Evidence for a Role of the Multifunctional Calcium/Calmodulin-Dependent Protein Kinase II in Insulin Secretion

Calcium/calmodulin-dependent protein kinase II (CaM kinase II) is demonstrated to exist in the ß-cell and immunopecipitation. Glucose and potassium significantly stimulate the rapid autophosphorylation of CaM kinase II and proportionally induce autonomous activity of the kinase in a dose-dependent manner that parallels insulin secretion. The activation of CaM kinase II, alloxan, KN-62 and KN-93, suggest that the enzyme is an integral component of insulin secretion and/or related processes in the β-cell

A randomized phase 2 study of sapanisertib in combination with paclitaxel versus paclitaxel alone in women with advanced, recurrent, or persistent endometrial cancer

Endometrial cancer; Metastatic; RecurrentCàncer d'endometri; Metastàtic; RecurrentCáncer endometrial; Metastásico; RecurrenteObjective This phase 2 study investigated sapanisertib (selective dual inhibitor of mTORC1/2) alone, or in combination with paclitaxel or TAK-117 (a selective small molecule inhibitor of PI3K), versus paclitaxel alone in advanced, recurrent, or persistent endometrial cancer. Methods Patients with histologic diagnosis of endometrial cancer (1–2 prior regimens) were randomized to 28-day cycles on four treatment arms: 1) weekly paclitaxel 80 mg/m2 (days 1, 8, and 15); 2) weekly paclitaxel 80 mg/m2 + oral sapanisertib 4 mg on days 2–4, 9–11, 16–18, and 23–25; 3) weekly sapanisertib 30 mg, or 4) sapanisertib 4 mg + TAK-117 200 mg on days 1–3, 8–10, 15–17, and 22–24. Results Of 241 patients randomized, 234 received treatment (paclitaxel, n = 87 [3 ongoing]; paclitaxel+sapanisertib, n = 86 [3 ongoing]; sapanisertib, n = 41; sapanisertib+TAK-117, n = 20). The sapanisertib and sapanisertib+TAK-117 arms were closed to enrollment after futility analyses. After a median follow-up of 14.4 (paclitaxel) versus 17.2 (paclitaxel+sapanisertib) months, median progression-free survival (PFS; primary endpoint) was 3.7 versus 5.6 months (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.58–1.15; p = 0.139); in patients with endometrioid histology (n = 116), median PFS was 3.3 versus 5.7 months (HR 0.66; 95% CI 0.43–1.03). Grade ≥ 3 treatment-emergent adverse event rates were 54.0% with paclitaxel versus 89.5% paclitaxel+sapanisertib. Conclusions Our findings support inclusion of chemotherapy combinations with investigational agents for advanced or metastatic disease. The primary endpoint was not met and toxicity was manageable. Trial registration: ClinicalTrials.gov number, NCT02725268Takeda Development Center Americas, Inc., Lexington, MA, USA. This work was supported by funding from Takeda Development Center Americas, Inc. The study was designed by the authors in conjunction with the sponsors. Data were gathered and analyzed by the investigator and the sponsor; all the authors had access to the data. The authors received medical writing support for drafting the manuscript, which was funded by Takeda Pharmaceuticals USA, Inc. Manuscript drafts were reviewed by all authors and the sponsor and all the authors made the decision to submit the manuscript for publication

Niraparib Maintenance Therapy in Patients With Recurrent Ovarian Cancer After a Partial Response to the Last Platinum-Based Chemotherapy in the ENGOT-OV16/NOVA Trial

PURPOSEIn the ENGOT-OV16/NOVA trial (ClinicalTrials.gov identifier: NCT01847274), maintenance therapy with niraparib, a poly(ADP-ribose) polymerase inhibitor, prolonged progression-free survival in patients with platinum-sensitive, recurrent ovarian cancer who had a response to their last platinum-based chemotherapy. The objective of the study was to assess the clinical benefit and patient-reported outcomes in patients who had a partial response (PR) and complete response (CR) to their last platinum-based therapy.PATIENTS AND METHODSA total of 553 patients were enrolled in the trial. Of 203 patients with a germline BRCA mutation (gBRCAmut), 99 had a PR and 104 had a CR to their last platinum-based therapy; of 350 patients without a confirmed gBRCAmut (non?gBRCAmut), 173 had a PR and 177 had a CR. Post hoc analyses were carried out to evaluate safety and the risk of progression in these patients according to gBRCAmut status and response to their last platinum-based therapy. Ovarian cancer?specific symptoms and quality of life were assessed using the Functional Assessment of Cancer Therapy?Ovarian Symptom Index.RESULTSProgression-free survival was improved in patients treated with niraparib compared with placebo in both the gBRCAmut cohort (PR: hazard ratio [HR], 0.24; 95% CI, 0.131 to 0.441; P < .0001; CR: HR, 0.30; 95% CI, 0.160 to 0.546; P < .0001) and the non?gBRCAmut cohort (PR: HR, 0.35; 95% CI, 0.230 to 0.532; P < .0001; CR: HR, 0.58; 95% CI, 0.383 to 0.868; P = .0082). The incidence of any-grade and grade 3 or greater adverse events was manageable. No meaningful differences were observed between niraparib and placebo in PR and CR subgroups with respect to patient-reported outcomes.CONCLUSIONPatients achieved clinical benefit from maintenance treatment with niraparib regardless of response to the last platinum-based therapy

Genome-wide association study evaluating single-nucleotide polymorphisms and outcomes in patients with advanced stage serous ovarian or primary peritoneal cancer: An NRG Oncology/Gynecologic Oncology Group study

This study evaluated single nucleotide polymorphisms (SNPs) associated with progression free (PFS) and overall survival (OS) in patients with advanced stage serous EOC

Illuminating the Numbers: Integrating Mathematical Models to Optimize Photomedicine Dosimetry and Combination Therapies

Cancer photomedicine offers unique mechanisms for inducing local tumor damage with the potential to stimulate local and systemic anti-tumor immunity. Optically-active nanomedicine offers these features as well as spatiotemporal control of tumor-focused drug release to realize synergistic combination therapies. Achieving quantitative dosimetry is a major challenge, and dosimetry is fundamental to photomedicine for personalizing and tailoring therapeutic regimens to specific patients and anatomical locations. The challenge of dosimetry is perhaps greater for photomedicine than many standard therapies given the complexity of light delivery and light–tissue interactions as well as the resulting photochemistry responsible for tumor damage and drug-release, in addition to the usual intricacies of therapeutic agent delivery. An emerging multidisciplinary approach in oncology utilizes mathematical and computational models to iteratively and quantitively analyze complex dosimetry, and biological response parameters. These models are parameterized by preclinical and clinical observations and then tested against previously unseen data. Such calibrated and validated models can be deployed to simulate treatment doses, protocols, and combinations that have not yet been experimentally or clinically evaluated and can provide testable optimal treatment outcomes in a practical workflow. Here, we foresee the utility of these computational approaches to guide adaptive therapy, and how mathematical models might be further developed and integrated as a novel methodology to guide precision photomedicine

Niraparib maintenance treatment improves time without symptoms or toxicity (TWiST) versus routine surveillance in recurrent ovarian cancer: a TWiST analysis of the ENGOT-OV16/NOVA trial

Purpose: this study estimated time without symptoms or toxicity (TWiST) with niraparib compared with routine surveillance (RS) in the maintenance treatment of patients with recurrent ovarian cancer. Patients and methods: mean progression-free survival (PFS) was estimated for niraparib and RS by fitting parametric survival distributions to Kaplan-Meier data for 553 patients with recurrent ovarian cancer who were enrolled in the phase III ENGOT-OV16/NOVA trial. Patients were categorized according to the presence or absence of a germline BRCA mutation-gBRCAmut and non-gBRCAmut cohorts. Mean time with toxicity was estimated based on the area under the Kaplan-Meier curve for symptomatic grade 2 or greater fatigue, nausea, and vomiting adverse events (AEs). Time with toxicity was the number of days a patient experienced an AE post-random assignment and before disease progression. TWiST was estimated as the difference between mean PFS and time with toxicity. Uncertainty was explored using alternative PFS estimates and considering all symptomatic grade 2 or greater AEs. Results: in the gBRCAmut and non-gBRCAmut cohorts, niraparib treatment resulted in a mean PFS benefit of 3.23 years and 1.44 years, respectively, and a mean time with toxicity of 0.28 years and 0.10 years, respectively, compared with RS. Hence, niraparib treatment resulted in a mean TWiST benefit of 2.95 years and 1.34 years, respectively, compared with RS, which is equivalent to more than four-fold and two-fold increases in mean TWiST between niraparib and RS in the gBRCAmut and non-gBRCAmut cohorts, respectively. This TWiST benefit was consistent across all sensitivity analyses, including modeling PFS over 5-, 10-, and 15-year time horizons. Conclusion: patients who were treated with niraparib compared with RS experienced increased mean TWiST. Thus, patients who were treated with niraparib in the ENGOT-OV16/NOVA trial experienced more time without symptoms or symptomatic toxicities compared with control

WHO systematic review of maternal morbidity and mortality: the prevalence of severe acute maternal morbidity (near miss)

AIM: To determine the prevalence of severe acute maternal morbidity (SAMM) worldwide (near miss). METHOD: Systematic review of all available data. The methodology followed a pre-defined protocol, an extensive search strategy of 10 electronic databases as well as other sources. Articles were evaluated according to specified inclusion criteria. Data were extracted using data extraction instrument which collects additional information on the quality of reporting including definitions and identification of cases. Data were entered into a specially constructed database and tabulated using SAS statistical management and analysis software. RESULTS: A total of 30 studies are included in the systematic review. Designs are mainly cross-sectional and 24 were conducted in hospital settings, mostly teaching hospitals. Fourteen studies report on a defined SAMM condition while the remainder use a response to an event such as admission to intensive care unit as a proxy for SAMM. Criteria for identification of cases vary widely across studies. Prevalences vary between 0.80% – 8.23% in studies that use disease-specific criteria while the range is 0.38% – 1.09% in the group that use organ-system based criteria and included unselected group of women. Rates are within the range of 0.01% and 2.99% in studies using management-based criteria. It is not possible to pool data together to provide summary estimates or comparisons between different settings due to variations in case-identification criteria. Nevertheless, there seems to be an inverse trend in prevalence with development status of a country. CONCLUSION: There is a clear need to set uniform criteria to classify patients as SAMM. This standardisation could be made for similar settings separately. An organ-system dysfunction/failure approach is the most epidemiologically sound as it is least open to bias, and thus could permit developing summary estimates

The UK needs a sustainable strategy for COVID-19

The UK is well into the second wave of COVID-19, with 60 051 lives lost to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to date, according to provisional data from the&nbsp;Office for National Statistics. Official UK Government&nbsp;data&nbsp;show that cases have been rising exponentially since late August, 2020, with increases across all regions in England in recent weeks. &nbsp;As of Nov 4, 2020, the UK had 25 177 confirmed daily cases. These are almost certainly underestimates as between Oct 17 and Oct 23, 2020, England alone had 52 000 estimated daily cases. &nbsp;Estimates of the effective reproduction number in England vary between 1·1 and 1·6.</p

Implementation of an early rule-out pathway for myocardial infarction using a high-sensitivity cardiac troponin T assay.

OBJECTIVES: Patients with suspected acute coronary syndrome and high-sensitivity cardiac troponin (hs-cTn) concentrations below the limit of detection at presentation are low risk. We aim to determine whether implementing this approach facilitates the safe early discharge of patients. METHODS: In a prospective single-centre cohort study, consecutive patients with suspected acute coronary syndrome were included before (standard care) and after (intervention) implementation of an early rule-out pathway. During standard care, myocardial infarction was ruled out if hs-cTnT concentrations were <99th centile (14 ng/L) at presentation and at 6-12 hours after symptom onset. In the intervention, patients were ruled out if hs-cTnT concentrations were <5 ng/L at presentation and symptoms present for ≥3 hours or were ≥5 ng/L and unchanged within the reference range at 3 hours. We compared duration of stay (efficacy) and all-cause death at 1 year (safety) before and after implementation. RESULTS: We included 10 315 consecutive patients (64±16 years, 46% women) with 6642 (64%) and 3673 (36%) in the standard care and intervention groups, respectively. Duration of stay was reduced from 534 (IQR, 220-2279) to 390 (IQR, 218-1910) min (p<0.001) after implementation. At 1 year, all-cause death occurred in 10.9% (721 of 6642) and 10.4% (381 of 3673) of patients in the standard care group (referent) and intervention group, respectively (adjusted OR 1.02, 95% CI 0.88 to 1.18). CONCLUSION: In patients with suspected acute coronary syndrome, implementing an early rule-out pathway using hs-cTnT concentrations <5 ng/L at presentation reduced the duration of stay in hospital without compromising safety