Probing Multiple Transplant Delivery Routes of CD+34 Stem Cells for Promoting Behavioral and Histological Benefits in Experimental Ischemic Stroke.

Stroke is a leading cause of death in the US and around the world but with limited treatment options. Survivors often present with long-term cognitive and neurological deficits. Stem cell-based therapy has emerged as a potential treatment for stroke. While stem cell transplantation in stroke has reached clinical trials, mostly safety outcomes have been reported with efficacy readouts warranting more studies. In an effort to optimize the stem cell regimen for stroke, here we conducted vis-a-vis comparison of different routes of transplantation, namely, intracerebral, intraarterial, and intranasal delivery of expanded human CD34 + stem cells, called ProtheraCytes, in the established stroke model of transient middle cerebral artery occlusion (MCAO) using adult Sprague-Dawley rats. After adjusting for the dose and subacute timing of cell delivery, animals were randomly assigned to receive either ProtheraCytes or vehicle. Motor and neurological assays from days 7 to 28 post-stroke revealed significant functional recovery across all 3 delivery routes of ProtheraCytes compared to vehicle-treated stroke rats. Additionally, ProtheraCytes-transplanted stroke rats displayed significantly reduced infarct size and cell loss in the peri-infarct area coupled with enhanced neurogenesis and angiogenesis compared to vehicle-treated stroke rats. These results highlight the safety and efficacy of transplanting ProtheraCytes, including via the minimally invasive intranasal route, in conferring robust and stable behavioral and histological positive outcomes in experimental stroke.

Inhibition of the Phosphatidylinositol-3 Kinase Pathway Using Bimiralisib in Loss-of-Function NOTCH1-Mutant Head and Neck Cancer.

BACKGROUND: PI3K/mTOR inhibition leads to apoptosis of NOTCH1-mutant head and neck squamous cell carcinoma (HNSCC) cells. We tested the efficacy of the PI3K/mTOR inhibitor bimiralisib in patients with NOTCH1-mutant HNSCC. METHODS: Patients with recurrent/metastatic NOTCH1-mutant HNSCC who had progressed during chemotherapy and immunotherapy received bimiralisib until unacceptable toxicity or progression. To assess whether NOTCH1 mutations can be detected in blood, we measured circulating tumor DNA (ctDNA). To assess activated NOTCH1 protein levels, we quantitated cleaved NOTCH1 (cl-NOTCH) by immunohistochemistry. RESULTS: Eight patients were treated, and 6 were evaluable for response. The objective response rate was 17%. For all 8 patients, median progression-free and overall survival was 5 and 7 months, respectively. Bimiralisib was well tolerated, with expected hyperglycemia. Pharmacokinetic values were consistent with published studies. NOTCH1 mutations were detected in 83.3% of ctDNA. Staining for tumor cl-NOTCH1 was negative. The trial closed early due to sponsor insolvency. CONCLUSION: Although the trial was small, outcomes with bimiralisib were better than the historical standard of care; Results will need to be confirmed in a larger trial. The lack of cl-NOTCH1 was consistent with loss-of-function mutations and validated our mutation function algorithm. The ability to detect NOTCH1 mutations in blood will help future studies. (ClinicalTrials.gov Identifier: NCT03740100).

Angioedema in heart failure patients treated with sacubitril/valsartan (LCZ696) or enalapril in the PARADIGM-HF study.

BACKGROUND: PARADIGM-HF demonstrated significant clinical benefits for sacubitril/valsartan (LCZ696, an angiotensin receptor neprilysin inhibitor) versus the angiotensin-converting enzyme inhibitor (ACEI) enalapril in patients with heart failure with reduced ejection fraction. As inhibition of ACE, and co-inhibition of ACE and neprilysin, may increase the risk of angioedema, this was an adverse event of special interest. METHODS: Following sequential enalapril and sacubitril/valsartan run-ins, patients were randomized to twice-daily sacubitril/valsartan 200 mg or enalapril 10 mg. The study design incorporated two wash-out periods (~36 h each) to minimize any potential risk of angioedema due to overlapping ACE and neprilysin inhibition. Suspected cases of angioedema were reported to, and blindly adjudicated by, an independent angioedema adjudication committee (AAC). RESULTS: Of the 10,513 patients entering the enalapril run-in, 9419 entered the sacubitril/valsartan run-in and 8432 received double-blind treatment. Overall, 148 suspected angioedema events occurring in 144 patients were reported to AAC, with one event reported during screening period. Of the remaining 147 events, 54 were confirmed as angioedema by AAC. A confirmed event was experienced by 15 (0.14%) and 10 (0.11%) patients, during the enalapril and sacubitril/valsartan run-ins, respectively, and by 10 (0.24%) and 19 (0.45%) patients in the corresponding randomized arms during the double-blind phase. The frequency of confirmed angioedema was higher in black patients. Most events were mild. Only five patients required hospitalization and none required mechanical airway support. CONCLUSION: The number of confirmed angioedema events in PARADIGM-HF was low and there was no-marked excess risk of angioedema with sacubitril/valsartan versus enalapril.

A Database Cohort Study to Assess the Risk of Angioedema Among Patients with Heart Failure Initiating Angiotensin-Converting Enzyme Inhibitors in the USA.

INTRODUCTION: Real-world evidence on the risk of angioedema associated with angiotensin-converting enzyme inhibitors (ACEIs) in patients with heart failure (HF) is scarce. OBJECTIVE: This non-interventional study aimed to estimate the incidence of and risk factors for angioedema in patients with HF initiating an ACEI in real-world practice. METHODS: This was a retrospective cohort study using claims data from the PharMetrics Plus database, supplemented with consumer health data, from 1 January 2007 to 31 March 2015. Patients with HF initiating an ACEI were followed up for a maximum of 1 year, until the first occurrence of angioedema or until cohort exit. Angioedema incidence rates were estimated and stratified by potential risk factors such as race, age, sex, and time from initiation of ACEI therapy. For each risk factor, the unadjusted and adjusted hazard ratio (HR) was calculated; exploratory analyses were carried out to account for all potential confounders. RESULTS: We identified 21,639 patients with HF initiating an ACEI (mean age 58 years; 35.6% women; mean follow-up 205 days). The 1-year incidence of angioedema per 1000 patient-years was 3.3 [95% confidence interval (CI) 2.4-4.5]. The incidence was higher in Black [6.2 (95% CI 3.1-12.5)] than in non-black [2.9 (95% CI 2.1-4.1)] patients, higher in women [5.2 (95% CI 3.4-7.9)] than in men [2.3 (95% CI 1.5-3.6)], and greatest in the first 30 days of ACEI therapy. CONCLUSIONS: The risk of angioedema in patients with HF initiating an ACEI observed in this study is in line with published estimates for the general patient population treated with ACEIs.