR pathway activity comparing to other adenomas (33 %). No significant correlation was found between mTOR activation and any of the morphopathological features in the studied samples. mTOR kinase phosphorylation was independent of Erk and Akt in primary cultures. Erk activity was significant in all types of adenomas but was the highest in control samples. Its phosphorylation correlated inversely with the Knosp's grading in nonfunctional pituitary adenomas and directly with somatostatin receptor subtype 2 A expression in GHomas. Presented data point to the noteworthy mTOR activity in GHomas. However, the lack of correlation with morphopathological features, its independence of Erk and Akt phosphorylation, and high level of Erk activity in control pituitary necessitate further research for clarifying the role of these pathways in pituitary adenomas.