Citations

Abstract Amyotrophic lateral sclerosis (ALS) therapeutic development has largely relied on staff-administered functional rating scales to determine treatment efficacy. We sought to determine if mobile applications (apps) and wearable devices can be used to quantify ALS disease progression through active (surveys) and passive (sensors) data collection. Forty ambulatory adults with ALS were followed for 6-months. The Beiwe app was used to administer self-entry ALS functional rating scale-revised (ALSFRS-RSE) and the Rasch Overall ALS Disability Scale (ROADS) surveys every 2-4 weeks. A wrist-worn activity monitor (ActiGraph's Insight Watch) or an ankle-worn activity monitor (Modus' StepWatch) was used continuously by each participant. Wearable device wear and app survey compliance were adequate. ALSFRS-R highly correlated with ALSFRS-RSE. Several wearable data daily physical activity measures demonstrated statistically significant change over time and associations with ALSFRS-RSE and ROADS. Active and passive digital data collection hold promise for novel ALS trial outcomes development.

Abstract While the allure of targeted therapies in oncology has been their high degree of specificity and potency for key tumor drivers, they have been disappointing in glioblastoma (GBM), even for drugs that are blood brain barrier permeable and CNS retained. This point is highlighted by the experience with mitotic spindle inhibitors, drugs which block the G2M transition and induce mitotic catastrophe—a phenotype characterized by cell enlargement and polyploidy that leads to apoptotic cell death. We have shown that one of these, a potent inhibitor of the mitotic kinesin Kif11 (ispinesib), is highly active against GBM tumor initiating cells and prolongs survival in murine models of this disease. However, tumors eventually progress, reflecting the development of drug resistance. Although ispinesib resistant GBM cells develop mitotic catastrophe, they become highly resistant to the apoptosis that typically follows and continue to proliferate. We find that this apoptosis resistance requires phosphorylation of the transcription factor STAT3 at two residues—Y705 and S727. Phosphorylation of Y705, mediated by SRC kinase, translocates STAT3 to the nucleus where it induces transcription of anti-apoptotic proteins. Phosphorylation at S727, mediated by EGFR, translocates STAT3 to the mitochondria where it blocks release of cytochrome c—the penultimate effector in apoptosis. Simultaneously inhibiting both SRC and EGFR with FDA-approved, CNS permeant inhibitors reverses this resistance and significantly prolongs survival in ispinesib-treated GBM-bearing mice. Furthermore, we find that resistance to several other mitotic inhibitors also utilizes this STAT3-driven mechanism and can likewise be reversed with combined EGFR and SRC inhibition. Thus, our work demonstrates how a promising therapeutic approach, which has been disappointing in GBM, can in fact be rendered effective by anticipating and prospectively treating ab initio the mechanism that drives treatment resistance.

AbstractBackgroundBilateral idiopathic hyperaldosteronism (IHA) is responsible for 60% of primary aldosteronism (PA) cases. Medical management is standard of care for IHA. Unilateral adrenalectomy (UA) with the intent of debulking total aldosterone production as a palliative measure remains controversial.MethodsSingle‐center retrospective review (2010–2020) of patients undergoing UA with a diagnosis of PA due to IHA (lateralization index [LI] on adrenal venous sampling [AVS] < 4). Demographic, pre‐operative, intra‐operative, and post‐operative variables were assessed. Hypertensive regimens were converted to the WHO Defined Daily Dose (DDD).ResultsTwenty‐four patients were identified, 14, 58% male and mean age 52 ± 10 years. Preoperative hypokalemia was present in 22, 92% of patients. Median number of antihypertensives taken was 3 (interquartile range [IQR], 2–4) and median DDD was 4 (IQR, 3–5.3). Median lateralization index on AVS was 3.52 (range, 1.19–3.88). All operations were performed in minimally invasive fashion. There were no conversions to open procedure, ICU admissions, or post‐operative complications. Median follow‐up was 10.5 months (range, 1–145 months). Hypokalemia resolved in 17, 76% of patients at last follow‐up. Post‐operative median number of antihypertensives taken was 1 (IQR, 1–3) and median DDD was 2 (IQR, 0.5–2.75) from 4, P = 0.003. Three (%) patients required continuation of mineralocorticoid receptor antagonists post‐operatively. Blood pressure control improved in 65% of patients.ConclusionUnilateral adrenalectomy in the setting of bilateral hyperaldosteronism can improve blood pressure control and stabilize potassium levels in selected patients. Further prospective studies in larger cohorts will be necessary to further define the role of unilateral adrenalectomy in the setting of PA due to bilateral adrenal disease.

Background. With donation after circulatory death (DCD) liver transplantation (LT), the goal of the recipient implantation procedure is to minimize surgical complexity to avoid a tenuous environment for an already marginal graft. The presence of portal vein thrombosis (PVT) at the time of LT adds surgical complexity, yet‚ to date, no studies have investigated the utilization of DCD liver grafts for patients with PVT. Methods. All DCD LT performed at Mayo Clinic-Florida, Mayo Clinic-Arizona, and Mayo Clinic-Rochester from 2006 to 2020 were reviewed (N = 771). Patients with PVT at the time of transplant were graded using Yerdel classification. A 1:3 propensity match between patients with PVT and those without PVT was performed. Results. A total of 91 (11.8%) patients with PVT undergoing DCD LT were identified. Grade I PVT was present in 62.6% of patients, grade II PVT in 27.5%, grade III in 8.8%, and grade 4 in 1.1%. At the time of LT, thromboendovenectomy was performed in 89 cases (97.8%). There was no difference in the rates of early allograft dysfunction (43.2% versus 52.4%; P = 0.13) or primary nonfunction (1.1% versus 1.1%; P = 0.41) between the DCD PVT and DCD without PVT groups, respectively. The rate of ischemic cholangiopathy was not significantly different between the DCD PVT (11.0%) and DCD without PVT groups (10.6%; P = 0.92). Graft (P = 0.58) and patient survival (P = 0.08) were similar between the 2 groups. Graft survival at 1-, 3-, and 5-y was 89.9%, 84.5%, and 79.3% in the DCD PVT group. Conclusions. In appropriately selected recipients with grades I–II PVT, DCD liver grafts can be utilized safely with excellent outcomes.

Abstract Crohn’s disease is a chronic gastrointestinal inflammatory disorder, characterized by episodes of relapsing and remitting flares. As the disease mechanism becomes better elucidated, there is a significant increase in the number of available biologic therapies. This article summarizes and synthesizes current Food and Drug Administration-approved biological therapy for Crohn’s disease and examines the positioning of medical therapy as emerging biologics break onto the market.