Clinical Audit of Survival Outcomes and Prognostic Factors in Adolescents and Adults with Medulloblastoma.

Purpose: Medulloblastomas, comprising 20%-25% of all primary brain tumors in children are much rarer in adulthood. Disease biology varies substantially across different age groups; however, owing to rarity, adults with medulloblastoma are traditionally treated using pediatric protocols. This is a retrospective audit of adolescent and adult medulloblastoma from a comprehensive cancer center. Methods: Data regarding demography, clinical presentation, imaging characteristics, histopathological features, molecular profiling, risk stratification, treatment details, and outcomes were retrieved from medical records. All time-to-event outcomes were analyzed using Kaplan-Meier method and compared with the log-rank test. Univariate and multivariate analysis of relevant prognostic factors was done with p value <0.05 being considered statistically significant. Results: A total of 162 patients ≥15 years of age with medulloblastoma were included. The median age was 25 years (range: 15-59 years) with leptomeningeal metastases seen in 31 (19%) patients at initial diagnosis. Following surgery, patients were treated with appropriate risk-stratified adjuvant therapy comprising of craniospinal irradiation plus boost with or without systemic chemotherapy. At a median follow-up of 50 months, 5-year Kaplan-Meier estimates of progression-free survival and overall survival were 53.5% and 59.5%, respectively. The addition of adjuvant systemic chemotherapy did not impact upon survival in standard-risk medulloblastoma. High-risk (HR) disease and anaplastic histology emerged as significant and independent predictors of poor survival on multivariate analysis. Conclusion: Medulloblastoma is a rare tumor in adolescents and adults with key differences in disease biology and resultant outcomes compared with the pediatric population. Contemporary management comprising maximal safe resection followed by appropriate risk-stratified adjuvant therapy provides acceptable survival outcomes.

Mitochondrial plasticity supports proliferative outgrowth and invasion of ovarian cancer spheroids during adhesion.

Background: Ovarian cancer cells aggregate during or after exfoliation from the primary tumor to form threedimensional spheroids. Spheroid formation provides a survival advantage during peritoneal dissemination in nutrient and oxygen-depleted conditions which is accompanied by a suppressed metabolic phenotype and fragmented mitochondria. Upon arrival to their metastatic sites, spheroids adhere to peritoneal organs and transition to a more epithelial phenotype to support outgrowth and invasion. In this study, we investigated the plasticity of mitochondrial morphology, dynamics, and function upon adhesion. Methods: Using our slow-developing (MOSE-L) and fast-developing (MOSE-LTICv) ovarian cancer models, we mimicked adhesion and reoxygenation conditions by plating the spheroids onto tissue culture dishes and changing culture conditions from hypoxia and low glucose to normoxia with high glucose levels after adhesion. We used Western Blot, microscopy and Seahorse analyses to determine the plasticity of mitochondrial morphology and functions upon adhesion, and the impact on proliferation and invasion capacities. Results: Independent of culture conditions, all spheroids adhered to and began to grow onto the culture plates. While the bulk of the spheroid was unresponsive, the mitochondrial morphology in the outgrowing cells was indistinguishable from cells growing in monolayers, indicating that mitochondrial fragmentation in spheroids was indeed reversible. This was accompanied by an increase in regulators of mitobiogenesis, PGC1a, mitochondrial mass, and respiration. Reoxygenation increased migration and invasion in both cell types but only the MOSE-L responded with increased proliferation to reoxygenation. The highly aggressive phenotype of the MOSE-LTICv was characterized by a relative independence of oxygen and the preservation of higher levels of proliferation, migration and invasion even in limiting culture conditions but a higher reliance on mitophagy. Further, the outgrowth in these aggressive cells relies mostly on proliferation while the MOSE-L cells both utilize proliferation and migration to achieve outgrowth. Suppression of proliferation with cycloheximide impeded aggregation, reduced outgrowth and invasion via repression of MMP2 expression and the flattening of the spheroids. Discussion: Our studies indicate that the fragmentation of the mitochondria is reversible upon adhesion. The identification of regulatory signaling molecules and pathways of these key phenotypic alterations that occur during primary adhesion and invasion is critical for the identification of druggable targets for therapeutic intervention to prevent aggressive metastatic disease.

Hippocampal radiotherapy dose constraints for predicting long-term neurocognitive outcomes: mature data from a prospective trial in young patients with brain tumors.

BACKGROUND: Hippocampus is considered to be the seat for neurocognitive functions. Avoidance of hippocampus during radiotherapy to brain may serve to preserve various domains of neurocognition. We aimed to derive radiotherapy dose constraints to hippocampi for preserving neurocognition in young patients with brain tumors by measuring various neurocognitive parameters. METHODS: Forty-eight patients with residual/progressive benign or low-grade brain tumors treated with stereotactic conformal radiotherapy (SCRT) to a dose of 54 Gy in 30 fractions underwent prospective neuropsychological assessments at baseline before SCRT and at 6 months and 2, 3, 4, and 5 years. Hippocampi were drawn as per the Radiation Therapy Oncology Group atlas. Longitudinal change in intelligence quotient scores was correlated with hippocampal doses. RESULTS: Mean volume of bilateral hippocampi was 4.35 cc (range: 2.12-8.41 cc). Craniopharyngioma was the commonest histologic subtype. A drop of >10% in mean full-scale intelligence quotient (FSIQ) scores at 3 and 5 years post SCRT was observed in patients in whom left hippocampus received a mean dose of 30.7 Gy (P = 0.04) and 31 Gy (P = 0.04), respectively. Mean performance quotient (PQ) scores dropped > 10% at 5 years when the left hippocampus received a dose of > 32 Gy (P = 0.03). There was no significant correlation of radiotherapy doses with verbal quotient, or with doses received by the right hippocampus. Multivariate analysis revealed young age (<13 y) and left hippocampus dose predicted for clinically relevant decline in certain neurocognitive domains. CONCLUSIONS: A mean dose of ≤30 Gy to the left hippocampus as a dose constraint for preserving intelligence quotient is suggested. KEY POINTS: 1. Children and young adults with benign and low-grade gliomas survive long after therapy.2. Higher dose to the hippocampi may result in long-term neurocognitive impairment.3. Mean dose of <30 Gy to left hippocampus could be used as a pragmatic dose constraint to prevent long-term neurocognitive decline.

Antimicrobial Sensitivity Pattern of Salmonella Typhi: Emergence of Resistant Strains.

Background Typhoid fever is still an important public health problem in developing countries. Increasing resistance of Salmonella Typhi to antibiotics is alarming. New extensively drug-resistant strains of Salmonella reported first time in Pakistan, resistant not only to first-line drugs and ciprofloxacin but also resistant to ceftriaxone, had spread globally, including the USA. Due to this continuously changing pattern of antimicrobial resistance in typhoid fever due to Salmonella Typhi, there is a substantial need to study the resistance pattern of Salmonella Typhi frequently in different areas to detect the new resistant strains timely. The objective of this study was to evaluate the current trends in the resistance pattern of Salmonella Typhi in a tertiary care hospital in Northern Punjab. Methods This cross-sectional study was conducted at the Department of Medicine, Pakistan Ordnance Factories (POF) Hospital Wah Cant in collaboration with the Department of Pathology, from 1st January 2019 to 30th September 2019. Culture-positive patients of typhoid fever age more than 12 years, either male or female, were included in the study. The antimicrobial susceptibility of the isolates was determined by the disc diffusion method of Kirby Bauer on Mueller-Hinton agar using Clinical Laboratory Standards Institute (CLSI) guidelines. The antimicrobial agents tested were ampicillin (10 µg), chloramphenicol (30 µg), trimethoprim/sulfamethoxazole (1.25/23.75 µg), ciprofloxacin (5 µg), ceftriaxone (30µg), azithromycin (15µg), imipenem (10µg) and meropenem (10µg). Results A total of 81 culture-positive patients were included in the study. Out of these, 59% were male, and 41 % were female. Mean age was 23.8±19.1 years ranging from 12 to 91 years. Salmonella Typhi showed the highest sensitivity to imipenem 100% and azithromycin 95%; the lowest sensitivity was to ciprofloxacin 3.7%. Almost 50% of patients were resistant to ceftriaxone, and 48% were resistant to meropenem. The number of multidrug-resistant cases reported was 20%, whereas 47% of strains were extensively drug-resistant. Conclusion Resistance to antimicrobial agents is increasing in patients with typhoid fever due to Salmonella Typhi; especially the extensively drug-resistant strains of Salmonella Typhi are increasing rapidly. New emerging strains resistant to carbapenems found in our study are a big threat. Prescription of antibiotics according to culture and sensitivity for sufficient duration in patients of typhoid fever due to Salmonella Typhi is necessary to prevent the emergence of new resistant strains.

Impact of WHO 2016 update of brain tumor classification, molecular markers and clinical outcomes in pleomorphic xanthoastrocytoma.

We present outcomes of pleomorphic xanthoastrocytoma (PXA) and correlate the impact of clinical, pathologic and molecular markers. Between 2006 and 2016, 37 patients with histologically verified PXA form the study cohort. All underwent maximal safe resection; those who had good resection and young age were observed. Adjuvant radiotherapy was given in patients with some atypical features such as high MIB-1 index (> 5%), residual disease or at recurrence. Patients with anaplastic PXA were administered adjuvant radiotherapy and systemic therapy. Median age at diagnosis was 20 years (range 4-45). At median follow-up of 33 months, 3-year and 5-year overall survival (OS) was 80.2 and 74% respectively. Patients who underwent GTR (23 cases, 62%) had significantly better 3-year PFS of 85.6% compared to 32.3% (p = 0.001) achieved with STR (13 cases, 35%). PFS was significantly superior in PXA grade II as compared to anaplastic PXA group (3-year estimates 80.2 vs. 32%; p = 0.007). 13 out of 27 patients where BRAFV600E testing was successful showed a mutation (48%). 3-year PFS and OS survival in BRAFV600E mutated patients was 51.9 and 76.9% compared to 73 and 75% in BRAFV600E non-mutated patients, respectively. No patient had IDH1 mutation. This data may provide valuable insights and act as a benchmark for future studies.

Demographic profile, clinicopathological spectrum, and treatment outcomes of primary central nervous system tumors: Retrospective audit from an academic neuro-oncology unit.

Primary tumors of the central nervous system are relatively uncommon, comprising only 1%-2% of all neoplasms. However, they constitute the second most common type of malignancy in children (after leukemia) and the leading cause of cancer-related morbidity and mortality in children and young adults worldwide. Globally, there is substantial variability with nearly five-fold difference in incidence between various parts of the world. Brain tumors are quite heterogeneous with regard to histology, biological behavior, and prognosis mandating multidisciplinary therapeutic decision-making. This retrospective audit of all consecutive patients registered in a single calendar year (2013) in the neuro-oncology disease management group at Tata Memorial Centre is reflective of the ground reality and fair representation of outcomes in routine neuro-oncologic practice.