Implementation of Recommendations for Long-Acting Contraception Among Women Aged 13 to 18 Years in Primary Care

ObjectiveClinical specialty societies recommend long-acting reversible contraceptives (LARCs) as first-line contraception for adolescent women. We evaluated whether a combined educational and process improvement intervention enhanced LARC placement in primary care within an integrated health care system.MethodsThe intervention included journal clubs, live continuing education, point-of-care guidelines, and new patient materials. We conducted a retrospective cohort study across 3 time periods: baseline (January 2013?September 2015), early implementation (October 2015–March 2016), and full implementation (April 2016–June 2017). The primary outcome was the proportion of LARCs placed by primary care clinicians among women aged 13 to 18 years compared with gynecology clinicians.ResultsKaiser Foundation Health Plan of Colorado cared for approximately 20,000 women aged 13 to 18 years in each calendar quarter between 2013 and 2017. Overall, LARC placement increased from 7.0 per 1000 members per quarter at baseline to 13.0 per 1000 during the full intervention. Primary care clinicians placed 6.2% of all LARCs in 2013, increasing to 32.1% by 2017 (P < .001), including 45.5% of contraceptive implants. Clinicians who attended educational sessions were more likely to adopt LARCs than those who did not (17.9% vs 6.4% respectively, P = .009). Neither overall LARC placement rates (relative risk, 1.9; 95% confidence interval, 0.7?5.6) nor contraceptive implant rates (relative risk, 3.0; 95% confidence interval, 0.9?9.8) increased significantly in clinicians who attended educational activities.ConclusionsThis multimodal intervention was associated with increased LARC placement for adolescent women in primary care. The combination of education and process improvement is a promising strategy to promote clinician behavior change.     

Cucurbitacin-I inhibits Aurora kinase A,Aurora kinase B and survivin,induces defects in cell cycle progression and promotes ABT-737-induced cell death in a caspase-independent manner in malignant human glioma cells

Because STAT signaling is commonly activated in malignant gliomas as a result of constitutive EGFR activation, strategies for inhibiting the EGFR/JAK/STAT cascade are of significant interest. We, therefore, treated a panel of established glioma cell lines, including EGFR overexpressors, and primary cultures derived from patients diagnosed with glioblastoma with the JAK/STAT inhibitor cucurbitacin-I. Treatment with cucurbitacin-I depleted p-STAT3, p-STAT5, p-JAK1 and p-JAK2 levels, inhibited cell proliferation, and induced G2/M accumulation, DNA endoreduplication, and multipolar mitotic spindles. Longer exposure to cucurbitacin-I significantly reduced the number of viable cells and this decrease in viability was associated with cell death, as confirmed by an increase in the subG1 fraction. Our data also demonstrated that cucurbitacin-I strikingly downregulated Aurora kinase A, Aurora kinase B and survivin. We then searched for agents that exhibited a synergistic effect on cell death in combination with cucurbitacin-I. We found that cotreatment with cucurbitacin-I significantly increased Bcl^-2/Bcl^-xL family member antagonist ABT-737-induced cell death regardless of EGFR/PTEN/p53 status of malignant human glioma cell lines. Although >50% of the cucurbitacin-I plus ABT-737 treated cells were annexin V and propidium iodide positive, PARP cleavage or caspase activation was not observed. Pretreatment of z-VAD-fmk, a pan caspase inhibitor did not inhibit cell death, suggesting a caspase-independent mechanism of cell death. Genetic inhibition of Aurora kinase A or Aurora kinase B or survivin by RNA interference also sensitized glioma cells to ABT-737, suggesting a link between STAT activation and Aurora kinases in malignant gliomas.     

Targeting Aurora B kinase prevents and overcomes resistance to EGFR inhibitors in lung cancer by enhancing BIM- and PUMA-mediated apoptosis

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Randomized Phase II Study of Paclitaxel plus Alisertib versus Paclitaxel plus Placebo as Second-Line Therapy for SCLC: Primary and Correlative Biomarker Analyses

IntroductionWe assessed the Aurora A kinase inhibitor, alisertib, plus paclitaxel (henceforth referred to as alisertib/paclitaxel) as second-line treatment for SCLC.MethodsIn this double-blind study, patients with relapsed or refractory SCLC were stratified by relapse type (sensitive versus resistant or refractory) and brain metastases and randomized 1:1 to alisertib/paclitaxel or placebo plus paclitaxel (henceforth referred to as placebo/paclitaxel) in 28-day cycles. The primary end point was progression-free survival (PFS). Associations of c-Myc expression in tumor tissue (prespecified) and genetic alterations in circulating tumor DNA (retrospective) with clinical outcome were evaluated.ResultsA total of 178 patients were enrolled (89 in each arm). The median PFS was 3.32 months with alisertib/paclitaxel versus 2.17 months with placebo/paclitaxel (hazard ratio [HR] = 0.77, 95% confidence limit [CI]: 0.557–1.067, p = 0.113 in the intent-to-treat population versus HR = 0.71, 95% CI: 0.509–0.985, p = 0.038 with corrected analysis applied). Among 140 patients with genetic alternations, patients with cell cycle regulator mutations (cyclin-dependent kinase 6 gene [CDK6], retinoblastoma-like 1 gene [RBL1], retinoblastoma-like 2 gene [RBL2], and retinoblastoma 1 gene [RB1]) had significantly improved PFS with alisertib/paclitaxel versus with placebo/paclitaxel (3.68 versus 1.80 months, respectively [HR = 0.395, 95% CI: 0.239–0.654, p = 0.0003]), and overall survival (7.20 versus 4.47 months, respectively [HR = 0.427, 95% CI: 0.259–0.704, p = 0.00085]). A subset of patients with c-Myc expression showed significantly improved PFS with alisertib/paclitaxel. The incidence of grade 3 or higher drug-related adverse events was 67% (58 patients) with alisertib/paclitaxel versus 22% (25 patients) with placebo/paclitaxel. Twelve patients (14%) versus 11 (12%) died on study, including four versus zero treatment-related deaths.ConclusionsEfficacy signals were seen with alisertib/paclitaxel in relapsed or refractory SCLC. c-Myc expression and mutations in cell cycle regulators may be potential predictive biomarkers of alisertib efficacy; further prospective validations are warranted.     

Renal Effects of Crizotinib in Patients With ALK-Positive Advanced NSCLC

IntroductionWe retrospectively analyzed the effects of crizotinib on serum creatinine and creatinine-based estimated glomerular filtration rate (eGFR) in patients with anaplastic lymphoma kinase–positive advanced NSCLC across four trials (NCT00585195, NCT00932451, NCT00932893, and NCT01154140).MethodsChanges from baseline data in serum creatinine and eGFR, calculated using the Chronic Kidney Disease Epidemiology Collaboration creatinine-based equation, were assessed over time. eGFR was graded using standard chronic kidney disease criteria.ResultsMedian serum creatinine increased from 0.79 mg/dL at baseline to 0.93 mg/dL after 2 weeks of treatment (median percentage increase from baseline, 21.2%), was stable from week 12 (0.96 mg/dL) to week 104 (1.00 mg/dL), and decreased to 0.90 mg/dL at 28 days after last dose (median percentage increase from baseline, 13.1%). Median eGFR decreased over time (96.42, 80.23, 78.06 and 75.45 mL/min/1.73 m² at baseline, week 2, week 12, and week 104, respectively) and increased to 83.02 mL/min/1.73 m² at 28 days after the last dose. Median percentage decrease from baseline was 14.9%, 17.0%, and 10.4% at week 2, week 12, and 28 days after last dose of crizotinib, respectively. Overall, 12.6% of patients had a shift from eGFR grade less than or equal to 3a (≥45 mL/min/1.73 m²) at baseline to greater than or equal to 3b (<45 mL/min/1.73 m²) post-baseline.ConclusionsCrizotinib resulted in a decline in creatinine-based estimates of renal function mostly over the first 2 weeks of treatment. However, there was minimal evidence of cumulative effects with prolonged treatment and these changes were largely reversible following treatment discontinuation, consistent with previous reports suggesting this may be predominantly an effect on creatinine secretion as opposed to true nephrotoxicity.     

Oral Vancomycin Prophylaxis as Secondary Prevention Against Clostridioides difficile Infection in the Hematopoietic Stem Cell Transplantation and Hematologic Malignancy Population

Clostridioides difficile infection (CDI) is a common complication in the hematopoietic stem cell transplantation (HSCT) and hematologic malignancy (HM) population. CDI is associated with increased hospital length of stay, health care and societal costs, morbidity, and mortality. Identifying strategies for secondary prevention of CDI is of extreme importance in the HSCT/HM population. In this study, our primary objective was to evaluate the effectiveness and safety of an oral vancomycin prophylaxis (OVP) protocol for secondary prevention of CDI in a retrospective cohort of adult autologous/allogeneic HSCT recipients and patients with HM who did not undergo HSCT with a first CDI episode treated with concomitant broad-spectrum antibiotics (BSA). Patients were diagnosed and treated for CDI as inpatients and/or outpatients and were divided into 2 groups based on a preprotocol versus postprotocol analysis: the OVP group, comprising patients who received planned monotherapy with oral vancomycin 125 mg every 6 hours for 14 days for a first episode of CDI and subsequently received OVP posttreatment and a no OVP (NOVP) group, comprising patients who received planned monotherapy with oral vancomycin 125 mg every 6 hours for 14 days for a first episode of CDI and subsequently did not receive OVP posttreatment. OVP was defined as vancomycin 125 mg every 12 hours for up to 7 days after BSA discontinuation. The primary endpoint was recurrent CDI (rCDI), defined as symptoms of loose stools/diarrhea with high clinical suspicion for CDI prompting empiric therapy within 60 days of completion of treatment/prophylaxis for the first CDI episode. The incidence of vancomycin-resistant enterococcal (VRE) infection and 60-day mortality were also compared between the 2 groups. Multivariate logistic regression was created from associated variables to identify independent associations with rCDI. A total of 50 patients were included, 21 in the OVP group (42%) and 29 in the NOVP group (58%). The mean patient age was 58 years, and the cohort was 60% male and 86% Caucasian. HSCT was performed in 60% of the patients, and 76% of CDI cases were diagnosed during hospitalization. The rate of rCDI was significantly lower in the OVP group compared with the NOVP group (5% [1 of 21] versus 35% [10 of 29]; P= .016), with no subsequent increase in VRE infection rate (14% [3 of 21] versus 10% [3 of 29]; P = .686). By multivariable logistic regression, rCDI was inversely associated with OVP (odds ratio [OR], .14; 95% confidence interval [CI], .007 to .994; P = .049) and directly associated with outpatient CDI diagnosis (OR, 8.72; 95% CI, 1.816 to 49.158; P = .007). No between-group differences were found in 60-day mortality (10% [2 of 21] for OVP versus 7% [2 of 29] for NOVP; P > 0.999). OVP appears to be safe and effective for secondary prevention of CDI in the HSCT/HM population. Prospective trials are needed to validate the effectiveness of OVP in this vulnerable population to prevent rCDI.