Tumor Of Childhood Research Articles

ОПЫТ ПРИМЕНЕНИЯ ИММУНОТЕРАПИИ АНТИ-GD2 МОНОКЛОНАЛЬНЫМИ АНТИТЕЛАМИ У ПАЦИЕНТОВ С НЕЙРОБЛАСТОМОЙ ГРУППЫ ВЫСОКОГО РИСКА В АМБУЛАТОРНЫХ УСЛОВИЯХ

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. Prior to the introduction of intensive multimodal therapy, overall survival (OS) in patients with high-risk NB was below 15%. The addition of immunotherapy with dinutuximab beta in post-consolidation to multimodal treatment can increase the 5-year event-free survival rate for patients with high-risk NB up to 56.6%, and the 5-year OS up to 73.2%. The purpose of the research was to study the efficacy and safety of dinutuximab beta therapy in high-risk NB patients. Materials and methods used: the study included 8 pediatric patients with high-risk NB who had been treated with dinutuximab beta immunotherapy during postconsolidation on the basis of the Morozov Children’s City Clinical Hospital (Moscow, Russia) in 2020 to 2022. In case a patient's vital parameters normalization coupled with the absence of the need for accompanying therapy for 24 hours in a hospital, the patient was then considered as a candidate for outpatient treatment with possible no need for admission in the hospital. Results: 6 patients (75%) completed the full course of therapy with dinutuximab beta. The course of immunotherapy was not completed in 2 patients due to further progression of the disease. The most common adverse events were recorded as follows: pain (100%), fever (100%), diarrhea (62.5%), edematous syndrome (37.5%), allergic reactions (25%), hematological toxicity (25%). The period of time to becoming the candidates for outpatient treatment was 10.38±2.56 days for the 1st cycle of therapy and 2.67±1.63 days for the last, 5th cycle of the immunotherapy. In 6 out of 8 cases described the immunotherapy with dinutuximab beta allowed maintaining the response to treatment achieved after the end of consolidation preventing further development of the disease. The overall good tolerance to the drug made it possible to carry out the immunotherapy on an outpatient basis using microinfusing pump. Conclusion: an adequate route of administration and accompanying treatment make dinutuximab beta toxicity profile sufficient for outpatient management of patients with high-risk NB.

ОПЫТ ПРИМЕНЕНИЯ ИММУНОТЕРАПИИ АНТИ-GD2 МОНОКЛОНАЛЬНЫМИ АНТИТЕЛАМИ У ПАЦИЕНТОВ С НЕЙРОБЛАСТОМОЙ ГРУППЫ ВЫСОКОГО РИСКА В АМБУЛАТОРНЫХ УСЛОВИЯХ

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. Prior to the introduction of intensive multimodal therapy, overall survival (OS) in patients with high-risk NB was below 15%. The addition of immunotherapy with dinutuximab beta in post-consolidation to multimodal treatment can increase the 5-year event-free survival rate for patients with high-risk NB up to 56.6%, and the 5-year OS up to 73.2%. The purpose of the research was to study the efficacy and safety of dinutuximab beta therapy in high-risk NB patients. Materials and methods used: the study included 8 pediatric patients with high-risk NB who had been treated with dinutuximab beta immunotherapy during postconsolidation on the basis of the Morozov Children’s City Clinical Hospital (Moscow, Russia) in 2020 to 2022. In case a patient's vital parameters normalization coupled with the absence of the need for accompanying therapy for 24 hours in a hospital, the patient was then considered as a candidate for outpatient treatment with possible no need for admission in the hospital. Results: 6 patients (75%) completed the full course of therapy with dinutuximab beta. The course of immunotherapy was not completed in 2 patients due to further progression of the disease. The most common adverse events were recorded as follows: pain (100%), fever (100%), diarrhea (62.5%), edematous syndrome (37.5%), allergic reactions (25%), hematological toxicity (25%). The period of time to becoming the candidates for outpatient treatment was 10.38±2.56 days for the 1st cycle of therapy and 2.67±1.63 days for the last, 5th cycle of the immunotherapy. In 6 out of 8 cases described the immunotherapy with dinutuximab beta allowed maintaining the response to treatment achieved after the end of consolidation preventing further development of the disease. The overall good tolerance to the drug made it possible to carry out the immunotherapy on an outpatient basis using microinfusing pump. Conclusion: an adequate route of administration and accompanying treatment make dinutuximab beta toxicity profile sufficient for outpatient management of patients with high-risk NB.

Clinical activity of pan-RAF inhibitor tovorafenib in the registrational pediatric low-grade glioma arm of the phase 2 FIREFLY-1 (PNOC026) study.

10004 Background: Pediatric low-grade gliomas (LGGs) are the most common brain tumors of childhood. Genomic alterations of BRAF ( KIAA1549-BRAF fusions, 50–60% and BRAF V600E mutations, 5–15%) are the most frequent oncogenic drivers in pLGGs. Tovorafenib is an investigational, oral, selective, brain-penetrant, small molecule, type II pan-RAF inhibitor. Tovorafenib has demonstrated clinically meaningful responses in 24/35 patients (2 CR, 7 PR and 15 SD) in the pediatric phase 1B PNOC014 (NCT03429803) trial in patients with RAF-altered cancers (Wright, SNO 2022). Methods: FIREFLY-1 (NCT04775485) is a multicenter phase 2 study evaluating the efficacy and safety of tovorafenib monotherapy in patients with BRAF-altered cancers. Registrational arm 1 of FIREFLY-1 includes patients 6 months–25 years of age with recurrent or progressive LGG previously treated with ≥1 prior line of systemic therapy. Tovorafenib 420 mg/m2 (not to exceed 600 mg) is administered weekly, in 28-day cycles, (tablet or liquid suspension formulation) until progression. The primary endpoint of arm 1 is ORR, as defined by Response Assessment in Neuro-Oncology (RANO) criteria and determined by blinded independent review. Results: As of September 28, 2022, arm 1 had enrolled 77 patients and is fully accrued. All patients had ≥6 months of follow-up. Median age at enrollment was 8 years (range 2–21). Patients were pretreated with a median of 3 prior lines of systemic therapy (range: 1–9); 60% had received prior MAPK pathway-targeted agents. The most common tumor site was optic pathway (51%). Sixty-four patients harbored a BRAF fusion/rearrangement (83%) in their tumors, and 13 (17%) had a BRAF V600E mutation. Median duration of tovorafenib treatment is 8.4 months (range 0.7–16.8), with 59 patients (77%) remaining on treatment at the time of data cutoff. Per independent assessment in 69 RANO-evaluable patients, ORR was 64%, [3 CR, 41 PR (10 unconfirmed) and 19 SD] with a clinical benefit rate of 91%. Responses were achieved in tumors with BRAF fusions and V600E mutations, including those previously treated with MAPK inhibitors. The most common treatment-related adverse events (TRAEs) of any grade were hair color changes (75%), increased creatine phosphokinase (64%), anemia (46%), fatigue (42%) and maculopapular rash (42%). Tovorafenib dose modifications occurred in 16 (21%) and discontinuations in 2 (3%) patients due to TRAEs. Updates from a longer follow-up on the 77 patients in arm 1 will be presented at the meeting. Conclusions: Tovorafenib was generally well tolerated and showed encouraging evidence of antitumor activity in children and young adults with recurrent/progressive BRAF-altered pLGG. LOGGIC/FIREFLY-2 (NCT05566795), a global, phase 3 trial is evaluating once-weekly tovorafenib monotherapy in newly-diagnosed patients with pLGG harboring a known activating RAF alteration. Clinical trial information: NCT04775485 .

LOGGIC/FIREFLY-2: A phase 3, randomized trial of tovorafenib vs. chemotherapy in pediatric and young adult patients with newly diagnosed low-grade glioma harboring an activating RAF alteration.

TPS10067 Background: Pediatric low-grade gliomas (pLGGs) are the most common CNS tumors of childhood. Genomic alterations of BRAF are oncogenic drivers in almost all pLGGs. Approximately 50%‒60% of pLGGs harbor a KIAA1549-BRAF fusion and 5%‒15% a BRAF V600E mutation. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan-RAF inhibitor. The registrational, phase 2 FIREFLY-1 (NCT04775485) study of tovorafenib in pediatric patients with recurrent/progressive LGG is ongoing and interim analysis has shown encouraging anticancer activity. Methods: LOGGIC/FIREFLY-2 (NCT05566795) is a registrational, 2-arm, randomized, multicenter, global (~100 sites across Australia, Canada, Europe, New Zealand, Singapore, South Korea, and USA), phase 3 trial being conducted in collaboration with the SIOPe Brain Tumor Group LOGGIC Consortium. The study is evaluating the efficacy, safety, and tolerability of tovorafenib vs. standard of care (SoC) chemotherapy in patients < 25 years old with pLGG harboring an activating RAF-alteration and requiring first-line systemic therapy. Approximately 400 patients will be randomized 1:1 to receive oral tovorafenib, 420 mg/m2 (≤600 mg) once weekly (tablet or liquid suspension), or an investigator’s choice of SoC chemotherapy: COG-V/C regimen (60 weeks), SIOPe-LGG-V/C regimen (81 weeks), or single-agent vinblastine (70 weeks). Tovorafenib will be continued until the occurrence of radiographic progression (based on Response Assessment in Neuro-Oncology [RANO] criteria as determined by the investigator and confirmed by independent review) or unacceptable toxicity; patients with radiographic progression may be allowed to continue tovorafenib if, in the opinion of the treating investigator, they are deriving clinical benefit from study treatment. Patients who progress in the SoC arm during or after completion of chemotherapy are eligible to cross-over to receive tovorafenib. The primary endpoint is the objective response rate based on RANO criteria, as determined by independent review. Key secondary endpoints are progression-free survival and duration of response per RANO criteria by independent review and overall survival. Other secondary endpoints include efficacy assessments per Response Assessment in Pediatric Neuro-Oncology (RAPNO) criteria, changes in neurological and visual function, and safety and tolerability. Exploratory endpoints include efficacy assessments per investigator, tumor volume, adaptive behavior and quality of life. Prognostic and predictive molecular biomarkers, including senescence profiles for treatment outcome, response prediction, and treatment resistance, will be explored in parallel studies. Clinical trial information: NCT05566795 .

Outcome of nasopharyngeal carcinoma (epithelial undifferentiated NOS) in children and adolescents: SEER database analysis.

e22016 Background: Nasopharyngeal carcinoma (NPC) is a rare malignant epithelial tumor of the nasopharynx and account for less than 1% of childhood tumors. Undifferentiated epithelial tumors are one of the commonest histologies. This study aimed to demonstrate the characteristics and outcome of NPC in children and adolescents. Methods: The Surveillance, Epidemiology and End Results database (SEER Research Data 18 Registries Nov 2020Sub (2000-2018)was analyzed for patients diagnosed with carcinoma undifferentiated NOS, NPC ( ICD-O-WHO-3 code 8020). Patients were excluded if the cause of death was not associated with their cancer according to SEER’s cancer-specific death categorization. Overall Survival were estimated using the Kaplan-Meier method, and variables were compared using the log-rank test. P values < .05 were considered significant. Results: A total of 62 patients aged ≤19 years with undifferentiated nasopharyngeal carcinoma were identified. The cohort included 39 (62.9%) males and 23 (37.1%) females .Among them, 40.3 % were white, 40.3% were black,17.7% were Asians/Pacific Islanders, and 1.6% were American Indian. The age of diagnosis distribution included 2 (3.2%)children with 5-9 year, 17 (27.4%) children with 10-14 years and 43(69.4%) children with 15-19 years. With a median follow up of 7.9 years, 3 year OS of the entire cohort was 84.5%. 3 year OS for children aged ≤14 years was 82.1% and for children aged 15-19 years was 85.5% (p- value = 0.649). When stratified by treatment era, the 3-year OS of all patients treated after 2009 was not statistically significant than those treated before (3-year OS, 85.5% vs 82%, P = .0649). Conclusions: Children and adolescents with undifferentiated epithelial neoplasm NOS, NPC had excellent survival. Age and treatment era has no prognostic impact on outcomes.

INTRAMEDULLARY FIXATION OF DOUBLE-BARREL VASCULARIZED FIBULA GRAFTS WITH SUBSEQUENT LENGTHENING FOR RECONSTRUCTION OF THE DISTAL FEMUR IN PATIENTS WITH OSTEOSARCOMA

IntroductionThe use of vascularised fibula grafts is an accepted method for reconstructing the distal femur following resection of malignant childhood tumours. Limitations relate to the mismatch of the cross-sectional area of the transplanted fibula graft and thel ocal bone, instability of the construct and union difficulties. We present midterm results of a unique staged technique—an immediate defect reconstruction using a double-barrel vascularised fibula graft set in in A-frame configuration and a subsequent intramedullary femoral lengthening.Materials & MethodsWe retrospectively included 10 patients (mean age 10 y)with an osteosarcoma of the distal femur, who were treated ac-cording to the above-mentioned surgical technique. All patients were evaluated with regards to consolidation of the transplanted grafts, hypertrophy at the graft-host junctions, leg length discrepancies, lengthening indices, complications as well as functional outcome.ResultsThe mean defect size after tumour resection was 14.5 cm, the mean length of the harvested fibula graft 22 cm, resulting in a mean (acute) shortening of 4.7 cm (in 8 patients). Consolidation was achieved in all cases, 4 patients required supplementary bone grafting. Hypertrophy at the graft-host junctions was observed in78% of the evaluable junctions. In total 11 intramedullary lengthening procedures in 9 patients had been performed at the last follow up. The mean Muskuloskeletal Society Rating Scale(MSTS) score of the evaluable 9 patients was 85% (57% to 100%)with good or excellent results in 7 patients.ConclusionsA-frame vascularised fibula reconstructions showed encouraging results with respect to defect reconstruction, length as well as function and should therefore be considered a valuable option for reconstruction of the distal femur after osteosarcoma resection. The surgical implementation is demanding though, which is emphasized by the considerable high number of com-plications requiring surgical intervention, even though most were not serious.

A CASE REPORT ON INFANTILE HEMANGIOMA

Infantile hemangiomas are the most common benign vascular tumors in childhood. They usually appear as macular or raised bluish nodular swelling.It most commonly involves head and neck region which results in tissue damage, ulceration, bleeding, functional impairment and disfigurement. We present a case of 4-year-old patient with infantile hemangioma in the left side of face.

Retrospective analysis of mediastinal tumors in childhood

Background: The aim of this study was to determine etiologic distribution, epidemiologic properties, treatment, clinical course and late effects of the treatment of the patients diagnosed with mediastinal tumor. Methods: Patients under 18 years old diagnosed with mediastinal tumors between January 1990 and June 2011 at the 19 Mayis university department of child oncology were examined retrospectively. Results: There were 50 (61%) males, 32 (39%) females with mediastinal tumor. Median age at diagnosis was 9.28 years (30 days-17.4 years). Most common symptoms were respiratory distress (29.2%) and cough (23.1%). Sixty eight cases (82.9%) were malignant. Two cases died before diagnosis. Thirty seven cases (45.1%) were located in anterior followed by 16 (19.5%) in middle and 23 (28%) in posterior mediastinum. Most common malignant tumors were lymphomas (n=46, 67.6%), followed by sarcomas (n=12, 17.6%), neural crest tumors (n=8, 11.8%) and germ cell tumors (n=2, 2.9%). Thirteen cases had vena cava superior syndrome and 4 cases had signs of spinal cord compression at the time of diagnosis. Forty eight cases (58.5%) were alive and symptom free on follow-up (mean 39.5 months, 3-139 months), and 22 (26.8%) were died. Sixteen cases (23.5%) had late effects. Overall survival for all malignant tumors were 60.5±7.8%. Conclusions: Mediastinal tumors should be considered in children with acute progressive respiratory distress and cough. Early diagnosis is still most important factor for prognosis.

The Swedish childhood tumor biobank: systematic collection and molecular characterization of all pediatric CNS and other solid tumors in Sweden

The Swedish Childhood Tumor Biobank (BTB) is a nonprofit national infrastructure for collecting tissue samples and genomic data from pediatric patients diagnosed with central nervous system (CNS) and other solid tumors. The BTB is built on a multidisciplinary network established to provide the scientific community with standardized biospecimens and genomic data, thereby improving knowledge of the biology, treatment and outcome of childhood tumors. As of 2022, over 1100 fresh-frozen tumor samples are available for researchers. We present the workflow of the BTB from sample collection and processing to the generation of genomic data and services offered. To determine the research and clinical utility of the data, we performed bioinformatics analyses on next-generation sequencing (NGS) data obtained from a subset of 82 brain tumors and patient blood-derived DNA combined with methylation profiling to enhance the diagnostic accuracy and identified germline and somatic alterations with potential biological or clinical significance. The BTB procedures for collection, processing, sequencing, and bioinformatics deliver high-quality data. We observed that the findings could impact patient management by confirming or clarifying the diagnosis in 79 of the 82 tumors and detecting known or likely driver mutations in 68 of 79 patients. In addition to revealing known mutations in a broad spectrum of genes implicated in pediatric cancer, we discovered numerous alterations that may represent novel driver events and specific tumor entities. In summary, these examples reveal the power of NGS to identify a wide number of actionable gene alterations. Making the power of NGS available in healthcare is a challenging task requiring the integration of the work of clinical specialists and cancer biologists; this approach requires a dedicated infrastructure, as exemplified here by the BTB.

Quality of Life Outcomes for Patients Who Underwent Conventional Resection and Liver Transplantation for Locally Advanced Hepatoblastoma.

Hepatoblastoma is the most common malignant liver tumor of childhood, with liver transplant and extended resection used as surgical treatments for locally advanced tumors. Although each approach has well-described post-operative complications, quality-of-life outcomes have not been described following the two interventions. Long-term pediatric survivors of hepatoblastoma who underwent conventional liver resection or liver transplantation at a single institution from January 2000-December 2013 were recruited to complete quality-of-life surveys. Survey responses for the Pediatric Quality of Life Generic Core 4.0 (PedsQL, n = 30 patient and n = 31 parent surveys) and Pediatric Quality of Life Cancer Module 3.0 (PedsQL-Cancer, n = 29 patient and n = 31 parent surveys) were collected from patients and parents. The mean total patient-reported PedsQL score was 73.7, and the parent-reported score was 73.9. There were no significant differences in scores on the PedsQL between patients who underwent resection compared to those who underwent transplantation (p > 0.05 for all comparisons). On the PedsQL-Cancer module, procedural anxiety scores were significantly lower for patients who underwent resection as compared to transplant (M = 33.47 points less, CI [-60.41, -6.53], p-value 0.017). This cross-sectional study demonstrates that quality of life outcomes are overall similar among patients receiving transplants and resections. Patients who received a resection reported worse procedural anxiety.

Pediatric Brain Tumours: Lessons from the Immune Microenvironment.

In spite of recent advances in tumour molecular subtyping, pediatric brain tumours (PBTs) remain the leading cause of cancer-related deaths in children. While some PBTs are treatable with favourable outcomes, recurrent and metastatic disease for certain types of PBTs remains challenging and is often fatal. Tumour immunotherapy has emerged as a hopeful avenue for the treatment of childhood tumours, and recent immunotherapy efforts have been directed towards PBTs. This strategy has the potential to combat otherwise incurable PBTs, while minimizing off-target effects and long-term sequelae. As the infiltration and activation states of immune cells, including tumour-infiltrating lymphocytes and tumour-associated macrophages, are key to shaping responses towards immunotherapy, this review explores the immune landscape of the developing brain and discusses the tumour immune microenvironments of common PBTs, with hopes of conferring insights that may inform future treatment design.

Surgically Amenable Childhood Cancers: An Overview of the Burden and Challenges of Management in Low- and Middle-Income Countries.

The World Health Organization's Global Initiative for Childhood Cancer was launched to decrease the disparities in childhood cancer outcomes and improve treatments for childhood cancer in resource-limited settings. Low-grade glioma, retinoblastoma, and Wilms tumors are among the index cancers included in this global initiative, as these cancers represent a large percentage of childhood tumors and are curable with cost-effective, evidence-based interventions. Herein, we discuss the global childhood tumor burden, the status of pediatric cancer surgery capacity and services around the world, and the strategic considerations for building pediatric surgical oncology capacity.

Integrated genomic analysis reveals aberrations in WNT signaling in germ cell tumors of childhood and adolescence

Germ cell tumors (GCTs) are neoplasms of the testis, ovary and extragonadal sites that occur in infants, children, adolescents and adults. Post-pubertal (type II) malignant GCTs may present as seminoma, non-seminoma or mixed histologies. In contrast, pre-pubertal (type I) GCTs are limited to (benign) teratoma and (malignant) yolk sac tumor (YST). Epidemiologic and molecular data have shown that pre- and post-pubertal GCTs arise by distinct mechanisms. Dedicated studies of the genomic landscape of type I and II GCT in children and adolescents are lacking. Here we present an integrated genomic analysis of extracranial GCTs across the age spectrum from 0–24 years. Activation of the WNT pathway by somatic mutation, copy-number alteration, and differential promoter methylation is a prominent feature of GCTs in children, adolescents and young adults, and is associated with poor clinical outcomes. Significantly, we find that small molecule WNT inhibitors can suppress GCT cells both in vitro and in vivo. These results highlight the importance of WNT pathway signaling in GCTs across all ages and provide a foundation for future efforts to develop targeted therapies for these cancers.

ÇOCUKLUK ÇAĞI HEMANJİOMLARININ TEDAVİSİNDE TOPİKAL VE ORAL BETA-BLOKERLERİN ETKİNLİĞİNİN KARŞILAŞTIRILMASI

Purpose: Hemangiomas are the most common vascular tumors of childhood, and the treatment options have undergone profound changes in recent years. We aimed to compare the effectiveness and safety of non-pharmacological treatment, topical beta blocker treatment, and and oral beta blocker treatment in the treatment of superficial and deep hemangiomas in the pediatric age group. 
 Material and Methods: We retrospectively reviewed the medical records of pediatric patients with hemangioma. 
 Results: Fifty-three patients (F/M=40/13) were enrolled in this study. Superficial hemangiomas were detected in 14 (26.4%) patients, and deep hemangiomas in 39 (73.6%). Seventeen patients were followed without medication, 19 patients were treated with a topical beta blocker , and 17 patients were treated with an oral beta blocker. Twelve patients with a superficial hemangioma were followed without medication while two patients received topical timolol treatment.
 A comparison of the lesion progress in the patients with superficial hemangiomas in non-pharmacological treatment and topical treatment groups, the mean scores of success in terms of mean fading and reduction in lesion depth were significantly higher at 1st month (7.0 vs 1.66; p=0.049; 6.0 vs 1.5; p=0.045). 
 Among patients with deep hemangiomas, a comparison of mean fading scores showed no difference between the oral and topical treatment groups at both 1st and 4th month (p=0.551, p=0.551). 
 Conclusion: We believe that topical treatment can replace oral beta blockers in the future, and will likely be more preferred by clinicians and families because of their fewer side effects.

SEOM clinical guideline on heritable TP53-related cancer syndrome (2022)

Li-Fraumeni syndrome is caused by heterozygous germline pathogenic variants in the TP53 gene. It involves a high risk of a variety of malignant tumors in childhood and adulthood, the main ones being premenopausal breast cancer, soft tissue sarcomas and osteosarcomas, central nervous system tumors, and adrenocortical carcinomas. The variability of the associated clinical manifestations, which do not always fit the classic criteria of Li-Fraumeni syndrome, has led the concept of SLF to extend to a more overarching cancer predisposition syndrome, termed hereditable TP53-related cancer syndrome (hTP53rc). However, prospective studies are needed to assess genotype–phenotype characteristics, as well as to evaluate and validate risk-adjusted recommendations. This guideline aims to establish the basis for interpreting pathogenic variants in the TP53 gene and provide recommendations for effective screening and prevention of associated cancers in carrier individuals.

Long-Term Endocrinologic Follow-Up of Children with Brain Tumors and Comparison of Growth Hormone Therapy Outcomes: A SingleCenter Experience.

Brain tumors in childhood carry a high risk for endocrine disorders due to the direct effects of the tumor and/or surgery and radiotherapy. Somatotropes are vulnerable to pressure and radiotherapy; therefore, growth hormone deficiency is one of the most frequent abnormalities. This study aimed to evaluate endocrine disorders and recombinant growth hormone treatment outcomes in brain tumor survivors. In this study, 65 (27 female) patients were classified into 3 groups as craniopharyngioma (n = 29), medulloblastoma (n = 17), and others (n = 19). "Others" group included astrocytoma, ependymoma, germinoma, pineoblastoma, and meningioma patients. Anthropometric data and endocrine parameters of patients and their growth outcome with/without recombinant growth hormone therapy were collected from medical records, retrospectively. Mean age at the first endocrinological evaluation was 8.7 ± 3.6 years (range: 1.0- 17.1 years). Height, weight, and body mass index standard deviation score, mean ± standard deviation (median) values were -1.7 ± 1.7 (-1.5), -0.8 ± 1.9 (-0.8), and 0.2 ± 1.5 (0.4), respectively. Hypothyroidism (central 86.9%, primary 13.1%) was detected during follow-up in 81.5% of patients. Primary hypothyroidism in medulloblastoma (29.4%) was significantly higher compared to other groups (P = .002). The frequency of hypogonadotropic hypogonadism, central adrenal insufficiency, and diabetes insipidus was significantly high in the craniopharyngioma cases. In our study, endocrine disorders other than growth hormone deficiency were also frequently observed. In craniopharyngioma cases, the response to recombinant growth hormone therapy was satisfactory. However, there was no improvement in height prognosis during recombinant growth hormone therapy in medulloblastoma patients. A multidisciplinary approach to the care of these patients, referral for endocrine complications, and guidelines on when recombinant growth hormone therapy is required.

Oncohistones and disrupted development in pediatric-type diffuse high-grade glioma.

Recurrent, clonal somatic mutations in histone H3 are molecular hallmarks that distinguish the genetic mechanisms underlying pediatric and adult high-grade glioma (HGG), define biological subgroups of diffuse glioma, and highlight connections between cancer, development, and epigenetics. These oncogenic mutations in histones, now termed "oncohistones", were discovered through genome-wide sequencing of pediatric diffuse high-grade glioma. Up to 80% of diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG) and diffuse glioma arising in other midline structures including thalamus or spinal cord, contain histone H3 lysine 27 to methionine (K27M) mutations or, rarely, other alterations that result in a depletion of H3K27me3 similar to that induced by H3 K27M. This subgroup of glioma is now defined as diffuse midline glioma, H3K27-altered. In contrast, histone H3 Gly34Arg/Val (G34R/V) mutations are found in approximately 30% of diffuse glioma arising in the cerebral hemispheres of older adolescents and young adults, now classified as diffuse hemispheric glioma, H3G34-mutant. Here, we review how oncohistones modulate the epigenome and discuss the mutational landscape and invasive properties of histone mutant HGGs of childhood. The distinct mechanisms through which oncohistones and other mutations rewrite the epigenetic landscape provide novel insights into development and tumorigenesis and may present unique vulnerabilities for pHGGs. Lessons learned from these rare incurable brain tumors of childhood may have broader implications for cancer, as additional high- and low-frequency oncohistone mutations have been identified in other tumor types.

Predictive Factors for Pediatric Craniopharyngioma Recurrence: An Extensive Narrative Review.

Despite being classified as benign tumors, craniopharyngiomas (CPs) are associated with significant morbidity and mortality due to their location, growth pattern, and tendency to recur. Two types can be identified depending on age distribution, morphology, and growth pattern, adamantinomatous and papillary. The adamantinomatous CP is one of the most frequently encountered central nervous system tumors in childhood. Our aim was to review the relevant literature to identify clinical, morphological, and immunohistochemical prognostic factors that have been implicated in childhood-onset CP recurrence. Lack of radical surgical removal of the primary tumor by an experienced neurosurgical team and radiotherapy after a subtotal excision has been proven to significantly increase the recurrence rate of CP. Other risk factors that have been consistently recognized in the literature include younger age at diagnosis (especially <5 years), larger tumor size at presentation, cystic appearance, difficult tumor location, and tight adherence to surrounding structures, as well as the histological presence of whorl-like arrays. In addition, several other risk factors have been studied, albeit with conflicting results, especially in the pediatric population. Identifying risk factors for CP recurrence is of utmost importance for the successful management of these patients in order to ultimately ensure the best prognosis.

Unusual Presentation of Brain Tumor in a Child: A Case Report

The most popular type of neurological tumor in childhood is medulloblastoma, which is the most malignant neoplasm of the posterior fossa and cerebellum. Central nervous system neoplasms can cause symptoms and signs due to local invasion, compression of normal structures, and increased intracranial pressure by either a mass effect or obstruction of cerebrospinal fluid flow, resulting in hydrocephalus. Usually, headache is the most common symptom of central nervous system tumors, and the median duration between symptoms beginning and diagnosis of brain tumors in children ranges from 2.5 to 3.5 months. Furthermore, several predisposing factors for brain tumors have been identified such as Epstein–Barr virus infection, exposure to ionizing radiation, and inherited diseases. Recently, the advances in diagnosis and treatment have improved the survival of many children with neurological neoplasms. However, this therapy is associated with long-term complications, and its prognosis remains poor. We present the case of a 4-year-old girl with adequate neuropsychomotor development who presented to the pediatric emergency center with a 14-day history of headache, which was prominent in the morning, neck, back, and bilateral leg pain two days prior to presentation. Brain and Spine Magnetic resonance imaging revealed a cerebellar mass lesion in the posterior fossa. The patient underwent surgery, followed by histopathological and immunohistochemical staining. This case is considered rare and distinctive because the symptoms included only headache for two weeks, no impaired vision, no vomiting, no mental disorders, no abnormal gait, and no ataxia or body imbalance. We report this case to focus on the features of the manifestation and hence increase the chances of timely diagnosis in the future. Consequently, the probability of central nervous system tumors should always be considered in children with headache, and they must be under regular follow-up for early diagnosis and treatment.

Oxygen availability influences the incidence of testicular teratoma in Dnd1Ter/+ mice.

Testicular teratomas and teratocarcinomas are the most common testicular germ cell tumors in early childhood and young men, and they are frequently found unilaterally in the left testis. In 129/SvJ mice carrying a heterozygous copy of the potent modifier of tumor incidence Ter, a point mutation in the dead-end homolog one gene (Dnd1 Ter/+), ∼70% of the unilateral teratomas arise in the left testis. We previously showed that in mice, left/right differences in vascular architecture are associated with reduced hemoglobin saturation and increased levels of the hypoxia inducible factor-1 alpha (HIF-1α) in the left compared to the right testis. To test the hypothesis that systemic reduction of oxygen availability in Dnd1 Ter/+ mice would lead to an increased incidence of bilateral tumors, we placed pregnant females from 129/SvJ Dnd1 Ter/+ intercross matings in a hypobaric chamber for 12-h intervals. Our results show that in 129/SvJ Dnd1 Ter/+ male gonads, the incidence of bilateral teratoma increased from 3.3% to 64% when fetuses were exposed to acute low oxygen conditions for 12-h between E13.8 and E14.3. The increase in tumor incidence correlated with the maintenance of high expression of pluripotency genes Oct4, Sox2 and Nanog, elevated activity of the Nodal signaling pathway, and suppression of germ cell mitotic arrest. We propose that the combination of heterozygosity for the Ter mutation and hypoxia causes a delay in male germ cell differentiation that promotes teratoma initiation.