Autophagy-dependent alternative splicing of ribosomal protein S24 produces a more stable isoform that aids in hypoxic cell survival.

Cells remodel splicing and translation machineries to mount specialized gene expression responses to stress. Here, we show that hypoxic human cells in 2D and 3D culture models increase the relative abundance of a longer mRNA variant of ribosomal protein S24 (RPS24L) compared to a shorter mRNA variant (RPS24S) by favoring the inclusion of a 22 bp cassette exon. Mechanistically, RPS24L and RPS24S are induced and repressed, respectively, by distinct pathways in hypoxia: RPS24L is induced in an autophagy-dependent manner, while RPS24S is reduced by mTORC1 repression in a hypoxia-inducible factor-dependent manner. RPS24L produces a more stable protein isoform that aids in hypoxic cell survival and growth, which could be exploited by cancer cells in the tumor microenvironment.

Contraindications to use of neuraxial anesthesia for lower limb revascularization surgery in adults: a cross-sectional study.

PURPOSE: Nonrandomized and some randomized data suggest neuraxial anesthesia may improve outcomes after lower limb revascularization surgery. Nevertheless, the prevalence of contraindications to neuraxial anesthesia in vascular surgery patients is unknown. We aimed to identify the prevalence of patients with contraindications to neuraxial anesthesia, and to derive and validate a case ascertainment algorithm identifying individuals likely to have contraindications. METHODS: We conducted a historical cross-sectional study of open lower limb revascularization surgeries performed between 2019 and 2021 at The Ottawa Hospital. Medical records were reviewed for demographic data, admission, procedural characteristics, and presence of contraindications to neuraxial anesthesia. Case ascertainment algorithms to predict the presence of absolute contraindications to neuraxial anesthesia were derived and internally validated. RESULTS: We identified 340 cases. General anesthesia was used in 219 (64.4%) cases, isolated neuraxial (spinal and/or epidural) in 106 (31.2%) cases, and general plus neuraxial in 15 (4.4%) cases. Seventy-eight (22.9%; 95% confidence interval [CI], 18.8 to 27.7) patients had absolute contraindications to neuraxial anesthesia, primarily because of anticoagulation or antiplatelet medication (89.4%); 21 (6.2%; 95% CI, 4.1 to 9.3) had relative contraindications, primarily long anticipated duration of surgery (16/21, 76.2%). We derived and validated three nested case-ascertainment algorithms. Using admission and procedure variables, discrimination was moderate with moderately explained variance, and calibration was inadequate for reliable use. Patient comorbidity and laboratory data did not improve algorithm performance. CONCLUSION: Most patients undergoing lower limb revascularization surgery did not have absolute contraindications to neuraxial anesthesia. When present, contraindications typically related to anticoagulation. Admission, procedure, comorbidity, and laboratory data did not provide adequate accuracy to ascertain contraindication status.

RéSUMé: OBJECTIF: Les données non randomisées et certaines données randomisées suggèrent que l'anesthésie neuraxiale pourrait améliorer les devenirs après une chirurgie de revascularisation des membres inférieurs. Néanmoins, la prévalence de contre-indications à l'anesthésie neuraxiale chez la patientèle de chirurgie vasculaire est inconnue. Notre objectif était d'identifier la prévalence de la patientèle présentant des contre-indications à l'anesthésie neuraxiale, et de dériver et valider un algorithme de détermination des cas identifiant les personnes susceptibles de présenter des contre-indications. MéTHODE: Nous avons mené une étude transversale historique sur les chirurgies ouvertes de revascularisation des membres inférieurs réalisées entre 2019 et 2021 à l'Hôpital d'Ottawa. Les dossiers médicaux ont été passés en revue pour en tirer les données démographiques, les détails d'admission, les caractéristiques procédurales et la présence de contre-indications à l'anesthésie neuraxiale. Des algorithmes de détermination des cas pour prédire la présence de contre-indications absolues à l'anesthésie neuraxiale ont été dérivés et validés en interne. RéSULTATS: Nous avons identifié 340 cas. L'anesthésie générale a été utilisée dans 219 cas (64,4 %), une anesthésie neuraxiale isolée (rachidienne et/ou péridurale) dans 106 cas (31,2 %) et une anesthésie générale plus neuraxiale dans 15 cas (4,4 %). Soixante-dix-huit (22,9 %; intervalle de confiance [IC] à 95 %, 18,8 à 27,7) patient·es présentaient des contre-indications absolues à l'anesthésie neuraxiale, principalement en raison d'une anticoagulation ou de médicaments antiplaquettaires (89,4 %); 21 (6,2 %; IC 95 %, 4,1 à 9,3) présentaient des contre-indications relatives, principalement une longue durée anticipée de chirurgie (16/21, 76,2 %). Nous avons dérivé et validé trois algorithmes imbriqués de détermination des cas. En utilisant les variables d'admission et de procédure, la discrimination était modérée, avec une variance modérément expliquée, et l'étalonnage était inadéquat pour une utilisation fiable. Les données portant sur les comorbidités des patient·es et de laboratoire n'ont pas amélioré les performances de l'algorithme. CONCLUSION: La plupart des patient·es bénéficiant d'une chirurgie de revascularisation des membres inférieurs n'avaient pas de contre-indications absolues à l'anesthésie neuraxiale. Les contre-indications, lorsque présentes, étaient généralement liées à l'anticoagulation. Les données d'admission, d'intervention, de comorbidité et de laboratoire n'ont pas fourni de précisions suffisantes pour confirmer un statut de contre-indication.

Hospital-, Anesthesiologist-, Surgeon-, and Patient-Level Variations in Neuraxial Anesthesia Use for Lower Limb Revascularization Surgery: A Population-Based Cross-Sectional Study.

BACKGROUND: Although neuraxial anesthesia may promote improved outcomes for patients undergoing lower limb revascularization surgery, its use is decreasing over time. Our objective was to estimate variation in neuraxial (versus general) anesthesia use for lower limb revascularization at the hospital, anesthesiologist, surgeon, and patient levels, which could inform strategies to increase uptake. METHODS: Following protocol registration, we conducted a historical cross-sectional analysis of population-based linked health administrative data in Ontario, Canada. All adults undergoing lower limb revascularization surgery between 2009 and 2018 were identified. Generalized linear models with binomial response distributions, logit links and random intercepts for hospitals, anesthesiologists, and surgeons were used to estimate the variation in neuraxial anesthesia use at the hospital, anesthesiologist, surgeon, and patient levels using variance partition coefficients and median odds ratios. Patient- and hospital-level predictors of neuraxial anesthesia use were identified. RESULTS: We identified 11,849 patients; 3489 (29.4%) received neuraxial anesthesia. The largest proportion of variation was attributable to the hospital level (50.3%), followed by the patient level (35.7%); anesthesiologists and surgeons had small attributable variation (11.3% and 2.8%, respectively). Mean odds ratio estimates suggested that 2 similar patients would experience a 5.7-fold difference in their odds of receiving a neuraxial anesthetic were they randomly sent to 2 different hospitals. Results were consistent in sensitivity analyses, including limiting analysis to patients with diagnosed peripheral artery disease and separately to those aged >66 years with complete prescription anticoagulant and antiplatelet usage data. CONCLUSIONS: Neuraxial anesthesia use primarily varies at the hospital level. Efforts to promote use of neuraxial anesthesia for lower limb revascularization should likely focus on the hospital context.

Analysis of Rates of Brain Metastases and Association With Breast Cancer Subtypes in Ontario, Canada.

Importance: Approximately 1 in 7 patients with metastatic breast cancer (MBC) will receive radiotherapy for brain metastases (BRM). Significant differences in cumulative incidence of BRM by breast cancer subtype may inform future BRM screening protocols. Objective: To describe cumulative incidence of BRM among patients with de novo MBC. Design, Setting, and Participants: In this population-based cohort study, population health administrative databases in Ontario, Canada, held at the ICES were used to identify patients diagnosed with de novo MBC between 2009 and 2018. Given that a code for BRM does not exist within ICES, we analyzed the incidence of radiotherapy for BRM. The median (IQR) follow-up was 19.3 (6.2-39.5) months. A total of 100 747 patients with a new diagnosis of breast cancer between January 2009 and December 2018 were identified. Of these patients, 17 955 were excluded because they had previous or subsequent malignant neoplasms, 583 were excluded because they were younger than 18 years, 974 were excluded because there was an invalid Ontario Health Insurance Plan number or a date of death on or before the index date. Among 81 235 remaining patients, 3916 were identified as having de novo MBC. Exposures: Treatment with radiotherapy for breast cancer BRM. Main Outcomes and Measures: Cumulative incidence of radiotherapy for BRM accounting for the competing risk of death, and time from MBC diagnosis to brain radiotherapy. Kaplan-Meier analyses were performed for time-to-event end points. Logistic regression was used to account for confounding variables. Results: Among 3916 patients with MBC, 1215 (31.0%) had HR-positive/ERBB2 (formerly HER2)-negative cancer, 310 (7.9%) had ERBB2-positive/HR-positive cancer, 200 (5.1%) had ERBB2-positive/HR-negative cancer, 258 (6.6%) had TNBC, and the remaining 1933 patients (49.4%) had an unknown breast cancer subtype. The median (IQR) age at diagnosis was 63 (52-75). A total of 549 (14.0%) underwent stereotactic radiosurgery or whole brain radiotherapy for breast cancer BRM. Cumulative incidence of BRM was higher among patients with ERBB2-positive/HR-negative breast cancer (34.7%), ERBB2-positive/HR-positive breast cancer (28.1%), and triple-negative breast cancer (21.9%) compared to those with HR-positive/ERBB2-negative breast cancer (12.1%). The median (IQR) time from MBC diagnosis to brain radiotherapy ranged from 7.5 (2.3-17.4) months for patients with TNBC to 19.8 (12.2-35.1) months for those with ERBB2-positive/HR-positive breast cancer. Conclusions and Relevance: Incidence and time to development of BRM vary significantly by breast cancer subtype. A better understanding of the biology of intracranial metastatic disease may help inform potential screening programs or preventative interventions.

BRCA mutated pancreatic cancer: A change is coming.

Pancreatic cancer remains a leading cause of cancer-related death with few available therapies for advanced disease. Recently, patients with germline BRCA mutations have received increased attention due to advances in the management of BRCA mutated ovarian and breast tumors. Germline BRCA mutations significantly increase risk of developing pancreatic cancer and can be found in up to 8% of patients with sporadic pancreatic cancer. In patients with germline BRCA mutations, platinum-based chemotherapies and poly (ADP-ribose) polymerase inhibitors are effective treatment options which may offer survival benefits. This review will focus on the molecular biology, epidemiology, and management of BRCA-mutated pancreatic cancer. Furthermore, we will discuss future directions for this area of research and promising active areas of research.