Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. METHODS: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. FINDINGS: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. INTERPRETATION: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. FUNDING: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.

Using comprehensive genomic and functional analyses for resolving genotype-phenotype mismatches in children with suspected CMMRD in Lebanon: an IRRDC study.

Constitutional mismatch repair deficiency (CMMRD) is an aggressive and highly penetrant cancer predisposition syndrome. Because of its variable clinical presentation and phenotypical overlap with neurofibromatosis, timely diagnosis remains challenging, especially in countries with limited resources. Since current tests are either difficult to implement or interpret or both we used a novel and relatively inexpensive functional genomic assay (LOGIC) which has been recently reported to have high sensitivity and specificity in diagnosing CMMRD. Here we report the clinical and molecular characteristics of nine patients diagnosed with cancer and suspected to have CMMRD and highlight the challenges with variant interpretation and immunohistochemical analysis that led to an uncertain interpretation of genetic findings in 6 of the 9 patients. Using LOGIC, we were able to confirm the diagnosis of CMMRD in 7 and likely exclude it in 2 patients, resolving ambiguous result interpretation. LOGIC also enabled predictive testing of asymptomatic siblings for early diagnosis and implementation of surveillance. This study highlights the varied manifestations and practical limitations of current diagnostic criteria for CMMRD, and the importance of international collaboration for implementing robust and low-cost functional assays for resolving diagnostic challenges.

Vincristine-induced neurotoxicity in pediatric patients with rhabdomyosarcoma: A retrospective analysis of clinical features and outcome.

Vincristine is an essential component of rhabdomyosarcoma treatment. However, it can cause motor neurotoxicity, necessitating dose reductions. We retrospectively reviewed the rates and patterns of vincristine-induced motor neuropathy in children treated for rhabdomyosarcoma, and investigated effects on outcome. Fifteen of 43 patients (35%) developed motor neuropathies necessitating dose reductions, which ranged from 1.7% to 58% of planned cumulative dose. Older age was the only significant clinical risk factor. Almost half (47%) recovered during treatment with subsequent dose escalation. Most patients had complete resolution of symptoms upon follow-up. There was no discernible effect of treatment reduction on survival or relapse rates.

Isolated Central Nervous System Relapse Following Treatment Reduction in Low-risk Acute Lymphoblastic Leukemia at the Children's Cancer Center of Lebanon.

The aim of this trial was to decrease the incidence of life-threatening infections by decreasing the dose and the duration of dexamethasone treatment during maintenance therapy. This was a prospective, nonrandomized trial of low-risk acute lymphoblastic leukemia patients 1 to 18 years of age who were treated at the Children's Cancer Center of Lebanon (CCCL). Patients consecutively diagnosed between 2002 and 2013 were divided into groups 1 and 2 receiving total dexamethasone doses of 1144 and 618 mg/m, respectively. A total of 84 patients were assigned to group 1 and 33 patients to group 2. The 5-year cumulative incidence of isolated central nervous system relapse increased from (n=0% [95% confidence interval: 0%-4.4%]) in group 1 to 9.1% [95% confidence interval: 3%-23%]; P=0.021) in group 2. Decreasing cumulative dose of dexamethasone for low-risk childhood acute lymphoblastic leukemia patients aiming to avoid serious viral infections led to a significant increase in isolated central nervous system relapse.

Establishment of a formal program for retinoblastoma: Feasibility of clinical coordination across borders and impact on outcome.

Retinoblastoma is an ocular tumor that occurs in young children, in either heritable or sporadic manner. The relative rarity of retinoblastoma, and the need for expensive equipment, anesthesia, and pediatric ophthalmologic expertise, are barriers for effective treatment in developing countries. Also, with an average age-adjusted incidence of two to five cases per million children, patient number limits development of local expertise in countries with small populations. Lebanon is a small country with a population of approximately 4.5 million. In 2012, a comprehensive retinoblastoma program was formalized at the Children's Cancer Institute (CCI) at the American University of Beirut Medical Center, and resources were allocated for efficient interdisciplinary coordination to attract patients from neighboring countries such as Syria and Iraq, where such specialized therapy is also lacking. Through this program, care was coordinated across hospitals and borders such that patients would receive scheduled chemotherapy at their institution, and monthly retinal examinations and focal laser therapy at the CCI in Lebanon. Our results show the feasibility of successful collaboration across borders, with excellent patient and physician adherence to treatment plans. This was accompanied by an increase in patient referrals, which enables continued expertise development. However, the majority of patients presented with advanced intraocular disease, necessitating enucleation in 90% of eyes in unilateral cases, and more than 50% of eyes in bilateral cases. Future efforts need to focus on expanding the program that reaches to additional hospitals in both countries, and promoting early diagnosis, for further improvement of globe salvage rates.

Malignant rhabdoid tumors originating within and outside the central nervous system are clinically and molecularly heterogeneous.

Multifocal synchronous or metachronous atypical teratoid rhabdoid tumors (ATRTs) and non-central nervous system malignant rhabdoid tumors (extra-CNS MRTs) are rare cancers. We reviewed the clinical and radiologic characteristics of affected patients seen at our institution. Genotyping and analysis of copy number abnormalities (CNAs) in SMARCB1 were performed in germline and tumor samples. Tumor samples underwent genome-wide DNA methylation and CNA analysis. The median age at diagnosis of 21 patients was 0.6 years. Two-thirds of ATRTs and extra-CNS MRTs were diagnosed synchronously. Although kidney tumors predominated, including two patients with bilateral involvement, at least 30% of cases lacked renal involvement. Histopathologic review confirmed MRTs in all cases and INI1 expression loss in all tumors tested. Fourteen (78%) of 18 patients tested had heterozygous germline SMARCB1 abnormalities. At least one allelic SMARCB1 abnormality was confirmed in 81 and 88% of ATRTs and extra-CNS MRTs, respectively. Unsupervised hierarchical clustering analysis of DNA methylation in 27 tumors and comparison with a reference group of 150 ATRTs classified the CNS tumors (n = 14) as sonic hedgehog (64%), tyrosinase (21%), and MYC (14%). The MYC subgroup accounted for 85% of 13 extra-CNS MRTs. Of 16 paired ATRTs and extra-CNS MRTs, the tumors in seven of eight patients showed a different pattern of genome-wide DNA methylation and/or CNAs suggestive of non-clonal origin. CNS and extra-CNS tumors had an identical SMARCB1 amplification (n = 1) or very similar DNA methylation pattern (n = 1) suggestive of clonal origin. All patients died of tumor progression. The clinical and molecular characteristics of multifocal ATRTs and extra-CNS MRTs are heterogeneous with most patients harboring a cancer predisposition. Although independent tumor origin was confirmed in most cases, metastatic spread was also documented. The recognition of their distinct molecular characteristics is critical in selecting new biologic therapies against these deadly cancers.

Phase 1 trial, pharmacokinetics, and pharmacodynamics of dasatinib combined with crizotinib in children with recurrent or progressive high-grade and diffuse intrinsic pontine glioma.

BACKGROUND: Progressive/recurrent high-grade and diffuse intrinsic pontine gliomas (DIPGs) are fatal. Treatments targeting molecular pathways critical for these cancers are needed. METHODS: We conducted a phase 1 study (rolling-six design) to establish the safety and maximum tolerated dose (MTD) of dasatinib, an oral platelet-derived growth factor receptor A (PDGFRA) inhibitor, and crizotinib, an oral c-Met inhibitor, in such patients. Pharmacokinetics of both agents were performed. Biomarkers of cellular pathway activation in peripheral-blood mononuclear cells (PBMC) were evaluated before and after administration of dasatinib. PDGFRA and MET amplification, and PDGFRA mutations were studied in tumor samples. RESULTS: Twenty-five patients were enrolled in this study (median age: 11.9 years). Eleven patients had DIPG. Glioblastoma accounted for 40% of cases. Dasatinib at 50 mg/m2 and crizotinib at 130 mg/m2 or 100 mg/m2 were poorly tolerated when administered twice daily. Drug administration was then switched to once daily. Dasatinib administered at 50 mg/m2 and crizotinib at 215 mg/m2 once daily was the MTD. Dose-limiting toxicities consisted of diarrhea, fatigue, proteinuria, hyponatremia, rash, and grade 4 neutropenia. Only two patients received therapy for at least 6 months. No objective radiologic responses were observed. Pharmacokinetics of dasatinib and crizotinib were comparable to previous studies. A statistically significant decrease in the ratio of p-AKT/total AKT in PBMC occurred after dasatinib administration. PDGFRA and MET amplification were found in four and two cases, respectively. Only one of 10 tumors harbored a PDGFRA mutation. CONCLUSIONS: This drug combination was poorly tolerated and its activity was minimal. We do not recommend further testing of this combination in children.

Abnormalities in renal tubular phosphate handling in children with sickle cell disease.

BACKGROUND: The mechanisms responsible for the hyperphosphatemia in patients with sickle cell disease (SCD) and preserved glomerular filtration rate (GFR) are not fully understood. The role of fibroblast growth factor 23 (FGF23), a phosphaturic hormone has not been investigated in SCD. Hence, we evaluated parameters of renal tubular phosphorus handling and their relation to prevailing FGF23 levels in a cohort of young SCD patients. METHODS: Renal tubular phosphate handling and circulating levels of various analytes including FGF23 and parathyroid hormone (PTH) were measured in 24 children with SCD and normal estimated GFR in a cross sectional study. Correlation and regression analysis were employed to derive relationships between serum phosphorus and several variables. RESULTS: Most children showed elevated age- adjusted serum phosphorus (5.1 ± 0.7 mg/dl) levels. Tubular re-absorption of phosphorus(TRP) (96.3 ± 2.1%) and tubular maximum re-absorption of phosphorus per unit volume of GFR (TMP/GFR) (4.9 ± 0.6 mg/dl) were both elevated. Plasma intact FGF23 concentrations were elevated (81 ± 38 pg/ml) while the average PTH values were normal in most patients (50 ± 27 pg/ml). Univariate analysis showed significant correlations of serum phosphorus with TMP/GFR, alkaline phosphatase, age, lactate dehydrogenase (LDH), and log intact FGF23. TMP/GFR correlated with log intact FGF23 (r = 0.5, P< or = 0.01) but not with PTH. Multiple regression analysis yielded an independent relationship of serum phosphorus with TMP/GFR. CONCLUSION: The elevated serum phosphorus concentrations with simultaneously increased TMP/GFR and elevated FGF23 levels collectively suggest that patients with SCD display proximal tubular resistance to the action of FGF23 before any decline in GFR.

Albuminuria correlates with hemolysis and NAG and KIM-1 in patients with sickle cell anemia.

BACKGROUND: Although hyperfiltration and albuminuria are common pathological conditions, kidney injury (KI) biomarkers have been seldom studied in individuals with sickle cell anemia (SCA). METHODS: We undertook a cross-sectional assessment of urine KI biomarkers in children and adults with SCA with and without albuminuria and a normal estimated glomerular filtration rate (eGFR). Albumin, KI molecule 1 (KIM-1), N-acetyl-ß-D-glucosaminidase (NAG), endothelin-1 and transforming growth factor-ß1 (TGF-ß1) were measured. Assays were normalized by urine creatinine. Urine intracellular hemosiderin and serum lactate dehydrogenase (LDH) were assessed as markers of hemolysis. Albuminuria was associated to the biomarkers by Pearson and Spearman correlation coefficients. Differences between the albuminuria (yes, no) groups were assessed by the t test. RESULTS: Nineteen patients with albuminuria (mean urine albumin/creatinine 527.14 ± 1070 mg/g, range 38.3--190 mg/g) and 19 patients without albuminuria (mean urine albumin/creatinine 15.93 ± 5.17 mg/g, range 7.9-28.4 mg/g) were studied. The age range for the whole group was 11-48 years, and 47 % were males. Patients with albuminuria were older, had lower hematocrit, were more likely to test positive for urine hemosiderin and had a higher KIM-1 (P = 0.0035) and NAG/ creatinine ratios (P = 0.0062). Urine hemosiderin strongly correlated to a higher LDH level (P < 0.001). CONCLUSIONS: Despite a normal or increased eGFR, KI biomarkers were detected in the urine of individuals with SCA. NAG, KIM-1 and urine hemosiderin correlated with the presence of albuminuria.

Predictors of radiographic pneumonia in febrile children with cancer presenting to the emergency department.

BACKGROUND: Fever is a common presenting complaint to the pediatric emergency department (PED), especially among oncology patients. While bacteremia has been extensively studied in this population, pneumonia has not. Some studies suggest that chest X-ray (CXR) does not have a role in the investigation of neutropenic fever in the absence of respiratory symptoms, yet non-neutropenic pediatric oncology patients were excluded from these studies. OBJECTIVE: We aimed to determine the incidence of CXRs ordered for febrile pediatric oncology patients, irrespective of their absolute neutrophil count (ANC), and to evaluate the rates of radiographic pneumonia as well as predictors of the latter in this group. METHOD: This study was conducted in the PED at the American University of Beirut Medical Center (AUBMC), an Eastern Mediterranean tertiary-care hospital. We conducted a retrospective cohort study of acutely febrile pediatric cancer patients, younger than 18 years, presenting to a tertiary center from 2014 to 2018. We included one randomly selected febrile visit per patient. Fever was defined as a single oral temperature ≥38 °C within 24 h of presentation. We collected data on patient characteristics and outcomes. Our primary outcome was radiographic pneumonia; our secondary outcome was whether a CXR was done or not. We defined radiographic pneumonia as a consolidation, pleural effusion, infiltrate, pneumonia, "infiltrate vs. atelectasis," or possible pneumonia mentioned by the radiologist. SPSS was used for the statistical analysis. RESULTS: We reviewed a total of 664 medical charts and included data from 342 febrile pediatric patients in our analysis. Of these, 64 (18.7%) had a CXR performed. Overall, 16 (25%) had radiographic pneumonia while 48 (75%) did not. Patients were significantly more likely to have a CXR performed if they presented with upper respiratory tract symptoms, cough (p < 0.001 for both), or abnormal lung auscultation at the bedside (p = 0.004). Patients were also less likely to have a CXR done if they were asymptomatic upon admission to the PED (p < 0.001). However, neither cough nor shortness of breath nor abnormal lung examinations were significant predictors of a positive CXR (p = 0.17, 0.43, and 0.669, respectively). Patients with radiographic pneumonia were found to be significantly younger (4.29 vs. 6 years, p = 0.03), with a longer time since their last chemotherapy (15 vs. 7 days, p = 0.005), and were given intravenous (IV) bolus in the PED (87.5% vs. 56.3%, p = 0.02). Interestingly, patients with higher white blood cell (WBC) counts were more likely to have radiographic pneumonia (4850 vs. 1750, p = 0.01). Having a cough and an abnormal lung examination on presentation increased the odds of having a CXR (adjusted odds ratio [aOR]: 6.6; 95% confidence interval [CI]: 3.4-12.8 and aOR: 4.5; 95% CI: 1.1-18.3, respectively). Returning to the PED for the same complaint within 2 weeks was associated with lower odds of a CXR at the index visit (aOR: 0.3; 95% CI: 0.1-0.6). For every year the child is older, the odds of having radiographic pneumonia decreased by 0.8 (95% CI: 0.6-0.98). However, for every day since the last chemotherapy session, the odds increased by 1.1 (95% CI: 1.01-1.12). CONCLUSION: In our sample, CXR was not commonly performed in the initial assessment of febrile cancer patients in the PED, unless respiratory symptoms or an abnormal lung examination was noted. However, these were not significant predictors of radiographic pneumonia. Further studies are needed to identify better predictors of pneumonia in this high-risk population.

Sickle cell disease related mortality in the United States (1999-2009).

BACKGROUND: Little is known about the national outcome of children and adults with sickle cell disease (SCD) given contemporary care. PROCEDURE: We investigated the number of deaths, standardized crude and age-adjusted mortality rates, and causes of death among individuals with SCD across the United States during 1999-2009 according to death certificates by using a publicly available website (http://wonder.cdc.gov/). Data were compared to mortality during 1979-1998. RESULTS: When compared to 1979-1998, mortality significantly decreased by 61% in infants <1 year of age, by 67% in children aged 1-4 years, and by 22-35% in children aged 5-19 years. After 19 years of age, mortality rates increased from 0.6 in the 15-19 year group to 1.4/100,000 in the 20-24 year group, corresponding to the transition period from pediatric to adult medical care, and this increase was similar during 1979-1998. Although the age groups with the highest mortality were 35-44 years for males and 45-54 years for females, there was a tendency for longer survival because there were more deaths among those individuals 55-74 years of age compared to previous years. For all individuals, the causes of deaths were cardiac disease (31.6%), respiratory (28.1%), renal (16.4%), infectious (14.4%), neurologic (11.9%), and gastrointestinal and hepatobiliary (9.2%) in nature. Cancer was the cause of death in <1%. CONCLUSION: Mortality during childhood has decreased significantly. However, the transition period from pediatric to adult care is critical. Risk-reduction, monitoring, and early treatment intervention of cardiovascular disease in adults is warranted.

A Massive Ewing Sarcoma of the Rib: A Case Report with Literature Review.

A 9-year-old boy with a 16 cm chest wall mass, presenting with progressive cough and exertional dyspnea, was finally diagnosed with Ewing sarcoma of the rib. Such massive tumors usually present with metastasis and carry a bad prognosis. Fortunately, we present here a successful treatment approach for Ewing sarcoma of the ribs, defeating the overwhelming obstacles commonly faced in chest wall tumors. Delays in diagnosis, misdiagnosis, difficulty with general anesthesia, opportunistic infections, disruptions in chemotherapy delivery, and debilitating chest wall deformities are all potential challenges that could complicate the course of treatment.

Characteristics of patients ≥10 years of age with diffuse intrinsic pontine glioma: a report from the International DIPG/DMG Registry.

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG) generally occur in young school-age children, although can occur in adolescents and young adults. The purpose of this study was to describe clinical, radiological, pathologic, and molecular characteristics in patients ≥10 years of age with DIPG enrolled in the International DIPG Registry (IDIPGR). METHODS: Patients ≥10 years of age at diagnosis enrolled in the IDIPGR with imaging confirmed DIPG diagnosis were included. The primary outcome was overall survival (OS) categorized as long-term survivors (LTS) (≥24 months) or short-term survivors (STS) (<24 months). RESULTS: Among 1010 patients, 208 (21%) were ≥10 years of age at diagnosis; 152 were eligible with a median age of 12 years (range 10-26.8). Median OS was 13 (2-82) months. The 1-, 3-, and 5-year OS was 59.2%, 5.3%, and 3.3%, respectively. The 18/152 (11.8%) LTS were more likely to be older (P < .01) and present with longer symptom duration (P < .01). Biopsy and/or autopsy were performed in 50 (33%) patients; 77%, 61%, 33%, and 6% of patients tested had H3K27M (H3F3A or HIST1H3B), TP53, ATRX, and ACVR1 mutations/genome alterations, respectively. Two of 18 patients with IDH1 testing were IDH1-mutant and 1 was a LTS. The presence or absence of H3 alterations did not affect survival. CONCLUSION: Patients ≥10 years old with DIPG have a median survival of 13 months. LTS present with longer symptom duration and are likely to be older at presentation compared to STS. ATRX mutation rates were higher in this population than the general DIPG population.

Surgical techniques in the management of supratentorial pediatric brain tumors: 10 years' experience at a tertiary care center in the Middle East.

BACKGROUND: The goal of this retrospective study is to present the first epidemiological data on pediatric supratentorial central nervous system (CNS) tumors in Lebanon and to review the various surgical management strategies used. METHODS: We conducted a retrospective case series of all pediatric patients who presented with a supratentorial CNS tumor and underwent surgery at our institution between 2006 and 2016. We collected and analyzed demographic characteristics, tumor location, clinical manifestations, histopathology, and surgical management strategies and outcome, and discussed them after dividing the tumors as per location and in view of published literature. RESULTS: Ninety-nine children were studied with a male-to-female ratio of 2.3:1 and a mean age of 8.5 years. The most common location was convexity (44%) and included low-grade and high-grade glial tumors, along with other miscellaneous lesions. The next location was sellar/diencephalic (34%), including craniopharyngiomas, hypothalamic/optic pathway/thalamic gliomas, hamartomas, and pituitary/Rathke's cyst, where there was notable use of endoscopic techniques (21%). Tumors in the pineal region (13%) were tectal gliomas, germ cell tumors, and pineoblastomas and were mostly treated endoscopically. The last group was lateral intraventricular tumors (8%) and was mostly choroid plexus lesions and ependymomas. Overall, the surgical objective was achieved in 95% with mild/moderate complications in 17%. CONCLUSION: A variety of pathologies may affect the pediatric population in the supratentorial region. Different surgical strategies, including microsurgical and endoscopic techniques, may be employed to remove, debulk, or biopsy these tumors depending on their location, suspected diagnosis, prognosis, and the need for treatment of possible associated hydrocephalus.

Pediatric posterior fossa tumors outcomes: Experience in a tertiary care center in the Middle East.

BACKGROUND: Among all childhood cancers, brain tumors are second only to leukemia in incidence and are the most common solid pediatric tumors. More than 60 % of pediatric brain tumors are infra-tentorial. The first-line treatment for most infra-tentorial tumors in pediatric patients is surgical resection, with the goal of gross-total resection, relief of symptoms and hydrocephalus, and increased survival. The proximity to the fourth ventricle, and therefore, the cerebrospinal fluid (CSF) pathways, predisposes children with posterior fossa tumors to the development of obstructive hydrocephalus and multiple other co-morbidities pre and post-surgery. OBJECTIVES: This study aims to present our series of pediatric posterior fossa tumor surgeries in the Neurosurgical Department at the American University of Beirut Medical Center(AUBMC) and perform internal quality control for our single-institution consecutive series as one of the largest referral and tertiary care centers in the region. The second purpose of this retrospective study is to weigh the risks of surgery against the presumed advantages and to have specific knowledge about the complication rates, especially those related to the CSF pathway, comparing our results to those in the literature. METHODS: All pediatric patients (< 18 years of age), referred to our center from different regions in the middle east, and surgically treated for a posterior fossa tumor from June 2006 to June 2018 at the American University of Beirut Medical Center were included. A thorough review of all medical charts was performed to validate all the database records. RESULTS: The patient sample consisted of 64 patients having a mean age of 6.19 ±â€¯4.42 years and 59.37 % of whom were males. The most common tumor pathology was pilocytic astrocytoma (40.62 %) followed by medulloblastoma (35.93 %) and ependymoma. The most common type of tumor that was seen in patients that developed mutism postoperatively (n = 6, 9.37 %) was medulloblastoma (n = 4, 66.66 %). In this patient sample, 12.28 % (n = 7) of the patients developed hydrocephalus postoperatively.Midline tumors were more associated with the development of mutism(OR = 4.632, p = 0.306) and hydrocephalus (OR = 5.056, p = 0.135) postoperatively, albeit not statistically significantly.The presence of a preoperative shunt was shown to be protective against the development of CSF leak (OR = 0.636, p = 0.767), as none of the patients that came in with CSF diversion developed a CSF leak after their surgery. CONCLUSION: This study from a single center experience accompanied by a thorough literature review sheds light on the complications frequently encountered after posterior fossa tumor surgery in children. These included transient cerebellar mutism, CSF leak, and hydrocephalus as seen in some of our patients. Our findings highlight the need for prospective studies with well-defined protocols directed at assessing novel ways and approaches to minimize the risk of these complications.

Alternative lengthening of telomeres, ATRX loss and H3-K27M mutations in histologically defined pilocytic astrocytoma with anaplasia.

Anaplasia may be identified in a subset of tumors with a presumed pilocytic astrocytoma (PA) component or piloid features, which may be associated with aggressive behavior, but the biologic basis of this change remains unclear. Fifty-seven resections from 36 patients (23 M, 13 F, mean age 32 years, range 3-75) were included. A clinical diagnosis of NF1 was present in 8 (22%). Alternative lengthening of telomeres (ALT) was assessed by telomere-specific FISH and/or CISH. A combination of immunohistochemistry, DNA sequencing and FISH were used to study BRAF, ATRX, CDKN2A/p16, mutant IDH1 p.R132H and H3-K27M proteins. ALT was present in 25 (69%) cases and ATRX loss in 20 (57%), mostly in the expected association of ALT+/ATRX- (20/24, 83%) or ALT-/ATRX+ (11/11, 100%). BRAF duplication was present in 8 (of 26) (31%). H3-K27M was present in 5 of 32 (16%) cases, all with concurrent ATRX loss and ALT. ALT was also present in 9 (of 11) cases in the benign PA precursor, 7 of which also had ATRX loss in both the precursor and the anaplastic tumor. In a single pediatric case, ALT and ATRX loss developed in the anaplastic component only, and in another adult case, ALT was present in the PA-A component only, but ATRX was not tested. Features associated with worse prognosis included subtotal resection, adult vs. pediatric, presence of a PA precursor preceding a diagnosis of anaplasia, necrosis, presence of ALT and ATRX expression loss. ALT and ATRX loss, as well as alterations involving the MAPK pathway, are frequent in PA with anaplasia at the time of development of anaplasia or in their precursors. Additionally, a small subset of PA with anaplasia have H3-K27M mutations. These findings further support the concept that PA with anaplasia is a neoplasm with heterogeneous genetic features and alterations typical of both PA and diffuse gliomas.

Isolated Optic Nerve Glioma in Children With and Without Neurofibromatosis: Retrospective Characterization and Analysis of Outcomes.

Isolated optic nerve glioma is a rare tumor with no consensus for the best therapeutic approach. Therefore, tumor control and preservation of visual function remain a challenge. In this retrospective study, we describe our experience over 30 years in a single-institutional cohort of children with isolated optic nerve glioma, focusing on treatments and visual outcomes. Seventeen children were followed for a median period of 8 years (range, 2-22 years). Diagnosis was based on typical neuroradiologic findings, and 3 patients had histologic confirmation of their tumors. In our study, conservative management preserved the vision of most patients with neurofibromatosis type 1 (NF1). NF1-related optic nerve gliomas were less often treated but were associated with a lower probability of progression and with occasional spontaneous regression. Sporadic tumors more frequently exhibited aggressive clinical behavior with a higher propensity for posterior extension, often requiring surgical intervention.