Pediatric Tumor Patients Research Articles

Clinical trio genome sequencing facilitates the interpretation of variants in cancer predisposition genes in paediatric tumour patients

The prevalence of pathogenic and likely pathogenic (P/LP) variants in genes associated with cancer predisposition syndromes (CPS) is estimated to be 8-18% for paediatric cancer patients. In more than half of the carriers, the family history is unsuspicious for CPS. Therefore, broad genetic testing could identify germline predisposition in additional children with cancer resulting in important implications for themselves and their families. We thus evaluated clinical trio genome sequencing (TGS) in a cohort of 72 paediatric patients with solid cancers other than retinoblastoma or CNS-tumours. The most prevalent cancer types were sarcoma (n = 26), neuroblastoma (n = 15), and nephroblastoma (n = 10). Overall, P/LP variants in CPS genes were identified in 18.1% of patients (13/72) and P/LP variants in autosomal-dominant CPS genes in 9.7% (7/72). Genetic evaluation would have been recommended for the majority of patients with P/LP variants according to the Jongmans criteria. Four patients (5.6%, 4/72) carried P/LP variants in autosomal-dominant genes known to be associated with their tumour type. With the immediate information on variant inheritance, TGS facilitated the identification of a de novo P/LP in NF1, a gonadosomatic mosaic in WT1 and two pathogenic variants in one patient (DICER1 and PALB2). TGS allows a more detailed characterization of structural variants with base-pair resolution of breakpoints which can be relevant for the interpretation of copy number variants. Altogether, TGS allows comprehensive identification of children with a CPS and supports the individualised clinical management of index patients and high-risk relatives.

Pott's Puffy Tumor in Pediatric Patients: Case Series and Literature Review.

Pott's puffy tumor (PPT) is a rare complication of frontal sinusitis. Although it may occur at any age, the incidence is higher during adolescence. We report a series of 10 pediatric patients (9-17 years of age) who presented with PPT in 2 tertiary care pediatric hospitals in central Israel between January 2018 and August 2022 and review the published literature on pediatric PPT. The most common clinical presentations included headache (10 cases), frontal swelling (6 cases) and fever (5 cases). Symptom duration before admission was between 1 and 28 days (median 10 days). The diagnosis of PPT was made by imaging studies at a median of 1 day after admission. All 10 patients underwent computed tomography studies, and 6 patients also underwent magnetic resonance imaging. The overall rate of intracranial complications was 70%. All 10 children were treated with systemic antibiotics and surgical interventions. Streptococcus constellatus group was the most common causal bacteria. All 10 patients recovered uneventfully. Our findings show that a high index of suspicion for PPT should be applied to adolescents presenting with prolonged headache and frontal swelling. Contrast-enhanced computed tomography is an appropriate first tool for the evaluation; however, an magnetic resonance imaging should be performed to determine the necessity of intracranial interventional treatments if there is any suspicion of intracranial involvement. Complete recovery can be expected with appropriate antibiotic treatment and surgical intervention in most of the cases.

Vasospasm following brain tumor resection in children: institutional experience and systematic review.

Delayed cerebral ischemia (DCI) associated with vasospasm is well described in the setting of aneurysmal subarachnoid hemorrhage (SAH). In addition, DCI is very infrequently encountered in patients who have undergone resection of a brain tumor with unclear pathophysiology. The occurrence of DCI in the pediatric population is exceedingly rare, and outcomes in this population have, to the authors' knowledge, never been systematically reviewed. Therefore, the authors present what is to their knowledge the largest series of pediatric patients with this complication and systematically reviewed the literature for individual participant data. The authors conducted a retrospective review of 172 sellar and suprasellar tumors in pediatric patients who underwent surgery at the Montreal Children's Hospital between 1999 and 2017 to identify cases of vasospasm occurring after tumor resection. Descriptive statistics, including patient characteristics, intraoperative and postoperative findings, and outcome status, were collected. A systematic review was also conducted using three databases (PubMed, Web of Science, Embase) to identify reported cases available in the literature of vasospasm after tumor resection in children and collect individual participant data on these patients for further analysis. Six patients treated at Montreal Children's Hospital were identified, with an average age of 9.5 years (range 6-15 years). The prevalence of vasospasm after tumor resection was 3.5% (6/172). Vasospasm in all 6 patients occurred after craniotomy was performed to treat a suprasellar tumor. The average interval from surgery to symptoms was 3.25 days (range 12 hours-10 days). The most common tumor etiology was craniopharyngioma, seen in 4 cases. Extensive tumor encasement of blood vessels requiring significant operative manipulation was described in all 6 patients. A rapid decrease in serum sodium (exceeding 12 mEq/L/24 hrs or below 135 mEq/L) was seen in 4 patients. On final follow-up, 3 patients were left with significant disability, and all patients had persistent deficits. A systematic review of the literature revealed a total of 10 other patients whose characteristics and treatment were compared with those of the 6 patients treated at Montreal Children's Hospital. Vasospasm after tumor resection in children and youth is likely a rare entity, with a prevalence of 3.5% in this case series. Suprasellar tumor location (particularly craniopharyngioma tumor etiology), significant encasement of blood vessels by the tumor, and postoperative hyponatremia may be predictive factors. Outcome is poor, with most patients having significant persistent neurological deficits.

A single-institution pediatric and young adult interventional oncology collaborative: Novel therapeutic options for relapsed/refractory solid tumors.

Pediatric interventional oncology (PIO) is a growing field intended to provide additional or alternative treatment options for pediatric patients with benign or malignant tumors. Large series of patients treated uniformly and subjected to rigorous endpoints for efficacy are not available. We designed a collaborative initiative to capture data from pediatric patients with benign and malignant tumors who underwent a therapeutic interventional radiology procedure. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) was utilized as a measure of radiologic response and data were collected regarding improvement in pain and functional endpoints. Cumulative incidence of progressive disease was calculated using both the treated site and the patient as the analytic unit. Forty patients, 16 with malignant tumors and 24 with benign tumors, underwent a total of 88 procedures. Cryo- and radiofrequency ablation were the most frequently utilized techniques for both cohorts of patients. A complete or partial response, or prolonged disease stability, were achieved in approximately 40% of patients with malignant tumors and 60% of patients with benign tumors. No patients had progressive disease as their best response. Resolution of pain and improved mobility with return-to-baseline activity were demonstrated across patients from both cohorts. Only minor complications were experienced. Interventional radiology-guided interventions can serve as an alternative or complementary approach to the treatment of benign and malignant tumors in pediatric patients. Prospective, multi-institutional trials are required to adequately study utility, treatment endpoints, and durability of response.

The Extended-Sphenoid Ridge Approach: A New Technique for the Surgical Treatment of Skull Base Tumors in Pediatric Patients.

This report aimed to evaluate the advantages of the extradural removal of the orbital roof, pterion, sphenoid wing, and anterior clinoid process as a complement to the sphenoid ridge approach in pediatric patients. We enrolled 36 patients with suspected neoplastic diseases in different regions. The E-SRA was performed to treat the patients. Patients were included based on the a priori objective of a biopsy or a total gross resection. The surgical time required to complete the approach, associated bleeding, and any complications were documented. Our results demonstrated that the proposed a priori surgical goal, biopsy, or resection were successfully achieved in all cases. In addition, using the E-SRA technique was associated with a shorter operative time, minimal bleeding, and a lower incidence of complications. The most frequently encountered complications were related to dural closure. The extended sphenoid ridge approach represents a safe and effective option for managing intracranial tumors in pediatrics.

Prognostic factors of pediatric pineal region tumors at a single institution.

This study aimed to identify factors of a worse prognosis among different histological types of pineal region tumors in pediatric patients treat at a single institution in a 30-year period. Pediatric patients (151; < 18years of age) treated between 1991 and 2020 were analyzed. Kaplan-Meyer survival curves were created, and the log-rank test was used to compare the main prognostic factors in the different histological types. Germinoma was found in 33.1%, with an overall 60-month survival rate of 88%; the female sex was the only factor of a worse prognosis. Non-germinomatous germ cell tumors were found in 27.1%, with an overall 60-month survival rate of 67.2%; metastasis upon diagnosis, residual tumor, and the absence of radiotherapy were associated with a worse diagnosis. Pineoblastoma was found in 22.5%, with an overall 60-month survival rate of 40.7%; the male sex was the only factor of a worse prognosis; a tendency toward a worse outcome was found in patients < 3years of age and those with metastasis upon diagnosis. Glioma was identified in 12.5%, with an overall 60-month survival rate of 72.6%; high-grade gliomas were associated with a worse prognosis. Atypical teratoid rhabdoid tumors was found in 3.3%, and all patients died within a 19-month period. Pineal region tumors are characterized by the heterogeneity of histological types, which exert an influence on the outcome. Knowledge of the prognostic factors for each histological types is of extreme importance to the determination of guided multidisciplinary treatment.

Marine Cyanobacterial Peptides in Neuroblastoma: Search for Better Therapeutic Options.

Neuroblastoma is the most prevalent extracranial solid tumor in pediatric patients, originating from sympathetic nervous system cells. Metastasis can be observed in approximately 70% of individuals after diagnosis, and the prognosis is poor. The current care methods used, which include surgical removal as well as radio and chemotherapy, are largely unsuccessful, with high mortality and relapse rates. Therefore, attempts have been made to incorporate natural compounds as new alternative treatments. Marine cyanobacteria are a key source of physiologically active metabolites, which have recently received attention owing to their anticancer potential. This review addresses cyanobacterial peptides' anticancer efficacy against neuroblastoma. Numerous prospective studies have been carried out with marine peptides for pharmaceutical development including in research for anticancer potential. Marine peptides possess several advantages over proteins or antibodies, including small size, simple manufacturing, cell membrane crossing capabilities, minimal drug-drug interactions, minimal changes in blood-brain barrier (BBB) integrity, selective targeting, chemical and biological diversities, and effects on liver and kidney functions. We discussed the significance of cyanobacterial peptides in generating cytotoxic effects and their potential to prevent cancer cell proliferation via apoptosis, the activation of caspases, cell cycle arrest, sodium channel blocking, autophagy, and anti-metastasis behavior.

Utilizing RENAL nephrometry in pediatric patients undergoing nephron-sparing surgery for renal tumors: A single-institutional cohort

RENAL Nephrometry is a complexity score validated in adults with renal tumors and describes the likelihood of complication after partial nephrectomy (PN). Utilization in pediatrics has been limited. Thus, our goal is to quantify inter-rater agreement as well as determine how scores correlate with outcomes. We hypothesize that the RENAL Nephrometry Score is reproducible in children with renal tumors and is related to perioperative and post-operative complications. All pediatric patients who underwent PN for a renal mass from 2006 to 2019 were identified. Patient data, operative details, and outcomes were aggregated. Pre-operative CT/MR imaging was anonymized and scored by 2 pediatric radiologists and 2 pediatric urologists using RENAL Nephrometry metrics. Statistical analysis utilized Fleiss' kappa and the intraclass correlation coefficient (ICC). Comparative analyses were performed based on Nephrometry Score <9 and≥9. 28 patients undergoing 33PN were identified. Median age at surgery was 3.2 years (IQR 1.8-4.0). There is moderate-good agreement across scorers on the domains of RENAL Nephrometry Score, with the lowest agreement noted for anterior vs posterior tumors. Comparing patients with scores <9 and≥9, there was increased operative time (357 vs 267min, p=0.003) and LOS for those with a higher score, but no difference in the incidence of 30-day complications. RENAL Nephrometry Score is an easily reproducible complexity score for renal tumors in pediatric patients. Higher scores are associated with increased length of stay and estimated blood loss but not complications. Reporting of nephrometry scores in future publications on pediatric renal tumors should become standard in the literature.

Papillary thyroid cancer in children. Clinical cases

Thyroid cancer (TC) is the most common endocrine tumor in pediatric patients. Papillary carcinoma accounts for the highest rate among differentiated TCs (80—90%). Papillary thyroid cancer in children is clinically different from this pathology in adults. In comparison with adults, papillary thyroid cancer in children is diagnosed at later stages and is associated with a more aggressive course of the disease. Despite the high frequency of metastases and recurrences of papillary thyroid cancer in children, the prognosis remains favorable. In Ukraine, 10 years after the accident at the Chernobyl nuclear power plant, the average incidence rates of papillary thyroid cancer among children of all ages gradually decreased, but since 2010—2011, a negative trend towards an increase in the number of new cases of pathology, especially children under 14 years of age, has been restored. Several studies suggest that the increase in the incidence of papillary thyroid cancer is only partially explained by the increase in the number of preventive examinations performed, as there is also an increase in the detection of large tumors and the diagnosis of advanced stages of the disease.Over the past 14 years, 759 children aged 3 to 18 from all regions of Ukraine were operated in the clinic of the Ukrainian Scientific and Practical Center for Endocrine Surgery, Transplantation of Endocrine Organs and Tissues of the Ministry of Health of Ukraine (Center). From them, based on the results of histopathological examinations, papillary thyroid cancer was diagnosed in 290 (38.2%) children (including 73.45% girls and 26.55% boys). In most cases, the disease was diagnosed during adolescence, except for isolated cases among children of primary school and preschool age. The paper presents two clinical cases.Annual preventive thyroid ultrasound investigation is required for early diagnosis of nodular goiter, including malignant thyroid tumors, especially in children with a burdened family history of these tumors. Any nodular goiter in children should be considered potentially malignant until its benign nature is proven by appropriate qualified investigations. To ensure proper and timely verification of malignant thyroid tumors in pediatric patients, to avoid unjustified (insufficient or excessive) surgical treatment of children with thyroid tumors, such patients should be referred to medical institutions with modern diagnostic capabilities and expert‑level surgical experience in the treatment of children with nodular goiter and malignant thyroid tumors.

Risk factors for testicular adrenal rest tumors in pediatric patients with congenital adrenal hyperplasia

Testicular adrenal rest tumors (TARTs) predominantly occur in patients with congenital adrenal hyperplasia (CAH) and may interfere with the function of the testicles. This study aimed to identify the factors that contribute to the occurrence of TARTs in patients with CAH and influence their volume. This was a comparative cross-sectional study. Male patients aged 0-16 years with CAH were included. Weight, height, bone age determination, biochemical and androgenic profiles, and testicular ultrasound were performed. Patients were divided into those with and without TARTs and the between-group differences were assessed using the Mann-Whitey U test and Fisher's exact test. A ROC curve was created for serum ACTH levels to identify the cut-off point to diagnose TARTs. Variables that influenced the volume of the TARTs were identified using Spearman's correlation coefficient. TARTs were observed in seven (19.4%) of 36 male children with CAH. Of the patients with TARTs, 85.7% were pubertal. Serum concentrations of adrenocorticotropic hormone (ACTH) levels were significantly higher in patients with TARTs than in those without (309.0pg/mL vs. 45.2pg/mL; p=0.006). ACTH levels >200pg/mL were found to predict the presence of TARTs (sensitivity 85.7%; specificity 86.2%) (Figure). The factors found to correlate with TARTs volume were ACTH levels (coefficient 0.004; p=0.009) and the three-year average of serum testosterone levels (coefficient 9.64; p=0.003).] DISCUSSION: The main limitation of this study was the small sample size. However, an ACTH cut-off point to predict insufficient hormonal treatment and consequently the presence of TART had not been described. High ACTH (>200pg/mL) was found to be predictive insufficient hormonal treatment in patients with CAH. The three-year average of serum testosterone levels and ACTH concentrations were correlated with the volume of TARTs.

The usefulness of intraoperative sodium fluorescein in the surgical treatment of relapsed high-grade brain tumors in pediatric patients.

We report the usefulness of intraoperative sodium fluorescein (SF) in the surgical treatment of relapsed high-grade brain tumors in pediatric neurosurgery. We describe our protocol for intraoperative SF and three cases of patients between 5 and 11years diagnosed and surgically treated for relapsed high-grade brain tumors using SF. The 560-nm microscope filter enables the use of low doses of this fluorochrome. A dose of 3mg/kg of patient weight of 10% SF, administered intravenously, is safe and effective in children. The effect of SF was immediate, providing a clear margin between the tumor and healthy tissue, which enabled good tumor resection. We observed no adverse effects in the postoperative period, and the patients evolved satisfactorily. To the best of our knowledge, we describe for the first time the use of fluorescein in reoperations of relapsed high-grade brain tumors in childhood with promising results. Using SF in children is a safe, affordable, and effective technique that offers an excellent intraoperative image, being a feasible option to improve oncological resection. This study is one of the few that uses SF in pediatric neurosurgery, where it could be very beneficial.

Interhospital transfer of pediatric patients with malignant brain tumor not associated with increased mortality, but safe routine discharge.

Interhospital transfer (IHT) to obtain a higher level of care for pediatric patients requiring neurosurgical interventions is common. Pediatric patients with malignant brain tumors often require subspecialty care commonly provided at specialized centers. The authors aimed to assess the impact of IHT in pediatric neurosurgical patients with malignant brain tumors to identify areas of improvement in treatment of this patient population. Pediatric patients (age < 19 years) with malignant primary brain tumors undergoing craniotomy for resection between 2010 and 2018 were retrospectively identified in the Nationwide Readmissions Database. Patient and hospital data for each index admission provided by the Nationwide Readmissions Database was analyzed by univariate and multivariate analyses. Further analysis evaluated association of IHT on specific patient- or hospital-related characteristics. In a total of 2279 nonelective admissions for malignant brain tumors in pediatric patients, the authors found only 132 patients (5.8%) who underwent IHT for a higher level of care. There is an increased likelihood of transfer when a patient is younger (< 7 years old, p = 0.006) or the disease process is more severe, as characterized by higher pediatric complex chronic conditions (p = 0.0004) and increased all patient refined diagnosis-related group mortality index (p = 0.02). Patients who are transferred (OR 1.87, 95% CI 1.04-3.35; p = 0.04) and patients who are treated at pediatric centers (OR 6.89, 95% CI 4.23-11.22; p < 0.0001) are more likely to have a routine discharge home. On multivariate analysis, transfer status was not associated with a longer length of stay (incident rate ratio 1.04, 95% CI 0.94-1.16; p = 0.5) or greater overall costs per patient ($20,947.58, 95% CI -$35,078.80 to $76,974.00; p = 0.50). Additionally, IHT is not associated with increased likelihood of death or major complication. IHT has a significant role in the outcome of pediatric patients with malignant brain tumors. Transfer of this patient population to hospitals providing subspecialized care results in a higher level of care without a significant burden on overall costs, risks, or mortality.

Robotic-assisted resection of mediastinal tumors in pediatric patients

Robotic-assisted resection of mediastinal tumors in pediatric patients

Navigated Transcranial Magnetic Stimulation Motor Mapping and Diffusion Tensor Imaging Tractography for Diencephalic Tumor in Pediatric Patients

Background. In deep-seated brain tumors, adequate preoperative planning is mandatory to assess the best surgical corridor to obtain maximal safe resection. Functional diffusor tensor imaging (DTI) tractography based on navigated transcranial magnetic stimulation (nTMS) motor mapping has proven to be a valid preoperative examination method in adults. The aim of this paper is to present the application of nTMS and functional DTI tractography in a series of pediatric diencephalic tumors. Material and methods. Three patients affected by thalamic (one) and thalamopeduncular tumor (two) were successfully examined with nTMS motor mapping and DTI tractography between October 2020 and October 2021 (F:M 3:0, mean age 12 years ± 0.8). Cortical representation of leg, hand and mouth were determined in the affected hemisphere and the positive stimulation spots were set as seeds point for tractography. Results. Mapping of the motor cortex and tracts reconstruction for leg and hand were successful in all patients, while facial function was properly mapped in one patient only. In all cases, the procedure was well tolerated and no adverse events were recorded. Spatial relationships between tumor and functional tissue guided the surgical planning. Extent of the resection varied from 96.1% to 100% with a postoperative new motor deficit in one patient. Conclusions. nTMS and DTI fiber tracking is a feasible, effective and well-tolerated method to identify motor pathway in deep-seated lesion in pediatric population.

Artificial intelligence in the diagnosis of benign skin tumors in pediatric patients. Neural network integration into a mobile app

Введение. Десятилетие назад искусственный интеллект (ИИ), в частности нейронные сети (НС), как диагностическая опция в практике врача казался лишь отдаленной перспективой. На сегодняшний день применение ИИ во всех сферах клинической и фундаментальной медицины является все более востребованным и ежедневно совершенствующимся подходом. Цель исследования. Разработка НС и ее обучение распознаванию четырех типов доброкачественных меланоцитарных новообразований кожи, интеграция искусственного интеллекта в мобильное приложение. Материал и методы. 600 пациентам детского возраста были проведены клиническое и дерматоскопическое исследования новообразований кожи. У части пациентов (n=65) элементы были удалены и патоморфологически верифицированы. В 43% (n=28) был выявлен дермальный невус, в 33,8% (n=22) ― сложный невус, в 10,8% (n=7) ― пиогенная гранулема, в 6,2% (n=4) ― невус Шпиц, по 3,1% (n=2) были вариантами голубой невус и меланома кожи. Семь пациентов с пиогенными гранулемами и 2 с меланомой были исключены из тестовой выборки во время обучения НС. В обучающей выборке была проведена аугментация, тем самым, база была увеличена с 600 до 1800 изображений. НС написана на языке программирования Python с использованием фрэймворка для машинного обучения TensorFlow 2.0. Архитектура сети основана на предварительно обученной модели «EfficientNet B7» с применением парадигмы «обучения с учителем». Результаты. После периода обучения на тестовой когорте достигнута 83 % точность распознавания четырех типов меланоцитарных невусов. Несмотря на ограниченную выборку, чувствительность метода в зависимости от класса новообразования составила 100% (голубой невус), 73% (сложный невус), 93% (дермальный невус) и 75% (невус Шпиц), специфичность ― 98, 94, 82 и 98% соответственно. Помимо разработки и обучения искусственный интеллект интегрирован в мобильное приложение «KIDS NEVI», что обеспечило практическое применение метода. Заключение. ИИ в качестве вспомогательного метода диагностики меланоцитарных новообразований кожи у детей и подростков продемонстрировал высокий потенциал. Несмотря на ограниченную выборку, в настоящем исследовании представлены большие достижения в информативности данной диагностической методики.

Preoperative and early postoperative rehabilitation of children and adolescents with bone tumors at different stages lower of limb joint replacement

Endoprosthetic replacement is a surgical part of treatment for bone tumors in pediatric patients. Due to the large extent of such surgery, patients require not only postoperative rehabilitation of motor deficits but also preoperative rehabilitation. Objective: to undertake a comparative analysis of the effectiveness of preoperative rehabilitation before lower limb joint replacement and early postoperative rehabilitation (e.g. supine-to-stand transfer). We conducted a retrospective non-randomized study which included patients (n = 81) with malignant bone tumors of the lower limb (osteosarcoma and Ewing sarcoma). The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. Patients allocated to the group of interest (n = 46) received preoperative rehabilitation therapy which started two weeks before surgery; patients in the control group (n = 35) started their rehabilitation on the first postoperative day. In both groups, we assessed muscle strength, autonomic nervous system function and the recovery of range of motion in the reconstructed joint on the first postoperative day and before discharge from the hospital. Patients from the group of interest showed normal autonomic responses more frequently; they demonstrated better restoration of autonomic nervous system function and recovery of range of motion and higher average muscle strength score. The study showed that preoperative rehabilitation has a positive effect on the recovery of motor function post surgery in patients treated with lower limb joint replacement.

Two-Stage Resection of a Giant Trigeminal Schwannoma in a Non–Neurofibromatosis Type 2 Pediatric Patient: A Case Report, Systematic Review, and Intraoperative Video

Trigeminal schwannoma is an uncommon tumor in pediatric patients. Several surgical approaches have been described in the literature. The case of an 11-year-old boy with a giant dumbbell-shaped trigeminal schwannoma removed through a 2-stage approach was presented with an intraoperative video. Using PubMed and Scopus, the literature on trigeminal schwannoma in pediatric patients was searched according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The search strategy yielded 312 titles, of which 13 were included in the review. Cases of trigeminal schwannoma were described, with a highly variable clinical presentation and anatomical arrangement in cranial fossae. Two-stage approaches were reported, although most studies described single-stage approaches. Common postoperative outcomes were a range of disturbances of cranial nerve V. The surgical approach varies based on the tumor conformation. However, a 2-stage pterional subtemporal and semisitting retrosigmoid approach is a safe, practical, and effective strategy for the removal of dumbbell-shaped trigeminal schwannoma in a pediatric patient.

Abstract PR003: Lineage plasticity dictates responsiveness to anti-GD2 therapy in neuroblastoma

Abstract Epigenetic dysregulation is frequently observed in the disease pathology of pediatric cancers, including neuroblastoma, the most common extracranial solid tumor in pediatric patients. Neuroblastoma tumors co-opt developmentally linked adrenergic or mesenchymal super-enhancer landscapes that rewire their transcriptional programs. Here, we describe that the lineage commitment to a mesenchymal epigenetic state is an important mechanism of resistance to anti-GD2 therapy through loss of GD2 antigen, a ganglioside glycolipid expressed on the cell surface. Low GD2 expression was significantly correlated with the mesenchymal state in a large panel of neuroblastoma cell lines and a forced adrenergic-to-mesenchymal transition conferred downregulation of GD2 and resistance to anti-GD2 antibody. Mechanistically, low-GD2 expressing cell lines demonstrated significantly reduced expression of the ganglioside synthesis enzyme ST8SIA1 (GD3 synthase), resulting in a bottlenecking of GD2 synthesis. Genome-wide CRISPR/Cas9 screening to identify regulators of GD2 in neuroblastoma revealed that the ablation of the polycomb repressive complex 2 (PRC2) significantly upregulates GD2 expression in GD2-low cells. Pharmacologic inhibition of EZH2 resulted in epigenetic rewiring of mesenchymal neuroblastoma cells into an adrenergic-like state, re-expressed ST8SIA1, and restored surface expression of GD2 and sensitivity to anti-GD2 antibody. These data identify developmental lineage as a key determinant of sensitivity to anti-GD2 based immunotherapies and credential PRC2 inhibitors for clinical testing in combination with anti-GD2 antibody to enhance outcomes for children with neuroblastoma. Citation Format: Nathaniel W. Mabe, Min Huang, Daniel A. Schaefer, Guillermo N. Dalton, Giulia Digiovanni, Gabriela Alexe, Anna C. Geraghty, Delan Khalid, Marius M. Mader, Michal Sheffer, Miles H. Linde, Nghi Ly, Maria Caterina Rotiroti, Benjamin A. H. Smith, Marius Wernig, Carolyn R. Bertozzi, Michelle Monje, Constantine Mitsiades, Ravindra Majeti, Ansuman T. Satpathy, Kimberly Stegmaier, Robbie G. Majzner. Lineage plasticity dictates responsiveness to anti-GD2 therapy in neuroblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr PR003.

Expanding the Spectrum of Perioral Myogenic Tumors in Pediatric Patients: An SRF::NCOA2 Fused Perivascular Tumor of the Philtrum.

Perivascular tumors, which include myopericytoma and myofibroma, are rare benign soft tissue neoplasms composed of perivascular smooth muscle cells. Most demonstrate characteristic morphology and are readily diagnosed. However, a recently identified hypercellular subset shows atypical histologic features and harbor unique SRF gene fusions. These cellular perivascular tumors can mimic other more common sarcomas with myogenic differentiation. Clinical, radiological, morphological, immunohistochemical, and molecular findings were reviewed. A slow-growing, fluctuant mass was noted within the philtrum at 16 months. Ultrasonography revealed a well-circumscribed cystic hypoechoic lesion. A small (1.0 cm), tan, well-circumscribed soft-tissue mass was excised after continued growth. Histologically, the encapsulated tumor was hypercellular and composed of spindle cells with predominantly-storiform architecture, focal perivascular condensation, dilated branching thin-walled vessels, increased mitoses, and a smooth muscle immunophenotype. An SRF::NCOA2 fusion was identified. We report the first case of an SRF-rearranged cellular myopericytoma in the perioral region in a young child. This case expands the differential diagnosis of perioral soft tissue tumors with myogenic differentiation. We highlight key clinical, pathological, and molecular features. As we illustrate, these rare tumors pose a considerable diagnostic challenge, and risk misdiagnosis as sarcoma, most notably spindle cell rhabdomyosarcoma.

Mortality of central nervous system tumors in pediatric patients of Brazil from 1979 to 2019.

Cancer is the second leading cause of death in children from 2001 to 2005 in Brazil. This study aimed to describe the pattern of mortality from central nervous system (CNS) tumors in children in Brazil from 1979 to 2019. A descriptive study was carried out using data from the Mortality Information System (SIM) of the Ministry of Health, according to the International Classification of Diseases (ICD-9 and ICD-10), between 1979 and 2019. The frequencies of the distribution of available variables were calculated: age (0 - 19years), s skin color, tumor behavior, year and place of death (by region), ICD-10, and all of these, excluding skin color (by ICD-9). Mortality rates in general, mortality from neoplasms, and specific rates of CNS tumors were calculated considering the variables described above. In 40years (1979 - 2019), there were 21,940 deaths due to brain tumors in children. A different pattern of the mortality rate of brain tumors was shown in children per age (increasing until age 5 - 9years (28.9%) and then decreasing until age 15 - 19years (20.2%)). The Southeast (44.3%), Northeast (23.4%), and South (17.5%) regions of Brazil had the highest rates; 94.7% of tumors were malignant, and 91.1% of deaths were observed in hospitals. To our knowledge, this is the first description of the mortality rate epidemiology of brain/CNS tumors in children in Brazil over 40years. Furthermore, tumor malignancy, hospitals, and the Southeast and Northeast region of Brazil are factors associated with a higher mortality rate.