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Mona Mohammad,1,* Hamzeh Mohammad Alrawashdeh,2,* Mustafa Mehyar,1 Nisreen Amayiri,3 Dima Abu Laban,4 Ibrahim Alnawaiseh,1 Yacoub Yousef1 1Department of Surgery, Division of Ophthalmology, King Hussein Cancer Center (KHCC), Amman, Jordan; 2Department of Ophthalmology, Sharif Eye Centers, Irbid, Jordan; 3Department of Pediatric Oncology, King Hussein Cancer Center (KHCC), Amman, Jordan; 4Department of Diagnostic Radiology, King Hussein Cancer Center (KHCC), Amman, Jordan*These authors contributed equally to this workCorrespondence: Mona Mohammad; Yacoub Yousef, Department of Surgery, Division of Ophthalmology, King Hussein Cancer Center, P.O. Box 1269, Amman, 11941, Jordan, Tel +962 795372321 ; +962 79 100 3333, Fax +962 6 5345 567, Email Dm.11804@khcc.jo; yyousef@Khcc.joPurpose: This study aims to report visual acuity outcomes for patients with optic pathway gliomas (OPG) treated with systemic chemotherapy and analyze the associated factors.Patients and Methods: A retrospective study of 29 children with OPG treated with chemotherapy at King Hussein Cancer Center (KHCC), Amman, Jordan, between May/2005 and August/2020. Details on patient demographics, tumor location, systemic chemotherapy, and progression of disease were extracted from medical records.Results: Fifty-four eyes of twenty-nine patients were included in this study with a follow-up range from 2 to 17 years. Sixteen patients (55%) had a history of neurofibromatosis-1 (NF1). Most of the eyes (31, 57%) had visual acuity ranges in the moderate or better group. The age group ≥ 5 years at diagnosis, those with hydrocephalus, and patients with non-NF1 presented the worst visual acuity ranges from severe or worse; the p-value was 0.043, 0.0320, and 0.0054, respectively. Following treatment with systemic chemotherapy, visual acuity improved in 5 (17%) patients, remained the same in 23 (79%) patients, and only one patient (3%) had vision deterioration. Of the five patients who showed vision improvement, only one had radiological regression of the tumor. Parallel to this, three (10%) patients showed tumor progression in the final magnetic resonance image (MRI) findings without affecting the final vision.Conclusion: Children older than 5 years at diagnosis, in sporadic OPG, and those with hydrocephalus had the worst vision at presentation. Treatment with systemic chemotherapy prevented further deterioration of vision, and following treatment with systemic chemotherapy, most of the patients had the same vision; this stability indicates that vision at diagnosis is an important predictor for the final visual outcome.Keywords: glioma, neurofibromatosis, neuro-oncology, pediatric tumors, vision

Pediatric intracranial germ cell tumors (iGCT) are rare, with limited data available from Arabic countries.We retrospectively reviewed the medical charts of children18 years diagnosed with iGCT at King Hussein Cancer Center/Jordan (January 2003 to December 2020) for clinical characteristics, treatment, and morbidities.Sixteen patients had germinoma; median age was 6.9 years and median symptoms duration 8 months. Nine tumors were suprasellar, five pineal, and two bifocal. Four were metastatic. Eight patients had slightly elevated beta subunit human chorionic gonadotropin and 11 patients had resection/biopsy. Fifteen patients received chemotherapy; mostly carboplatin (450 mg/mWe achieved excellent survival in treating germinoma using a feasible protocol for low middle-income countries. However, patients encountered significant morbidities exacerbated by delayed diagnosis and unnecessary surgical interventions despite abnormal tumor markers. Raising awareness on iGCT symptomatology and diagnosis may help limit these morbidities.

Ependymal tumors are the third most common brain tumor under 14 years old. Even though metastatic disease is a rare event, it affects mostly young children and carries an adverse prognosis. The factors associated with dissemination and the best treatment approach have not yet been established and there is limited published data on how to manage metastatic disease, especially in patients under 3 years of age. We provide a review of the literature on clinical characteristics and radiation-sparing treatments for metastatic ependymoma in children under 3 years of age treated. The majority (73%) of the identified cases were above 12 months old and had the PF as the primary site at diagnosis. Chemotherapy-based approaches, in different regimens, were used with radiation reserved for progression or relapse. The prognosis varied among the studies, with an average of 50%-58% overall survival. This study also describes the case of a 7-month-old boy with metastatic posterior fossa (PF) ependymoma, for whom we identified a novel SPECC1L-RAF1 gene fusion using a patient-centric comprehensive molecular profiling protocol. The patient was successfully treated with intensive induction chemotherapy followed by high-dose chemotherapy and autologous hematopoietic progenitor cell rescue (AuHSCR). Currently, the patient is in continuous remission 5 years after his diagnosis, without radiation therapy. The understanding of the available therapeutic approaches may assist physicians in their management of such patients. This report also opens the perspective of newly identified molecular alterations in metastatic ependymomas that might drive more chemo-sensitive tumors.

Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition syndrome that presents with brain, gastrointestinal and haematological malignancies. We conducted a retrospective analysis of 9 pediatric patients (

Background: Venous thromboembolism (VTE) in children is relatively rare, and more so among those with cancer. In this study, we report the characteristics and outcomes of children with cancer-associated thrombosis. Methods: We reviewed institutional databases for all children with cancer and a diagnosis of VTE at King Hussein Cancer Center in Jordan. Variables reviewed are patients’ clinical characteristics, treatment for cancer, and anticoagulation therapy. Results: Between January 2011 and December 2018, a total of 45 patients fulfilled the inclusion criteria, and the median age was 10.4 (0.8-17.9) years. The most common underlying diagnosis was acute lymphoblastic leukemia (n = 13, 29%). At the time of VTE, 29 (64.4%) patients were receiving chemotherapy, and eight (17.8%) had a central venous catheter (CVC). The majority of patients (n = 37, 82%) developed VTE within 30 days of hospitalization. Thrombosis mostly involved the extremities (n = 23, 51%) and sagittal vein (n = 12, 26.7%). All patients were treated with low-molecular-weight heparin (LMWH), complicated by bleeding in three (6.6%) patients. Conclusion: In contrast to adults, VTE in pediatric cancer patients is more associated with chemotherapy and recent hospitalization. LMWH is a safe and effective therapy for children with cancer who develop VTE.

Introduction: Ventriculo-Peritoneal Shunt (VPS) related ascites is a rare complication of pediatric Low Grade Gliomas (pLGG). Physiopathology of this complication is not fully understood and there is paucity of data regarding the molecular profile of pLGG gliomas complicating with ascites and the optimal management of this unusual event. Methods: International multi-institutional retrospective analysis of patients diagnosed with BRAF altered pLGG and ascites arising as a complication of VPS. Demographics, tumor characteristics, therapeutic approaches and outcomes were recorded. Results: Nineteen patients were identified. Median age at diagnosis was 14 months (IQR:7-16). Most patients (16;84.2%) presented with lesions involving the optic pathway. Mean tumor standard volume was 34.8 cm2 (range:12.5-85.4). Pilocytic Astrocytoma was the most frequent histological diagnosis (14;73.7%). Eight (42.1%) tumors harbored BRAF V600-E mutation and seven (36.8%) KIAA1549 fusion. The onset of ascites was documented at a median time of 5 months following VPS insertion. Four (21%) patients were managed with paracentesis only, 7(36.8%) required both paracentesis and shunt diversion, 7(36.8%) required only a shunt diversion and 1 (5,2%) patient was managed conservatively. Ascites was the indication to change chemotherapy regimen in 10 patients. Eight patients received targeted therapy (4 dabrafenib/4 trametinib) and 5 were radiated. Eleven patients were alive at the time of this report with a median OS of 69 months (range:3-144). Conclusions: Ascites is an early feature in the course of pLGG irrespective of alterations in the RAS/MAPK pathway with high mortality rate and should be considered as an adverse prognostic risk factor in pLGG.

Ventriculo-peritoneal shunt (VPS) related ascites is a rare complication of pediatric low grade gliomas (pLGG). Physiopathology of this complication is not fully understood and there is paucity of data regarding the molecular profile of pLGG gliomas complicating with ascites and the optimal management of this unusual event.International multi-institutional retrospective analysis of patients diagnosed with BRAF altered pLGG and ascites arising as a complication of VPS. Demographics, tumor characteristics, therapeutic approaches and outcomes were recorded.Nineteen patients were identified. Median age at diagnosis was 14 months (R: 2-144). Most patients (17; 89.4%) presented with lesions involving the optic pathway. Mean tumor standard volume was 34.8 cmAscites is an early feature in the clinical course of young patients with midline BRAF altered pLGG, with high mortality rate observed in our cohort. The hypothesis of ascites as an adverse prognostic factor in pLGG warrants further prospective research.

BACKGROUND Treatment abandonment and refusal are reported to contribute significantly to poor survival of children with cancer in low- and middle-income countries. We aimed to assess this phenomenon among children diagnosed with central nervous system (CNS) tumors in Jordan. METHODS We retrospectively reviewed the medical charts of children

Medulloepithelioma is a rare brain tumor that has been classified as embryonal tumor with multilayered rosettes (ETMR) if it harbors C19MC amplification. In rare instances, it shows evidence of heterologous differentiation. We report a case of a 10-year-old female who presented with headache, squint, and minimal left sided weakness of 1 week duration. Microscopy revealed a small round blue cell tumor with focal glandular and tubular differentiation. In one focus, well-developed osteoid was identified. The tumor labeled with LIN28A immunostain. Unusual features can be encountered in medulloepithelioma which should be in the differential diagnosis of CNS embryonal tumors. Full description of the case with review of the literature and comparison between cases with and without heterologous elements is presented.

BACKGROUND/RATIONAL: Following initial irradiation sparing therapy, many young children with relapsed medulloblastoma can be salvaged with craniospinal irradiation (CSI). However, the interval to relapse is short and neurocognitive sequelae remain a major concern. The contribution of molecular subgrouping may help refine indications and modalities of salvage strategies in this population. METHOD: From a cohort of 151 young children with molecularly characterized relapsed medulloblastoma, subset analysis of the SHH medulloblastoma was conducted to describe the practice of salvage radiotherapy and associated post-relapse survival (PRS). RESULTS: Sixty-seven SHH medulloblastoma patients (46 M0; 54 GTR; 11 non-ND/MBEN) received salvage therapy with curative intent. Before relapse, 54 (80.6%) received conventional chemotherapy (CC), 13 (19.4%) high-dose chemotherapy (HDC), while seven had additional focal radiotherapy (fRT). Median time to relapse was 11.1 months (range 3.8-41.0) and 43.3% were localized. Thirty patients (16 localized relapse) underwent surgery. Forty-seven (71.2%) received salvage radiotherapy (20 with CC; 10 with HDC; 15 alone, two unknown). CSI and fRT accounted for 82% and 18% respectively. CSI median dose was 36Gy (range 18-39Gy). Ten patients (eight with localized relapse) received CSI doses ≤23.4Gy. Nineteen patients (28.8%) did not receive any radiotherapy (nine HDC; 10 CC only). Radiotherapy was associated with better 3-year PRS (73.0% versus 36.1%; p=0.001). All patients treated with CSI ≤ 23.4Gy were alive at median follow-up of 69 months(24-142). Six of nine patients treated with HDC without irradiation were alive at last follow-up. Sixty-three percent of patients received reduced dose CSI(≤23.4Gy), fRT, or no radiotherapy, and their PRS did not significantly differ from those who received CSI ≥ 30.6Gy (p = 0.54). CONCLUSION: While salvage CSI provided PRS benefit in this SHH medulloblastoma cohort, we report the use of reduced salvage radiotherapy and irradiation avoidance in 63% of the patients, with 60% alive at last follow-up.

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.

Germline biallelic mutations in one of the mismatch repair genes, mutS homolog 2, mutS homolog 6, mutL homolog 1, or postmeiotic segregation increased 2, result in one of the most aggressive cancer syndromes in humans termed as constitutional mismatch repair deficiency (CMMRD). Individuals with CMMRD are affected with multiple tumors arising from multiple organs during childhood, and these individuals rarely reach adulthood without specific interventions. The most common tumors observed are central nervous system, hematological, and gastrointestinal malignancies. The incidence of CMMRD is expected to be high in low-resource settings due to a high rate of consanguinity in these regions, and it is thought to be underrecognized and consequently underdiagnosed. This position paper is therefore important to provide a summary of the current situation, and to highlight the necessity of increasing awareness, diagnostic criteria, and surveillance to improve survival for patients and family members.

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

Pediatric craniopharyngioma is a rare tumor with excellent survival but significant long-term morbidities due to the loco-regional tumor growth or secondary to its treatment. Visual impairment, panhypopituitarism, hypothalamic damage and behavioral changes are amongst the main challenges. This tumor should be managed under the care of a multidisciplinary team to determine the optimum treatment within the available resources. This is particularly important for low middle-income countries (LMICs) where resources are variable. We provide a risk-stratified management guideline for children diagnosed with craniopharyngioma in a resource limited setting based on the service levels describing the facilities and personnel required for management as previously specified by the Pediatric Oncology in Developing Countries (PODC) committee of The International Society of Pediatric Oncology (SIOP). A multi-disciplinary group of neurosurgeons, radiation and pediatric oncologists, radiologists, pediatric endocrinologists and an ophthalmologist with experience in managing children with craniopharyngioma in LMIC setting was formed and carried online meetings to form a consensus guideline. The clinical characteristics (including the visual and endocrine presentations), suggestive radiological features as well as potential treatment options including surgery, radiotherapy and intra-cystic therapies were discussed in depth and in relation to available resources. In addition, hormonal management, pre- and post-operative PICU care and expected future complications related to craniopharyngioma and to follow up these children were discussed and documented in the guideline. We believe this guideline is a useful reference for health care providers in LMIC.

Management of craniopharyngioma in children is challenging, and their quality of life can be significantly affected. Series describing this from low-middle income countries (LMIC) are few.The study provides a retrospective chart review of pediatric patients18 years old, diagnosed with craniopharyngioma between 2003 and 2014, and treated at King Hussein Cancer Center, Jordan.Twenty-four patients (12 males) were identified. Median age at diagnosis was 7.4 years (0.9-16.4 years). Commonest symptoms were visual impairment and headache (71%). Review of seventeen preoperative MRIs showed hypothalamic involvement in 88% and hydrocephalus in 76%. Thirteen patients (54%) had multiple surgical interventions. Five patients (21%) had initial gross total resection. Eleven patients (46%) received radiotherapy and six (25%) intra-cystic interferon. Five years' survival was 87 ± 7% with a median follow-up of 4.5 years (0.3-12.3 years). Four patients (17%) died; one after post-operative cerebral infarction and three secondary to hypothalamic damage. At their last evaluation, all but one patient required multiple hormonal supplements. Ten patients (42%) had best eye visual acuity (VA)20/40, and four (16%) were legally blind. Eleven patients (46%) were overweight/obese; one had gastric bypass surgery. Seven patients had hyperlipidemia, and eight developed fatty liver infiltration. Eleven patients (65%) were attending schools and one at college. Nine of the living patients (53%) expressed difficulty to engage in the community.Management of pediatric craniopharyngioma is particularly complex and demanding in LMIC. Multidisciplinary care is integral to optimize the care and minimize the morbidities. A management outline for LMIC is proposed.

BackgroundCerebellar mutism syndrome (CMS) is a common complication following resection of posterior fossa tumors, most commonly after surgery for medulloblastoma. Medulloblastoma subgroups have historically been treated as a single entity when assessing CMS risk; however, recent studies highlighting their clinical heterogeneity suggest the need for subgroup-specific analysis. Here, we examine a large international multicenter cohort of molecularly characterized medulloblastoma patients to assess predictors of CMS.MethodsWe assembled a cohort of 370 molecularly characterized medulloblastoma subjects with available neuroimaging from 5 sites globally, including Great Ormond Street Hospital, Christian Medical College and Hospital, the Hospital for Sick Children, King Hussein Cancer Center, and Lucile Packard Children’s Hospital. Age at diagnosis, sex, tumor volume, and CMS development were assessed in addition to molecular subgroup.ResultsOverall, 23.8% of patients developed CMS. CMS patients were younger (mean difference −2.05 years ± 0.50, P = 0.0218) and had larger tumors (mean difference 10.25 cm3 ± 4.60, P = 0.0010) that were more often midline (odds ratio [OR] = 5.72, P < 0.0001). In a multivariable analysis adjusting for age, sex, midline location, and tumor volume, Wingless (adjusted OR = 4.91, P = 0.0063), Group 3 (adjusted OR = 5.56, P = 0.0022), and Group 4 (adjusted OR = 8.57 P = 9.1 × 10−5) tumors were found to be independently associated with higher risk of CMS compared with sonic hedgehog tumors.ConclusionsMedulloblastoma subgroup is a very strong predictor of CMS development, independent of tumor volume and midline location. These findings have significant implications for management of both the tumor and CMS.

Pediatric craniopharyngioma is a rare tumor with excellent survival but significant long-term morbidities due to the loco-regional tumor growth or secondary to its treatment. Visual impairment, panhypopituitarism, hypothalamic damage, and behavioral changes are among the main challenges. This tumor should be managed under the care of a multidisciplinary team to determine the optimum treatment within the available resources. This is particularly important for low middle-income countries where resources are variable. This report provides risk-stratified management guidelines for children diagnosed with craniopharyngioma in a resource-limited setting.

Germline biallelic mutations in one of the mismatch repair genes (MSH2/MSH6/MLH1/PMS2 results in constitutional mismatch repair deficiency (CMMRD), a condition associated with multiple tumors arising from multiple organs during childhood, and these individuals rarely reach adulthood. The paucity of information with respect to these conditions leads to mismanagement and may be a factor in the high mortality of patients with CMMRD. Two international consortia, the European CARE4CMMRD, and the international replication repair deficiency (RRD) consortium, are addressing the many challenges associated with this condition. To address specific issues surrounding the management of CMMRD in low and middle income countries (LMIC), a multidisciplinary taskforce of 11 specialists from nine countries was formed. Preliminary conclusions are: 1) Immunohistochemistry for CMMRD should be considered for all patients with suggestive clinical features. In countries where CMMRD is common, malignant gliomas, colon cancers and T cell lymphomas should be stained routinely as the prevalence of CMMRD in these tumors can exceed 40%. 2) Temozolomide should not be used in the management of malignant glioma. By contrast, preclinical studies have suggested increased sensitivity to nitrosoureas. For the management of CMMRD related lymphoma and leukemia, mercaptopurines should not be avoided or discontinued as a part of the standard of care before more data are collected. 3) Management with checkpoint inhibitors should be limited to centers with intensive care units and expertise in complex supportive care to manage side effects of immune therapy. 4) Surveillance protocols have demonstrated long term survival benefits and should be implemented in LMIC.

Purpose The management of central nervous system tumors is challenging in low- and middle-income countries. Little is known about applicability of twinning initiatives with high-income countries in neuro-oncology. In 2004, a monthly neuro-oncology video-teleconference program was started between King Hussein Cancer Center (Amman, Jordan) and the Hospital for Sick Children (Toronto, Ontario, Canada). More than 100 conferences were held and > 400 cases were discussed. The aim of this work was to assess the sustainability of such an initiative and the evolution of the impact over time. Methods We divided the duration in to three eras according to the initial 2 to 3 years of work of three consecutive oncologists in charge of the neuro-oncology program at King Hussein Cancer Center. We retrospectively reviewed the written minutes and compared the preconference suggested plans with the postconference recommendations. Impact of changes on the patient care was recorded. Results Thirty-three sets of written minutes (covering 161 cases) in the middle era and 32 sets of written minutes (covering 122 cases) in the last era were compared with the initial experience (20 meetings, 72 cases). Running costs of these conferences has dropped from $360/h to < $40/h. Important concepts were introduced, such as multidisciplinary teamwork, second-look surgery, and early referral. Suggestions for plan changes have decreased from 44% to 30% and 24% in the respective consecutive eras. Most recommendations involved alternative intervention modalities or pathology review. Most of these recommendations were followed. Conclusion Video-teleconferencing in neuro-oncology is feasible and sustainable. With time, team experience is built while the percentage and the type of treatment modifications change. Commitment and motivation helped maintain this initiative rather than availability of financial resources. Improvement in patients’ care was achieved, in particular, with the implementation of a multidisciplinary team and the continuous effort to implement recommendations.

Diffuse Intrinsic Pontine Glioma (DIPG) is a universally fatal tumor with significant burden on families. Experiences from a developing country are rarely reported. We reviewed the medical charts of children treated for DIPG at KHCC/Jordan between 1/2008 and 9/2015 and fulfilled the radiological diagnostic criteria. We evaluated their clinical characteristics and disease burden. Twenty-eight patients were identified (50% females, 20 Jordanians). Median age 7.9years (3.1–17.6years). Twenty-three patients (82%) had 2/3 symptoms of long tracts, ataxia and cranial nerve deficits at median duration 7weeks (2-24weeks). Two patients had initial spinal metastasis; one was paralyzed. Five (19%) had attempted tumor biopsy. Three patients didn’t receive radiotherapy; two refused and one intubated earlier. Median time to begin radiation was 15days (2-35days) with median duration 42days (35-64days). All patients except 3 received dexamethasone at diagnosis, mostly high dose >8mg/day for > 60days. Fifteen patients (63%) improved with radiation and 4 stabilized. Seventeen follow-up MRIs showed tumor shrinkage (5), stability (8) and progression (4). Seventeen patients required 1–5 hospitalizations (median 4 total days/ patient, 1-150days) most due to respiratory distress, altered-consciousness and near-death. All patients had DNR code except two died intubated (parental refusal). Median duration between DNR code and death was 127days (25-478days). While ten patients lost follow up, eighteen died at median 7.9months (1.3-16months); sixteen died hospitalized. With the disease rapid course and dismal prognosis, oncologists in developing countries should avoid unnecessary interventions (biopsy, follow-up MRIs, intubation) and advocate for palliative home care.

Background Results of high-dose chemotherapy (HDCT) protocols for the management of malignant central nervous system (CNS) tumors in infants are mostly reported in high-income countries. We evaluated the feasibility and results of such protocols in a middle-income country (Jordan). Methods A retrospective study of infants' charts with CNS tumors between 2006 and 2015 who were treated according to HeadStart (HS) protocols. Data included patients' demographics, chemotherapy complications, and cost. Results We identified 18 patients with median age 29 months (range, 9-62 months) at diagnosis (12 HS-I and six HS-II). Distribution according to pathology was: atypical teratoid rhabdoid tumors (ATRT) (nine), primitive neuoroectodermal tumors (PNET)/pineoblastoma (five), and medulloblastoma (four). Six patients (33%) had metastatic disease, and 14 (78%) had an incomplete resection. Eleven patients achieved partial or complete remission, two stabilized, and five progressed. Ten patients did not proceed to HDCT due to progression (five), financial reasons (two), failure to collect stem cells (one), and undocumented reasons (two). Seventy-eight chemotherapy cycles were administered (median interval 26 days). Main complications during induction and consolidation were febrile neutropenia (73% and 100%), documented infections (8% and 13%), and mucositis (12% and 88%), respectively. Three patients developed moderate hearing loss. No protocol-related mortality was reported. At the last follow-up, five patients were alive: three with medulloblastoma (19, 29, and 89 months) and two with ATRT (18 and 42 months). Three survivors received focal/craniospinal radiation. The median cost of a complete HS protocol, excluding surgery/radiotherapy, was $103 500 per patient; 39% of the median cost was related to pharmacy expenses. Conclusions These protocols were manageable in our context of limited health care resources. However, considering the significant costs and the modest survival rate, better selection criteria need to be used to identify patients likely to benefit from this approach.

Pleomorphic xanthoastrocytoma is a rare brain tumor with unique high frequency of BRAF V600E mutation which is plausible for targeted therapy. The anaplastic variant has generally worse prognosis. We present an adolescent patient with a disseminated relapse of anaplastic pleomorphic xanthoastrocytoma following surgery, radiotherapy, and chemotherapy. She had a dramatic and prolonged response to a BRAF inhibitor (Dabrafinib) and later to addition of a MEK inhibitor (Trametinib) on tumor progression. With minimal side effects and a good quality of life, the patient is alive more than 2 years after initiation of targeted therapy. This experience confirms the potential role of targeted treatments in high-grade BRAF-mutated brain tumors.

Biallelic mismatch repair deficiency (bMMRD) is a cancer predisposition syndrome affecting primarily individuals from consanguinous families resulting in multiple childhood cancers including high grade gliomas (HGG). This is the first study to assess the prevalence of bMMRD among patients with HGG in countries where consanguinity is high. We collected molecular and clinical information on all children diagnosed with HGG and supratentorial primitive neuroectodermal tumors (sPNET) between 2003 and 2013 at King Hussein Cancer Center, Jordan. Comparison was made to a similar cohort from Toronto. Clinical data regarding presence of cafe au lait macules(CAL), family history of cancer, consanguinity, pathology and treatment were collected. Tumors were centrally reviewed and tested for MMRD by immunohistochemistry of the corresponding proteins. Forty-two patients fulfilled the inclusion criteria, including 36 with HGG. MMRD was observed in 39% of HGG of whom 79% also lost MMR staining in the corresponding normal cells suggestive of bMMRD. P53 dysfunction was highly enriched in MMR deficient tumors (p = 0.0003).The frequency of MMRD was significantly lower in Toronto cohort (23%, p = 0.03). Both evidence of CAL and consanguinity correlated with bMMRD (p = 0.005 and 0.05,respectively) but family history of cancer didn't. HGG with all three bMMRD risk factors had evidence of MMRD and all children affected by multiple bMMRD related cancers had identical gene loss by immunohistochemical staining. In Jordan, the frequency of clinical and immunohistochemical alterations suggestive of bMMRD in pediatric HGG is high. Genetic testing will enable appropriate counseling and cancer screening to improve survival of these patients.

Synchronous primary malignant brain tumors are rare. We present a 5-year-old boy with synchronous glioblastoma and medulloblastoma. Both tumor samples had positive p53 stain and loss of PMS2 and MLH1 stains. The child had multiple café au lait spots and a significant family history of cancer. After subtotal resection of both tumors, he received craniospinal radiation with concomitant temozolomide followed by chemotherapy, alternating cycles of cisplatin/lomustine/vincristine with temozolomide. Then, he started maintenance treatment with cis-retinoic acid (100 mg/m(2)/day for 21 days). He remained asymptomatic for 34 months despite a follow-up brain MRI consistent with glioblastoma relapse 9 months before his death. Cis-retinoic acid may have contributed to prolong survival in this child with a probable biallelic mismatch repair syndrome.

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare tumor of the CNS mostly seen in infants and is often associated with a dismal outcome. Despite the heterogeneous morphology and/or immunoprofile, its diagnosis nowadays relies on the negative INI-1/BAF47 nuclear immunostain in tumor cells. We aim to investigate a number of immunohistochemical antibodies as potential diagnostic and prognostic markers. All AT/RT cases in patients younger than 18 years of age were included. Demographics, clinical features and outcome were collected. Immunostains tested included SALL-4, OCT3/4, CD99, FLI-1, cyclin-D1, β-catenin, P53, P16, CDX2 and WT-1. Nineteen cases (10 males) were identified at our center between 2004-2013 with a median age of 24 months. Ten (52.6%) cases were supratentorial. Six (42.9%) cases showed metastasis at time of presentation. Chemotherapy was administered to 10 (62.5%) and radiotherapy to seven (43.8%). The median overall survival was 11 months. A single long-term survival of 104 months was identified. Pathologically, most cases showed an admixture of rhabdoid cells and/or small cells and/or pale cells in variable proportions. Of all tested antibodies, only positivity for FLI-1 was associated with improved survival (P = 0.0012), while positivity for cyclin-D1 showed a trend toward improved survival (P = 0.0547). CDX2 was positive only in the single long-term survival. Interestingly, two cases showed co-expression of CD99 and FLI-1, and some were positive for SALL-4. In conclusion, FLI-1 and cyclin-D1 are potential prognostic markers associated with better outcome. Occasional AT/RT cases might co-express CD99 and FLI-1 as well as SALL-4, a potential diagnostic pitfall with Ewing sarcoma/ primitive neuroectodermal tumors and germ cell tumors, respectively.

The BRAF-V600E mutation is found in 15–20% of pediatric low grade gliomas (PLGG) and result in worse outcome and higher risk of transformation to high grade gliomas (PHGG). Although ongoing trials are assessing the role of BRAF inhibitors (BRAFi) in these children, data are still limited. We aimed to report overall response rates and predictors of outcome in childhood BRAF-V600E gliomas. We collected clinical, imaging and molecular information of patients treated with BRAFi outside trials from centers participating in the PLGG taskforce. Response was calculated by RANO criteria and follow up data were collected for all patients. Sixty-six patients were treated with BRAFi (55 PLGG and 11 PHGG); median follow-up time was 1.5 years (0.1-5y). In PLGG, objective response (tumor reduction of >25%) was observed in 77% compared to 15% in a cohort treated with conventional chemotherapy (pCDKN2A deletion was not associated with lack of response, while specific enhancing patterns correlated strongly with response to BRAFi. Two-year PFS for the BRAF-V600E PLGG was 74% vs 47% for BRAFi vs chemotherapy, respectively (p=0.02). Our data reveal rapid, dramatic and sustained response of BRAF-V600E PLGG to BRAFi. These are in contrast to BRAF-V600E PHGG and non-enhancing PLGG. Additional molecular analyses are being performed to identify poor responders and emerging mechanisms of resistance in these tumors.

Background Limited data are available on disease characteristics and outcome of children with cancer who contracted the H1N1 influenza infection during the 2009 pandemic. Methods All 76 pediatric patients with cancer and documented H1N1 infection who presented to the Pediatric Department at King Hussein Cancer Center (KHCC) between October 1 and December 1, 2009 were reviewed for clinical characteristics and course of the disease. Results Two-thirds of the patients had hematological malignancies and half were receiving non-intensive chemotherapy at the time of infection. With the exception of two patients who needed pediatric intensive care unit admission, the course of the remaining patients was uneventful whether they were hospitalized or not. No deaths related to H1N1 influenza infection were reported. Sixty-three percent of patients became afebrile within 48 hr of receiving oseltamivir. One-third of hospitalized patients were discharged in

BACKGROUND: Medulloblastoma is comprised of four distinct molecular subgroups (WNT, SHH, Group3,Group4) with unique clinical and prognostic implications. However, this relationship is rarely reported in the Middle East. METHODS: We assembled an institutional cohort of children

Activation of the MAPK pathway represents a hallmark of pediatric low-grade glioma (pLGG) and is frequently caused by BRAF alterations. BRAF-V600E represent an aggressive type of pLGG with less than optimal response to conventional chemo-radiation approaches. While clinical trials using BRAF-V600E inhibitors are ongoing, these data are not yet available. We have assembled an international cohort of BRAF-V600E glioma patients treated off-label with BRAF inhibitors as a monotherapy. Complete molecular, clinical and imaging data is being collected and compared to previous chemo-radiation therapies. Ongoing data form the taskforce on 40 BRAF-V600E gliomas from 25 international institutions is summarized below. The most prevalent histologies were ganglioglioma, pilocytic astrocytoma and pleomorphic xanthoastrocytoma, located mainly in the chiasm, brainstem and temporal lobes. Strikingly, 66% of BRAF V600E pLGG patients achieved partial response (PR) to targeted inhibitors versus only 6.6% response to conventional chemotherapy (p

e22506Background: Medulloblastoma is comprised of four distinct molecular subgroups (Wnt, SHH, Group3 ,Group4) with unique clinical and prognostic implications. However, this relationship is rarely...

Effective treatment of children with low grade glioma (LGG) requires a functioning multi-disciplinary team with adequate neurosurgical, neuroradiological, pathological, radiotherapy and chemotherapy facilities and personnel. In addition, the treating centre should have the capacity to manage a variety of LGG and treatment-associated complications. These requirements have made it difficult for many centers in low and middle-income countries (LMIC) to offer effective treatment and follow up. This article provides management recommendations for children with LGG according to the level of facilities available.

Biallelic mismatch repair deficiency (bMMRD) is a cancer predisposition syndrome affecting primarily individuals from consanguinous families resulting in multiple childhood cancers including high grade gliomas (HGG). This is the first study to assess the prevalence of bMMRD among patients with HGG in countries where consanguinity is high. We collected molecular and clinical information on all children diagnosed with HGG and supratentorial primitive neuroectodermal tumors (sPNET) between 2003 and 2013 at King Hussein Cancer Center, Jordan. Comparison was made to a similar cohort from Toronto. Clinical data regarding presence of café au lait macules(CAL), family history of cancer, consanguinity, pathology and treatment were collected. Tumors were centrally reviewed and tested for MMRD by immunohistochemistry of the corresponding proteins. Forty-two patients fulfilled the inclusion criteria, including 36 with HGG. MMRD was observed in 39% of HGG of whom 79% also lost MMR staining in the corresponding normal cells suggestive of bMMRD. P53 dysfunction was highly enriched in MMR deficient tumors (p = 0.0003).The frequency of MMRD was significantly lower in Toronto cohort (23%, p = 0.03). Both evidence of CAL and consanguinity correlated with bMMRD (p = 0.005 and 0.05,respectively) but family history of cancer didn't. HGG with all three bMMRD risk factors had evidence of MMRD and all children affected by multiple bMMRD related cancers had identical gene loss by immunohistochemical staining. In Jordan, the frequency of clinical and immunohistochemical alterations suggestive of bMMRD in pediatric HGG is high. Genetic testing will enable appropriate counseling and cancer screening to improve survival of these patients.

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare tumor of the CNS mostly seen in infants and is often associated with a dismal outcome. Despite the heterogeneous morphology and/or immunoprofile, its diagnosis nowadays relies on the negative INI-1/BAF47 nuclear immunostain in tumor cells. We aim to investigate a number of immunohistochemical antibodies as potential diagnostic and prognostic markers. All AT/RT cases in patients younger than 18 years of age were included. Demographics, clinical features and outcome were collected. Immunostains tested included SALL-4, OCT3/4, CD99, FLI-1, cyclin-D1, β-catenin, P53, P16, CDX2 and WT-1. Nineteen cases (10 males) were identified at our center between 2004-2013 with a median age of 24 months. Ten (52.6%) cases were supratentorial. Six (42.9%) cases showed metastasis at time of presentation. Chemotherapy was administered to 10 (62.5%) and radiotherapy to seven (43.8%). The median overall survival was 11 months. A single long-term survival of 104 months was identified. Pathologically, most cases showed an admixture of rhabdoid cells and/or small cells and/or pale cells in variable proportions. Of all tested antibodies, only positivity for FLI-1 was associated with improved survival (P = 0.0012), while positivity for cyclin-D1 showed a trend toward improved survival (P = 0.0547). CDX2 was positive only in the single long-term survival. Interestingly, two cases showed co-expression of CD99 and FLI-1, and some were positive for SALL-4. In conclusion, FLI-1 and cyclin-D1 are potential prognostic markers associated with better outcome. Occasional AT/RT cases might co-express CD99 and FLI-1 as well as SALL-4, a potential diagnostic pitfall with Ewing sarcoma/ primitive neuroectodermal tumors and germ cell tumors, respectively.

Pediatric central nervous system tumors are a leading cause of cancer-related mortality and morbidity in high-income countries. Limited data are available concerning the incidence of these tumors in low-income countries, due to lack of proper cancer registries and shortage of publications. The management of childhood brain tumors faces several challenges in countries with limited resources. Delayed presentation, insufficient number of specialists (pediatric neurosurgeons, pediatric oncologists, and radiation oncologists), and shortage of radiological diagnostic tools like MRI, of neurosurgical equipment, or of radiation machines are significant obstacles. In addition, abandonment of treatment and loss of follow-up are common, mostly for social or economic reasons. Pediatric neuro-oncology is relatively a new subspecialty and requires close multidisciplinary teamwork. This is attempted but not efficiently executed in many developing countries. Some of these difficulties can be managed by enriching the resources through international collaborations; others may need shared experience with more advanced countries through twinning programs. Successful experiences have been conducted in the recent years that demonstrate the possibility to improve the care of children with brain tumors in countries with limited resources.

Purpose To describe a medication error of intrathecal Cytarabine overdose that was managed conservatively with no apparent toxicities. Summary An 11-year-old girl was diagnosed with bone marrow relapsed precursor B-cell acute lymphoblastic leukemia. According to her chemotherapy protocol, she was started on triple intrathecal chemotherapy consisting of Methotrexate, Cytarabine and Hydrocortisone on day 1 of the protocol. After the intrathecal therapy being administered to the patient, the pharmacist who checked the medication realized that the wrong formulation of Cytarabine was used to prepare the intrathecal therapy; this error resulted in five times overdose of Cytarabine. The patient was then managed conservatively without cerebrospinal fluid exchange. Our patient remained clinically and neurologically stable without apparent toxicities and was discharged safely from hospital. Conclusion Supportive care without the need for invasive procedures such as cerebrospinal fluid exchange may be adequate for managing intrathecal Cytarabine overdose.

Paediatric central nervous system tumours are a leading cause of cancer-related mortality and morbidity in high-income countries. Limited data are available concerning the incidence of these tumours in low-income countries, due to lack of proper cancer registries and shortage of publications. The management of childhood brain tumours face several challenges in countries with limited resources. Delayed presentation, insufficient number of specialists (paediatric neurosurgeons, paediatric oncologists and radiation oncologists), shortage of radiological diagnostic tools like MRI, of neurosurgical equipment or radiation machines are significant obstacles. In addition, abandonment of treatment and loss of follow-up are common, mostly for social or economic reasons. Paediatric neuro-oncology is relatively a new subspecialty and requires close multidisciplinary team work. This concept is not emphasized in many developing countries. Some of these difficulties can be managed by enriching the resources through international collaborations; others may need shared experience with more advanced countries through twinning programs. Successful experiences have been conducted in the recent years that demonstrate the possibility to improve the care of children with brain tumours in countries with limited resources.

Limited data are available on disease characteristics and outcome of children with cancer who contracted the H1N1 influenza infection during the 2009 pandemic.All 76 pediatric patients with cancer and documented H1N1 infection who presented to the Pediatric Department at King Hussein Cancer Center (KHCC) between October 1 and December 1, 2009 were reviewed for clinical characteristics and course of the disease.Two-thirds of the patients had hematological malignancies and half were receiving non-intensive chemotherapy at the time of infection. With the exception of two patients who needed pediatric intensive care unit admission, the course of the remaining patients was uneventful whether they were hospitalized or not. No deaths related to H1N1 influenza infection were reported. Sixty-three percent of patients became afebrile within 48 hr of receiving oseltamivir. One-third of hospitalized patients were discharged in3 days.The course of H1N1 influenza infection in children with cancer appears to be mild in most cases.

e21023 Background: Children with high grade gliomas (HGG) continue to have a poor prognosis despite the use of multimodality therapy. HGG may rarely occur as part of cancer predisposition syndromes (CPS) and to be associated with other primary second cancers (PSC). We aim to evaluate the incidence of PSC with HGG at King Hussein Cancer Center, Jordan Methods: We retrospectively reviewed neurooncology database between 2003 -2013. We included patients > 3 and < 18 years and in whom we could review and confirm HGG diagnosis. We described their clinical characteristics, survival and incidence of PSC Results: 42 patients were identified (29 males, 24 Jordanians). Median age was 11.3 years (3.1-17.9). Main presenting symptoms were increased intracranial pressure in 22 (52%), focal deficits in 13 and convulsions in 10. Fourteen (67%) patients with available clinical data had cafe au lait spots (CAL). Family history of cancer was reported in 13/31 and consanguinity in 10/30. Twelve patients (29%) had near total t...