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Exposure to cranial radiotherapy is associated with an increased risk of subsequent CNS neoplasms among childhood, adolescent, and young adult (CAYA) cancer survivors. Surveillance for subsequent neoplasms can translate into early diagnoses and interventions that could improve cancer survivors' health and quality of life. The practice guideline presented here by the International Late Effects of Childhood Cancer Guideline Harmonization Group was developed with an evidence-based method that entailed the gathering and appraisal of published evidence associated with subsequent CNS neoplasms among CAYA cancer survivors. The preparation of these guidelines showed a paucity of high-quality evidence and highlighted the need for additional research to inform survivorship care. The recommendations are based on careful consideration of the evidence supporting the benefits, risks, and harms of the surveillance interventions, clinical judgment regarding individual patient circumstances, and the need to maintain flexibility of application across different health-care systems. Currently, there is insufficient evidence to establish whether early detection of subsequent CNS neoplasms reduces morbidity and mortality, and therefore no recommendation can be formulated for or against routine MRI surveillance. The decision to start surveillance should be made by the CAYA cancer survivor and health-care provider after careful consideration of the potential harms and benefits of surveillance for CNS neoplasms, including meningioma.

Since the original description of pathogenic germline DICER1 variation underlying pleuropulmonary blastoma (PPB), the spectrum of extrapulmonary neoplasms known to be associated with DICER1 has continued to expand and now includes tumors of the ovary, thyroid, kidney, eye, and brain among other sites. This report documents our experience with another manifestation: a primitive sarcoma that resembles PPB and DICER1-associated sarcoma of the kidney. These tumors are distinguished by their unusual location in the peritoneal cavity, associated with visceral and/or parietal mesothelium. A total of seven cases were identified through pathology review in children presenting at a median age of 13 years (range 3-14 years). Primary sites of origin included the fallopian tube (four cases), serosal surface of the colon (one case), and pelvic sidewall (two cases). One case had pathologic features of type I PPB, another type Ir (regressed) PPB, and the remaining five had features of type II or III PPB with a mixed primitive sarcomatous pattern with or without cystic elements. All had a pathogenic DICER1 variation identified in germline and/or tumor DNA. PPB-like peritoneal tumors represent a newly described manifestation of DICER1 pathogenic variation whose pathologic features are also recapitulated in DICER1-related renal sarcoma, cervical embryonal rhabdomyosarcoma, and some Sertoli-Leydig cell tumors with heterologous elements. Tumors arising from the fallopian tube or elsewhere in the abdomen/pelvis, especially those with heterogeneous rhabdomyosarcomatous and/or cartilaginous differentiation, should prompt consideration of germline and tumor DICER1 testing.

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.

© 2021 by American Society of Clinical Oncology. Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/, Purpose: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. Methods: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. Results: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. Conclusion: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.

BackgroundETMRs are a newly recognized rare paediatric brain tumor with alterations of the C19MC microRNA locus. Due to varied diagnostic practices and limited clinical data, disease features and determinants of outcome are poorly defined. We performed an integrated clinico-pathologic and molecular analyses of 159 primary ETMRs to define clinical phenotypes, identify predictors of survival and critical treatment modalities for this orphan disease.MethodsPrimary ETMR patients were identified from the Rare Brain Tumor Consortium (rarebraintumorconsortium.ca) global registry using histopathologic and molecular assays. Event-Free (EFS) and Overall Survival (OS) for 108 patients treated with curative multi-modal regimens were determined using Cox proportional hazard and log rank analyses.FindingsETMRs were predominantly non-metastatic (73%) tumors arising from multiple sites; 55% were cerebral tumors, 45% arose at sites characteristic of other brain tumors. Hallmark C19MC alterations were seen in 91%; 9% were ETMR-NOS. Survival and hazard analyses showed a 6 month median EFS and 2-4yr OS of 27-29% with metastatic disease (HR=0.44, 95% CI 0.26-0.74; p=0.002) and brainstem location (HR=0.40, 95% CI 0.021-0.75; p=0.005) correlating with adverse OS. Gross total resection (GTR: HR=0.38, 95% CI 0.21-0.68; p=0.001), high dose chemotherapy (HDC: HR=0.55, 95% CI 0.31-0.97; p=0.04) and radiation (RT: HR=0.32, 95% CI 0.16-0.60; p=InterpretationPrompt molecular diagnosis and post-surgical treatment with multi-modal therapy tailored to patient-specific risk features improves ETMR survival.FundingThis work was supported by the Canadian Institute of Health Research Grant No. 137011, Canada Research Chair Awards to AH. Funds from Miracle Marnie, Phoebe Rose Rocks, Tali’s Funds, Garron Cancer Centre, Grace’s Walk, Meagan’s Walk, Nelina’s Hope and Jean Martel Foundation are gratefully acknowledged. SK and PS were respectively supported by the Australian Lions Children’s Cancer Foundation and the Spanish Society of Pediatrics, Consejería de Salud y Familias de la Junta de Andalucía Project EF-0451-2017.

Context Pituitary blastoma is a rare, dysontogenetic hypophyseal tumor of infancy first described in 2008, strongly suggestive of DICER1 syndrome. Objective This work aims to describe genetic alterations, clinical courses, outcomes, and complications in all known pituitary blastoma cases. Design and Setting A multi-institutional case series is presented from tertiary pediatric oncology centers. Patients Patients included children with pituitary blastoma. Interventions Genetic testing, surgery, oncologic therapy, endocrine support are reported. Outcome Measures Outcome measures included survival, long-term morbidities, and germline and tumor DICER1 genotypes. Results Seventeen pituitary blastoma cases were studied (10 girls and 7 boys); median age at diagnosis was 11 months (range, 2-24 months). Cushing syndrome was the most frequent presentation (n = 10). Cushingoid stigmata were absent in 7 children (2 with increased adrenocorticotropin [ACTH]; 5 with normal/unmeasured ACTH). Ophthalmoplegia and increased intracranial pressure were also observed. Surgical procedures included gross/near-total resection (n = 7), subtotal resection (n = 9), and biopsy (n = 1). Six children received adjuvant therapy. At a median follow-up of 6.7 years, 9 patients were alive; 8 patients died of the following causes: early medical/surgical complications (n = 3), sepsis (n = 1), catheter-related complication (n = 1), aneurysmal bleeding (n = 1), second brain tumor (n = 1), and progression (n = 1). Surgery was the only intervention for 5 of 9 survivors. Extent of resection, but neither Ki67 labeling index nor adjuvant therapy, was significantly associated with survival. Chronic complications included neuroendocrine (n = 8), visual (n = 4), and neurodevelopmental (n = 3) deficits. Sixteen pituitary blastomas were attributed to DICER1 abnormalities. Conclusions Pituitary blastoma is a locally destructive tumor associated with high mortality. Surgical resection alone provides long-term disease control for some patients. Quality survival is possible with long-term neuroendocrine management.

Background “Head Start” III, was a prospective clinical trial using intensive induction followed by myeloablative chemotherapy and autologous hematopoietic cell rescue (AuHCR) to either avoid or reduce the dose/volume of irradiation in young children with medulloblastoma. Methods Following surgery, patients received 5 cycles of induction followed by myeloablative chemotherapy using carboplatin, thiotepa, and etoposide with AuHCR. Irradiation was reserved for children >6 years old at diagnosis or with residual tumor post-induction. Results Between 2003 and 2009, 92 children Conclusion We report excellent survival and preservation of mean IQ and memory for young children with ND medulloblastoma using high-dose chemotherapy, with most patients surviving without irradiation.

ETMR, an aggressive disease characterised by C19MC alterations, were previously categorised as various histologic diagnoses. The clinical spectrum and impact of conventional multi-modal therapy on this new WHO diagnostic category remains poorly understood as a majority of ~200 cases reported to date lack molecular confirmation. We undertook comprehensive clinico-pathologic studies of a large molecularly confirmed cohort to improve disease recognition and treatment approaches. Amongst 623 CNS-PNETs patients enrolled in the RBTC registry, 159 primary ETMRs were confirmed based on a combination of FISH (125), methylation analysis (88), SNP and RNAseq (32) analyses; 91% had C19MC amplification/gains/fusions, 9% lacked C19MC alterations but had global methylation features of ETMR NOS. ETMRs arose in young patients (median age 26 months) predominantly as localized disease (M0-72%, M2-3 -18%) at multiple locations including cerebrum (60%) cerebellum (18%), midline structures (6%); notably 10% were brainstem primaries mimicking DIPG. Uni-and multivariate analyses of clinical and treatment details of curative regimens available for 110 patients identified metastatic disease (p=0.002), brainstem locations(p=0.005), extent of surgery, receipt of multi-modal therapy including high dose chemotherapy and radiation (P

Objective To describe safety and efficacy of dual targeted therapy with dabrafenib (BRAFi) and trametinib (MEKi) in an infant with inoperable low grade glioma with BRAF V600E mutation. Introduction Safety and efficacy of dual targeted therapy with BRAFi and MEKi for pediatric low grade glioma (pLGG) is currently being evaluated, however, infants are usually not included in these clinical trials. Case We report a case of a 2-month-old male infant who presented with involuntary movements and gaze deviation concerning for seizures. MRI brain revealed a tumor involving the medulla, T2/FLAIR dimensions: 2.5 x 2.2 x 2.7 cm and drop metastases to the cauda equina. An EEG ruled out seizure activity. Tumor biopsy was performed revealing Ganglioglioma, WHO grade I. IHC and somatic next generation sequencing revealed BRAF V600E point mutation. Germline testing was negative. Due to tumor progression on traditional chemotherapy, compassionate use of dual targeted therapy with dabrafenib (5.25mg/kg/day divided twice daily) and trametinib (0.032mg/kg daily) was initiated at 4.5 months of age. The patient has tolerated dual therapy for nearly 1 year without significant toxicity with exception of grade I skin rash. In terms of functional outcomes, previously noticed vocal cord paresis has resolved and our patient with global developmental delay continues to make developmental gains, albeit slowly. On recent neuroimaging, pLGG has continued to grow T2/FLAIR dimensions: 3.5 x 3.5 x 3.7 cm, however, combination therapy has halted the rate of growth of this tumor. Conclusion To our knowledge, our patient is the youngest to receive combination of BRAFi and MEKi. Tumor targeted therapy could be an important treatment option for infants with inoperable pLGG where aggressive surgery and radiation therapy are associated with significant morbidity. Multi-institutional clinical trials that include infants are needed to further comment on safety and efficacy of these agents.

Introduction The oncogenic drivers of pediatric CNS tumors are rapidly being identified with the implementation of high throughput genetic screening. Precision medicine approaches to treatment have shown promising results, but data remains limited in the community oncology setting. We aim to describe our institutional experience using targeted therapies for plexiform neurofibroma and recurrent/progressive pediatric low-grade glioma (pLGG). Methods We performed a retrospective chart review of all patients treated with tumor targeted therapies for recurrent/progressive pLGG and plexiform neurofibroma over the past 5 years. Results Ten patients treated with tumor targeted therapies were identified. Regimens included combination Dabrafenib and Trametinib (n=3), Trametinib monotherapy (n=2), Selumetinib (n=3), Vemurafenib (n=1), and Larotrectinib (n=1). Median age at therapy initiation was 11.5 years (range 1.1 - 18 years). Tumor molecular status included BRAFV600E mutation (n=4), NF1 mutation (n=2), KIAA1549-BRAF fusion (n=1), NACC-NTRK fusion (n=1), and FGFR1 mutation (n=1). Patients trialed an average of 2 treatment regimens prior to targeted therapy initiation (range 0–5). Mean duration of therapy was 14.5 months (range .5–33 months) with 8 patients remaining on treatment. Based on modified RANO criteria, responses included partial (n=1), stable disease (n=8), and progressive disease (n=1). Progressive disease was noted after 4 months of treatment with Dabrafenib and Trametinib combination therapy, but rate of tumor growth was decreased. Subjective functional improvement was seen in 50% of patients. The most common toxicities included rash (n=5) and pyrexia (n=2). Trametinib was discontinued in one patient due to intra-tumoral hemorrhage of unclear etiology. Conclusion Treatment of pediatric CNS tumors with targeted agents appears to be feasible and efficacious in the community oncology setting. Multi-institutional clinical trials are currently ongoing for each of these therapies. There remains a need for community oncology institutional data regarding their use.

Introduction Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare diagnosis first incorporated into the WHO Classification of Tumors of the Central Nervous System in 2016. Though historically considered indolent, emerging evidence suggests that the biological behavior of these tumors may be further classified by molecular features of prognostic significance. Methods A retrospective review was conducted in accordance with IRB approval of patients with the histologic diagnosis of DLGNT. Demographic, clinical, and molecular data where abstracted from the medical record when available. Results 10 patients were identified (M = 8, F = 2). Median age at diagnosis was 6 years (range 0.3–21 years), and the most common symptoms at diagnosis were related to obstructive hydrocephalus, for which 3 patients required CSF diversion. MRI findings included diffuse leptomeningeal thickening, nodularity, or coating of the subarachnoid or ependymal surfaces. Histologically, these tumors expressed variable features of neuronal and/or glial differentiation. Four patients (40%) were treated with radiation therapy (all craniospinal), which was upfront for 2 patients. Chemotherapy regimens used included temozolomide, carboplatin and vincristine and vinblastine. NTRK or BRAF-targeted therapy were used upon progression. At follow-up, 6/10 had stable disease (4/6 of whom were on second line therapy), 1 had partial response, 1 passed away from sepsis and 2 were lost to follow-up. The median progression-free survival for the four patients who developed disease progression was 26 months (range 12–34 months). Next generation sequencing of the tumor tissue performed using a high-multiplex PCR-based NGS panel detected BRAF-KIAA1549 (4 patients) and NTRK (1 patient) fusions. Conclusions DLGNT are rare tumors with scarce data about imaging characteristic and standard of care treatment. Our case series reinforces current literature that although these tumors appear low-grade, they can be clinically aggressive. Further study is needed regarding molecular diagnosis and profiling treatment strategies.

Childhood cancer remains the leading cause of non-accidental death in children, with brain and central nervous system malignancies comprising about 18% of new diagnoses each year. Combination therapy, including surgery, chemotherapy and radiation therapy in standard-risk medulloblastoma has led to cure rates of 80% or better. The 20% of tumors that do not respond to traditional therapies, or relapse early, could be due to activation of tumor predisposition genes. CHEK2 is cell cycle checkpoint kinase 2, a tumor suppressor gene associated with increased risk of malignancies, most commonly breast and prostate cancer. Here we discuss a case of medulloblastoma, with evidence of germline and tumor CHEK2 mutation. This 4 year-old child was initially treated with surgery, achieving gross total resection, chemotherapy, tandem stem cell rescue, as well as local radiation therapy to posterior fossa. One year after completion of therapy, she relapsed with disease outside of the radiation field. Next generation sequencing of the whole genome performed on tumor tissue resulted in CHEK2 T367 mutation in the absence of TP53 mutation, or other mutations of known tumor suppressor genes. TP53 mutation is a cancer predisposition syndrome, associated with Li Fraumeni syndrome. CHEK2 mutation has been associated with worse progression-free survival in cases of non-Hodgkin’s lymphoma. Thus far, there have been no reported primary brain and central nervous system malignancies associated with CHEK2 mutation. This finding of CHEK2 mutation in medulloblastoma further supports the need for next generation sequencing on high-risk tumor types to predict response to therapy and overall prognosis.

Intracranial non-germinomatous germ cell tumors are a rare, heterogenous group of neoplasms, commonly occurring in the pineal and/or suprasellar regions. The subtypes include yolk sac tumor (YST) or endodermal sinus tumor (EST), embryonal carcinoma (EC), choriocarcinoma (CHC), and mixed malignant subtypes. Diagnosis is usually made without a biopsy, through detection of elevated levels of Alpha-fetoprotein (AFP) and/or beta-human chorionic gonadotropin (βHCG) in the serum and/or cerebrospinal fluid. Three patients with intracranial NGGCT were treated at our institution, using a combination of surgery, chemotherapy, and/or radiation therapy. The clinical presentation of all cases included signs and symptoms of obstructive hydrocephalus. Patient #1 was diagnosed with malignant teratoma at birth via neuroimaging; she died from complications due to surgical resection. Patient #2 was diagnosed with choriocarcinoma of the pituitary gland at age 5 years via elevated AFP in serum and CSF; he was treated with alternating cycles of carboplatin/etoposide and ifosfamide/etoposide, followed by whole ventricle radiation therapy. He is now 28 months off-therapy, without evidence of disease. Patient #3 was diagnosed with choriocarcinoma of the pineal and suprasellar regions at the age 7 years, via elevated beta-HCG in serum and CSF, with evidence of bimodal disease. Treatment included 6 cycles of risk-adapted chemotherapy followed by whole ventricle radiation therapy. Neuroimaging continues to show no evidence of disease with normalization of tumor markers, at 24 months off-therapy. Patients #2 and #3 have residual neuroendocrine and neuropsychological deficits, but remain neurodevelopmentally appropriate. Combination of chemotherapy and radiation therapy is required for optimal prognosis.

Schwannomatosis is a rare neurofibromatosis clinically diagnosed by age-dependent criteria, with bilateral vestibular schwannoma and/or a constitutional NF2 mutation representing exclusion criteria. Following SMARCB1 germline mutations, constitutional mutations in LZTR1 were discovered. We report on the molecular investigation in a patient presenting at 14 years with a unilateral vestibular schwannoma, ultimately causing blindness and unilateral hearing loss, in the absence of other schwannomas or a positive family history. In DNA derived from frozen tumor tissue, a comprehensive NF2, SMARCB1 and LZTR1 analysis showed an NF2 truncating mutation c.1006_1021delins16; an LZTR1 mutation c.791+1G>A; and a partial 22q deletion including NF2, SMARCB1 and LZTR1. Sequence analysis on peripheral blood derived DNA showed the LZTR1 mutation to be constitutional, but the NF2 mutation and partial 22q deletion were not found, indicating them to be somatic events. RNA-based targeted analysis confirmed missplicing of LZTR1 intron 8, predicted to result in a premature stop codon. This LZTR1 mutation was paternally inherited. While isolated vestibular schwannoma or NF2 may be considered in a young individual with a unilateral vestibular schwannoma, this report suggests that LZTR1 -related schwannomatosis be added to this differential diagnosis.

Pediatric central nervous system (CNS) malignancies are the most common malignancies of childhood. The standard treatment plan for most CNS malignancies involves surgery, chemotherapy, radiation, and/or a combination of above therapies. Unresectable symptomatic low grade gliomas, such as pilocytic astrocytomas and gangliogliomas, are slow growing tumors that are typically responsive to a single course of intravenous chemotherapy, but in select patients these WHO grade I or II tumors can recur and be refractory to multiple courses. Molecular diagnostics can offer valuable insight into the tumor microenvironment, where targeted therapies can be offered for specific actionable mutations. Here we report a case series of 3 pediatric patients, with unique CNS malignancies, currently on targeted therapies for tumor-specific somatic mutations. Patient A is a 5 year old male with unresectable Neurofibromatosis-1 related plexiform neurofibroma of the nasopharyngeal space as well as optic pathway glioma, with a mutation of the MAPK/ERK pathway. Patient B is a 6 year old male with recurrent, refractory pilocytic astrocytoma of the optic pathway and hypothalamus, with progression through several courses of intravenous chemotherapy, noted to have somatic NACC2-NTRK mutation. Patient C is a 17 year old female with unresectable, pontomedullary ganglioglioma, noted to have BRAF-V600E mutation. Patient A is treated with Selumetinib, for about 6 months, with near resolution of nasopharyngeal mass. Patient B is treated with Larotrectinib, for about 3 months, with stability of clinical symptoms. Patient C is treated with Vemurafenib, for about 10 months, with stability of lesion size and patient-reported clinical improvement. No adverse events were noted for any of these patients and all medications were administered orally. Significant improvement in quality of life was reported, as they did not have central lines or bone marrow suppression. Targeted inhibitors provide a reasonable treatment option for relapsed, refractory CNS malignancies with actionable mutations.

Posterior reversible encephalopathy syndrome (PRES) and cerebral sinus thrombosis are 2 known complications of acute lymphoblastic leukemia and its treatment. We describe a patient with acute lymphoblastic leukemia whose course was complicated by both of these conditions. This case is novel both for the fact that PRES developed before the initiation of therapy and that PRES was followed shortly by the development of cerebral sinus thrombosis. Our patient's story raises questions about our current understanding of the pathophysiology of PRES, and it suggests that PRES may actually be a predisposing risk factor for cerebral sinus thrombosis.

This paper is the second in a series on the Tyco Fire Products LP Sediment Removal Project, Marinette, Wisconsin, describing the dredging, stabilization and solidification (S/S) treatment, and nonhazardous disposal of arsenic (As)–impacted sediments. The high spatial variability of the As effects drove the need to develop a screening program to assess the environmental quality of sediments in scows within their 6-h decanting period before off-loading for purposes of reagent dose optimization, versus a default dose of 25% by weight ferric sulfate (60% aqueous) plus 10% by weight portland cement ($78.82/t). Portable X-ray fluorescence (XRF) and 3-h mini–toxicity characteristic leaching procedure (TCLP) techniques calibrated to wet sediments (plus moisture content) were shown to be a quick, reliable means of assessing sediment quality (10 samples per scow) to enable reagent dose optimization on a scow-by-scow basis. The maximum measured XRF As and TCLP As values were 76,981 mg/kg and 195 mg/L, resp...

Multiple myeloma is a malignant plasma cell disorder that is rare in the pediatric population, with only approximately 0.3% of cases diagnosed before the age of 30. In this report, we present two patients diagnosed with multiple myeloma between the ages of 12 and 16. Their respective treatment regimens are discussed, including the use of both autologous and allogeneic stem cell transplant.

Sturge-Weber syndrome (SWS) is a neurocutaneous disorder characterized by vascular malformations involving brain, skin, and occasionally eyes. There is no recognized tumor predisposition in patients with SWS as there is with some other phakomatoses. We present a patient with SWS who developed a low-grade glioma (LGG). We hypothesize that there could be an association between SWS and LGG formation, noting that GNAQ mutations have been implicated in the underlying biology of both SWS and a subset of pediatric LGG. It is suggested that SWS may be a cancer predisposition syndrome.

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (

Pediatric brain tumors are a challenging group of very divergent diseases. Considerable controversy exists concerning the accurate diagnosis and treatment of these patients. Aggressive therapy is often needed to cure aggressive and potentially lethal disease, yet late effects, especially injury to the developing brain, remain a profound problem. The discipline of pediatric neuro-oncology remains one of the most productive areas for continued clinical and basic research because of these and other challenges.

Brain tumor is the leading cause of cancer related death in children. To develop new therapies and to understand tumor biology, many efforts are made to develop patient derived orthotopic xenograft mouse models (PDOX). There are, however, some concerns about the potential impact of animal genders on tumor take rate, xenograft growth and in vivo drug responses. To systematically analyze such impact, we retrospectively examined >1,000 mice of 59 PDOX models, including glioblastoma (GBM), medulloblastoma (MB), primitive neuroectodermal tumor (PENT) and ependymoma (EPN) and diffuse intrinsic pontine glioma (DIPG), in which there were age-matched (within 2 wks differences) with relatively even numbers of male and female animals. All the animals were injected with identical number of tumor cells (1x10^5) in the mouse brains matching that in human patients. Animals were monitored daily and euthanized when they were moribund. Differences between male and female mice were analyzed by t-test. In 25 GBM models (15 adult and 10 pediatric) involving 419 mice, there was an average of number of mice was 17.8±9.5 mice per model (male: female = 9.88±5.8:7.93±3.6) (P>0.05). In 26 MB models with total 488 mice, the average animal number was 17.24±8.8 mice per model (male:female= 9.54±5.34 :7.71±3.45) (P>0.05). The tumor take rate was near >95% in both male and female mice (P>0.05). In GBM models, the survival times was 94.1±21.7 days in male mice and 92.3±20.8 days in female (P>0.05); wherease in MB models, they were 134.95±39.86 day in male and 121.08±31.68 days in female mice (P>0.05). The impact of animal gender on drug responses in vivo is essential to the preclinical drug testing. A total of 468 mice from 11 GBM, 5 MB, 3 EPN, 3 DIPG and 2 PNET were treated a series of standard and investigational drugs/compounds, including radiation, oncolytic virus (SVV-001), ABT888, BMI1-inhibitor, MLN8237, TMZ, Flavopiridol, SYC-435, SYC-719, SYC-836, Olig 2 inhibitor, VPA, SAHA, Echinomycin, MCB613, and PARPi. The overall survival times were 104.55±23.63 day in male mice, and 98.64±25.66 in female mice (P>0.05). The only model that exhibited the increased responses in male mice was found in IC-2305GBM treated with TMZ and PTC-596 (P Citation Format: Lin Qi, Mari Kogiso, Yuchen Du, Huiyuan Zhang, Frank Braun, Holly Lindsay, Sibo Zhao, Sarah Injac, Patricia Baxter, Zhigang Liu, Yujing Zhang, Jack Su, Adekunle Adesina, Andrew Walter, Jeffery Murray, Javad Nazarian, Will Parsons, Murali Chintagumpala, Xiao-nan Li. Impact of SCID mouse gender on tumorigenicity, xenograft growth and drug-responses in patient derived orthotopic xenograft models (PDOX) of malignant brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2821. doi:10.1158/1538-7445.AM2017-2821

A 6-week-old boy presented with fever, pallor, and hepatomegaly. Ultrasound showed a huge midline abdominal mass. β-human chorionic gonadotropin was markedly elevated, suggesting a diagnosis of infantile choriocarcinoma of the liver. A biopsy confirmed the diagnosis. The patient received 6 cycles of bleomycin, cisplatin, and etoposide with significant decrease in tumor size. However, the tumor remained unresectable. A donor liver became available, and the infant underwent successful liver transplantation. He received 2 posttransplant cycles of moderate dose of methotrexate. This case shows the use of liver transplantation in cases of infantile choriocarcinoma of the liver where the tumor remains unresectable despite chemotherapy.

During chemotherapy for bilineal leukemia, a 6-month-old infant presented with a necrotizing skin and soft-tissue infection of the chest wall due to Rhizopus sp. Successful outcome was achieved by systemically administered liposomal amphotericin B and local wound control with the novel administration of topical deoxycholate amphotericin B and surgical resection.

Two children presented with a history of fever and rash. Lab values revealed pancytopenia, elevated ferritin, coagulopathy, and elevated triglycerides. Both children quickly developed respiratory distress and hypotension requiring admission to the ICU. Bone marrow biopsies revealed hemophagocytosis. Studies for Ehrlichia returned positive. The patients were started on doxycycline and treated for hemophagocytic lymphohistiocytosis (HLH). Each made a full recovery. In both patients, testing for MUNC and perforin genes were found to have no mutation. These two cases demonstrate the importance of considering Ehrlichiosis as a possible trigger of HLH.

Neonatal alloimmune neutropenia (NAIN) is a rare cause of congenital neutropenia seen in

Purpose: The authors conducted a single-arm, prospective study using tamoxifen and carboplatin for the treatment of children with progressive or symptomatic low-grade gliomas. Patients and Methods: Fourteen children with consecutively diagnosed cases of low-grade glioma were enrolled in this study; all patients were younger than 14 years. One patient was excluded after induction chemotherapy because of the diagnosis of a nonmalignant condition. Patients were treated with daily tamoxifen (20 mg/m 2 administered twice per day) in addition to targeted, monthly intravenous carboplatin at an area under the curve (AUC) exposure of 6.5 mg/mL x minute for 1 year or until they had clinical or radiologic evidence of disease progression. Results: The median age at diagnosis was 5.3 years, the median age at initiation of chemotherapy was 8.3 years. Eight patients had tumors of the hypothalamus/optic pathway, two patients had thalamic tumors, and one patient each had tumors in the temporal lobe, tectum, and brain stem. Tumor histologic findings included fibrillary astrocytoma (n = 2), juvenile pilocytic astrocytoma (n = 6), and oligodendroglioma (n = 1). The best response to therapy was a partial response in two patients, stable disease in nine patients, and progressive disease in two patients. The overall survival at 3 years is 69%. The 3-year progression-free survival is 47%. Tamoxifen and carboplatin chemotherapy did not result in a significant number of objective responses in children with low-grade gliomas. The progression-free survival is similar to that of other published series. Nonmyelosuppressive agents such as tamoxifen deserve additional evaluation in the treatment of children with low-grade gliomas.

PURPOSE: Young children treated for medulloblastoma are at especially high risk for morbidity and mortality from their disease and therapy. This study sought to assess the relationship, if any, between patient outcome and M stage. Neuropsychologic and endocrine outcomes were also assessed. PATIENTS AND METHODS: Twenty-nine consecutively diagnosed infants and young children were treated for medulloblastoma at St Jude Children's Research Hospital between November 1984 and December 1995. All patients were treated with the intent of using postoperative chemotherapy to delay planned irradiation. RESULTS: The median age at diagnosis was 2.6 years. Six patients completed planned chemotherapy without progressive disease and underwent irradiation at completion of chemotherapy. Twenty-three children experienced disease progression during chemotherapy and underwent irradiation at the time of progression. The 5-year overall survival rate for the entire cohort was 51% ± 10%. The 5-year progression-free survival rate was 21% ± 8%. M stage did not impact survival. All patients lost cognitive function during and after therapy at a rate of −3.9 intelligence quotient points per year (P = .0028). Sensory functions declined significantly after therapy (P = .007). All long-term survivors required hormone replacement therapy and had growth abnormalities. CONCLUSION: The majority of infants treated for medulloblastoma experienced disease progression during initial chemotherapy. However, more than half of these patients can be cured with salvage radiation therapy, regardless of M stage. The presence of metastatic disease did not increase the risk of dying from medulloblastoma. All patients treated in this fashion have significant neuropsychologic deficits. Our experience demonstrates that medulloblastoma in infancy is a curable disease, albeit at a significant cost.

PURPOSE To evaluate the incidence of and potential risk factors for second malignant neoplasms of the brain following treatment for childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS The study population consisted of 1,612 consecutively enrolled protocol patients treated on sequential institutional protocols for newly diagnosed ALL at St Jude Children's Research Hospital (SJCRH) between 1967 and 1988. The median follow-up duration is 15.9 years (range, 5.5 to 29.9 y). RESULTS The cumulative incidence of brain tumors at 20 years is 1.39% (95% confidence interval [CI], 0.63% to 2.15%). Twenty-two brain tumors (10 high-grade gliomas, one low-grade glioma, and 11 meningiomas) were diagnosed among 21 patients after a median latency of 12.6 years (high-grade gliomas, 9.1 years; meningiomas, 19 years). Tumor type was linked to outcome, with patients who developed high-grade tumors doing poorly and those who developed low-grade tumors doing well. Risk factors for developing any secondary brain tumor included the presence of CNS leukemia at diagnosis, treatment on Total X therapy, and the use of cranial irradiation, which was dose-dependent. Age less than 6 years was associated with an increased risk of developing a high-grade glioma. CONCLUSION This single-institution study, with a high rate of long-term data capture, demonstrated that brain tumors are a rare, late complication of therapy for ALL. We report many more low-grade tumors than others probably because of exhaustive long-term follow-up evaluation. The importance of limiting cranial radiation is underscored by the dose-dependent tumorigenic effect of radiation therapy seen in this study.

Background. Standard therapy for pediatric nonrhabdomyosarcoma soft tissue sarcomas (PNRSTS) consists of surgical resection with or without radiotherapy. The role of chemotherapy in the treatment of these tumors has not yet been defined. We investigated the efficacy and toxicity of an ifosfamide-based regimen in controlling disease in children with high-risk PNRSTS. Patients and Methods. Between January 1992 and June 1994 at St. Jude Children's Research Hospital, we treated 11 children and young adults with PNRSTS who were at high risk for treatment failure by using a combined modality regimen that comprised aggressive surgery, radiotherapy, and chemotherapy including vincristine, ifosfamide, and doxorubicin (VID). Nine of these patients had grade 3 disease and one had grade 2 tumor; due to insufficient tissue, the disease grade of the remaining patient could not be established. Metastases were present at diagnosis in 2 children. Results. Therapy was generally well tolerated, with minimal morbidity and no mortality. The most common toxicity was grade 4 neutropenia, which occurred in 51% of evaluable courses. Among 4 patients evaluable for response to chemotherapy alone, 1 child attained a partial response and 3 had stable disease. One child had a response to chemotherapy and concurrent irradiation. At a median follow-up of 30 months, 10 of 11 patients are alive; 8 of 11 patients are alive without evidence of disease. Conclusion. Aggressive multimodality therapy for PNRSTS is well tolerated, despite frequent and profound neutropenia. Although adjuvant chemotherapy for this group of cancers remains unproved, the rate of tumor control achieved in this pilot study encourages further investigation in a multi-institutional setting.

Background Diffuse pontine gliomas remain one of the most lethal of pediatric malignancies despite the use of increasingly intensive therapies. We delivered intensive chemotherapy during and following 70.2 Gy of hyperfractionated radiation therapy in an attempt to improve survival. Procedure Nine consecutive children with diffuse pontine gliomas were treated on this single arm study. Carboplatin, given in combination with fixed dose etoposide, was escalated in successive cohorts to determine its maximum tolerated systemic exposure (AUC). Outcome was coded based on imaging characteristics and clinical status. Results Eight of the nine children on thisstudy died of their disease at a median of 44 weeks, essentially the same survival as those treated on a previous Pediatric Oncology Group study using hyperfractionated radiation therapy alone. Toxicity was almost exclusively hematologic and not associated with significant morbidity. Conclusions The use of concurrent carboplatin and etoposide with hyperfractionated radiation therapy did not appear to improve the survival in this group of children with diffuse pontine gliomas. The toxicity of this chemotherapy during radiation therapy was primarily hematologic and well tolerated. New approaches to the treatment of these tumors need to be investigated. Med. Pediatr. Oncol. 30:28–33, 1998. © 1998 Wiley-Liss, Inc.

Clinical features and treatment of 36 consecutive pediatric patients with thalamic glial tumors confirmed by histology and characterized by neuroimaging were reviewed to identify prognostic factors. The median age at diagnosis was 10 years (range 1–18 years). Twenty-four patients had low-grade tumors (juvenile pilocytic astrocytoma n = 9, fibrillary astrocytoma n = 6, astrocytomas not otherwise specified n = 6, ganglioglioma n = 2 and oligodendroglioma n = 1) and 12 patients had high-grade tumors (glioblastoma multiforme n = 7, anaplastic astrocytoma n = 4 and unclassified malignant tumor n = 1). With a median follow-up of 4.3 years among survivors, estimates of 4-year progression-free survival (PFS) and overall survival (OS) for the entire group are 28 ± 10 and 37 ± 10%, respectively. Low-grade tumors were associated with a significantly better 4-year PFS (36 ± 12 vs. 0% for the high-grade group; p = 0.03) and OS (52 ± 12 vs. 0%; p < 0.001). This review identified that bithalamic involvement, characterized by neuroimaging, exerted an independent and significant negative impact on PFS and OS for patients with low-grade tumors. Estimates of 4-year PFS and OS among patients with low-grade bithalamic versus monothalamic tumors were 58 ± 15 vs. 0% and 85 ± 11 vs. 0% (p < 0.00001), respectively. The presence of bithalamic involvement did not affect outcome among patients with high-grade tumors. Additionally, age at diagnosis, enhancement with neuroimaging contrast, extension beyond the thalamus and extent of surgical resection did not correlate with overall outcome. Because treatment approaches varied during the study period, the impact of radiation therapy or chemotherapy could not be assessed. This contemporary, single-institution series of pediatric thalamic glial tumors demonstrates, for the first time, the statistical significance of bithalamic involvement as a marker of poor prognosis among patients with low-grade glial lesions.

✓ Twenty-seven patients aged 1 to 18 years harboring supratentorial (20 in the cerebrum and seven in the thalamus) malignant gliomas were treated between 1975 and 1982. There were four glioblastomas multiforme, 14 anaplastic astrocytomas, and nine malignant gliomas. All patients had a subtotal resection or biopsy as the initial procedure and received postoperative radiation therapy (RT). Fifteen of 27 patients were treated by RT alone; 14 had tumor progression with a median time to tumor progression (MTP) of 65 weeks. Twelve patients were treated with chemotherapy as an adjuvant to RT; only seven had tumor recurrence, with an MTP of 130 weeks. Of the 21 patients with recurrent tumors in both groups, 18 were treated with chemotherapy alone, or chemotherapy with a second surgical procedure or second course of RT. For all histological grades of tumor, the MTP for first recurrence was 75 weeks and the median survival time was 180 weeks. Age at initial diagnosis was found to be a statistically significant prog...

Purpose: We report that patients with nevoid basal cell carcinoma syndrome (Gorlin syndrome) are at risk for developing neoplasms, especially basal cell carcinomas and rarely medul-loblastoma. Methods: A case report is presented of a 5-year-old child with medulloblastoma and multiple basal cell carcinomas who was diagnosed with nevoid basal cell carcinoma syndrome. Genetic analyses were performed on tumor DNA from the patient's medulloblastoma and basal cell carcinomas as well as germline DNA from the patient and unaffected family members. Results: After radiation therapy for medulloblastoma, the patient developed thousands of additional basal cell carcinomas. Analysis of tumor DNA revealed the characteristic defect of nevoid basal cell carcinoma syndrome, loss of heterozygosity at 9q22. Photodynamic therapy was successfully used to control the majority of her cutaneous tumors. Conclusion: DNA analysis confirmed the presence of the distinctive genetic lesion of nevoid basal cell carcinoma syndrome in both medulloblastoma and basal cell carcinoma. Omitting or limiting radiation therapy for children with nevoid basal cell carcinoma syndrome and medulloblastoma should be considered.

Recurrent medulloblastoma is a therapeutic challenge because it is almost always fatal. Studies have confirmed that medulloblastoma consists of at least four distinct subgroups. We sought to delineate subgroup-specific differences in medulloblastoma recurrence patterns.We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children (Toronto, ON, Canada) from 1994 to 2012 (cohort 1), and established molecular subgroups using a nanoString-based assay on formalin-fixed paraffin-embedded tissues or frozen tissue. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence, and survival after recurrence were assessed in a subgroup-specific manner. Two independent, non-overlapping cohorts (cohort 2: samples from patients with recurrent medulloblastomas from 13 centres worldwide, obtained between 1991 and 2012; cohort 3: samples from patients with recurrent medulloblastoma obtained at the NN Burdenko Neurosurgical Institute [Moscow, Russia] between 1994 and 2011) were analysed to confirm and validate observations. When possible, molecular subgrouping was done on tissue obtained from both the initial surgery and at recurrence.Cohort 1 consisted of 30 patients with recurrent medulloblastomas; nine with local recurrences, and 21 with metastatic recurrences. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients with recurrent medulloblastoma. Subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs (five pairs from cohort 1 and 29 pairs from cohort 2 [15 SHH, five group 3, 14 group 4]). This finding was validated in 17 pairs from cohort 3. When analysed in a subgroup-specific manner, local recurrences in cohort 1 were more frequent in SHH tumours (eight of nine [89%]) and metastatic recurrences were more common in group 3 and group 4 tumours (17 of 20 [85%] with one WNT, p=0·0014, local vs metastatic recurrence, SHH vs group 3 vs group 4). The subgroup-specific location of recurrence was confirmed in cohort 2 (p=0·0013 for local vs metastatic recurrence, SHH vs group 3 vs group 4,), and cohort 3 (p0·0001). Treatment with craniospinal irradiation at diagnosis was not significantly associated with the anatomical pattern of recurrence. Survival after recurrence was significantly longer in patients with group 4 tumours in cohort 1 (p=0·013) than with other subgroups, which was confirmed in cohort 2 (p=0·0075), but not cohort 3 (p=0·70).Medulloblastoma does not change subgroup at the time of recurrence, reinforcing the stability of the four main medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of patients with SHH tumours. Refinement of therapy for patients with group 3 or group 4 tumours should focus on metastases.

A 13-year-old child presented with three simultaneous malignancies: glioblastoma multiforme, Burkitt lymphoma, and colonic adenocarcinoma. She was treated for her diseases without success and died 8 months after presentation. Genetic analysis revealed a homozygous mutation in the PMS2 gene, consistent with constitutional mismatch repair deficiency. Her siblings and parents were screened: three of four siblings and both parents were heterozygous for this mutation; the fourth sibling did not have the mutation.

BACKGROUND Approximately 30 patients with malignant mesothelioma following radiotherapy have been described. Population-based studies of this occurrence have not been reported. METHODS Patients with malignant mesothelioma of the pleura were collected. All of the patients had a prior cancer and had received radiotherapy to the region in which the malignant mesothelioma developed. Data from the National Cancer Institute's Surveillance, Epidemiology and End Results Program and the Connecticut Tumor Registry were evaluated for cases of malignant mesothelioma of the pleura occurring in patients with a previous cancer. The literature on post-irradiation malignant mesotheliomas was reviewed. RESULTS Eight patients (4 men, 4 women) with malignant mesothelioma occurring in sites of radiotherapy for a prior tumor were identified. The mean age at diagnosis of mesothelioma was 45 years (range: 22–78 years), and the average interval between radiotherapy and the mesothelioma was 21 years (range: 11–29 years). Three of the patients had also received chemotherapy. Histologically, the mesotheliomas were epithelial in five cases, biphasic in one, and sarcomatous in one. One hundred forty-two patients were identified in the epidemiologic survey. The majority were men (89%), with a median age for all patients of 68.5 years (range: 35–86 years) and a median latency between first cancer and mesothelioma of 4.3 years (range: 2 months–29.9 years). CONCLUSIONS Mesotheliomas rarely develop as second malignant neoplasms. Within a large, population-based survey of patients with cancer, temporal patterns and demographic features of most second primary mesotheliomas were similar to asbestos-related tumors, although the late effects of cancer treatment might have contributed to the occurrence of cancer in some patients. Cancer 1996;77:1379-85.

We studied the impact of gross total resection on progression-free survival (PFS) and postoperative morbidity in 40 children with locally advanced medulloblastoma characterized by tumor invading the brain stem. These patients represented 40% of children treated for newly diagnosed medulloblastoma at a pediatric oncology center over a 10-year period. All patients underwent aggressive initial surgical resection. Review of surgical and neuroimaging findings documented gross total resection in 13 cases, near-total resection (1.5 cm2 residual tumor on imaging) in 14 cases, and subtotal resection (than 50% resection withor = 1.5 cm2 residual) in 13 cases. Overall, 85% of patients had a90% resection. Subsequent therapy comprised craniospinal irradiation in all cases and chemotherapy on institutional or cooperative group protocols in 35 cases. At a median follow-up of 4 years, postirradiation PFS is 61% (SE = 10%). There was no difference in PFS for patients who underwent gross total resection compared to those with any detectable residual tumor (p0.70). The posterior fossa syndrome occurred in 25% of cases, and had no apparent relationship to the extent of resection (p0.5, exact test). In this series, true gross total resection was not associated with a PFS advantage when compared to strictly defined near-total and subtotal resection. Although there was no operative mortality, the frequency of the posterior fossa syndrome is of concern and emphasizes the need for careful consideration of the risk/benefit ratio in the surgical approach to this subgroup of patients.

This study will evaluate the safety and efficacy of in vivo gene transfer of the herpes simplex thymidine kinase (HSV-Tk1) gene using PA317/G1Tk1SvNa.7 vector producer cells (VPC) in pediatric patients with progressive or recurrent primary supratentorial malignant brain tumors. Insertion of the HSV-Tk1 gene confers a sensitivity to the anti-herpes drug ganciclovir. It has been demonstrated that the direct injection of HSV-Tk vector producer cells into growing tumors in animals can result in their complete destruction with ganciclovir therapy. This selective destruction of growing tumors in situ is thought to result from the transfer of the HSV-Tk gene into the tumor cells and the production of toxic ganciclovir metabolites which result from the interaction of HSV-Tk and ganciclovir. This procedure can result in the cure of some experimental animals with limited systemic toxicity due to selective gene transfer into tumors. This clinical trial will focus on maximizing the relative number of vector producer cells to the tumor mass by stereotactically injecting VPCs into the tumor mass. Children with progressive or recurrent primary supratentorial malignant brain tumor which is accessible to stereotactic injection will be evaluated for the extent and location(s) of their disease before being entered into the study. Fifteen days after stereotactic injection of the tumor mass, ganciclovir will be administered at 5 mg/kg IV b.i.d. for 14 days. Upon completion of the treatment with HSV-Tk1 vector producer cells and ganciclovir, the patient will be followed monthly for the first three months, then every two months for the next twenty-one months, and annually for life thereafter.

✓ Little is known about low-grade astrocytoma with neuraxis dissemination at diagnosis. A review of medical records identified this phenomenon in eight of 150 pediatric patients evaluated between 1985 and 1994 for histologically confirmed low-grade astrocytoma. These patients (five male and three female) ranged in age from 5 months to 20 years (median 8 years). Symptoms of neuraxis disease were minimal or absent. Primary tumor sites were the hypothalamus in four cases, brainstem/spinal cord in three, and temporal lobe in one. Patterns of dissemination (evaluated by computerized tomography and/or magnetic resonance imaging techniques) appeared to be related to the primary site: hypothalamic tumors metastasized along the ventricular cerebrospinal fluid pathways, and tumors in other locations disseminated along subarachnoid pathways. Following initial treatment with chemotherapy (in three), partial resection (in one), radiation therapy (in three), and chemotherapy plus irradiation (in one), four patients required salvage therapy for progressive or recurrent disease. Seven of the eight patients are alive with stable or progressive disease 6 to 105 months postdiagnosis (median 15 months). Low-grade astrocytoma with initial neuraxis dissemination is responsive to chemotherapy and radiation, a proportion showing periods of stable disease. The optimum therapy or combination of therapies remains unclear.

Paraneoplastic cerebellar degeneration (PCD) is a rare neurological syndrome associated with lung cancer, breast adenocarcinoma,ovarian adenocarcinoma, and Hodgkin disease. It is rarely seen in pediatrics. We report a case of a 10-year-old boy with a 2-year prodrome that led to a diagnosis of PCD in association with stage IV Hodgkin disease. He received radiation and chemotherapy for his Hodgkin disease with resolution of his lymphoma. Based on promising data in adults on the efficacy of rituximab over other immuno suppressive agents in paraneoplastic disorders, he was treated with rituximab with marked improvement of the cerebellar syndrome.

BACKGROUND Pancytopenia in hospitalized children is not a common occurrence. The causes may vary in different patients and in diverse areas of the world. There are no reports in the literature describing these etiologies in a developed country. Our review focused on children presenting with pancytopenia at a children's hospital in the United States with the purpose to allow us to better evaluate and care for children. PROCEDURE Charts of children aged 2 months to 18 years who were admitted to our hospital over a 5-year period were retrospectively reviewed to identify the diagnosis of pancytopenia. The diagnosis of pancytopenia was confirmed by laboratory values showing neutropenia, anemia, and thrombocytopenia. These etiologies and patient characteristics were reported in our review. RESULTS A total of 64 children were identified with the diagnosis of pancytopenia. The most common diagnoses were infectious in origin (64%), followed by hematologic (28%), and miscellaneous (8%) etiologies. CONCLUSIONS The most common etiology of pancytopenia in hospitalized children without cancer was infections. This differs from earlier reports in other countries, where megaloblastic anemia was found most often. Our review should provide guidance to the diagnoses which should be considered when evaluating a child with pancytopenia.

Two children presented with a history of fever and rash. Lab values revealed pancytopenia, elevated ferritin, coagulopathy, and elevated triglycerides. Both children quickly developed respiratory distress and hypotension requiring admission to the ICU. Bone marrow biopsies revealed hemophagocytosis. Studies for Ehrlichia returned positive. The patients were started on doxycycline and treated for hemophagocytic lymphohistiocytosis (HLH). Each made a full recovery. In both patients, testing for MUNC and perforin genes were found to have no mutation. These two cases demonstrate the importance of considering Ehrlichiosis as a possible trigger of HLH.

Neonatal alloimmune neutropenia (NAIN) is a rare cause of congenital neutropenia seen in1% of births. Significant morbidity, usually infections, may result from this disease. The pathophysiology of NAIN, mediated by maternal antibodies crossing the placenta to destroy fetal cells expressing paternal antigens, is similar to that of neonatal alloimmune thrombocytopenia, as well as Rh/ABO hemolytic disease of the newborn. The use of high-dose granulocyte colony stimulating factor in patients with NAIN may cause a reversible thrombocytopenia in some patients.

Brain tumors are the leading cause of cancer related death in children, and there is biological differences between treatment naïve tumors and their therapy resistant relapses. As surgery is rarely an option for terminal brain tumors that have failed existing therapies, autopsy is frequently the only chance to obtain tumor tissues. Despite the urgent need of models of terminal brain tumors, it remains unknown if autopsied tumors can be used for in vitro and in vivo model development. To determine if (some) tumor cells can survival postmortem anoxia/starvation to proliferate in vitro and, more importantly, to form orthotopic xenograft tumors, we collected 29 autopsied brain tumors, including 15 diffuse intrinsic pontine gliomas (DIPG), 7 glioblastomas (GBM), 4 medulloblastomas (MB), 2 ependymoma and 1 atypical teratoid/rhabdoid tumor (ATRT), and made the following discoveries. i) A small fraction of tumor cells exhibited strong survival capacity and remained viable, ranging from 0.5%-40% (13.5% ± 10.9%), in tumors harvested 5-72 hrs (31.2 ± 25 hrs) after patients’ death. Cell viability, however, did not appear to be strictly correlated with the length of autopsy time (r = 0.17), suggesting that ample time should be given to the families to say goodbye to their loved ones. ii) While many autopsied tumor cells appear to have stayed alive for short terms in culture, only one pair of permanent lines (monolayer in FBS media and neurosphere in serum-free media) were established from a GBM tumor. iii) Direct implantation of tumor cells into matched locations in the brains of SCID mice led to the formation of xenograft tumors in 17 of 22 tumors (7 additional tumors are still pending). 8 of the 17 autopsy derived orthotopic (ADOX) models have been subtransplanted in mouse brains for > 3 times (5 DIPGs and 1 each of GBM, MB and ATRT). Detailed characterization confirmed their replication of histopathological features and genetic/genomic abnormalities of the patient tumors. iv) To identify the cellular origin of surviving patient tumor cells that propagated ADOX model formation, time course analysis of putative cancer stem cells (CD133, CD15, CD24/CD44, CD57, CD117) was performed. CD57+ tumor cells were found to be the most abundant subpopulations in the autopsied tumors, and their fractions increased in the ADOX tumors during serial subtransplantations. Additionally, CD57+ cells alone were able to form orthotopic xenografts, establishing their role as cancer stem cells. In conclusion, we have demonstrated that a fraction of tumor cells can survive the lengthy period of postmortem anoxia/starvation and regain tumorigenic capabilities in mouse brains; and identified CD57 as a new marker of the therapy-resistant cells with extraordinary survival and tumorigenic (TREST) capabilities. This novel panel of ADOX models should facilitate biological studies and preclinical drug screening of therapy-resistant pediatric brain tumors. Citation Format: Lin Qi, Baxter A. Patricia, Kogiso Mari, Du Yuchen, Lindsay Holly, Liu Zhigang, Xiumei Zhao, Yujing Zhang, Jack MF Su, Adekunle Adesina, Andrew W. Walter, Jeffery Murray, Rene McNall-Knapp, Javad Nazarian, Will Parsons, Murali Chintagumpala, Susan Blaney, Xiao-Nan Li. Autopsy derived orthotopic xenograft (ADOX) mouse models for terminal pediatric brain tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1450. doi:10.1158/1538-7445.AM2015-1450

Ependymomas are rare gliomas that have been associated with a poor outcome despite aggressive therapy including surgery, chemotherapy and radiation therapy. We present a case report of a 16-year-old male with an untreated supratentorial ependymoma that lay dormant for 15 years without significant morbidity. Supratentorial ependymomas are thought to have a better outcome than infratentorial ependymomas, primarily because of the increased likelihood of achieving a gross total resection in the supratentorial space. Our case report suggests that the improved outcome may be due in part to the biologically benign nature of some supratentorial ependymomas. This highly unusual case illustrates the unpredictable heterogeneity of pediatric ependymomas.

A 13-year-old child presented with three simultaneous malignancies: glioblastoma multiforme, Burkitt lymphoma, and colonic adenocarcinoma. She was treated for her diseases without success and died 8 months after presentation. Genetic analysis revealed a homozygous mutation in the PMS2 gene, consistent with constitutional mismatch repair deficiency. Her siblings and parents were screened: three of four siblings and both parents were heterozygous for this mutation; the fourth sibling did not have the mutation.