Acute Pancreatitis in Pediatric Acute Lymphoblastic Leukemia (AcuPA Study): A Nationwide Survey in Poland.

PURPOSE: This study aimed to identify the risk factors for acute pancreatitis (AP) and its impact on outcomes in Polish children treated for ALL. METHODS: The study group included 2303 children receiving intensive chemotherapy for ALL. The group was divided into patients with at least one episode of AP and those who did not develop AP after treatment for ALL. RESULTS: The cumulative incidence of AP in the study group was 4.08%. Older age was an independent risk factor for the development of AP (OR = 1.05; 95%CI = 1.006-1.098; p = 0.03). The overall mortality associated with AP was 2.13%. The probabilities of disease-free survival (p-DFS) and event-free survival (p-EFS) in both subgroups were 0.84 vs. 0.86, log-rank p = 0.65 and 0.75 vs. 0.80, log-rank p = 0.12, respectively. A total of 22 out of 94 patients (23.4%) with AP were re-exposed to asparaginase (ASP) during the subsequent treatment phases. Only one patient re-exposed to ASP (4.5%) developed a second episode of AP. There were no significant differences in p-DFS and p-EFS between patients re-exposed and not re-exposed to asparaginase (0.78 vs. 0.86, log-rank p = 0.27 and 0.63 vs. 0.79, log-rank p = 0.09, respectively). CONCLUSIONS: The incidence of AP in children with ALL is low and related to patients' age. The development of AP does not seem to influence p-DFS and p-EFS in children with ALL. Recurrence of AP after re-exposure to asparaginase in patients with ALL and a history of AP is low (4.5%). Re-exposure to asparaginase after the first episode of AP does not improve either p-DFS or p-EFS in children with ALL.

Neuroblastoma-A Review of Combination Immunotherapy.

Neuroblastoma is the most common extracranial solid tumor found in childhood and is responsible for 15% of deaths among children with cancer. Although multimodal therapies focused on surgery, chemotherapy, radiotherapy, and stem cell transplants have favorable results in many cases, the use of conventional therapies has probably reached the limit their possibility. Almost half of the patients with neuroblastoma belong to the high-risk group. Patients in this group require a combination of several therapeutic approaches. It has been shown that various immunotherapies combined with conventional methods can work synergistically. Due to the development of such therapeutic methods, we present combinations and forms of combining immunotherapy, focusing on their mechanisms and benefits but also their limitations and potential side effects.

Pre-Exposure Prophylaxis and Treatment with Tixagevimab/Cilgavimab for COVID-19 among Immunocompromised Pediatric Patients.

Background: Patients treated with hemato-oncological malignancies (HO) or undergoing cellular therapies such as hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor T cells (CAR-T) were significantly affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite the success of SARS-CoV-2 vaccination, immunocompromised patients remain at increased risk for severe coronavirus disease (COVID-19), rendering this group of population a high priority for additional prevention and treatment options. Tixagevimab and Cilgavimab (TIXA/CILGA, AZD7442, Evusheld®) is a combination of two fully human, long-acting monoclonal antibodies. TIXA/CILGA have been approved as pre-exposure prophylaxis and treatment in patients at risk of severe disease with impaired vaccine response. Our objective was to describe the efficacy and safety among immunocompromised pediatric patients. Methods: This was an observational multicenter cohort study of immunocompromised pediatric patients receiving TIXA/CILGA conducted at nine Polish centers of Pediatric Oncology, Hematology and Bone Marrow Transplantation. We analyzed patients in two groups; those treated with HO and those undergoing cellular therapies: HSCT or CAR-T cells. In addition, two other cohorts were identified: patients given TIXA/CILGA as pre-exposure prophylactic and therapeutic intervention. Results: A total of 78 patients were evaluated during the study period: 69 (88.5%) received TIXA/CILGA as pre-exposure prophylaxis and 9 (11.5%) as a treatment strategy. A total of 52 (66.6%) patients were treated with standard chemotherapy at HO departments; 21 (27%) underwent HSCT, and 5 (6.4%) received CAR-T cell therapy. All children with COVID-19 receiving TIXA/CILGA presented a mild degree of severity. The most common clinical manifestations were fever, cough and coryza. At least one adverse event (AE) was reported in two (3.8%) patients excluding standard injection site reactions. Reported AEs were mild or moderate in intensity. One child reported mild myalgia and one reported moderate bone pain and weakness. Conclusions: In our observational multicenter cohort study, we explored the use of TIXA/CILGA as pre-exposure prophylaxis and treatment for COVID-19 among immunocompromised pediatric patients. While our findings suggest a potential benefit in preventing and managing COVID-19 in this vulnerable population, it is important to note the study's non-comparative design. Our results highlight the need for well-designed clinical trials to confirm these observations and further assess the efficacy and safety of TIXA/CILGA in immunocompromised children.

Fusarium oxysporum disseminated infection in a teenage patient with a relapse of acute lymphoblastic leukemia - Case report and review of the literature.

Infections are still a significant cause of mortality in children with hematologic malignancies. Fusariosis is a relatively rare and opportunistic infection, which may present dangerous course and a poor prognosis. Below, we describe the fatal course of a 15-years old patient with a combined bone marrow and testicular relapse of ALL and multisystemic Fusariosis oxysporum infection with fulminant evolution. Despite aggressive therapy, which included multiagent antifungal treatment and surgical debridement, patient succumbed to the disease. The review of the literature was conducted and the need for early detection of fusarium symptoms was emphasized. The case encourages further research in the prevention and treatment of the illness.

Central Diabetes Insipidus in Children as a Diagnostic Challenge.

Central diabetes insipidus (CDI) is a disorder in the pediatric population resulting from antidiuretic hormone deficiency. The excessive production of dilute urine characterizes it and manifests with polyuria, nocturia, and polydipsia. The diagnostics of CDI is often challenging, especially concerning the underlying condition of the disease. This article highlights the diverse clinical presentation of children with CDI and diagnostic difficulties among patients with polyuria and polydipsia. The article also reviews the etiology, symptoms, diagnostic workup, and management of CDI. We present 4 pediatric patients (aged 3-13.5 years) diagnosed with CDI of different etiology: 1 due to septo-optic dysplasia/optic nerve hypoplasia and 3 due to acquired processes such as Langerhans cell histiocytosis and germ cell tumor in 2 patients. Central diabetes insipidus was the first manifestation of a tumor or granuloma in all presented patients with acquired pathology. The patients sometimes need long-term follow-up to establish the proper final diagnosis.

From KIT-mutated into wild-type: dedifferentiation of gastrointestinal stromal tumor in adolescent patient-a case report.

Background: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract, usually found in elderly adults. It is infrequent among pediatric patients and usually differs from adult-type disease in terms of histopathology and molecular features. Case Description: We describe the management of the disease in a 10-year-old female patient diagnosed with a GIST of the stomach. In total, she has undergone successively total tumor resection, unsuccessful imatinib treatment and subtotal gastric resection at relapse. The first genetic test from primary tumor confirmed KIT mutations in exons 13 and 17, while the repeated genetic screening using tumor sample from subtotal gastric resection revealed no KIT or platelet-derived growth factor receptor α (PDGFRA) genes mutations. Such dedifferentiation from adult type (thus KIT-mutated) into wild-type (without KIT or PDGFRA mutation) has not been reported so far to the best of our knowledge. Currently, the patient is observed, and no further pharmacological nor surgical treatment has been administered. Conclusions: The case underlines the importance of genetic profiling combined with non-standard diagnostics (both histopathological and radiological) due to the treatment efficacy prediction. We moreover emphasize the necessity to create worldwide standards on the diagnostics and treatment of GIST in pediatric patients that would include options of targeted therapies.

Constitutional Mismatch Repair Deficiency Syndrome as a Cause of Numerous Malignancies in a Teenage Patient-A Case Report.

Constitutional mismatch repair deficiency syndrome is a genetic disorder resulting from a biallelic mutation in one of the following genes: MLH1, MSH2, MSH6, or PMS2. Individuals with constitutional mismatch repair deficiency are highly predisposed to develop both hematological and solid cancers in childhood, particularly lymphoma, brain tumors, and gastrointestinal neoplasms. We report a case of a boy diagnosed with B-cell acute lymphoblastic leukemia at the age of 3. In 2013, at the age of 6, head magnetic resonance imaging revealed hamartoma and astrocytoma lesions in the central nervous system. Two years after treatment completion, a diagnosis of precursor T-cell lymphoblastic lymphoma, accompanied by the vena cava syndrome, was established and treated accordingly. During treatment, a genetic test using Sanger sequencing was performed-a biallelic mutation in the MSH6 gene was detected. The study revealed that the mutation 17-bp c.2277-2293del. was inherited from the patient's mother. The second mutation, 5-bp c.1135_1139delAGAGA, developed inpatient de novo. At the age of 14, the diagnosis of isolated bone marrow relapse of acute lymphoblastic leukemia B-cell type was established. Due to the almost exceeded total dose of anthracyclines, the patient's treatment included blinatumomab, and subsequently, he was qualified for allogeneic hematopoietic cell transplantation. The patient remains in complete remission for 11 months after allogeneic hematopoietic stem cell transplantation under the care of the transplant center.

An In Silico Study Investigating Camptothecin-Analog Interaction with Human Protein Tyrosine Phosphatase, SHP2 (PTPN11).

The human PTPN11 gene encodes for the src tyrosine phosphatase protein (SHP2) is now gaining much attention in many disorders, particularly its oncogenic involvement in many types of cancer. Efforts in developing molecules targeting SHP2 with high efficacy are the future of drug discovery and chemotherapy. However, the interaction of a new camptothecin analog with the catalytic domain of SHP2 protein remains unknown. Therefore, this study aims to provide in silico rationale for the recognition and binding of FL118 and irinotecan with the catalytic domain of human protein tyrosine phosphatase-SHP2 (PTPc-SH2-SHP2, chain A). The docking interaction of the human SHP2 protein's catalytic domain as well as Y279C and R465G mutants with FL118 and irinotecan ligands were calculated and analyzed using the Autodock 4.2 programme, setting the docking grid to target the protein's active site. The camptothecin analog FL118 had the best lowest negative affinity energies with PTPc-SHP2 wildtype and SHP2-Y279C mutant model (-7.54 Kcal/mol and -6.94 Kcal/mol, respectively). Moreover, the protein-ligand complexes revealed several hydrogen bond interactions reflecting the degree of stability that each structure possesses, with the FL118-SHP2-wildtype forming the most stable complex among the structures. In addition, the FL118-SHP2 wildtype complex was validated for RMSD, RMSF, hydrogen bonds, and salt bridges. This revealed that the complex generated became stable over time. This in silico rationale identifies the novel FL118 camptothecin analog as a potent selective inhibitor of PTPc-SH2 domain of SHP2 protein, paving way for further in vitro investigations into the interactions and binding activity of analogs with SHP2 for potential therapeutic applications in PTPN11-associated disorders.

Modern treatment strategies in pediatric oncology and hematology.

Every year, approximately 400 00 children worldwide are diagnosed with cancer. Although treatment results in most types of childhood neoplasms are excellent with survival more than 80%, there are some with poor prognosis. Also recurrent and resistant to treatment childhood cancer remain a therapeutic challenge. Besides chemotherapy, which has been the basis of cancer therapy for years, molecular methods and precisely targeted therapies have recently found their usage. As a result of that, survival has improved and has positively impacted the rate of toxicities associated with chemotherapy (Butler et al. in CA Cancer J Clin 71:315-332, 2021). These achievements have contributed to better quality of patients' lives. Current methods of treatment and ongoing trials give hope for patients with relapses and resistance to conventional chemotherapy. This review focuses on the most recent progress in pediatric oncology treatments and discusses specific therapy methods for particular cancers types of cancer. Targeted therapies and molecular approaches have become more beneficial but research need to be continued in this field. Despite significant breakthroughs in pediatric oncology in the last few years, there is still a need to find new and more specific methods of treatment to increase the survival of children with cancer.

Venetoclax Use in Paediatric Haemato-Oncology Centres in Poland: A 2022 Survey.

Venetoclax, the best established BH3-mimetic, is a practice-changing proapoptotic drug in blood cancers in adults. In paediatrics the data are fewer but exciting results were recently presented in relapsed or refractory leukaemias demonstrating significant clinical activity. Importantly, the in-terventions could be potentially molecularly guided as vulnerabilities to BH3-mimetics were re-ported. Currently venetoclax is not incorporated into paediatric treatment schedules in Poland but it has been already used in patients that failed conventional therapy in Polish paediatric haemato-oncology departments. The aim of the study was to gather clinical data and correlates of all paediatric patients treated so far with venetoclax in Poland. We set out to gather this experience to help choose the right clinical context for the drug and stimulate further research. The questionnaire regarding the use of venetoclax was sent to all 18 Polish paediatric haemato-oncology centres. The data as available in November 2022 were gathered and analysed for the diagnoses, triggers for the intervention, treatment schedules, outcomes and molecular associations. We received response from 11 centres, 5 of which administered venetoclax to their patients. Clinical benefit, in most cases consistent with hematologic complete remission (CR), was reported in 5 patients out of ten, whereas 5 patient did not show clinical benefit from the intervention. Importantly, patients with CR included subtypes expected to show venetoclax vulnerability, such as poor-prognosis ALL with TCF::HLF fusion. We believe BH3-mimetics have clinical activity in children and should be available to pae-diatric haemato-oncology practitioners in well-selected applications.

Comparison of diagnostic and treatment processes among pediatric and adolescents and young adults' populations suffering from acute lymphoblastic leukemia and lymphomas.

Introduction: Acute lymphoblastic leukemia (ALL) and lymphomas affect both pediatric and adult populations, therefore, they might be treated by pediatric or adult centers.It has been proven that the prognosis among adolescents and young adults (AYA) is poorer than among children, which remains a subject of research. Many factors are suspected to affect the diagnostic and treatment processes in adolescents and young adults, one of them being the organization of the healthcare system.The aimof the studywas to compare the time intervals between different events on disease trajectory in pediatric and AYA groups suffering from ALL and lymphomas. Methods: We collected data on 81 patients diagnosed with ALL (50 children and 31 AYAs) and 100 patients diagnosed with lymphomas (50 children and 50 AYAs). Statistical analysis was performed in order to compare the groups. Results: The results confirmed the hypothesis that the duration of the diagnostic process differs significantly between groups. For patients with ALL, the analyzed time intervals were significantly shorter in the pediatric group than in the AYA group: first contact with a GP - admission to Hematology Department (2 vs. 5 days; pvalue= 0.004), first contact with a GP - treatment (6 vs. 12 days, p-value=0.001), diagnosis - treatment (1 vs. 3 days, p-value=0.003). In the case of patients suffering from lymphomas, the results were similar. The analyzed time intervals were significantly shorter in the pediatric group than in the AYA group: first contact with a GP- diagnosis (21 vs. 40.5 days, p-value<0.0001), first contact with a GP - treatment (27 vs. 65 days, p-value<0.0001). Trend analysis showed that the longer patients had presented symptoms before contacting the primary care physician, the longer they waited for the beginning of treatment both in ALL and lymphomas groups (p-values=0.0129 and 0.0038 respectively). Discussion: As the diagnostic and treatment processes are longer for AYA patients, actions must be undertaken in order to ensure equality and improve the healthcare system in Poland and possibly other countries.

Successful Treatment of Large B-Cell Lymphoma in a Child with Compound Heterozygous Mutation in the ATM Gene.

Ataxia-telangiectasia (AT) is a multisystemic neurodegenerative inborn error of immunity (IEI) characterized by DNA repair defect, chromosomal instability, and hypersensitivity to ionizing radiation. Impaired DNA double-strand break repair determines a high risk of developing hematological malignancies, especially lymphoproliferative diseases. Poor response to treatment, excessive chemotherapy toxicities, and the need for avoiding exposure to ionizing radiation make the successful clinical management of patients with AT challenging for oncologists. We describe the favorable outcome of the LBCL with IRF4 rearrangement at stage III in a 7-year-old female patient diagnosed with AT. The patient was treated according to the B-HR arm of the INTER-B-NHL-COP 2010 protocol, including the administration of rituximab, cyclophosphamide, methotrexate, prednisone, etc. She presented excessive treatment toxicities despite individually reduced doses of methotrexate and cyclophosphamide. However, in the MRI there was no significant reduction in pathologic lymph nodes after three immunochemotherapy courses. Therefore, a lymph node biopsy was taken. Its subsequent histopathological examination revealed tuberculosis-like changes, though tuberculosis suspicion was excluded. After two following immunochemotherapy courses, PET-CT confirmed complete remission. From March 2022 onwards, the patient has remained in remission under the care of the outpatient children's oncology clinic.

Clinical use of polyvalent intravenous immunoglobulins during intensive polychemotherapy in children with acute lymphoblastic leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is seen in almost 30% of cases of cancer among children. Drop in absolute neutrophil count (ANC) and immunosuppression during chemotherapy are causing the significant increase in the risk of other complications, which can lead to prolonged hospitalization, higher costs of therapy and increased mortality. METHODS: The analysis concerned 78 patients treated for ALL at the Department of Pediatric Oncology, Hematology and Transplantology. The indications for the use of immunoglobulins, the regimen of administration, the dose and adverse reactions were analyzed. RESULTS: Intravenous immunoglobulins (IVIGs) were used in 66 (85%) of 78 patients. The standard risk group (SR) was represented by 10 (15%) patients, intermediate (IR) - 29 (44%), and high (HR) - 27 (41%). The most common were 1 and 2-day administrations - 60% and 28%, respectively, of transfusions. The spread of the IVIG doses used ranged from 43 mg to 882 mg/kg body weight. In the SR and IR groups, preparations were transfused at the reinduction stage, while in the HR-consolidation. Among the indications for IVIG, the most common was hypogammaglobulinemia-117 (42%), neutropenia-69 (25%) and infection-62 (22%). During the implementation of 279 patterns of immunoglobulin preparations, 8 (3%) post-transfusion reactions were registered. CONCLUSIONS: The vast majority of ALL patients required immunoglobulin substitution during polychemotherapy. The supply of preparations is safe, however, there are no unambiguous guidelines regarding their dosage.

Ophthalmologic Manifestations of Neuroblastoma: A Systemic Review.

Neuroblastoma (NBL) is the most common extracranial solid tumor found in pediatric patients. It develops from the sympathetic tract tissue. Although the symptoms are associated with tumor localization, sometimes NBL is manifested as ophthalmologic disorders. In this paper, we describe their incidence and the correlation with the prognosis. We searched 2 databases (PubMed and Web of Science) for papers published before April 2022, and concerned pediatric patients with NBL, which caused ophthalmologic changes. We collected 7 papers assessing the occurrence of ophthalmologic findings in the NBL patients, as well as 68 case reports presenting children with orbital changes and NBL, or with other tumors stemming from the sympathetic ganglia. The statistical analysis was performed to synthetize the data. The ophthalmologic signs occurred in 17.89% of the NBL cases; however, they were observed on presentation in 10.68%. The isolated ocular presentation was found in 2.56% of patients, whereas Horner syndrome was most frequent. The ophthalmologic symptoms correlated with patients' age, primary tumor site, and survival rate. NBL may be challenging to diagnose in cases with isolated ophthalmologic manifestations. Numerous possible ocular signs can be observed, which emphasize the need for multidisciplinary care with regard to the NBL patients.

Characteristics and treatment results of refractory and relapsed acute myeloid leukaemia in paediatric patients treated in Polish Paediatric Leukaemia/Lymphoma Study Group institutions according to the Protocol Acute Myeloid Leukaemia Berlin-Frankfurt-Munster 2012 and a review of novel treatment possibilities in paediatric acute myeloid leukaemia.

Introduction: This study aimed to present the clinical features and results of treatment of patients diagnosed with refractory or relapsed acute myeloid leukaemia (AML) in Polish Paediatric Leukaemia/Lymphoma Study Group (PPL/LSG) institutions, treated in accordance with the Protocol Acute Myeloid Leukaemia Berlin-Frankfurt-Munster 2012, as their first-line therapy. Material and methods: The outcome data of 10 patients with refractory AML (median age 9.5 years) and 30 with relapsed AML (median age 12 years) were analysed retrospectively. Re-induction was usually based on idarubicin, fludarabine, and cytarabine along with allogeneic haematopoietic stem cell transplant (allo-HSCT) in 5 patients with refractory AML and 7 relapsed AML children. Results: 37.5% (3/8) of refractory AML patients achieved second complete remission second complete remission (CRII). One of ten patients (1/10; 10%) was alive and stayed in complete remission for 34 months after the allo-HSCT. The probability of 3-year event-free survival (pEFS) in this group was 0.125 ±0.11. In the group of relapsed AML patients, the CRII was achieved in 9 patients (34%), and the probability of survival was: pEFS = 0.24 ±0.08; probability overall survival (pOS) = 0.34 ±0.09, with significantly better results achieved in patients who underwent allo-HSCT (pOS = 0.54 ±0.14 vs. 0.08 ±0.08, p < 0.0001). Conclusions: The prognosis of refractory AML and the first AML recurrence in children who were first-line treated in PPL/LSG centres according to Protocol Acute Myeloid Leukaemia Berlin-Frankfurt-Munster 2012 is poor. Failures of re-induction treatment particularly result from difficulties in achieving remission. Allogeneic HSCT improves prognosis in children with refractory and first recurrent AML, under the condition it is performed in complete remission. Novel therapeutic approaches are needed to increase the remission rate and improve the outcomes.

Latest Advances in the Management of Pediatric Gastrointestinal Stromal Tumors.

Gastrointestinal stromal tumor is the most common mesenchymal neoplasm of the gastrointestinal tract, usually found in elderly adults. It is infrequent among pediatric patients and usually differs biologically from adult-type diseases presenting mutations of KIT and PDGFR genes. In this population, more frequent is the wild-type GIST possessing SDH, TRK, RAS, NF1 mutations, among others. Both tumor types require individualized treatment with kinase inhibitors that are still being tested in the pediatric population due to the different neoplasm biology. We review the latest updates to the management of pediatric gastrointestinal tumors with a particular focus on the advances in molecular biology of the disease that enables the definition of possible resistance. Emerging treatment with kinase inhibitors that could serve as targeted therapy is discussed, especially with multikinase inhibitors of higher generation, the effectiveness of which has already been confirmed in the adult population.

Effects of Noonan Syndrome-Germline Mutations on Mitochondria and Energy Metabolism.

Noonan syndrome (NS) and related Noonan syndrome with multiple lentigines (NSML) contribute to the pathogenesis of human diseases in the RASopathy family. This family of genetic disorders constitute one of the largest groups of developmental disorders with variable penetrance and severity, associated with distinctive congenital disabilities, including facial features, cardiopathies, growth and skeletal abnormalities, developmental delay/mental retardation, and tumor predisposition. NS was first clinically described decades ago, and several genes have since been identified, providing a molecular foundation to understand their physiopathology and identify targets for therapeutic strategies. These genes encode proteins that participate in, or regulate, RAS/MAPK signalling. The RAS pathway regulates cellular metabolism by controlling mitochondrial homeostasis, dynamics, and energy production; however, little is known about the role of mitochondrial metabolism in NS and NSML. This manuscript comprehensively reviews the most frequently mutated genes responsible for NS and NSML, covering their role in the current knowledge of cellular signalling pathways, and focuses on the pathophysiological outcomes on mitochondria and energy metabolism.

Case Report: Brentuximab Vedotin Associated Acute Pancreatitis in a Pediatric Hodgkin Lymphoma Patient: Case Report and Literature Review.

Brentuximab vedotin is a conjugate drug used mainly in Hodgkin lymphoma, systemic and primary cutaneous anaplastic large cell lymphomas, and CD30-expressing peripheral T-cell lymphoma. We report a unique case of acute pancreatitis associated with brentuximab vedotin in a 17-year-old male patient suffering from classical Hodgkin lymphoma. Diagnosed in 2020, the patient was classified to an intermediate therapeutic group and disease's grade was IIIAE. The patient was treated with brentuximab vedotin and bendamustine in the third line. Two weeks after the drug administration, the patient developed acute epigastric pain. Laboratory and radiological findings confirmed the clinical suspicion of acute pancreatitis that was managed with opioid pain medications, meropenem, parenteral nutrition, ondansetron and omeprazole. This is the first case report of brentuximab vedotin-associated acute pancreatitis in the pediatric patient reported in the literature to the best of our knowledge.