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Treatment of the tumor and dural margin with surgery and sometimes radiation are cornerstones of therapy for meningioma. Molecular classifications have provided insights into the biology of disease; however, response to treatment remains heterogeneous. In this study, we used retrospective data on 2,824 meningiomas, including molecular data on 1,686 tumors and 100 prospective meningiomas, from the RTOG-0539 phase 2 trial to define molecular biomarkers of treatment response. Using propensity score matching, we found that gross tumor resection was associated with longer progression-free survival (PFS) across all molecular groups and longer overall survival in proliferative meningiomas. Dural margin treatment (Simpson grade 1/2) prolonged PFS compared to no treatment (Simpson grade 3). Molecular group classification predicted response to radiotherapy, including in the RTOG-0539 cohort. We subsequently developed a molecular model to predict response to radiotherapy that discriminates outcome better than standard-of-care classification. This study highlights the potential for molecular profiling to refine surgical and radiotherapy decision-making.
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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.
Assuntos
Glioma , Isocitrato Desidrogenase , Humanos , Isocitrato Desidrogenase/genética , Glioma/genética , Epigenômica , Mutação/genética , TranscriptomaRESUMO
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.
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Procedimentos Cirúrgicos Ambulatórios , Diabetes Mellitus , Adulto , Humanos , Analgésicos Opioides/uso terapêutico , Canadá , Diabetes Mellitus/tratamento farmacológico , Tempo de Internação , Readmissão do Paciente , Seleção de Pacientes , Complicações Pós-Operatórias/tratamento farmacológico , Estudos RetrospectivosRESUMO
In 1950, Dwight Parkinson was the first qualified neurosurgeon to arrive in Winnipeg, Manitoba. He played a monumental role in developing one of the earliest neurosurgical training programs in Western Canada. Parkinson was a pioneering neurosurgeon who served as the first president of the Canadian Neurosurgical Society in 1965. He was the epitome of the skull base neurosurgeon, which was not recognized as a distinct discipline at that time. He contributed to its development through detailed neuroanatomical study of the lateral sellar compartment (housing the parasellar venous plexus, a term he emphasized as more accurate than "cavernous sinus"). Parkinson also made seminal contributions to the management of cerebrovascular disease and offered new insights on cerebral concussion. Parkinson's dedication to clinical excellence and education laid a cornerstone for the development of neurosurgery and the neurosciences in Manitoba, making him a key figure in Canadian neurosurgery. Using published materials, online resources, hospital archives, and personal interviews, the authors conducted a systematic review of Parkinson's formative years, his development of the Section of Neurosurgery at the University of Manitoba, his achievements, and his legacy. This updated biography captures the exploits of this remarkable, and at times strictly disciplinarian, neurosurgeon-anatomist.
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OBJECTIVE: Diabetic sensorimotor polyneuropathy (DSPN) affects approximately half of diabetic patients leading to significant morbidity. There is impaired neurotrophic growth factor signaling, AMP-activated protein kinase (AMPK) activity and mitochondrial function in dorsal root ganglia (DRG) of animal models of type 1 and type 2 diabetes. We hypothesized that sub-optimal insulin-like growth factor 1 (IGF-1) signaling in diabetes drives loss of AMPK activity and mitochondrial function, both contributing to development of DSPN. METHODS: Age-matched control Sprague-Dawley rats and streptozotocin (STZ)-induced type 1 diabetic rats with/without IGF-1 therapy were used for in vivo studies. For in vitro studies, DRG neurons from control and STZ-diabetic rats were cultured and treated with/without IGF-1 in the presence or absence of inhibitors or siRNAs. RESULTS: Dysregulation of mRNAs for IGF-1, AMPKα2, ATP5a1 (subunit of ATPase), and PGC-1ß occurred in DRG of diabetic vs. control rats. IGF-1 up-regulated mRNA levels of these genes in cultured DRGs from control or diabetic rats. IGF-1 treatment of DRG cultures significantly (P < 0.05) increased phosphorylation of Akt, P70S6K, AMPK and acetyl-CoA carboxylase (ACC). Mitochondrial gene expression and oxygen consumption rate (spare respiratory capacity), ATP production, mtDNA/nDNA ratio and neurite outgrowth were augmented (P < 0.05). AMPK inhibitor, Compound C, or AMPKα1-specific siRNA suppressed IGF-1 elevation of mitochondrial function, mtDNA and neurite outgrowth. Diabetic rats treated with IGF-1 exhibited reversal of thermal hypoalgesia and, in a separate study, reversed the deficit in corneal nerve profiles. In diabetic rats, IGF-1 elevated the levels of AMPK and P70S6K phosphorylation, raised Complex IV-MTCO1 and Complex V-ATP5a protein expression, and restored the enzyme activities of Complex IV and I in the DRG. IGF-1 prevented TCA metabolite build-up in nerve. CONCLUSIONS: In DRG neuron cultures IGF-1 signals via AMPK to elevate mitochondrial function and drive axonal outgrowth. We propose that this signaling axis mediates IGF-1-dependent protection from distal dying-back of fibers in diabetic neuropathy.
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Diabetes Mellitus Tipo 1/metabolismo , Neuropatias Diabéticas/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Mitocôndrias/metabolismo , Proteínas Quinases/metabolismo , Células Receptoras Sensoriais/metabolismo , Quinases Proteína-Quinases Ativadas por AMP , Animais , Células Cultivadas , Diabetes Mellitus Tipo 1/complicações , Neuropatias Diabéticas/etiologia , Feminino , Masculino , Camundongos , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Crescimento Neuronal , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais/patologia , Transdução de SinaisRESUMO
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.