Philadelphia Prostate Cancer Genetic Consensus Conference 2019 and implications for military medicine.

INTRODUCTION The objective of our review is to summarize the 2019 Philadelphia Prostate Cancer Genetic Consensus recommendations and discuss their implications to the US Military Health System. MATERIALS AND METHODS: Literature review. RESULTS: Our fighting force and retired service members will significantly benefit from the Philadelphia Prostate Cancer Genetic Consensus recommendations. Moreover, the experience of the equal access US Military Health System may help advancing genetic testing for cancer at national levels. CONCLUSIONS: Priorities recommended by the 2019 Consensus for more research on genetic predisposition to prostate cancer in racially diverse populations is a promising step. The US Military Health System has the ability of providing equal access to implement advanced germline testing for its racially diverse population.

The Quiescent Metabolic Phenotype of Glioma Stem Cells.

INTRODUCTION: Glioblastoma (GBM) is the most common primary malignant brain tumor in humans and, even with aggressive treatment that includes surgical resection, radiation (IR), and chemotherapy administration, prognosis is poor due to tumor recurrence. There is evidence that within GBMs a small number of glioma stem-like cells (GSLCs) exist, which are thought to be therapy resistant and are thus capable of repopulating a tumor after treatment. Like most cancers, GBMs largely employ aerobic glycolysis to create ATP, a phenomenon known as the Warburg Effect. There is no consensus on the metabolic characteristics of cancer stem cells. GSLCs have been shown to rely more heavily on oxidative phosphorylation, but there is also evidence that cancer stem cells can adapt their metabolism by fluctuating between energy pathways or acquiring intermediate metabolic phenotypes. We hypothesized that the metabolism of GSLCs differs from that of differentiated GBM tumor cell lines, and that the steady state metabolism would be differentially altered following radiation treatment. MATERIALS AND METHODS: We evaluated the oxygen consumption rate, extracellular acidification rate, and metabolic enzyme levels of GBM cell lines and GSLCs before and after irradiation using extracellular flux assays. We also measured absolute metabolite levels in these cells via mass spectroscopy with and without radiation treatment. RESULTS: GSLCs were found to be significantly more quiescent in comparison to adherent GBM cell lines, highlighted by lower glycolytic and maximal respiratory capacities as well as lower oxygen consumption and extracellular acidification rates. Analysis of individual metabolite concentrations revealed lower total metabolite concentrations overall but also elevated levels of metabolites in different energy pathways for GSLCs compared to GBM cell lines. Additionally, the metabolism of both GSLCs and GBM cell lines were found to be altered by IR. CONCLUSIONS: While there is not one metabolic alteration that distinguishes irradiated GSLC metabolism from that of GBM cell lines, therapies targeting more metabolically quiescent tumor cells and thus the resistant GSLC population may increase a cancer's sensitivity to radiotherapy.

Re-irradiation for recurrent glioma- the NCI experience in tumor control, OAR toxicity and proposal of a novel prognostic scoring system.

PURPOSE/OBJECTIVES: Despite mounting evidence for the use of re-irradiation (re-RT) in recurrent high grade glioma, optimal patient selection criteria for re-RT remain unknown. We present a novel scoring system based on radiobiology principles including target independent factors, the likelihood of target control, and the anticipated organ at risk (OAR) toxicity to allow for proper patient selection in the setting of recurrent glioma. MATERIALS/METHODS: Thirty one patients with recurrent glioma who received re-RT (2008-2016) at NCI - NIH were included in the analysis. A novel scoring system for overall survival (OS) and progression free survival (PFS) was designed to include:1) target independent factors (age, KPS (Karnofsky Performance Status), histology, presence of symptoms), 2) target control, and 3) OAR toxicity risk. Normal tissue complication probability (NTCP) calculations were performed using the Lyman model. Kaplan-Meier analysis was performed for overall survival (OS) and progression free survival (PFS) for comparison amongst variables. RESULTS: No patient, including those who received dose to OAR above the published tolerance dose, experienced any treatment related grade 3-5 toxicity with a median PFS and OS from re-RT of 4 months (0.5-103) and 6 months (0.7-103) respectively. Based on cumulative maximum doses the average NTCP was 25% (0-99%) for the chiasm, 21% (0-99%) for the right optic nerve, 6% (0-92%) for the left optic nerve, and 59% (0-100%) for the brainstem. The independent factor and target control scores were each statistically significant for OS and the combination of independent factors plus target control was also significant for both OS (p = 0.02) and PFS (p = 0.006). The anticipated toxicity risk score was not statistically significant. CONCLUSION: Our scoring system may represent a novel approach to patient selection for re-RT in recurrent high grade glioma. Further validation in larger patient cohorts including compilation of doses to tumor and OAR may help refine this further for inclusion into clinical trials and general practice.