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Purpose: Checkpoint-inhibitors have limited efficacy for children with unselected solid and brain tumors. We report the first prospective pediatric trial (NCT02992964) using nivolumab exclusively for refractory non-hematological cancers harboring tumor mutation burden (TMB) ≥5 mutations/megabase (mut/Mb) and/or mismatch-repair deficiency (MMRD). Patients and methods: Twenty patients were screened, and ten ultimately included in the response cohort of whom nine had TMB >10mut/Mb (three initially eligible based on MMRD) and one patient had TMB between 5-10 mut/Mb. Results: Delayed immune responses contributed to best overall response of 50%, improving on initial objective responses (20%) and leading to 2-year overall survival (OS) of 50% (95% CI; 27, 93). Four children, including three with refractory malignant gliomas are in complete remission at a median follow-up of 37-months (range: 32.4-60), culminating in 2-year OS of 43% (95% CI; 18.2, 100). Biomarker analyses confirmed benefit in children with germline MMRD, microsatellite instability, higher activated and lower regulatory circulating T-cells. Stochastic mutation accumulation driven by underlying germline MMRD impacted the tumor microenvironment, contributing to delayed responses. No benefit was observed in the single patient with a MMR-proficient tumour and TMB 7.4 mut/Mb. Conclusions: Nivolumab resulted in durable responses and prolonged survival for the first time in a pediatric trial of refractory hypermutated cancers including malignant gliomas. Novel biomarkers identified here need to be translated rapidly to clinical care to identify children who can benefit from checkpoint-inhibitors, including for upfront management of their cancers.

Appendix

Figure S1. Sample flow-chart describing the number of biological samples and clinical data obtained through an international multi-institutional effort and the distribution of samples in each microarray

Table S1-S3. S1Choroid plexus tumor chromosomal instability reported in literature S2-Characterization of patient and sample cohort used in analysis S3 Frequency of TP53 mutations in CPTs and characterization of mutation types. Abbreviations: CPC: choroid plexus carcinoma, CPP: choroid plexus papilloma, aCPP: atypical choroid plexus papilloma, SH3: SRC Homology 3 Domain

supplemental figure and table legend

Purpose: To investigate molecular alterations in choroid plexus tumors (CPT) using a genome-wide high-throughput approach to identify diagnostic and prognostic signatures that will refine tumor stratification and guide therapeutic options.Experimental Design: One hundred CPTs were obtained from a multi-institutional tissue and clinical database. Copy-number (CN), DNA methylation, and gene expression signatures were assessed for 74, 36, and 40 samples, respectively. Molecular subgroups were correlated with clinical parameters and outcomes.Results: Unique molecular signatures distinguished choroid plexus carcinomas (CPC) from choroid plexus papillomas (CPP) and atypical choroid plexus papillomas (aCPP); however, no significantly distinct molecular alterations between CPPs and aCPPs were observed. Allele-specific CN analysis of CPCs revealed two novel subgroups according to DNA content: hypodiploid and hyperdiploid CPCs. Hyperdiploid CPCs exhibited recurrent acquired uniparental disomy events. Somatic mutations in TP53 were observed in 60% of CPCs. Investigating the number of mutated copies of p53 per sample revealed a high-risk group of patients with CPC carrying two copies of mutant p53, who exhibited poor 5-year event-free (EFS) and overall survival (OS) compared with patients with CPC carrying one copy of mutant p53 (OS: 14.3%, 95% confidence interval, 0.71%–46.5% vs. 66.7%, 28.2%–87.8%, respectively, P = 0.04; EFS: 0% vs. 44.4%, 13.6%–71.9%, respectively, P = 0.03). CPPs and aCPPs exhibited favorable survival.Discussion: Our data demonstrate that differences in CN, gene expression, and DNA methylation signatures distinguish CPCs from CPPs and aCPPs; however, molecular similarities among the papillomas suggest that these two histologic subgroups are indeed a single molecular entity. A greater number of copies of mutated TP53 were significantly associated to increased tumor aggressiveness and a worse survival outcome in CPCs. Collectively, these findings will facilitate stratified approaches to the clinical management of CPTs. Clin Cancer Res; 21(1); 184–92. ©2014 AACR.

Intramedullary spinal cord high-grade gliomas are rare and almost always fatal pediatric tumors. The current treatment paradigms are surgery, and radiotherapy. This is the first description of a toddler with an intramedullary cervical high-grade glioma harboring an anaplastic lymphoma kinase (ALK) fusion (KIF5B) whose treatment with the ALK inhibitor, alectinib, achieved clinical and radiological evidence of complete remission after six months of treatment. Our findings suggest that ALK inhibitors may emerge as an effective therapy in malignant spinal tumors with a dismal prognosis.

PURPOSE Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically ( P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively ( P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance ( P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

Traditional management of newly diagnosed pediatric brain tumors (PBTs) consists of cranial imaging, typically magnetic resonance imaging (MRI), and is frequently followed by tissue diagnosis, through either surgical biopsy or tumor resection. Therapy regimes are typically dependent on histological diagnosis. To date, many treatment regimens are based on molecular biology. The scope of this article is to discuss the role of diagnosis and further treatment of PBTs based solely on MRI features, in light of the latest treatment protocols. Typical MRI findings and indications for surgical biopsy of these lesions are described.

Rare Brain Tumor Registry., [Background] Embryonal tumours with multi-layered rosettes (ETMRs) are a newly recognised, rare paediatric brain tumour with alterations of the C19MC microRNA locus. Due to varied diagnostic practices and scarce clinical data, disease features and determinants of outcomes for these tumours are poorly defined. We did an integrated clinicopathological and molecular analysis of primary ETMRs to define clinical phenotypes, and to identify prognostic factors of survival and key treatment modalities for this orphan disease., [Methods] Paediatric patients with primary ETMRs and tissue available for analyses were identified from the Rare Brain Tumor Consortium global registry. The institutional histopathological diagnoses were centrally re-reviewed as per the current WHO CNS tumour guidelines, using histopathological and molecular assays. Only patients with complete clinical, treatment, and survival data on Nov 30, 2019, were included in clinicopathological analyses. Among patients who received primary multi-modal curative regimens, event-free survival and overall survival were determined using Cox proportional hazard and log-rank analyses. Univariate and multivariable Cox proportional hazard regression was used to estimate hazard ratios (HRs) with 95% CIs for clinical, molecular, or treatment-related prognostic factors., [Findings] 159 patients had a confirmed molecular diagnosis of primary ETMRs (median age at diagnosis 26 months, IQR 18–36) and were included in our clinicopathological analysis. ETMRs were predominantly non-metastatic (94 [73%] of 128 patients), arising from multiple sites; 84 (55%) of 154 were cerebral tumours and 70 (45%) of 154 arose at sites characteristic of other brain tumours. Hallmark C19MC alterations were seen in 144 (91%) of 159 patients; 15 (9%) were ETMR not otherwise specified. In patients treated with curative intent, event-free survival was 57% (95% CI 47–68) at 6 months and 31% (21–42) at 2 years; overall survival was 29% (20–38) at 2 years and 27% (18–37) at 4 years. Overall survival was associated with non-metastatic disease (HR 0·48, 95% CI 0·28–0·80; p=0·0057) and non-brainstem location (0·42 [0·22–0·81]; p=0·013) on univariate analysis, as well as with gross total resection (0·30, 0·16–0·58; p=0·0014), high-dose chemotherapy (0·35, 0·19–0·67; p=0·0020), and radiotherapy (0·21, 0·10–0·41; p, [Interpretation] Prompt molecular diagnosis and post-surgical treatment with intensive multi-modal therapy tailored to patient-specific risk features could improve ETMR survival., Canadian Institute of Health Research, Canada Research Chair Awards, Australian Lions Childhood Cancer Research Foundation, Spanish Society of Pediatrics, Consejería de Salud y Familias de la Junta de Andalucía, Miracle Marnie, Phoebe Rose Rocks, Tali's Funds, Garron Cancer Centre, Grace's Walk, Meagan's Hug, Brainchild, Nelina's Hope, and Jean Martel Foundation.

Purpose Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD. Patients and Methods In vitro MMR activity was quantified using a 3′-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus–transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome. Results All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 ± 1.56%) relative to controls (n = 6; mean, 44.00 ± 8.65%; P < .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days. Conclusion On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.

INTRODUCTION: Intramedullary spinal cord high grade gliomas are rare pediatric tumors , with a grim prognosis. Current therapeutical strategies include a surgical resection if feasible, and radiotherapy. Additional treatments with various chemotherapy agents have had a minor effect and did not change the course of the disease. New molecular targets are a source of hope. Recent molecular evidence regarding high grade infantile hemispheric gliomas describe specific tyrosine kinase receptor fusions or mutations in ALK, ROS, NTRK and MET domains which may lead to therapeutical targets. There is no data regarding these molecular changes in infantile intramedullary high grade gliomas. We present a two year old girl with a cervical high grade glioma with an ALK mutation which received targeted therapy. CASE REPORT: A two year old girl presented with progressive torticollis and hemiparesis. An intramedullary cervical tumor with ill -defined borders was diagnosed. A limited partial excision was performed and the pathological diagnosis was high grade glioma. Within weeks she developed progressive clinical and radiological deterioration. Molecular studies (Oncomine) revealed an ALK fusion (KIF5B) which was confirmed by immunohistochemistry. Treatment with ALK inhibitor alectinib at 150mg daily was initiated. Torticollis resolved within a week, and MRI after 3 months showed outstanding tumor shrinkage with a small residual mass. There were no adverse events to treatment. DISCUSSION: ALK fusion positive high grade glioma has recently been recognized in infants with hemispheric tumors, and a preliminary recent case report demonstrated excellent response to ALK inhibitors. Intramedullary spinal cord high grade gliomas are rare and harbor poor prognosis. This is the first case of ALK fusion glioma of the spine with excellent preliminary response to alectinib. The duration of treatment and long term prognosis is unknown. Molecular investigations can change the approach to pediatric rare CNS tumors.

INTRODUCTION: Current chemotherapy protocols for treatment of embryonal brain tumors in infants recommend administration of intrathecal chemotherapy either by a lumbar tap or via an Ommaya reservoir. Children with concurrent hydrocephalus and shunts may have sub-therapeutic levels of chemotherapy in the CSF due to constant CSF drainage to extra-CNS compartments. We present our experience in delivery of chemotherapy to young children via programmable valves. RESULTS: A retrospective analysis of infants with CNS malignancies and hydrocephalus treated with a shunt and a programmable valve (CERTAS™ Plus Programmable Valves - Integra Life Sciences) was conducted. Five infants 1.1-3 years of age (mean 2) were included. Pathologies included atypical teratoid rhabdoid tumor (ATRT N=2), medulloblastoma (N=2), and metastatic rhabdomyosarcoma(N=1). Intrathecal injections were conducted in an outpatient setting unless hospitalization was required for other reasons. Only one child required sedation due to noncompliance. A total of 61 chemotherapeutic administrations were performed directly through the valve while set on an extremely high opening pressure for several hours( 35 with hydrocortisone and cytarabine, 26 with topotecan). There were no infections, leaks or major complications. One child required a wound revision due to exposure of the proximal catheter related to extremely thin skin, one child developed somnolence and fever which were not related to a shunt malfunction or infection, and one child had clinical and radiological shunt over-drainage solved by increasing of valve settings. CONCLUSIONS: Programmable ventriculoperitoneal valves appear to a safe method for delivery of chemotherapy in infants with malignant CNS tumors .This technique may potentially have an added value for children with concurrent shunts, and may also obviate the need for an additional ventricular access device .

Cancers arising from germline DNA mismatch-repair or polymerase-proofreading deficiencies (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion/deletion (MS-indel) burden in humans and are lethal due to inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICI) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI in these patients. ICI treatment of 45 progressive/recurrent tumours from 38 patients revealed durable objective responses in the majority, culminating in 3-year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations/Mb) enriched for combined MMRD+PPD, while MS-indels predicted response in MMRD tumours with lower mutation burden (10-100 mutations/Mb). Further, both mechanisms were associated with increased immune infiltration even in “immunologically-cold” tumours such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and associated with immune activation in both the tumour microenvironment and systemically. Further, patients with flare continuing ICI treatment achieved durable responses. Our study demonstrates improved survival for patients with tumours not previously known to respond to ICI, including CNS and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained responses to immunotherapy.

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy., Hypermutation and microsatellite burden determine responses and long-term survival following PD-1 blockade in children and young adults with refractory cancers resulting from germline DNA replication repair deficiency.

Mucositis, a painful and debilitating condition, is a common side effect of chemotherapy. The role of tramadol in the treatment of mucositis in pediatric patients has not yet been determined. In this retrospective study, we evaluate whether tramadol as single agent achieved a reduction of pain intensity among oncologic children admitted for mucositis. In total, 34 of 54 (63%) episodes were treated with tramadol alone and achieved adequate pain relief. Tramadol's side effects were mild and manageable.

Intra-axial “pineal region” tumors include pineal, tectal, and aqueductal tumors. All three tumor subgroups cause obstruction of the aqueduct; however, they differ in radiological nuances, pathology, differential diagnosis, and treatment. The goal of this manuscript is to describe the radiological, clinical, and pathological nuances that differentiate between these subgroups. All patients with intra-axial pineal region tumors were analyzed retrospectively, including demographics, radiological characteristics, pathology, treatment, and outcome. Forty-nine patients (1–69 years of age) were included: 19 pineal, 10 tectal, 10 aqueductal, 4 periaqueductal, and 6 complex. The 3 main subgroups differed in various radiological and anatomical nuances. Age and gender did not differ between groups. Other factors that did not differ between groups included T1 and T2 signals, presence of blood products, a normally located (non-displaced) tectum, anterior tectal displacement, thalamic involvement, and presence of hydrocephalus. The pathological spectrum differed between the 3 main subgroups, as well as the surgical treatment, and outcome. Despite sharing a close anatomical location, as well as all causing obstruction of the aqueduct with secondary hydrocephalus, the differential diagnosis, diagnostic methods, and possible treatment and surgical options differ between the various subgroups. Anatomical nuances are described to better delineate the various tumor subgroups and recommend specific treatment approaches.

Introduction Very little is known about the characteristics of mesothelial tumours in the paediatric population. In adults with malignant mesothelioma, the pemetrexed-based regimen with cytoreductive surgery (CRS) is a standard of care in limited tumours, but long-term survival is uncommon. Material and methods The European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT) retrospectively reviewed children, adolescents and young adults (≤21 year) diagnosed with mesothelial tumours treated between 1987 and 2018. Results Thirty-three patients were identified, 15 male and 18 female patients. One patient's exposure to asbestos was documented. Primary tumour was mainly in the peritoneum (23 patients). Histology was multicystic mesothelioma of the peritoneum (MCM) (six patients) or malignant mesothelioma (MM) (27 patients). Among MM, the first-line treatment comprised preoperative chemotherapy (14 cases), surgery only (three cases), chemotherapy only (five cases), adjuvant chemotherapy (three cases) or palliative treatment (two cases). The response rate to cisplatin–pemetrexed was 50% (6/12 cases). CRS with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) was performed in 19 patients (upfront in three, after neoadjuvant therapy in 12, or after tumour progression in six patients, including three twice). After a median follow-up of 6.7 years (range, 0–20), five-year overall and event-free survivals were 82.3% (95% CI, confidential interval ((CI), 67.8–99.9) and 45.1% (95% CI, 28.4–71.7), respectively. All patients with MCM are alive after surgery (five patients) and CRS-HIPEC (one patient). Conclusions Paediatric mesothelioma is exceptional and seems to be different from its adult counterpart with few asbestos exposures, more peritoneal primary, and a better outcome. The cisplatin–pemetrexed regimen showed promising efficacy. Relapses could be salvaged with active therapy including CRS-HIPEC.

Immunocompromised patients exposed to varicella may experience significant morbidity and a 7% mortality rate. Management and outcome of an outbreak of varicella infection among hospitalized pediatric hemato-oncology patients using the guidelines of the American Academy of Pediatrics Committee on Infectious Diseases are presented.This retrospective study describes an outbreak of varicella infection between February 2011 and June 2011. Data were retrieved from the patients' files. Positive polymerase chain reaction results for varicella zoster virus from vesicular skin lesions were used for the diagnosis of varicella infection.Twelve pediatric hemato-oncology patients experienced 13 episodes of varicella infection, 11 underwent 1 episode each and 1 patient had 2 episodes. All exposed patients without immunity received varicella zoster immune globulins or intravenous immunoglobulin and were isolated as recommended by the guidelines. Infected patients received intravenous acyclovir. One patient with acute lymphoblastic leukemia at induction chemotherapy died. All the other patients survived.Our experience in the management of hospitalized immunocompromised patients exposed to varicella was that a positive IgG serology did not confer protection after exposure to varicella infection and thus can not serve as a marker for immunity. Unlike the isolation period sufficient for immunocompetent patients, crusted lesions can be contagious and thus require extended isolation for immunocompromised patients. Patients receiving rituximab are at greater risk of having persistent or recurrent disease. Studies with a larger sample size should be performed to better assess the management of immunocompromized patients exposed to varicella.

BACKGROUND Constitutional mismatch repair deficiency syndrome (CMMRD) is a severe cancer predisposition syndrome resulting in early onset central nervous system (CNS) and other cancers. International guidelines for surveillance exist but no study has systematically evaluated the efficacy of this protocol. METHODS We surveyed all confirmed CMMRD patients in the International Replication Repair Deficiency Consortium. A surveillance protocol consisting of frequent biochemical, endoscopic and imaging (CNS and total body MRI) studies were employed. Survival analyses and efficacy of each method were assessed. RESULTS Surveillance data were collected from 105 CMMRD individuals from 41 countries. Of the 193 malignant tumors, CNS malignancies were the most common (44%). The surveillance protocol uncovered 49 asymptomatic tumors including 16 glioblastomas and medulloblastomas. Five-year overall survival was 89% for tumors discovered by surveillance, and 61% for symptomatic tumors (p6 months as per protocol. Finally, of the low grade tumors identified asymptomatically, 5 were low grade gliomas. All of the low grade gliomas, which were not resected transformed to high grade tumors at a median of 1.6 ± 0.9 years. CONCLUSION These data support a survival benefit in CMMRD patients undergoing a surveillance protocol. Adherence to protocol and resection of lower grade lesions may improve survival for patients with CNS tumors.

Choroid plexus tumours (CPT) are relatively rare and include three pathological subtypes: papilloma (CPP) (benign); carcinoma (CPC) (malignant); atypical papilloma (ACPP) (intermediate). Most cases of CPT occur during early childhood and infancy; however, occurrence at all paediatric ages as well as adulthood has been documented. The main treatment of CPT is surgical, aiming for complete resection in all subtypes of CPT. The location and vascularity of CPT present a special surgical challenge. Surgical excision of CPP can be curative. In the malignant CPC form, adjuvant chemotherapy is indicated. The role of radiotherapy is controversial. A subset of patients with CPT harbour germline or somatic TP53 mutations characterized by greater tumour aggressiveness and decreased survival.

Pediatric brain tumors with replication repair deficiency (RRD) are hypermutant and may respond favorably to immune checkpoint inhibition (ICI). We are collecting ongoing clinical and molecular data from patients with RRD hypermutant cancers treated with ICI as a part of our consortium registry study. Companion biomarkers include tumor mutational burden (TMB), neoantigens and genetic signatures obtained from whole genome and exome sequencing. Immune inference is obtained from RNAseq. Additionally, T-cell receptor rearrangement data are collected from the tumor and blood throughout treatment. From 2015–2018, 53 patients were treated with ICI and combination therapies. Of these 39 had brain tumors, with 93% having high grade gliomas. Two-year overall survival for the entire cohort is 47+/-8%, which compares favorably with historical controls. Tumor location had major impact on outcome. Non-CNS solid tumor patients have 2-year OS of 78+/-11%, all failures occurring within the first 2 months, and sustained responses are observed for 3 years. In contrast, OS for brain tumors is 39+/-10% with late recurrences observed even after 2 years of therapy (p=0.02). Large tumor size and total tumor burden are associated with higher rates of “flare” and poor outcome throughout all cancers. While all tumors are hypermutant, TMB and predicted neoantigens do not correlate with response. However, specific signatures extracted from SNVs and indels are significantly associated with response to ICI and favorable outcome (p=0.005). Notably, RRD IDH1 mutant glioblastomas have particularly poor response to ICI. Interestingly, glioblastomas (n=8) which failed single agent ICI had favorable responses to combination immunotherapies with prolonged survival of 65%+/-8% one year after failure vs 0 for untreated patients (p=0.01). The favorable outcome and responses to ICI are encouraging. Since brain tumors respond less favorably to ICI than other solid tumors, combination therapies based on tumor and immune signatures of these cancers may be beneficial.

10011 Background: Responses to immune checkpoint inhibitors (ICI) in unselected pediatric solid tumors have been disappointing. We hypothesized that pediatric cancers with an increased tumor mutation burden (TMB) and/or replication repair deficiency (RRD) may be uniquely susceptible to ICI therapy. Methods: OZM-075 (NCT2992964) is a multicenter pilot study in patients (pts) aged 1-25 yrs with relapsed/refractory cancers (including CNS tumors). Pts were eligible only if tumor showed evidence of RRD (based on immunohistochemistry showing loss of expression of relevant RR protein) or elevated TMB > 5mut/Mb determined by gene panel DNA sequencing. Pts with measurable or evaluable disease were eligible. Enrolment began in May 2017 and was completed in Nov 2020. Pts received programmed death-1 (PD-1) inhibitor nivolumab (NIVO) at a fixed dose of 3mg/kg every 2 weeks. Primary objective was objective response rate (ORR) by iRECIST or iRANO for those with measurable disease. Tumor tissue and serial blood samples were collected for analysis of biomarkers of response and survival. Results: As of 26Jan2021, 6 male and 5 female patients aged 9-18 yrs received treatment with NIVO (5 glioblastoma (GBM), 2 anaplastic astrocytoma (AA), 2 neuroblastoma, 1 colorectal adenocarcinoma (CRC), 1 adrenocortical carcinoma). 3pts had TMB 5-10mut/Mb, 5pts had TMB > 10mut/Mb (range 14-837, median 64), 3 pts enrolled on basis of RRD. Time on treatment ranged from 0-21 months and 2 pts remain on therapy. Best OR was partial response (PR) in 2 pts (both GBM), with an additional patient with CRC achieving pathological CR. Remarkably one of the pts with PR showed early evidence of progression on imaging and elected to discontinue NIVO. Without further therapy, subsequent imaging 7 months later showed PR. Best response of stable disease was demonstrated in 5 further pts, lasting ≥5 months in 3 pts. Median overall survival (OS) not reached. Of 7 patients with relapsed GBM/AA, 5 were alive for ≥12 months following start of NIVO including 4 pts with confirmed TMB > 10mut/Mb. Conclusions: This pilot study showed evidence of impressive clinical benefit particularly for relapsed GBM/AA patients for whom median survival is typically ̃6 months (JCO 1995 13(1):112-). These data contrast previous pediatric data and suggest that in the context of RRD and hypermutation ICI therapy may provide profound long-term response and survival for these children. Analysis of other correlative biomarkers is ongoing. Clinical trial information: 2992964.

BACKGROUND Mutations in mismatch repair (MMR) and DNA-polymerase (POL) genes lead to DNA replication repair deficiency (RRD), resulting in a growing group of previously under-recognized childhood brain tumors. Medulloblastoma and embryonal tumors are rarely reported in RRD. Their biological and clinical significance is unknown. METHODS We analyzed the clinical and genomic data of embryonal tumors registered in the International RRD Consortium. RESULTS Twenty-six tumors were centrally reviewed to confirm medulloblastoma (n=18), embryonal-tumor, NOS (n=5), and three glioblastoma (excluded). Embryonal tumors were observed at a young age (median: 7-years, IQR: 5;11), and all but one exhibited clinical cues (café-au-lait macules/ family history) of germline RRD. Medulloblastomas with RRD exhibited high-risk features, including anaplastic histology (50%), and SHH-subgroup with TP53-mutation (50%). Importantly, 68% harbored POLE/POLD1 mutations, resulting in median tumor mutation burden of 164 mut/mb. POL-mutated tumors were significantly ultra-hypermutated (>100 mut/mb) than tumors with MMR-deficiency alone (p=0.015). Synchronous and metachronous tumors were observed in 40%. However 90% of the deaths were related to the diagnosis of embryonal CNS tumor. Median survival for the entire cohort was 17-months (95% CI: 10 to 23). Predicted 3-year survival was 37% for medulloblastoma, with no survivors among other embryonal tumors. CONCLUSIONS This is the largest cohort of replication repair deficient medulloblastoma reported till date. The tumors are hypermutated, harbor somatic mutations in TP53 and/or POLE/POLD1, and have very poor survival with current chemo-irradiation based approaches. These biologically unique tumors expand the spectrum of high-risk TP53-mutant SHH-medulloblastoma, and need novel strategies for treatment.

Pediatric brain tumors with replication repair deficiency (RRD) are hypermutant and may respond to immune checkpoint inhibition (ICI). We performed a consortium registry study of ICI in recurrent RRD cancers. Clinical and companion biomarkers were collected longitudinally on all patients. Biomarkers included tumor mutational burden (TMB), neoantigens and genetic signatures obtained from whole genome and exome sequencing. Immune inference was obtained by RNAseq and T cell rearrangement was collected in the tumor and in blood throughout treatment. Of the 46 tumors on the study, 32 were brain tumors with glioblastoma in 96%. Rapid, objective responses (>50%) were observed in 50% of glioblastomas. Three year overall survival for the whole cohort was 48+/-8% which compares favorably with historical controls. Brain tumors fared worse with OS of 39+/-10% and late recurrences observed even after 2 years of therapy (p=0.02). Tumor size and acute “flare” constitute poor outcome throughout all cancers. While all tumors are hypermutant, TMB and predicted neoantigens correlated with response to ICI (p=0.02). Specific signatures extracted from SNVs and total mutations predicted response to ICI and favorable outcome (p=0.005). RNA inference and TCR reveal that the FLARE phenotype is mostly acute nonspecific immune response and not true progression. Finally, glioblastomas (n=8) which failed single agent ICI had favorable responses to combinational immunotherapies with prolonged survival of 65%+/-8% at one year after failure vs 0 for other patients (p=0.01). RRD glioblastomas exhibit favorable outcome and responses to ICI. Combinational therapies based on tumor and immune signatures of these cancers are necessary.

Purpose Recurrent glioblastoma multiforme (GBM) is incurable with current therapies. Biallelic mismatch repair deficiency (bMMRD) is a highly penetrant childhood cancer syndrome often resulting in GBM characterized by a high mutational burden. Evidence suggests that high mutation and neoantigen loads are associated with response to immune checkpoint inhibition. Patients and Methods We performed exome sequencing and neoantigen prediction on 37 bMMRD cancers and compared them with childhood and adult brain neoplasms. Neoantigen prediction bMMRD GBM was compared with responsive adult cancers from multiple tissues. Two siblings with recurrent multifocal bMMRD GBM were treated with the immune checkpoint inhibitor nivolumab. Results All malignant tumors (n = 32) were hypermutant. Although bMMRD brain tumors had the highest mutational load because of secondary polymerase mutations (mean, 17,740 ± standard deviation, 7,703), all other high-grade tumors were hypermutant (mean, 1,589 ± standard deviation, 1,043), similar to other cancers that responded favorably to immune checkpoint inhibitors. bMMRD GBM had a significantly higher mutational load than sporadic pediatric and adult gliomas and all other brain tumors (P < .001). bMMRD GBM harbored mean neoantigen loads seven to 16 times higher than those in immunoresponsive melanomas, lung cancers, or microsatellite-unstable GI cancers (P < .001). On the basis of these preclinical data, we treated two bMMRD siblings with recurrent multifocal GBM with the anti–programmed death-1 inhibitor nivolumab, which resulted in clinically significant responses and a profound radiologic response. Conclusion This report of initial and durable responses of recurrent GBM to immune checkpoint inhibition may have implications for GBM in general and other hypermutant cancers arising from primary (genetic predisposition) or secondary MMRD.

PB is a source of HSC, especially for autologous HCT in solid tumors. However, there is a risk of failing to achieve the target number of SC after mobilization with growth factors alone in patients who were heavily pretreated with chemotherapy or those in need for tandem transplants. SC were harvested from seven pediatric patients with solid tumors who were in need of autologous HCT following combination GCSF and plerixafor. Six of them received plerixafor after failing to achieve enough SC with GCSF only, while the seventh patient received the combined protocol upfront. All seven patients achieved the target number of SC according to their treatment protocol. There were no adverse events. All patients underwent autologous HCT using the harvested HSC and achieved full engraftment. A protocol for harvesting autologous HCT using GCSF and plerixafor is feasible and safe in children with solid tumors who had been heavily pretreated with chemotherapy or needed tandem transplants.

Hereditary biallelic mismatch repair deficiency (BMMRD) is caused by biallelic mutations in the mismatch repair (MMR) genes and manifests features of neurofibromatosis type 1, gastrointestinal (GI) polyposis, and GI, brain, and hematological cancers. This is the first study to characterize the GI phenotype in BMMRD using both retrospective and prospective surveillance data.The International BMMRD Consortium was created to collect information on BMMRD families referred from around the world. All patients had germline biallelic MMR mutations or lack of MMR protein staining in normal and tumor tissue. GI screening data were obtained through medical records with annual updates.Thirty-five individuals from seven countries were identified with BMMRD. GI data were available on 24 of 33 individuals (73%) of screening age, totaling 53 person-years. The youngest age of colonic adenomas was 7, and small bowel adenoma was 11. Eight patients had 19 colorectal adenocarcinomas (CRC; median age 16.7 years, range 8-25), and 11 of 18 (61%) CRC were distal to the splenic flexure. Eleven patients had 15 colorectal surgeries (median 14 years, range 9-25). Four patients had five small bowel adenocarcinomas (SBC; median 18 years, range 11-33). Two CRC and two SBC were detected during surveillance within 6-11 months and 9-16 months, respectively, of last consecutive endoscopy. No patient undergoing surveillance died of a GI malignancy. Familial clustering of GI cancer was observed.The prevalence and penetrance of GI neoplasia in children with BMMRD is high, with rapid development of carcinoma. Colorectal and small bowel surveillance should commence at ages 3-5 and 8 years, respectively.

INTRODUCTION: TTFields are an established treatment for glioblastoma (GBM) in adults and have been shown to prolong OS, PFS and long-term survival with minimal side-effects. TTFields are not yet approved for children and the device (Optune®) was provided on a compassionate basis to all patients in this case series. We report our experience with TTFields at 4 major pediatric oncology centers in Israel. METHODS: Since September 2017 Optune has been offered to 7 pediatric patients of whom 5 (3 female, 2 male) gave consent immediately. These patients were aged 11.1 - 17.7 years at time of diagnosis. 4/5 had a midline diffuse glioma H3.3K27M positive and started Optune together with temozolomide following biopsy/subtotal resection and radiation. The fifth patient had a gross total resection of a right parietal GBM positive for the H3.3G34R mutation. He was treated with radiation and adjuvant temozolomide and had a multifocal right sided relapse at 20 months, and was then treated with Avastin and Optune. RESULTS: Two patients reported device-related mild itchy skin, which was easily treated topically. Four patients continued all normal activities despite carrying the device during school attendance, trips abroad and even at a waitressing job. One male refused to attend school and continues home learning. Three patients had programmable shunts, without any interference with Optune. Compliance was >90% in 3 patients, 80% in 1 individual and 60% in the relapsed patient. 2/5 patients have stopped treatment due to progression after 86 and 142 days on Optune, however all patients are still alive at the time of the report. CONCLUSION: In summary TTFields is a feasible and tolerable treatment even in children as young as 11 years. TTFields had no additional systemic side-effects and showed good acceptance rate. Further studies in pediatric patients are needed to evaluate efficacy in pediatric high-grade glioma.

BACKGROUND AND PURPOSE: Biallelic constitutional mutations in DNA mismatch repair genes cause a distinct syndrome, constitutional mismatch repair deficiency syndrome (CMMRD), characterized by cancers from multiple organs, most commonly brain tumors, during childhood. Surveillance protocols include total and brain MR imaging among other modalities to enable early detection of tumors. Brain surveillance scans revealed prominent brain developmental venous anomalies (DVAs) in some patients. DVAs are benign vascular anomalies, and their incidence in the general population is 2.6%–6.4%. Most developmental venous anomalies are asymptomatic and are found incidentally. Our purpose was to assess the prevalence of DVAs in CMMRD patients and describe their phenotype. MATERIALS AND METHODS: A retrospective descriptive analysis of brain MR imaging studies from 10 patients from 3 families with CMMRD was performed. Analysis included the number of developmental venous anomalies, location, draining vessels, and associated vascular anomalies (ie, cavernomas), with clinical correlation of symptoms and tumors. RESULTS: All 10 patients had ≥2 developmental venous anomalies, and 2 had, in addition, non-therapy-induced cavernomas. There was no clinically symptomatic intracranial bleeding from developmental venous anomalies. Six patients had malignant brain tumors. The location of brain tumors was not adjacent to the developmental venous anomalies. No new developmental venous anomalies developed during follow-up. CONCLUSIONS: The occurrence of multiple developmental venous anomalies in all our patients with CMMRD suggests that developmental venous anomalies may be a characteristic of this syndrome that has not been previously described. If confirmed, this quantifiable feature can be added to the current scoring system and could result in early implementation of genetic testing and surveillance protocols, which can be life-saving for these patients.

Numerous adults' studies demonstrated that preaphaeresis CD34+ cells significantly correlate with the number of CD34+ cells collected by the aphaeresis procedure. Equivalent studies in children are scarce. We studied retrospectively 92 aphaeresis procedures performed following chemotherapy (44) or in steady state (48) in 60 pediatric patients (40 males, 20 females), median age of 7.5 years. Aphaeresis procedures were performed using a SPECTRA Optica (TERUMOBCT) continuous flow cell separator. CD34+ cell concentrations were assessed using flow cytometry. A highly significant correlation between peripheral CD34 cell count on the day of aphaeresis and CD34 cell yield per kg (R2 = .824, P

Germline biallelic mismatch repair deficiency (bMMRD) results in a unique cancer predisposition syndrome in which the affected children are susceptible to the development of malignancies, especially brain, gastrointestinal, and lymphoid cancers. Acute myeloblastic leukemia is rarely reported in this syndrome. Here we report the decision-making challenges in a bMMRD child with acute myeloblastic leukemia. Our experience should alert physicians to include bMMRD in the differential diagnosis of a child with hyper/hypopigmented spots and leukemia. Furthermore, the presence of the above and consanguinity emphasizes the need to rule out bMMRD when an allogeneic bone marrow transplant is considered and to enable the surveillance of other family members for earlier detection of cancers in these children.

Background Optic pathway gliomas (OPG) represent 5% of pediatric brain tumors and compose a major therapeutic dilemma to the treating physicians. While chemotherapy is widely used for these tumors, our ability to predict radiological response is still lacking. In this study, we use volumetric imaging to examine in detail the long-term effect of chemotherapy on the tumor as well as its various sub-components. Procedure The tumors of 15 patients with OPG, treated with chemotherapy, were longitudinally measured using our novel, previously described volumetric method. Patients were treated with up to five lines of chemotherapy. Sufficient follow-up imaging data, and patient's numbers, allowed for analysis of two treatment lines. Volumetric measurements of the tumors were segmented into solid-non-enhancing, solid-enhancing, and cystic components. Outcome analysis was done per specific treatment line and for the overall follow-up period. Results An average reduction of 9.7% (±23%) in the gross-total-solid volume (GTSV) was noted following treatment with vincristine and carboplatin. The cystic component grew under therapy by an average of 12.6% (±39%). When measured over the course of the whole study period, the cystic component grew by an average of 35% (±100%) and the GTSV increased by 12% (±35%). Conclusion Initial treatment with vincristine and carboplatin seems to have a minimal initial effect, mostly on the solid components. The cystic component in itself seems to be unaffected by chemotherapy, and contributes to the subsequent growth of the total volume. During the overall treatment period, both solid and cystic components grew regardless of combined treatment methods. Pediatr Blood Cancer 2015;62:1353–1359. © 2015 Wiley Periodicals, Inc.

DNA replication-associated mutations are repaired by two components: polymerase proofreading and mismatch repair. The mutation consequences of disruption to both repair components in humans are not well studied. We sequenced cancer genomes from children with inherited biallelic mismatch repair deficiency (bMMRD). High-grade bMMRD brain tumors exhibited massive numbers of substitution mutations (>250/Mb), which was greater than all childhood and most cancers (>7,000 analyzed). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerase ɛ or δ. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germ-line bMMRD (P < 10(-13)). Sequential tumor biopsy analysis revealed that bMMRD/polymerase-mutant cancers rapidly amass an excess of simultaneous mutations (∼600 mutations/cell division), reaching but not exceeding ∼20,000 exonic mutations in

Purpose: To investigate molecular alterations in choroid plexus tumors (CPT) using a genome-wide high-throughput approach to identify diagnostic and prognostic signatures that will refine tumor stratification and guide therapeutic options. Experimental Design: One hundred CPTs were obtained from a multi-institutional tissue and clinical database. Copy-number (CN), DNA methylation, and gene expression signatures were assessed for 74, 36, and 40 samples, respectively. Molecular subgroups were correlated with clinical parameters and outcomes. Results: Unique molecular signatures distinguished choroid plexus carcinomas (CPC) from choroid plexus papillomas (CPP) and atypical choroid plexus papillomas (aCPP); however, no significantly distinct molecular alterations between CPPs and aCPPs were observed. Allele-specific CN analysis of CPCs revealed two novel subgroups according to DNA content: hypodiploid and hyperdiploid CPCs. Hyperdiploid CPCs exhibited recurrent acquired uniparental disomy events. Somatic mutations in TP53 were observed in 60% of CPCs. Investigating the number of mutated copies of p53 per sample revealed a high-risk group of patients with CPC carrying two copies of mutant p53, who exhibited poor 5-year event-free (EFS) and overall survival (OS) compared with patients with CPC carrying one copy of mutant p53 (OS: 14.3%, 95% confidence interval, 0.71%–46.5% vs. 66.7%, 28.2%–87.8%, respectively, P = 0.04; EFS: 0% vs. 44.4%, 13.6%–71.9%, respectively, P = 0.03). CPPs and aCPPs exhibited favorable survival. Discussion: Our data demonstrate that differences in CN, gene expression, and DNA methylation signatures distinguish CPCs from CPPs and aCPPs; however, molecular similarities among the papillomas suggest that these two histologic subgroups are indeed a single molecular entity. A greater number of copies of mutated TP53 were significantly associated to increased tumor aggressiveness and a worse survival outcome in CPCs. Collectively, these findings will facilitate stratified approaches to the clinical management of CPTs. Clin Cancer Res; 21(1); 184–92. ©2014 AACR.

Diffuse intrinsic pontine glioma (DIPG) is an incurable disease with a median overall survival of 10 months. Immune modulating antibodies have recently emerged as a highly promising treatment modality in multiple cancer types. We present results from the first study to evaluate the immune modulating antibody MDV9300 (pidilizumab) in pediatric patients with DIPG. All patients aged 3 years and older, diagnosed with DIPG between February 2014 and June 2015 in Israel, were offered to participate in the study. Enrolled patients were started on biweekly 6 mg/kg MDV9300 after radiation completion. Treatment was continued until disease progression on imaging. Patients were followed biweekly for the occurrence of neurological deficit toxicities and side effects. Secondary endpoints were event free survival and overall survival. Of 13 children diagnosed with DIPG during the study period, nine were enrolled in the study. The patients underwent radiotherapy and none had chemotherapy. A total of 83 cycles of MDV9300 (range 2–16) were applied. The main side effects were neutropenia (CTCAE grade 1–3), mild to moderate fatigue, and acute elevation of blood pressure. Four patients died within 1 year of the diagnosis, another three died within 2 years and two children are still alive nearly 30 months from diagnosis, with stable disease. The median event free survival is 9.3 months (range 6.8–24) and the median overall survival is 15.6 months (range 6.9–28). Preliminary results demonstrate that MDV9300 treatment is safe and may be effective in the treatment of children with DIPG.

Background: Craniopharyngiomas are frequent hypothalamo-pituitary tumors in children, presenting predominantly as cystic lesions. Morbidity from conventional treatment has focused attention on intracystic drug delivery, hypothesized to cause fewer clinical consequences. However, the efficacy of intracystic therapy remains unclear. We report the retrospective experiences of several global centers using intracystic interferon-alpha.Methods: European Societe Internationale d'Oncologie Pediatrique and International Society for Pediatric Neurosurgery centers were contacted to submit a datasheet capturing pediatric patients with cystic craniopharyngiomas who had received intracystic interferon-alpha. Patient demographics, administration schedules, adverse events, and outcomes were obtained. Progression was clinical or radiological (cyst reaccumulation, novel cysts, or solid growth).Results: Fifty-six children (median age, 6.3 y) from 21 international centers were identified. Median follow-up from diagnosis was 5.1 years (0.3-17.7 y). Lesions were cystic (n = 22; 39%) or cystic/solid (n = 34; 61%). Previous progression was treated in 43 (77%) patients before interferon use. In such cases, further progression was delayed by intracystic interferon compared with the preceding therapy for cystic lesions (P = 0.0005). Few significant attributable side effects were reported. Progression post interferon occurred in 42 patients (median 14 mo; 0-8 y), while the estimated median time to definitive therapy post interferon was 5.8 (1.8-9.7) years.Conclusions: Intracystic interferon-alpha can delay disease progression and potentially offer a protracted time to definitive surgery or radiotherapy in pediatric cystic craniopharyngioma, yet demonstrates a favorable toxicity profile compared with other therapeutic modalities-important factors for this developing age group. A prospective, randomized international clinical trial assessment is warranted.

Data on the clinical presentation of constitutional mismatch repair deficiency syndrome (CMMRD) is accumulating. However, as the extraintestinal manifestations are often fatal and occur at early age, data on the systematic evaluation of the gastrointestinal tract is scarce. Here we describe 11 subjects with verified biallelic carriage and who underwent colonoscopy, upper endoscopy and small bowel evaluation. Five subjects were symptomatic and in six subjects the findings were screen detected. Two subjects had colorectal cancer and few adenomatous polyps (19, 20 years), three subjects had polyposis-like phenotype (13, 14, 16 years), four subjects had few adenomatous polyps (8, 12-14 years) and two subjects had no polyps (both at age 6). Of the three subjects in the polyposis-like group, two subjects had already developed high-grade dysplasia or cancer and one subject had atypical juvenile polyps suggesting juvenile polyposis. Three out of the five subjects that underwent repeated exams had significant findings during short interval. The gastrointestinal manifestations of CMMRD are highly dependent upon age of examination and highly variable. The polyps may also resemble juvenile polyposis. Intensive surveillance according to current guidelines is mandatory.

Constitutional mismatch repair deficiency (CMMRD) is a devastating cancer predisposition syndrome for which data regarding clinical manifestations, molecular screening tools and management are limited.We established an international CMMRD consortium and collected comprehensive clinical and genetic data. Molecular diagnosis of tumour and germline biospecimens was performed. A surveillance protocol was developed and implemented.Overall, 22/23 (96%) of children with CMMRD developed 40 different tumours. While childhood CMMRD related tumours were observed in all families, Lynch related tumours in adults were observed in only 2/14 families (p=0.0007). All children with CMMRD had café-au-lait spots and 11/14 came from consanguineous families. Brain tumours were the most common cancers reported (48%) followed by gastrointestinal (32%) and haematological malignancies (15%). Importantly, 12 (30%) of these were low grade and resectable cancers. Tumour immunohistochemistry was 100% sensitive and specific in diagnosing mismatch repair (MMR) deficiency of the corresponding gene while microsatellite instability was neither sensitive nor specific as a diagnostic tool (p0.0001). Furthermore, screening of normal tissue by immunohistochemistry correlated with genetic confirmation of CMMRD. The surveillance protocol detected 39 lesions which included asymptomatic malignant gliomas and gastrointestinal carcinomas. All tumours were amenable to complete resection and all patients undergoing surveillance are alive.CMMRD is a highly penetrant syndrome where family history of cancer may not be contributory. Screening tumours and normal tissues using immunohistochemistry for abnormal expression of MMR gene products may help in diagnosis and early implementation of surveillance for these children.

BACKGROUND: TTFields are an established treatment for newly diagnosed or recurrent GBM in adults. TTFields have been shown to prolong OS, PFS and long term survival with minimal side effects in GBM. This treatment is not yet approved for children under 18 years and the device (Optune®, Manufacturer Novocure™) was provided on a compassionate basis to all patients in this case series. We report our experience with TTFields at 4 major pediatric oncology centers in Israel. MATERIAL AND METHODS: Since September 2017 the device has been offered to 7 pediatric patients of whom 5 (3 female, 2 male) gave consent immediately. These 5 patients were aged 11.1 - 17.7 years at the time of diagnosis. 4/5 had a midline diffuse glioma H3.3K27M positive and started Optune® together with temozolomide following biopsy/subtotal resection and radiation. The fifth patient had a gross total resection of a right parietal GBM positive for the H3.3G34R mutation. He was treated with radiation and adjuvant temozolomide and had a multifocal right sided relapse at 20 months, and was then treated with avastin and Optune®. RESULTS: Two of the five patients reported device-related mild itchy skin, which was easily treated topically. Four of the five patients continued all normal activities despite carrying the device during school attendance, trips abroad and even at a waitressing job. One male refused to attend school and continues home learning. Three of the 5 patients had programmable shunts and the Optune® device did not interfere with the settings in any of them. Compliance was >90% in 3 patients (77–150 days follow up), 80% in 1 individual (86 days) and 60% in the relapsed patient (39 days). Two of the 5 patients have stopped treatment due to progression after 86 and 142 days on Optune®, however all patients are still alive at the time of the report. CONCLUSION: In summary TTFields is a feasible and tolerable treatment even in children as young as 11 years. TTFields had no additional systemic side effects and showed good acceptance rate within this population. Further studies in pediatric patients are needed to evaluate efficacy in pediatric high-grade glioma patients.

Background Many survivors of pediatric brain tumors (SPBTs) suffer from long-term late effects (LEs). Our aim was to create a practical screening tool for detecting LEs in this population. Such a screening tool will improve our ability to identify those patients who may benefit from treatment in LE clinics while focusing on individual relevant issues. Procedure We developed the Treatment-Oriented Screening Questionnaire (TOSQ); a self-reported, risk-based questionnaire that addresses all LEs SPBTs can potentially suffer. As a basis for the TOSQ design we used the Long-Term Follow-Up Guidelines published by the Children's Oncology Group. Output includes individual recommendations for further treatment. We prospectively assessed whether the TOSQ can accurately detect treatment targets in SPBTs by comparing patient and caregiver questionnaire scores with physician evaluations. Data are presented from 41 SPBTs. Results The TOSQ is a precise screening tool for identifying LEs in SPBTs based on the significant correlation (P

Optic pathway gliomas (OPGs) are diagnosed based on typical MR features and require careful monitoring with serial MRI. Reliable, serial radiological comparison of OPGs is a difficult task, where accuracy becomes very important for clinical decisions on treatment initiation and results. Current radiological methodology usually includes linear measurements that are limited in terms of precision and reproducibility.We present a method that enables semiautomated segmentation and internal classification of OPGs using a novel algorithm. Our method begins with co-registration of the different sequences of an MR study so that T1 and T2 slices are realigned. The follow-up studies are then re-sliced according to the baseline study. The baseline tumor is segmented, with internal components classified into solid non-enhancing, solid-enhancing, and cystic components, and the volume is calculated. Tumor demarcation is then transferred onto the next study and the process repeated. Numerical values are correlated with clinical data such as treatment and visual ability.We have retrospectively implemented our method on 24 MR studies of three OPG patients. Clinical case reviews are presented here. The volumetric results have been correlated with clinical data and their implications are also discussed.The heterogeneity of OPGs, the long course, and the young age of the patients are all driving the demand for more efficient and accurate means of tumor follow-up. This method may allow better understanding of the natural history of the tumor and provide a more advanced means of treatment evaluation.

Background Optic pathway gliomas (OPG) are relatively indolent tumors that may occur sporadically or in association with neurofibromatosis 1. Treatment is initiated only when a clear clinical or radiological deterioration is documented. Chemotherapy is the standard first line of treatment. Due to the indolent nature of this tumor, the most important challenge in OPG treatment is vision preservation. Methods In this study we determined the visual outcome of 19 patients with progressive OPGs who received chemotherapy and correlated it with imaging. Results Mean neuro-ophthalmological follow-up is 4 years and 3 months. Indications for treatment were radiological tumor progression (6 patients), visual decline (6 patients), or both (7 patients). Fifteen patients (78%) had to change to 2nd line chemotherapy (7 due to allergies and 8 due to treatment failure). During the course of chemotherapy, 11 patients (57.8%) displayed radiological tumor progression, 4 (21.5%) demonstrated stable tumor, and 4 (21.5%) displayed tumor regression. During the follow-up period, 14 (73.6%) had an overall visual deterioration, 4 (21%) had stable vision, and 1 patient (5.2%) improved. Visual acuity was examined in 38 eyes. Seventeen eyes (47.2%) deteriorated, fourteen (38.8%) were stable, and five (13.8%) improved. Ten eyes (27.7%) deteriorated to legal blindness. There was no correlation between radiological tumor growth and visual deterioration. Conclusions The majority of our patients, who received chemotherapy for progressive OPG, experienced a decline in their visual function. New, more effective treatments are needed in order to preserve vision in this group. Pediatr Blood Cancer 2011; 57: 481–485. © 2011 Wiley-Liss, Inc.

Heparanase is an endo-beta D-glucuronidase capable of cleaving heparan sulfate side chains, yielding heparan sulfate fragments. Heparanase activity has been correlated with the metastatic potential of tumor-derived cells, angiogenesis, autoimmunity and inflammation. We performed a study of heparanase expression in specimens obtained from patients with Langerhans cell histiocytosis (LCH). Paraffin embedded slides from 25 patients were studied by immunohistochemistry for heparanase. Most patients had positive staining for heparanase (21/25). There was no positive association with severity of disease and other clinical characteristics. Further studies are required to clarify the role of heparanase in the pathogenesis of LCH. Pediatr Blood Cancer 2014; 61:1883–1885. © 2014 Wiley Periodicals, Inc.

INTRODUCTION: Premature ovarian dysfunction is increasingly documented in survivors of brain tumors particularly in girls who received high doses of radiotherapy and alkylating agents. Fertility preservation in girls is an important procedure which should be offered to patients with increased risk of gonadal failure. Risk groups for ovarian dysfunction have been previously documented (i.e. Edinburgh criteria). Our center provides a fertility counsel for all girls with pediatric cancer, and patients at increased risk are offered ovarian cryopreservation. PATIENTS AND METHODS: A retrospective analysis of girls treated with brain tumors between 2010-2016 was performed. We documented age, disease type, treatment protocols, preservation treatment details, treatment delay and complications. RESULTS: 41 girls with brain tumors were assessed. Eight underwent laparoscopic ovarian cryopreservation (6 medulloblastoma, 2 pineal tumors, age range 8-18 years, median 10.4 years). Five had insertion of portacath in the same operative session. Two girls had a prior V-P shunt. Fertility preservation was not performed in: 11 girls with high grade glioma, 4 metastatic tumors, 7 low grade glioma, 4 craniopharyngioma, 3 younger than 3 years and parental refusal in 4. Cryopreservation caused no complications or delays in treatment. CONCLUSIONS: Ovarian cryopreservation is recommended when there is a high risk of gonadal failure from oncologic treatment. Fertility counseling by a specialized clinic provides individualized recommendations. Ovarian cryopreservation can be safely performed in selected cases without complications even concurrently with central line insertion, or after V-P shunting. Current knowledge regarding future uses of cryopreserved tissue shall be discussed.

We analyzed the results of the French-American-British-LMB 96 protocol performed in 9 centers in Israel on 88 patients with B-cell non-Hodgkin lymphoma treated from 2000 to 2005.The majority of the patients was male (63/88, 72%), with a median age of 8.9 years (range, 2.5 to 20 y). Ethnic origin was Jewish in 73% (64/88), and Arabic in 27%. Fifty (57%) patients were classified as Burkitt lymphoma, 5 (5.7%) as Burkitt-like lymphoma, 22 (25%) as diffuse large B cell (DLBC), and 9 (10.2%) as Burkitt leukemia with over 25% of their bone marrow (BM) involved. Initial disease sites included the abdomen in 43%, head and neck in 45%, and mediastinum in 7%. Stage I: 9.1%; stage II: 28.4%; stage III: 45.5%, stage IV: 17%. Two patients had BM involvement alone, 5 patients had central nervous system (CNS) involvement alone, and 4 had both CNS and BM. The children were divided into 3 groups according to risk factors, with 5 in group A, 69 in group B, and 14 in group C.With a median follow-up of 3 years (12 mo to 7.6 y), the Kaplan-Meier for event-free survival (EFS) and overall survival (OS) according to whole group treatment was 88.6% and 90.9%, group A was 100% and 100%; group B was 89.9% and 92.8%; and group C was 78.6% and 78.6%. There were no untoward events or deaths in group A, whereas 6 patients relapsed in group B, 4 of whom died (all relapsed during the first year), with tumor lysis syndrome in 3 patients and death of toxicity in 1 patient who had multiorgan failure 2 days after initiation of COP. Three patients in group C relapsed and died (all patients relapsed during the first 6 months), with tumor lysis syndrome in 4 patients but no deaths from toxicity. EFS for LDH less than twice was 96.4%, EFS for LDH more than twice was 73.3% (P=0.002). OS according to primary site: bone and ovary: 100%; head and neck: 95%; abdomen: 92%; mediastinum: 50%. The difference between the mediastinal primary site to all other primary sites was statistically significant with P=0.003. All the mediastinal tumors were of DLBC origin but no significant differences in outcome were found when DLBC was compared with other histologies (DLBC: 81.8%, other B line: 90.9%). OS for patients of Arabic ethnic origin was 79.2%, for Jewish patients was 95.3%, P=0.02. We could not determine any prognostic factors that were different between the groups, which raises the question of a genetic influence.In nonresected mature B-cell lymphoma of childhood and adolescence with no BM or CNS involvement, a 93% cure rate can be achieved, similar to the French-American-British/LMB 96 trial. Patients with primary DLBC mediastinal mass had a significantly reduced OS, indicating the need for a different therapeutic approach.

Optic pathway gliomas (OPG) represent 5% of pediatric brain tumors and compose a major therapeutic dilemma to the treating physicians. While chemotherapy is widely used for these tumors, our ability to predict radiological response is still lacking. In this study, we use volumetric imaging to examine in detail the long-term effect of chemotherapy on the tumor as well as its various sub-components.The tumors of 15 patients with OPG, treated with chemotherapy, were longitudinally measured using our novel, previously described volumetric method. Patients were treated with up to five lines of chemotherapy. Sufficient follow-up imaging data, and patient's numbers, allowed for analysis of two treatment lines. Volumetric measurements of the tumors were segmented into solid-non-enhancing, solid-enhancing, and cystic components. Outcome analysis was done per specific treatment line and for the overall follow-up period.An average reduction of 9.7% (±23%) in the gross-total-solid volume (GTSV) was noted following treatment with vincristine and carboplatin. The cystic component grew under therapy by an average of 12.6% (±39%). When measured over the course of the whole study period, the cystic component grew by an average of 35% (±100%) and the GTSV increased by 12% (±35%).Initial treatment with vincristine and carboplatin seems to have a minimal initial effect, mostly on the solid components. The cystic component in itself seems to be unaffected by chemotherapy, and contributes to the subsequent growth of the total volume. During the overall treatment period, both solid and cystic components grew regardless of combined treatment methods.

Pediatric low-grade gliomas (LGGs) are the largest group of central nervous system neoplasms in children. Although these tumors are generally benign, 5 to 10% of patients with pediatric LGGs present with leptomeningeal dissemination. The genetic and biological nature of these tumors is poorly understood. The authors looked for certain molecular abnormalities that may differentiate disseminated gliomas from the other pediatric LGGs.Comparative genomic hybridization (CGH) was applied to 18 pediatric LGGs. Six cases featuring disseminated pediatric LGGs were compared with 12 control cases involving nondisseminated pediatric LGGs. Fluorescence in situ hybridization (FISH) analysis and immunohistochemical analysis were used to highlight further specific genetic targets. The CGH revealed multiple chromosomal abnormalities in five of six cases with disseminated gliomas and in six of 12 control cases. No correlation was found between the number of chromosomal abnormalities and dissemination status. Amplification of chromosome 7 was noted in four of six cases with disseminated gliomas as opposed to one of 12 control cases (p = 0.02). The FISH analysis revealed epidermal growth factor receptor (EGFR) amplification in one case negative to chromosome 7 amplification by CGH, raising the amplification cases to five of six (p = 0.0038). Immunohistochemical analysis for EGFR was positive in six of six cases and in two of 12 control cases (p = 0.0015). At the end of a mean follow-up period of 7.2 years, all patients with disseminated gliomas are alive with variable but slow disease progression.The high rate of EGFR gene amplification and protein expression in disseminated pediatric LGGs is intriguing and may have implications for our understanding of the role of EGFR in glioma genesis. Targeted therapies may be available for these children. Larger-scale studies are needed to establish further these findings.