Metabologenomic characterization uncovers a clinically aggressive IDH mutant glioma subtype.

Mutations in the pivotal metabolic isocitrate dehydrogenase (IDH) enzymes are recognized to drive the molecular footprint of diffuse gliomas, and patients with IDH mutant gliomas have overall favorable outcomes compared to patients with IDH wild-type tumors. However, survival still varies widely among patients with IDH mutated tumors. Here, we aimed to characterize molecular signatures that explain the range of IDH mutant gliomas. By integrating matched epigenome-wide methylome, transcriptome, and global metabolome data in 154 patients with gliomas, we identified a group of IDH mutant gliomas with globally altered metabolism that resembled IDH wild-type tumors. IDH-mutant gliomas with altered metabolism have significantly shorter overall survival from their IDH mutant counterparts that is not fully accounted for by recognized molecular prognostic markers of CDKN2A/B loss and glioma CpG Island Methylator Phenotype (GCIMP) status. IDH-mutant tumors with dysregulated metabolism harbored distinct epigenetic alterations that converged to drive proliferative and stem-like transcriptional profiles, providing a window to target novel dependencies in gliomas.

Patient Selection Criteria in Ambulatory Spine Surgery: Single Canadian Provincial Experience.

BACKGROUND: Ambulatory spinal surgery is a care delivery model meant to improve patient outcomes and reduce in-hospital length of stay (LOS). We reviewed the experience of implementing an outpatient spine surgery program in Manitoba, Canada and highlight elements that can be used to reduce LOS and re-presentation to hospital. METHODS: This is a retrospective cohort study using data from the Canadian Spine Outcomes and Research Network and independent chart review of adult patients undergoing outpatient spinal surgery between 2015 and 2018. Patient demographics, comorbidities, perioperative course, LOS, and readmissions were analyzed. RESULTS: We included 217 patients in this analysis. The mean LOS was 36.2 hours; 71.98% of patients had a LOS <24 hours. A Kruskal-Wallis test by ranks analysis was conducted and identified 7 elements that correlated with prolonged length of stay (>1 day): age older than 55 (P = 0.027), body mass index >25 (P = 0.045), uncontrolled diabetes (P = 0.015), preoperative use of opioid medication (P = 0.024), American Society of Anesthesiologists classification of 3 (P = 0.023), non-minimally invasive surgical approach, and multilevel procedures. Most (94.1%) of the patients with none of these elements (i.e., age <55, low body mass index, normal/controlled diabetes, minimal preoperative opioid use, American Society of Anesthesiologist classification <3, minimally invasive surgical procedure) had a favorable LOS, <24 hours, compared with 84.8% with 1 risk factor, 80.4% of those with two, 69.8% with three, 53.1% with four, and 31.2% with 5 or more. A small number of patients (14.98%) presented to an emergency department within 90 days of their operation, and there was a 6.28% readmission rate. CONCLUSIONS: We identified several patient and surgical criteria that correlate with prolonged length of stays following planned ambulatory spine surgery. Our work provides some empiric evidence to help guide surgeons on which patients and approaches are ideal for ambulatory surgery.

FLCN and AMPK Confer Resistance to Hyperosmotic Stress via Remodeling of Glycogen Stores.

Mechanisms of adaptation to environmental changes in osmolarity are fundamental for cellular and organismal survival. Here we identify a novel osmotic stress resistance pathway in Caenorhabditis elegans (C. elegans), which is dependent on the metabolic master regulator 5'-AMP-activated protein kinase (AMPK) and its negative regulator Folliculin (FLCN). FLCN-1 is the nematode ortholog of the tumor suppressor FLCN, responsible for the Birt-Hogg-Dubé (BHD) tumor syndrome. We show that flcn-1 mutants exhibit increased resistance to hyperosmotic stress via constitutive AMPK-dependent accumulation of glycogen reserves. Upon hyperosmotic stress exposure, glycogen stores are rapidly degraded, leading to a significant accumulation of the organic osmolyte glycerol through transcriptional upregulation of glycerol-3-phosphate dehydrogenase enzymes (gpdh-1 and gpdh-2). Importantly, the hyperosmotic stress resistance in flcn-1 mutant and wild-type animals is strongly suppressed by loss of AMPK, glycogen synthase, glycogen phosphorylase, or simultaneous loss of gpdh-1 and gpdh-2 enzymes. Our studies show for the first time that animals normally exhibit AMPK-dependent glycogen stores, which can be utilized for rapid adaptation to either energy stress or hyperosmotic stress. Importantly, we show that glycogen accumulates in kidneys from mice lacking FLCN and in renal tumors from a BHD patient. Our findings suggest a dual role for glycogen, acting as a reservoir for energy supply and osmolyte production, and both processes might be supporting tumorigenesis.