Introduction
Preclinical evidence suggests the feedforward cytokine loop of interleukin-6/Janus kinases (JAK)/STAT3 plays a role in epidermal growth factor receptor tyrosine kinase inhibitor (EGFR ...TKI) resistance in
EGFR
-mutated non-small cell lung cancer (NSCLC).
Methods
In this phase 1b study, the JAK1/2 and TANK-binding kinase 1 (TBK1) inhibitor momelotinib was evaluated in combination with erlotinib in patients with EGFR TKI-naive,
EGFR
-mutated NSCLC. After erlotinib lead-in (50, 75, 100, or 150 mg oral daily QD), momelotinib was combined and dose escalated in a 3 + 3 study design. The primary endpoint of maximum tolerated dose (MTD) of momelotinib was determined based on the incidence of dose-limiting toxicities (DLTs) during the first 28-day cycle. Secondary endpoints included efficacy and pharmacokinetics (PK).
Results
Eleven patients were enrolled across 3 dose levels of momelotinib (100 mg QD, 200 mg QD, and 100 mg twice daily BID). The MTD was momelotinib 200 mg QD in combination with erlotinib. Two DLTs of grade 4 neutropenia without fever and grade 3 diarrhea occurred at momelotinib 100 mg BID. Most common treatment-emergent adverse events included diarrhea, dry skin, fatigue, and decreased appetite; the vast majority being grades 1–2. The overall response rate was 54.5% (90% CI 27.1–80.0; all partial) and median progression-free survival was 9.2 months (90% CI 6.2–12.4). Momelotinib did not affect the PK of erlotinib.
Conclusions
The JAK1/2 and TBK1 inhibitor momelotinib in combination with erlotinib did not appear to enhance benefit over the historical data of erlotinib monotherapy in patients with
EGFR
-mutated NSCLC.
ClinicalTrials.gov identifier
NCT02206763.
To compare concentrations of antimüllerian hormone (AMH) in women with and without type 1 diabetes.
Cross-sectional analysis of longitudinal studies, adjusting for repeated measures.
Not applicable.
...Women aged 30-45 years who had not undergone oophorectomy, hysterectomy, or natural menopause at the time of AMH measurement were included (n = 376 in the Michigan Bone Health and Metabolism Study and n = 321 in the Epidemiology of Interventions and Complications Study). Linear mixed regression was used to evaluate whether AMH concentrations differed by diabetes status, adjusting for repeated measurements of AMH within individual women, body mass index, smoking status, and oral contraceptive use.
None.
Concentrations of AMH.
In unadjusted comparisons, women with and without diabetes had similar median AMH values before 35 years of age, although women with type 1 diabetes had a lower proportion of women with elevated AMH concentrations (≥5.0 ng/dL). After adjustment for covariates and multiple observations per woman, log AMH concentrations were significantly lower among women with type 1 diabetes compared with women without diabetes (β-coefficient -1.27, 95% confidence interval -2.18, -0.36 in fully adjusted models) before 35 years of age.
Before 35 years of age, women with type 1 diabetes have lower AMH levels than women without diabetes. Further investigation is needed to determine the etiologies of this difference and how it may contribute to reproductive disorders among women with type 1 diabetes.
Objectives
To examine the impact of a weight loss intervention upon follicle stimulating hormone (FSH) levels in postmenopause.
Methods
Participants were postmenopausal, overweight, ...glucose‐intolerant women not using exogenous estrogen (n = 382) in the Diabetes Prevention Program. Women were randomized to intensive lifestyle change (ILS) with the goals of weight reduction of at least 7% of initial weight and 150 min per week of moderate‐intensity exercise, metformin 850 mg twice a day, or placebo administered twice a day.
Results
Randomization to ILS led to small increases in FSH between baseline and 1‐year follow‐up vs. placebo (2.3 IU/l vs. −0.81 IU/l, P < 0.01). Increases in FSH were correlated with decreases in weight (r = −0.165, P < 0.01) and estradiol (E2) (r = −0.464, P < 0.0001) after adjustment for age, race/ethnicity, and randomization arm. Changes in FSH were still significantly associated with changes in weight even after adjustment for E2 levels. Metformin users had reductions in weight but non‐significant changes in FSH and E2 levels vs. placebo.
Conclusions
Weight loss leads to small increases in FSH among overweight, postmenopausal women, potentially through pathways mediated by endogenous estrogen as well as other pathways.
We consider generalized linear regression with a covariate left-censored at a lower detection limit. Complete-case analysis, where observations with values below the limit are eliminated, yields ...valid estimates for regression coefficients but loses efficiency, ad hoc substitution methods are biased, and parametric maximum likelihood estimation relies on parametric models for the unobservable tail probability distribution and may suffer from model misspecification. To obtain robust and more efficient results, we propose a semiparametric likelihood-based approach using an accelerated failure time model for the covariate subject to the detection limit. A twostage estimation procedure is developed, where the conditional distribution of this covariate given other variables is estimated prior to maximizing the likelihood function. The proposed method outperforms complete-case analysis and substitution methods in simulation studies. Technical conditions for desirable asymptotic properties are provided.
Context:
It is unknown whether intensive lifestyle modification (ILS) or metformin changes sex steroids among premenopausal women without a history of polycystic ovarian syndrome (PCOS).
Objectives:
...We examined 1-year intervention impact on sex steroids (estradiol, testosterone, dehydroepiandrosterone, and androstenedione A4) and SHBG and differences by race/ethnicity.
Participants:
A subgroup of Diabetes Prevention Program participants who were premenopausal, not using estrogen, without a history of PCOS or irregular menses, and who reported non-Hispanic white (NHW), Hispanic, or African-American race/ethnicity (n = 301).
Interventions:
Randomization arms were 1) ILS with the goals of weight reduction of 7% of initial weight and 150 minutes per week of moderate intensity exercise, 2) metformin 850 mg twice a day, or 3) placebo.
Results:
Neither intervention changed sex steroids compared to placebo. ILS, but not metformin, increased median SHBG by 3.1 nmol/L (∼11%) compared to decreases of 1.1 nmol/L in the placebo arm (P < .05). This comparison remained significant after adjustment for changes in covariates including waist circumference. However, associations with glucose were not significant. Median baseline A4 was lower in Hispanics compared to NHWs (5.7 nmol/L vs 6.5 nmol/L, P < .05) and increases in A4 were greater in Hispanics compared to NHWs (3.0 nmol/ vs 1.2 nmol/L, P < .05), and these differences did not differ significantly by intervention arm. No other racial/ethnic differences were significant.
Conclusions:
Among premenopausal glucose-intolerant women, no intervention changed sex steroids. ILS increased SHBG, although associations with glucose were not significant. SHBG and sex steroids were similar by race/ethnicity, with the possible exception of lower baseline A4 levels in Hispanics compared to NHWs.
Abstract Objective It is unclear how lipids change in response to lifestyle modification or metformin among postmenopausal glucose intolerant women using and not using hormone therapy (HT). We ...examined the one-year changes in lipids among postmenopausal, prediabetic women in the Diabetes Prevention Program (DPP), and whether changes were mediated by sex hormones. Materials/Methods We performed a secondary analysis of a randomized controlled trial of 342 women who used HT at baseline and year 1 and 382 women who did not use HT at either time point. Interventions included intensive lifestyle (ILS) with goals of weight reduction of at least 7% of initial weight and 150 minutes per week of moderate intensity exercise, or metformin or placebo administered 850 mg up to twice a day. Women were not randomized to HT. Main outcome measures were changes between baseline and study year 1 in low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. Results Compared to placebo, both ILS and metformin significantly reduced LDL-C and raised HDL-C among HT users, changes partially explained by change in estradiol and testosterone but independent of changes in waist circumference and 1/fasting insulin. In contrast, DPP interventions had no effect on LDL-C and HDL-C among non-HT users. ILS significantly lowered triglycerides among non-users but did not significantly change triglycerides among HT users. Metformin did not significantly change triglycerides among non-users but increased triglycerides among HT users. Conclusions The beneficial effects of ILS and metformin on lowering LDL-C and raising HDL-C differ depending upon concurrent HT use.
We consider finite sample properties of the regularized high-dimensional Cox regression via lasso. Existing literature focuses on linear models or generalized linear models with Lipschitz loss ...functions, where the empirical risk functions are the summations of independent and identically distributed (iid) losses. The summands in the negative log partial likelihood function for censored survival data, however, are neither iid nor Lipschitz. We first approximate the negative log partial likelihood function by a sum of iid non-Lipschitz terms, then derive the non-asymptotic oracle inequalities for the lasso penalized Cox regression using pointwise arguments to tackle the difficulties caused by lacking iid Lipschitz losses.
We report the final overall survival (OS) analyses of atezolizumab-carboplatin-paclitaxel (ACP experimental arm) and OS data with approximately 39.8 months of median follow-up with ...atezolizumab-bevacizumab-carboplatin-paclitaxel (ABCP) versus bevacizumab-carboplatin-paclitaxel (BCP) in chemotherapy-naive patients with metastatic nonsquamous NSCLC in the phase 3 IMpower150 study (NCT02366143).
In this randomized, open-label study (N = 1202), coprimary end points included investigator-assessed progression-free survival and OS in intention-to-treat (ITT) wild-type (WT; no EGFR or ALK alterations) patients. Secondary and exploratory end points included OS in ITT and programmed death-ligand 1 (PD-L1) subgroups defined by the VENTANA SP142 and SP263 immunohistochemistry assays.
At the final analysis with ACP versus BCP (data cutoff: September 13, 2019; minimum follow-up: 32.4 mo), ACP had numerical, but not statistically significant, improvements in OS (ITT-WT: median OS = 19.0 versus 14.7 mo; hazard ratio = 0.84; 95% confidence interval: 0.71–1.00). OS benefit was sustained with ABCP versus BCP (ITT-WT: 19.5 versus 14.7 mo; hazard ratio = 0.80; 95% confidence interval: 0.67–0.95). Exploratory analyses in the SP142-defined PD-L1 subgroups revealed longer median OS with ABCP and ACP versus BCP in PD-L1–high and PD-L1–positive subgroups; in the PD-L1–negative subgroups, median OS was similar with ACP and ABCP versus BCP. Safety was consistent with that in earlier analyses (data cutoff: January 22, 2018).
At the final IMpower150 OS analysis, ACP had numerical, but not statistically significant, OS improvement versus BCP. Updated data with an additional 20 months of follow-up revealed continued OS improvement with ABCP versus BCP in all patients.
We consider high‐dimensional inference for potentially misspecified Cox proportional hazard models based on low‐dimensional results by Lin and Wei (1989). A desparsified Lasso estimator is proposed ...based on the log partial likelihood function and shown to converge to a pseudo‐true parameter vector. Interestingly, the sparsity of the true parameter can be inferred from that of the above limiting parameter. Moreover, each component of the above (nonsparse) estimator is shown to be asymptotically normal with a variance that can be consistently estimated even under model misspecifications. In some cases, this asymptotic distribution leads to valid statistical inference procedures, whose empirical performances are illustrated through numerical examples.
This research is motivated by studying the progression of age‐related macular degeneration where both a covariate and the response variable are subject to censoring. We develop a general framework to ...handle regression with censored covariate where the response can be different types and the censoring can be random or subject to (constant) detection limits. Multiple imputation is a popular technique to handle missing data that requires compatibility between the imputation model and the substantive model to obtain valid estimates. With censored covariate, we propose a novel multiple imputation‐based approach, namely, the semiparametric two‐step importance sampling imputation (STISI) method, to impute the censored covariate. Specifically, STISI imputes the missing covariate from a semiparametric accelerated failure time model conditional on fully observed covariates (Step 1) with the acceptance probability derived from the substantive model (Step 2). The 2‐step procedure automatically ensures compatibility and takes full advantage of the relaxed semiparametric assumption in the imputation. Extensive simulations demonstrate that the STISI method yields valid estimates in all scenarios and outperforms some existing methods that are commonly used in practice. We apply STISI on data from the Age‐related Eye Disease Study, to investigate the association between the progression time of the less severe eye and that of the more severe eye. We also illustrate the method by analyzing the urine arsenic data for patients from National Health and Nutrition Examination Survey (2003‐2004) where the response is binary and 1 covariate is subject to detection limit.
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