Caregiver burden and risk of epithelial ovarian cancer in the Nurses' Health Studies.

Psychosocial stress may increase ovarian cancer risk and accelerate disease progression. We examined the association between caregiver burden, a common stressor, and risk of epithelial ovarian cancer. We prospectively followed 67,724 women in the Nurses' Health Study (NHS; 1992-2012) and 70,720 women in the NHSII (2001-2009) who answered questions on informal caregiving (i.e., caregiving outside of work). Women who reported no informal caregiving were considered non-caregivers while, among women who provided care outside of work, caregiver burden was categorized by time spent caregiving and perceived stress from caregiving. For the 34% of women who provided informal care for ≥15 hours per week, 42% described caregiving as moderately to extremely stressful. Pooled multivariate analyses indicated no difference in ovarian cancer risk for women providing ≥15 hours of care per week compared to non-caregivers (hazard ratio (HR)=0.96; 95% confidence interval (CI): 0.79-1.18), and no association was evident for women who reported moderate or extreme stress from caregiving compared to non-caregivers (HR=0.96; 95% CI: 0.75-1.22). Together with prior work evaluating job strain and ovarian cancer risk, our findings suggest that, when evaluating a stressor's role in cancer risk, it is critical to consider how the stressor contributes to the overall experience of distress.

Application of the Bayesian network theory in clinical trial data: Severity shift in spasticity numeric rating scale in patients with multiple sclerosis.

BACKGROUND: Data digitization expands data collection opportunities, representing both a chance to understand interrelationships between variables and a challenge to identify the most appropriate clinical factors. Applications of causal inference techniques to clinical trial data is becoming very attractive, especially with the intent to provide insights into the relationships between baseline characteristics and outcomes. Graphical representations of model structures and conditional probabilities can be powerful tools to illustrate relationships in a high-dimensional data setting. METHODS: We review and apply Bayesian network theory to a clinical case study, presenting an analytical approach to investigating and visualizing causal relationships. We propose the use of the adherence score to compare data networks' patterns based on different variables' discretization. Data from adult patients with spasticity related to multiple sclerosis (MSS) from two randomized placebo-controlled clinical trials of nabiximols were used as analysis sets. The training and validation sets included 106 (53 treated, 53 placebo) and 155 (76 treated, 79 placebo) participants, respectively. The primary objective was to create a network and estimate the causal dependencies between participants' characteristics, changes in MSS severity as reflected by shifts in the patient-reported numeric rating scale (NRS), and changes in symptoms, functional abilities, and quality of life factors. RESULTS: A causal network was identified between the key factors of assigned treatment, end of study spasticity NRS, and mental health/vitality subscales of the 36-Item Short Form Health Survey questionnaire (4 nodes and 3 edges; adherence score = 93%). In patients with mild spasticity, the impact of nabiximols on mental health or vitality subscales resulted in a probability ratio of 1.63. The decomposed mediation effect of spasticity NRS was observed through a mediation analysis between treatment and mental health (99.4%) or vitality (93.7%) subscales. CONCLUSIONS: The use of innovative methods such as causal networks is highly encouraged to identify dependent relationships among key factors in clinical trial data and drive insights for additional research.

Predictors of residual disease after debulking surgery in advanced stage ovarian cancer.

Objective: Optimal debulking with no macroscopic residual disease strongly predicts ovarian cancer survival. The ability to predict likelihood of optimal debulking, which may be partially dependent on tumor biology, could inform clinical decision-making regarding use of neoadjuvant chemotherapy. Thus, we developed a prediction model including epidemiological factors and tumor markers of residual disease after primary debulking surgery. Methods: Univariate analyses examined associations of 11 pre-diagnosis epidemiologic factors (n=593) and 24 tumor markers (n=204) with debulking status among incident, high-stage, epithelial ovarian cancer cases from the Nurses' Health Studies and New England Case Control study. We used Bayesian model averaging (BMA) to develop prediction models of optimal debulking with 5x5-fold cross-validation and calculated the area under the curve (AUC). Results: Current aspirin use was associated with lower odds of optimal debulking compared to never use (OR=0.52, 95%CI=0.31-0.86) and two tissue markers, ADRB2 (OR=2.21, 95%CI=1.23-4.41) and FAP (OR=1.91, 95%CI=1.24-3.05) were associated with increased odds of optimal debulking. The BMA selected aspirin, parity, and menopausal status as the epidemiologic/clinical predictors with the posterior effect probability ≥20%. While the prediction model with epidemiologic/clinical predictors had low performance (average AUC=0.49), the model adding tissue biomarkers showed improved, but weak, performance (average AUC=0.62). Conclusions: Addition of ovarian tumor tissue markers to our multivariable prediction models based on epidemiologic/clinical data slightly improved the model performance, suggesting debulking status may be in part driven by tumor characteristics. Larger studies are warranted to identify those at high risk of poor surgical outcomes informing personalized treatment.

Endocrine and multiple sclerosis outcomes in patients with autoimmune thyroid events in the alemtuzumab CARE-MS studies.

Background: Alemtuzumab is an effective therapy for relapsing multiple sclerosis. Autoimmune thyroid events are a common adverse event. Objective: Describe endocrine and multiple sclerosis outcomes over 6 years for alemtuzumab-treated relapsing multiple sclerosis patients in the phase 3 CARE-MS I, II, and extension studies who experienced adverse thyroid events. Methods: Endocrine and multiple sclerosis outcomes were evaluated over 6 years. Thyroid event cases, excluding those pre-existing or occurring after Year 6, were adjudicated retrospectively by expert endocrinologists independently of the sponsor and investigators. Results: Thyroid events were reported for 378/811 (46.6%) alemtuzumab-treated patients. Following adjudication, endocrinologists reached consensus on 286 cases (75.7%). Of these, 39.5% were adjudicated to Graves' disease, 2.5% Hashimoto's disease switching to hyperthyroidism, 15.4% Hashimoto's disease, 4.9% Graves' disease switching to hypothyroidism, 10.1% transient thyroiditis, and 27.6% with uncertain diagnosis; inclusion of anti-thyroid antibody status reduced the number of uncertain diagnoses. Multiple sclerosis outcomes of those with and without thyroid events were similar. Conclusion: Adjudicated thyroid events occurring over 6 years for alemtuzumab-treated relapsing multiple sclerosis patients were primarily autoimmune. Thyroid events were considered manageable and did not affect disease course. Thyroid autoimmunity is a common but manageable adverse event in alemtuzumab-treated relapsing multiple sclerosis patients.ClinicalTrials.gov Registration Numbers: CARE-MS I (NCT00530348); CARE-MS II (NCT00548405); CARE-MS Extension (NCT00930553).

Effects of teriflunomide treatment on cognitive performance and brain volume in patients with relapsing multiple sclerosis: Post hoc analysis of the TEMSO core and extension studies.

BACKGROUND: In post hoc analyses of Teriflunomide Multiple Sclerosis Oral study (TEMSO; NCT00134563), teriflunomide 14 mg significantly reduced brain volume loss (BVL) versus placebo in patients with relapsing multiple sclerosis (MS). OBJECTIVE: In this post hoc analysis of TEMSO and its long-term extension (NCT00803049), we examined the relationship between teriflunomide's effects on BVL and cognition. METHODS: We analyzed data from 709 patients who received teriflunomide 14 mg in TEMSO or its extension. The change in cognitive performance, assessed using the Paced Auditory Serial Addition Test 3 (PASAT-3), was measured in subgroups stratified by BVL over 2 years (least BVL: ⩽ 0.52%; intermediate BVL: >0.52%-2.18%; most BVL: >2.18%). BVL, MRI lesions, and relapses over 2 years were evaluated as potential mediators of the effect of teriflunomide on cognition. RESULTS: Teriflunomide 14 mg significantly improved PASAT-3 Z-scores versus placebo through year 2. In the least- and intermediate-BVL groups, significant improvements in PASAT-3 Z-score were demonstrated versus the most-BVL group over 3 years in the extension. According to the mediation analysis, 44% of the teriflunomide effect on cognition was due to effects on BVL at year 2. CONCLUSION: Teriflunomide improves cognition largely through its effects on BVL. Accelerated BVL earlier in the disease course may predict cognitive outcomes. CLINICALTRIALS.GOV IDENTIFIER: NCT00134563, NCT00803049.

Efficacy and Safety of Teriflunomide in Multiple Sclerosis across Age Groups: Analysis from Pooled Pivotal and Real-world Studies.

BACKGROUND: Evidence suggests that efficacy and safety of disease-modifying treatments for multiple sclerosis may differ with age. We evaluate efficacy and safety of teriflunomide across age subgroups of patients from pooled clinical trials and real-world studies. METHODS: Post hoc analyses of patients who received teriflunomide 14 mg in the pooled phase II and III TEMSO, TOWER, TENERE, and TOPIC core and extension studies (n = 1978), and the real-world Teri-PRO (n = 928) and TAURUS-MS I (n = 1126) studies were conducted. Data were stratified by age at study entry: ⩽25, >25 to ⩽35, >35 to ⩽45, and >45 years. In Teri-PRO and TAURUS-MS I, an additional group, >55 years, was assessed. RESULTS: In the pooled core studies, teriflunomide reduced annualized relapse rate (ARR) versus placebo across all ages. Unadjusted ARRs remained low across age groups in pooled extensions (0.18-0.30), Teri-PRO (0.10-0.35), and TAURUS-MS I (0.14-0.35). Baseline Expanded Disability Status Scale scores were higher with age, but stable through core and extension studies (mean increases over 7 years: ⩽25 years, +0.59; >25 to ⩽35 years, +0.46; >35 to ⩽45 years, +0.35; >45 years, +0.81). Across age groups, adverse event (AE) incidences were 78.4% to 90.7% in pooled core and extension studies and Teri-PRO, and 29.2% to 37.7% in TAURUS-MS I; serious AE incidences were ⩽21.3% in all studies. In pooled phase III and Teri-PRO studies, lymphocyte count decreases over 1 year after initiating teriflunomide, and proportions of patients developing lymphopenia, were small across age groups. CONCLUSIONS: Teriflunomide efficacy was demonstrated regardless of age. Safety was generally consistent across age groups.

Efficacy and Safety of Cabazitaxel Versus Abiraterone or Enzalutamide in Older Patients with Metastatic Castration-resistant Prostate Cancer in the CARD Study.

BACKGROUND: In the CARD study (NCT02485691), cabazitaxel significantly improved median radiographic progression-free survival (rPFS) and overall survival (OS) versus abiraterone/enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who had previously received docetaxel and progressed ≤12 mo on the alternative agent (abiraterone/enzalutamide). OBJECTIVE: To assess cabazitaxel versus abiraterone/enzalutamide in older (≥70 yr) and younger (<70 yr) patients in CARD. DESIGN, SETTING, AND PARTICIPANTS: Patients with mCRPC were randomized 1:1 to cabazitaxel (25 mg/m2 plus prednisone and granulocyte colony-stimulating factor) versus abiraterone (1000 mg plus prednisone) or enzalutamide (160 mg). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Analyses of rPFS (primary endpoint) and safety by age were prespecified; others were post hoc. Treatment groups were compared using stratified log-rank or Cochran-Mantel-Haenszel tests. RESULTS AND LIMITATIONS: Of the 255 patients randomized, 135 were aged ≥70 yr (median 76 yr). Cabazitaxel, compared with abiraterone/enzalutamide, significantly improved median rPFS in older (8.2 vs 4.5 mo; hazard ratio [HR] = 0.58; 95% confidence interval [CI] = 0.38-0.89; p = 0.012) and younger (7.4 vs 3.2 mo; HR = 0.47; 95% CI = 0.30-0.74; p < 0.001) patients. The median OS of cabazitaxel versus abiraterone/enzalutamide was 13.9 versus 9.4 mo in older patients (HR = 0.66; 95% CI = 0.41-1.06; p = 0.084), and it was 13.6 versus 11.8 mo in younger patients (HR = 0.66; 95% CI = 0.41-1.08; p = 0.093). Progression-free survival, prostate-specific antigen, and tumor and pain responses favored cabazitaxel, regardless of age. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 58% versus 49% of older patients receiving cabazitaxel versus abiraterone/enzalutamide and 48% versus 42% of younger patients. In older patients, cardiac adverse events were more frequent with abiraterone/enzalutamide; asthenia and diarrhea were more frequent with cabazitaxel. CONCLUSIONS: Cabazitaxel improved efficacy outcomes versus abiraterone/enzalutamide in patients with mCRPC after prior docetaxel and abiraterone/enzalutamide, regardless of age. TEAEs were more frequent among older patients. The cabazitaxel safety profile was manageable across age groups. PATIENT SUMMARY: Clinical trial data showed that cabazitaxel improved survival versus abiraterone/enzalutamide with manageable side effects in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel and the alternative agent (abiraterone/enzalutamide), irrespective of age.

Post Hoc Health-Related Quality of Life Analysis According to Response Among Patients with Prostate Cancer in the PROSELICA and FIRSTANA Studies.

BACKGROUND: The phase III PROSELICA (NCT01308580) and FIRSTANA (NCT01308567) trials investigated taxane chemotherapy among men with postdocetaxel metastatic, castration-resistant prostate cancer (mCRPC) or chemotherapy-naïve mCRPC, respectively. We present a post hoc analysis of patient-reported health-related quality of life (HRQL) among patients with or without a clinical (pain, tumor, or prostate-specific antigen [PSA]) response. MATERIALS AND METHODS: PROSELICA and FIRSTANA HRQL and pain data were collected and analyzed using protocol-defined Functional Assessment of Cancer Therapy-Prostate (FACT-P) and McGill-Melzack (Present Pain Intensity scale) questionnaires. Outcomes included definitive FACT-P Total Score (TS) improvements and longitudinal assessment of FACT-P TS. RESULTS: In PROSELICA and FIRSTANA, the proportion of patients receiving taxane chemotherapy with a definitive FACT-P TS improvement was significantly higher among patients with versus without a pain or PSA response (pain: PROSELICA: 67% vs. 33.5%; p < .001; FIRSTANA: 75.2% vs. 45.8%; p < .001; PSA: PROSELICA: 50.3% vs. 34.2%; p < .001; FIRSTANA: 49.8% vs. 38.9%; p = .001). In PROSELICA, the proportion of patients receiving taxane chemotherapy with a definitive FACT-P TS improvement was significantly higher among patients with versus without a tumor response; the proportion was numerically higher in FIRSTANA (PROSELICA: 54.4% vs. 36.7%; p = .001; FIRSTANA: 50.6% vs. 45.3%). FACT-P TS was significantly improved or maintained for the majority of treatment cycles analyzed. CONCLUSION: In PROSELICA and FIRSTANA, HRQL improvements were significantly higher among patients with a pain, tumor, or PSA response versus those without, with the exception of patients with a tumor response in FIRSTANA. IMPLICATIONS FOR PRACTICE: Using data from the FIRSTANA and PROSELICA phase III clinical trials, this study demonstrated that patients with metastatic, castration-resistant prostate cancer (mCRPC) receiving docetaxel or cabazitaxel who exhibited a response (pain, tumor, prostate-specific antigen), often experienced significantly greater improvements in health-related quality of life (HRQL) compared with patients without a response. For patients with a pain response, significant HRQL improvements occurred early and were maintained. This study provides further insight into the impact of taxane chemotherapy on the HRQL of patients with mCRPC and allows for a better understanding of the relationship between treatment, response, and HRQL, supporting therapeutic decision making.

Postdiagnostic Dietary Glycemic Index, Glycemic Load, Dietary Insulin Index, and Insulin Load and Breast Cancer Survival.

BACKGROUND: We investigated the associations of postdiagnostic dietary glycemic index (GI), glycemic load (GL), insulin index (II), and insulin load (IL) with breast cancer-specific and all-cause mortality. METHODS: Among 8,932 women with stage I-III breast cancer identified in the Nurses' Health Study (NHS; 1980-2010) and NHSII (1991-2011), we prospectively evaluated the associations between postdiagnostic GI, GL, II, and IL, and breast cancer-specific and all-cause mortality. Participants completed a validated food frequency questionnaire every 4 years after diagnosis. RESULTS: During follow-up by 2014 in the NHS and 2015 in the NHSII, 2,523 deaths, including 1,071 from breast cancer, were documented. Higher postdiagnostic GL was associated with higher risk of both breast cancer-specific mortality [HRQ5vsQ1 = 1.33; 95% confidence interval (CI) = 1.09-1.63; P trend = 0.008] and all-cause mortality (HRQ5vsQ1 = 1.26; 95% CI = 1.10-1.45; P trend = 0.0006). Higher all-cause mortality was also observed with higher postdiagnostic GI (HRQ5vsQ1 = 1.23; 95% CI = 1.08-1.40; P trend = 0.001), II (HRQ5vsQ1 = 1.20; 95% CI = 1.04-1.38; P trend = 0.005), and IL (HRQ5vsQ1 = 1.23; 95% CI = 1.07-1.42; P trend = 0.0003). The associations were not modified by insulin receptor or estrogen receptor status of the tumor, or body mass index. CONCLUSIONS: We found that higher dietary GL, reflecting postprandial glucose response, after a breast cancer diagnosis was associated with higher risk of breast cancer-specific mortality. Higher dietary GI, GL, II, and IL after a breast cancer diagnosis were associated with higher risk of death from any cause. IMPACT: These results suggest that carbohydrate quantity and quality may be important in breast cancer prognosis.See related commentary by McTiernan, p. 252.

Slowing of brain atrophy with teriflunomide and delayed conversion to clinically definite MS.

BACKGROUND: We explored the effect of teriflunomide on cortical gray matter (CGM) and whole brain (WB) atrophy in patients with clinically isolated syndrome (CIS) from the phase III TOPIC study and assessed the relationship between atrophy and risk of conversion to clinically definite MS (CDMS). METHODS: Patients (per McDonald 2005 criteria) were randomized 1:1:1 to placebo, teriflunomide 7 mg, or teriflunomide 14 mg for ⩽108 weeks (core study). In the extension, teriflunomide-treated patients maintained their original dose; placebo-treated patients were re-randomized 1:1 to teriflunomide 7 mg or 14 mg. Brain volume was assessed during years 1-2. RESULTS: Teriflunomide 14 mg significantly slowed annualized CGM and WB atrophy versus placebo during years 1-2 [percent reduction: month 12, 61.4% (CGM; p = 0.0359) and 28.6% (WB; p = 0.0286); month 24, 40.2% (CGM; p = 0.0416) and 43.0% (WB; p < 0.0001)]. For every 1% decrease in CGM or WB volume during years 1-2, risk of CDMS conversion increased by 14.5% (p = 0.0004) and 47.3% (p < 0.0001) during years 1-2, respectively, and 6.6% (p = 0.0570) and 35.9% (p = 0.0250) during years 1-5. In patients with the least (bottom quartile) versus most (top quartile) atrophy during years 1-2, risk of CDMS conversion was reduced by 58% (CGM; p = 0.0024) and 58% (WB; p = 0.0028) during years 1-2, and 42% (CGM; p = 0.0138) and 29% (WB; p = 0.1912) during years 1-5. CONCLUSION: These findings support the clinical relevance of CGM and WB atrophy and early intervention with teriflunomide in CIS.

Prior treatment status: impact on the efficacy and safety of teriflunomide in multiple sclerosis.

BACKGROUND: In this pooled, post hoc analysis of a phase 2 trial and the phase 3 TEMSO, TOWER, and TENERE clinical trials, long-term efficacy and safety of teriflunomide were assessed in subgroups of patients with relapsing multiple sclerosis (MS) defined by prior treatment status. METHODS: Patients were classified according to their prior treatment status in the core and core plus extension periods. In the core period, patients were grouped according to treatment status at the start of the study: treatment naive (no prior disease-modifying therapy [DMT] or DMT > 2 years prior to randomization), previously treated with another DMT (DMT > 6 to ≤24 months prior to randomization), and recently treated with another DMT (DMT ≤6 months prior to randomization). In the core plus extension period, patients were re-baselined to the time of starting teriflunomide 14 mg and grouped according to prior treatment status at that time point. Efficacy endpoints included annualized relapse rate (ARR), probability of confirmed disability worsening (CDW) over 12 weeks, and Expanded Disability Status Scale (EDSS) score. The incidence of adverse events was also assessed. RESULTS: Most frequently received prior DMTs at baseline were glatiramer acetate and interferon beta-1a across treatment groups. Teriflunomide 14 mg significantly reduced ARR versus placebo in the core period, regardless of prior treatment status. In the core and extension periods, adjusted ARRs were low (0.193-0.284) in patients treated with teriflunomide 14 mg across all subgroups. Probability of CDW by Year 4 was similar across subgroups; by Year 5, the percentage of patients with 12-week CDW was similar in treatment-naive patients and patients recently treated with another DMT (33.9 and 33.7%, respectively). EDSS scores were stable over time in all prior-treatment subgroups. There were no new or unexpected safety signals. Limitations include selective bias due to patient attrition, variability in subgroup size, and lack of magnetic resonance imaging outcomes. CONCLUSIONS: The efficacy and safety of teriflunomide 14 mg was similar in all patients with relapsing MS, regardless of prior treatment history. TRIAL REGISTRATION: Phase 2 trial core: NCT01487096 ; Phase 2 trial extension: NCT00228163 ; TEMSO core: NCT00134563 ; TEMSO extension: NCT00803049 ; TOWER: NCT00751881 ; TENERE: NCT00883337 .

Quality of life in patients with metastatic prostate cancer following treatment with cabazitaxel versus abiraterone or enzalutamide (CARD): an analysis of a randomised, multicentre, open-label, phase 4 study.

BACKGROUND: In the CARD study, cabazitaxel significantly improved radiographic progression-free survival and overall survival versus abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel and the alternative androgen signalling-targeted inhibitor. Here, we report the quality-of-life outcomes from the CARD study. METHODS: CARD was a randomised, multicentre, open-label, phase 4 study involving 62 clinical sites across 13 European countries. Patients (aged ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status ≤2) with confirmed metastatic castration-resistant prostate cancer were randomly assigned (1:1) by means of an interactive voice-web response system to receive cabazitaxel (25 mg/m2 intravenously every 3 weeks, 10 mg daily prednisone, and granulocyte colony-stimulating factor) versus abiraterone (1000 mg orally once daily plus 5 mg prednisone twice daily) or enzalutamide (160 mg orally daily). Stratification factors were ECOG performance status, time to disease progression on the previous androgen signalling-targeted inhibitor, and timing of the previous androgen signalling-targeted inhibitor. The primary endpoint was radiographic progression-free survival; here, we present more detailed analyses of pain (assessed using item 3 on the Brief Pain Inventory-Short Form [BPI-SF]) and symptomatic skeletal events, alongside preplanned patient-reported outcomes, assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire and the EuroQoL-5 dimensions, 5 level scale (EQ-5D-5L). Efficacy analyses were done in the intention-to-treat population. Pain response was analysed in the intention-to-treat population with baseline and at least one post-baseline assessment of BPI-SF item 3, and patient-reported outcomes (PROs) were analysed in the intention-to-treat population with baseline and at least one post-baseline assessment of either FACT-P or EQ-5D-5L (PRO population). Analyses of skeletal-related events were also done in the intention-to-treat population. The CARD study is registered with ClinicalTrials.gov, NCT02485691, and is no longer enrolling. FINDINGS: Between Nov 17, 2015, and Nov 28, 2018, of 303 patients screened, 255 were randomly assigned to cabazitaxel (n=129) or abiraterone or enzalutamide (n=126). Median follow-up was 9·2 months (IQR 5·6-13·1). Pain response was observed in 51 (46%) of 111 patients with cabazitaxel and 21 (19%) of 109 patients with abiraterone or enzalutamide (p<0·0001). Median time to pain progression was not estimable (NE; 95% CI NE-NE) with cabazitaxel and 8·5 months (4·9-NE) with abiraterone or enzalutamide (hazard ratio [HR] 0·55, 95% CI 0·32-0·97; log-rank p=0·035). Median time to symptomatic skeletal events was NE (95% CI 20·0-NE) with cabazitaxel and 16·7 months (10·8-NE) with abiraterone or enzalutamide (HR 0·59, 95% CI 0·35-1·01; log-rank p=0·050). Median time to FACT-P total score deterioration was 14·8 months (95% CI 6·3-NE) with cabazitaxel and 8·9 months (6·3-NE) with abiraterone or enzalutamide (HR 0·72, 95% CI 0·44-1·20; log-rank p=0·21). There was a significant treatment effect seen in changes from baseline in EQ-5D-5L utility index score in favour of cabazitaxel over abiraterone or enzalutamide (p=0·030) but no difference between treatment groups for change from baseline in EQ-5D-5L visual analogue scale (p=0·060). INTERPRETATION: Since cabazitaxel improved pain response, time to pain progression, time to symptomatic skeletal events, and EQ-5D-5L utility index, clinicians and patients with metastatic castration-resistant prostate cancer can be reassured that cabazitaxel will not reduce quality of life when compared with treatment with a second androgen signalling-targeted inhibitor. FUNDING: Sanofi.

A lipid-related metabolomic pattern of diet quality.

BACKGROUND: Adherence to a healthy diet has been associated with reduced risk of chronic diseases. Identifying nutritional biomarkers of diet quality may be complementary to traditional questionnaire-based methods and may provide insights concerning disease mechanisms and prevention. OBJECTIVE: To identify metabolites associated with diet quality assessed via the Alternate Healthy Eating Index (AHEI) and its components. METHODS: This cross-sectional study used FFQ data and plasma metabolomic profiles, mostly lipid related, from the Nurses' Health Study (NHS, n = 1460) and Health Professionals Follow-up Study (HPFS, n = 1051). Linear regression models assessed associations of the AHEI and its components with individual metabolites. Canonical correspondence analyses (CCAs) investigated overlapping patterns between AHEI components and metabolites. Principal component analysis (PCA) and explanatory factor analysis were used to consolidate correlated metabolites into uncorrelated factors. We used stepwise multivariable regression to create a metabolomic score that is an indicator of diet quality. RESULTS: The AHEI was associated with 83 metabolites in the NHS and 96 metabolites in the HPFS after false discovery rate adjustment. Sixty-three of these significant metabolites overlapped between the 2 cohorts. CCA identified "healthy" AHEI components (e.g., nuts, whole grains) and metabolites (n = 27 in the NHS and 33 in the HPFS) and "unhealthy" AHEI components (e.g., red meat, trans fat) and metabolites (n = 56 in the NHS and 63 in the HPFS). PCA-derived factors composed of highly saturated triglycerides, plasmalogens, and acylcarnitines were associated with unhealthy AHEI components while factors composed of highly unsaturated triglycerides were linked to healthy AHEI components. The stepwise regression analysis contributed to a metabolomics score as a predictor of diet quality. CONCLUSION: We identified metabolites associated with healthy and unhealthy eating behaviors. The observed associations were largely similar between men and women, suggesting that metabolomics can be a complementary approach to self-reported diet in studies of diet and chronic disease.

Pregnancy outcomes in patients treated with leflunomide, the parent compound of the multiple sclerosis drug teriflunomide.

Leflunomide is contraindicated in pregnant women, yet human data from leflunomide-exposed pregnancies do not indicate an embryofetal toxicity signal. The objective of the present analysis was to report pregnancy outcomes for leflunomide-exposed pregnancies in clinical trials and in the post-marketing setting. Pregnancy outcomes are summarized from leflunomide clinical trials and the post-marketing setting. The data cut-off was 31 December 2017. Of 1167 pregnancies reported in female patients exposed to leflunomide, 587 had a known outcome. Of these, 337 (57.4%) were reported prospectively and 250 (42.6%) were reported retrospectively. Of the 587 pregnancies with a known outcome (which involved 15 sets of twins), there were 333 (56.7%) live births, with 285 (48.6%) full-term births and 48 (8.2%) pre-term births. Birth defects were reported in 44 babies/fetuses/embryos from 587 pregnancies, with 2 reporting at least 3 minor defects and 20 reporting major defects. Major defects were reported in 3 of 337 (0.9%) prospectively-reported pregnancies; 1 major birth defect occurred in a live birth, and 2 were electively terminated due to a detected fetal anomaly. Two of the babies/fetuses/embryos, a live birth and an electively aborted baby/fetus/embryo, from 206 prospectively-reported pregnancies exposed to leflunomide during the first trimester experienced major defects. Birth defects showed no specific patterns and were distributed evenly across organ systems. Outcomes were consistent with the general population. These findings do not suggest an embryofetal toxicity signal for leflunomide, which is consistent with previous findings from leflunomide-exposed pregnancies.

A Prospective Analysis of Circulating Plasma Metabolites Associated with Ovarian Cancer Risk.

Ovarian cancer has few known risk factors, hampering identification of high-risk women. We assessed the association of prediagnostic plasma metabolites (N = 420) with risk of epithelial ovarian cancer, including both borderline and invasive tumors. A total of 252 cases and 252 matched controls from the Nurses' Health Studies were included. Multivariable logistic regression was used to estimate ORs and 95% confidence intervals (CI), comparing the 90th-10th percentile in metabolite levels, using the permutation-based Westfall and Young approach to account for testing multiple correlated hypotheses. Weighted gene coexpression network analysis (WGCNA; n = 10 metabolite modules) and metabolite set enrichment analysis (n = 23 metabolite classes) were also evaluated. An increase in pseudouridine levels from the 10th to the 90th percentile was associated with a 2.5-fold increased risk of overall ovarian cancer (OR = 2.56; 95% CI, 1.48-4.45; P = 0.001/adjusted P = 0.15); a similar risk estimate was observed for serous/poorly differentiated tumors (n = 176 cases; comparable OR = 2.38; 95% CI, 1.33-4.32; P = 0.004/adjusted P = 0.55). For nonserous tumors (n = 34 cases), pseudouridine and C36:2 phosphatidylcholine plasmalogen had the strongest statistical associations (OR = 9.84; 95% CI, 2.89-37.82; P < 0.001/adjusted P = 0.07; and OR = 0.11; 95% CI, 0.03-0.35; P < 0.001/adjusted P = 0.06, respectively). Five WGCNA modules and 9 classes were associated with risk overall at FDR ≤ 0.20. Triacylglycerols (TAG) showed heterogeneity by tumor aggressiveness (case-only heterogeneity P < 0.0001). The TAG association with risk overall and serous tumors differed by acyl carbon content and saturation. In summary, this study suggests that pseudouridine may be a novel risk factor for ovarian cancer and that TAGs may also be important, particularly for rapidly fatal tumors, with associations differing by structural features. SIGNIFICANCE: Pseudouridine represents a potential novel risk factor for ovarian cancer and triglycerides may be important particularly in rapidly fatal ovarian tumors.

Proportion of alemtuzumab-treated patients converting from relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis over 6 years.

BACKGROUND: Few data exist concerning conversion to secondary progressive MS in patients treated with disease-modifying therapies. OBJECTIVE: Determine the proportion of alemtuzumab-treated patients converting from relapsing-remitting to secondary progressive MS during the CARE-MS core and extension studies. METHODS: Patients (N = 811) were analyzed post hoc for secondary progressive MS conversion. Optimal conversion definition: Expanded Disability Status Scale (EDSS) score ≥4, pyramidal functional system score ≥2, and confirmed progression over ≥3 months including confirmation within the functional system leading to progression, independent of relapse. RESULTS: Over 6.2 years median follow-up, 20 alemtuzumab-treated patients converted (Kaplan-Meier estimate, 2.7%; 95% confidence interval, 1.8%-4.2%). Sensitivity analysis accounting for dropouts showed similar results (3%), as did analyses using alternative definitions with different EDSS thresholds and/or confirmation periods, and analysis of core study subcutaneous interferon beta-1a-treated patients who received alemtuzumab in the extension. Patients converting to secondary progressive MS were older, and had higher EDSS scores and greater brain lesion volumes at baseline, but did not need additional alemtuzumab or other therapies. CONCLUSIONS: The 6-year conversion rate to secondary progressive MS was low for alemtuzumab-treated patients, supporting further study of the role alemtuzumab may play in reducing risk of secondary progression.ClinicalTrials.gov identifiers: NCT00530348, NCT00548405, NCT00930553.

Association of brain volume loss and long-term disability outcomes in patients with multiple sclerosis treated with teriflunomide.

BACKGROUND: Teriflunomide 14 mg significantly reduced brain volume loss (BVL) and confirmed disability worsening (CDW) compared with placebo in the TEMSO core study. OBJECTIVE: To investigate the relationship between BVL from Baseline to Year 2 in the TEMSO core study and long-term CDW (Year 7) in the TEMSO long-term extension (NCT00803049). METHODS: Structural Image Evaluation using Normalization of Atrophy determined BVL. Long-term CDW was assessed by Expanded Disability Status Scale confirmed for 12 and 24 weeks. An additional analysis evaluated the relative contribution of BVL (Year 2) and other outcomes as potential mediators of the effect of teriflunomide 14 mg on 12-week CDW. RESULTS: Patients with the least BVL were significantly less likely to have 12- and 24-week CDW at Year 7 compared with patients with the most BVL. A mediation analysis revealed that BVL (Year 2) explained 51.3% of the treatment effect on CDW; new or enlarging T2w lesions over 2 years explained 30.8%, and relapses in the first 2 years explained 38.5%. CONCLUSIONS: These results highlight the potential predictive value of BVL earlier in the disease course on long-term disability outcomes. The mediation analysis suggests that teriflunomide may prevent disability worsening largely through its effects on BVL.

Pregnancy outcomes in patients with multiple sclerosis treated with teriflunomide: Clinical study data and 5 years of post-marketing experience.

BACKGROUND: Teriflunomide is contraindicated in pregnancy. Some pregnancies have occurred despite guidance to use effective contraception. OBJECTIVES: To report outcomes of pregnancies occurring in teriflunomide clinical trials and the post-marketing setting. METHODS: Outcomes are summarized for pregnancies in teriflunomide monotherapy clinical trials and the post-marketing setting (data cutoff: December 2017). RESULTS: Of 437 confirmed teriflunomide-exposed pregnancies, 222 had known outcomes (70 from clinical trials; 152 from the post-marketing setting); 161 were reported prospectively and 61 retrospectively. There were 107 (48.2%) live births, 63 (28.4%) elective abortions, 47 (21.2%) spontaneous abortions, 3 (1.4%) ectopic pregnancies, 1 (0.5%) stillbirth, and 1 (0.5%) maternal death leading to fetal death. Four birth defects were reported among cases with known pregnancy outcome: ureteropyeloectasia (only defect considered major); congenital hydrocephalus; ventricular septal defect; and malformation of right foot valgus. A case of cystic hygroma was identified on antenatal ultrasound (pregnancy outcome unknown). One elective abortion followed prenatal diagnosis of fetal anomaly (blighted ovum). The risk of major birth defects in prospectively reported live birth/stillbirth outcomes was 3.6% (1/28) in clinical trials and 0.0% (0/51) in post-marketing reports. CONCLUSIONS: Outcomes were consistent with the general population. Current human data do not indicate a teratogenic signal in teriflunomide-exposed pregnancies.

Adult dietary fat intake and ovarian cancer risk.

The association of dietary fat intake with ovarian cancer risk has been inconsistent across populations. We examined dietary fat intake, overall and by type and ovarian cancer risk in two prospective cohort studies. We assessed long-term dietary fat intake among Nurses' Health Study (NHS) and NHSII participants using food frequency questionnaires administered every 2-4 years beginning in 1984 and 1991, respectively. We examined cumulative energy-adjusted intake of total fat, specific types of fat (animal, vegetable, saturated, monounsaturated, polyunsaturated and trans fat) and cholesterol. We identified 700 ovarian cancer cases in NHS and 196 in NHSII with dietary information. Cox proportional hazards regression was used to estimate associations between intake and ovarian cancer risk. Dietary fat intake changed over time in both cohorts and was lower in NHS than NHSII. Higher cumulative average intakes of animal fat and cholesterol were significantly positively associated with risk of ovarian cancer in NHS (relative risk [RR] comparing extreme quartiles = 1.57, 95% CI: 1.20, 2.06 and 1.35, 95% CI: 1.08, 1.69, respectively), but not in NHSII. Other dietary fat sources were not clearly associated with risk in either population. We did not observe clear associations between dietary fat and ovarian cancer risk in two large prospective cohort studies.