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Results of this double-blind, phase 2 trial showed patients with metastatic castration-resistant prostate cancer given olaparib plus abiraterone versus placebo plus abiraterone had significantly improved progression-free survival. Here, we present an exploratory analysis of pain and health-related quality of life (HRQOL). This double-blind, randomised, placebo-controlled, phase 2 trial was conducted across 41 urological oncology sites in 11 countries in Europe and North America. Eligible patients were aged 18 years or older, had metastatic castration-resistant prostate cancer, and had previously received docetaxel and up to one additional line of previous chemotherapy. Metastatic castration-resistant prostate cancer was defined as increasing prostate-specific antigen (PSA) concentration or other signs of disease progression despite androgen-deprivation therapy and serum testosterone concentrations at castrate levels (≤50 ng/dL), and with at least one metastatic lesion on bone scan, CT, or MRI. Eligible patients were randomly assigned (1:1) to receive oral olaparib (300 mg twice per day) plus oral abiraterone (1000 mg once a day) and oral prednisone or prednisolone (5 mg twice a day) or placebo plus abiraterone (1000 mg once a day) and prednisone or prednisolone (5 mg twice a day). Randomisation was done without stratification and by use of an interactive voice or web response system. A randomised treatment kit ID number was assigned sequentially to each patient as they became eligible. The primary endpoint (radiographic progression-free survival) has previously been reported. HRQOL was a prespecified exploratory patient-reported outcome. Patients were asked to complete the Brief Pain Inventory-Short Form (BPI-SF), single-item worst bone pain, Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire, and EuroQol-5 five-dimension five level (EQ-5D-5L) assessment at baseline, at weeks 4, 8, and 12, then every 12 weeks until treatment discontinuation. Prespecified outcomes were change from baseline in BPI-SF worst pain, single-item worst bone pain and FACT-P Total Outcome Index (TOI) scale scores, time to deterioration in BPI-SF worst pain and worst bone pain, and assessment of the EQ-5D-5L pain and discomfort domain. All analyses were exploratory and done in the full analysis set (all randomly assigned patients, including patients who were randomly assigned but did not subsequently go on to receive study treatment), with the exception of mean baseline and total change from baseline analyses, for which we used the population who had a valid baseline and at least one post-baseline assessment. This trial is registered with Clinicaltrials.gov, NCT01972217, and is no longer recruiting patients. Between Nov 25, 2014, and July 14, 2015, 171 patients were assessed for eligibility. 29 patients were excluded, and 142 were enrolled and randomly assigned to receive olaparib and abiraterone (n=71) or placebo and abiraterone (n=71). Data cutoff was Sept 22, 2017. Median follow-up was 15·9 months (IQR 8·1–25·5) in the olaparib plus abiraterone group and 24·5 months (8·1–27·6) in the placebo plus abiraterone group. Questionnaire compliance was generally high (43–100%). Least-squares mean changes from baseline in BPI-SF worst pain, single-item worst bone pain, and FACT-P TOI remained stable across all visits for patients in both treatment groups. Adjusted mean change in FACT-P TOI from baseline across all visits was −0·10 (95% CI −2·50 to 2·71) in the olaparib plus abiraterone group and −1·20 (−4·15 to 1·74) in the placebo plus abiraterone group (difference 1·30, 95% CI −2·70 to 5·30; p=0·52). Time to deterioration in pain was similar in both groups (BPI-SF worst pain HR 0·90 [95% CI 0·62–1·32], p=0·30; worst bone pain HR 0·85 [0·59–1·22], p=0·18). Improvement rates in the pain and discomfort domain of the EQ-5D-5L were similar in both groups from baseline to week 48, beyond which a higher proportion of patients in the olaparib plus abiraterone arm reported an improvement compared to the placebo plus abiraterone group. In these prespecified exploratory analyses, there was no significant difference in pain or HRQOL when olaparib was added to abiraterone. In this phase 2 trial, a statistically significant radiographic progression-free survival benefit was observed with the olaparib plus abiraterone combination. These results suggest that the improved survival benefits observed when combining olaparib with abiraterone does not result in different HRQOL compared with placebo plus abiraterone. Phase 3 studies are required to validate these results. AstraZeneca and Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

The PROfound study showed significantly improved radiographical progression-free survival and overall survival in men with metastatic castration-resistant prostate cancer with alterations in homologous recombination repair genes and disease progression on a previous next-generation hormonal drug who received olaparib then those who received control. We aimed to assess pain and patient-centric health-related quality of life (HRQOL) measures in patients in the trial. In this open-label, randomised, phase 3 study, patients (aged ≥18 years) with metastatic castration-resistant prostate cancer and gene alterations to one of 15 genes (BRCA1, BRCA2, or ATM [cohort A] and BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L [cohort B]) and disease progression after a previous next-generation hormonal drug were randomly assigned (2:1) to receive olaparib tablets (300 mg orally twice daily) or a control drug (enzalutamide tablets [160 mg orally once daily] or abiraterone tablets [1000 mg orally once daily] plus prednisone tablets [5 mg orally twice daily]), stratified by previous taxane use and measurable disease. The primary endpoint (radiographical progression-free survival in cohort A) has been previously reported. The prespecified secondary endpoints reported here are on pain, HRQOL, symptomatic skeletal-related events, and time to first opiate use for cancer-related pain in cohort A. Pain was assessed with the Brief Pain Inventory-Short Form, and HRQOL was assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P). All endpoints were analysed in patients in cohort A by modified intention-to-treat. The study is registered with ClinicalTrials.gov, NCT02987543. Between Feb 6, 2017, and June 4, 2019, 245 patients were enrolled in cohort A and received study treatment (162 [66%] in the olaparib group and 83 [34%] in the control group). Median duration of follow-up at data cutoff in all patients was 6·2 months (IQR 2·2–10·4) for the olaparib group and 3·5 months (1·7–4·9) for the control group. In cohort A, median time to pain progression was significantly longer with olaparib than with control (median not reached [95% CI not reached–not reached] with olaparib vs 9·92 months [5·39–not reached] with control; HR 0·44 [95% CI 0·22–0·91]; p=0·019). Pain interference scores were also better in the olaparib group (difference in overall adjusted mean change from baseline score −0·85 [95% CI −1·31 to −0·39]; pnominal=0·0004). Median time to progression of pain severity was not reached in either group (95% CI not reached–not reached for both groups; HR 0·56 [95% CI 0·25–1·34]; pnominal=0·17). In patients who had not used opiates at baseline (113 in the olaparib group, 58 in the control group), median time to first opiate use for cancer-related pain was 18·0 months (95% CI 12·8–not reached) in the olaparib group versus 7·5 months (3·2–not reached) in the control group (HR 0·61; 95% CI 0·38–0·99; pnominal=0·044). The proportion of patients with clinically meaningful improvement in FACT-P total score during treatment was higher for the olaparib group than the control group: 15 (10%) of 152 evaluable patients had a response in the olaparib group compared with one (1%) of evaluable 77 patients in the control group (odds ratio 8·32 [95% CI 1·64–151·84]; pnominal=0·0065). Median time to first symptomatic skeletal-related event was not reached for either treatment group (olaparib group 95% CI not reached–not reached; control group 7·8–not reached; HR 0·37 [95% CI 0·20–0·70]; pnominal=0·0013). Olaparib was associated with reduced pain burden and better-preserved HRQOL compared with the two control drugs in men with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations who had disease progression after a previous next-generation hormonal drug. Our findings support the clinical benefit of improved radiographical progression-free survival and overall survival identified in PROfound. AstraZeneca and Merck Sharp & Dohme.

Background Sub-Saharan African (SSA) countries are currently experiencing one of the most rapid epidemiological transitions characterized by increasing urbanization and changing lifestyle factors. This has resulted in an increase in the incidence of non-communicable diseases, especially cardiovascular disease (CVD). This double burden of communicable and chronic non-communicable diseases has long-term public health impact as it undermines healthcare systems. Purpose The purpose of this paper is to explore the socio-cultural context of CVD risk prevention and treatment in sub-Saharan Africa. We discuss risk factors specific to the SSA context, including poverty, urbanization, developing healthcare systems, traditional healing, lifestyle and socio-cultural factors. Methodology We conducted a search on African Journals On-Line, Medline, PubMed, and PsycINFO databases using combinations of the key country/geographic terms, disease and risk factor specific terms such as \"diabetes and Congo\" and \"hypertension and Nigeria\". Research articles on clinical trials were excluded from this overview. Contrarily, articles that reported prevalence and incidence data on CVD risk and/or articles that report on CVD risk-related beliefs and behaviors were included. Both qualitative and quantitative articles were included. Results The epidemic of CVD in SSA is driven by multiple factors working collectively. Lifestyle factors such as diet, exercise and smoking contribute to the increasing rates of CVD in SSA. Some lifestyle factors are considered gendered in that some are salient for women and others for men. For instance, obesity is a predominant risk factor for women compared to men, but smoking still remains mostly a risk factor for men. Additionally, structural and system level issues such as lack of infrastructure for healthcare, urbanization, poverty and lack of government programs also drive this epidemic and hampers proper prevention, surveillance and treatment efforts. Conclusion Using an African-centered cultural framework, the PEN3 model, we explore future directions and efforts to address the epidemic of CVD risk in SSA.

PurposeThe recent increase in emerging novel therapies in the bladder cancer therapeutic area has increased the need for fit-for-purpose patient-reported outcome (PRO) measures for these patients. This study evaluates the psychometric properties of the Functional Assessment of Cancer Therapy-Bladder (FACT-Bl) in 182 patients with advanced urothelial cancer (UC) and fills an important gap by demonstrating its validity for use in clinical trials.MethodsData were collected as part of a multicentre, open-label study of durvalumab in patients with inoperable or metastatic solid tumours. Psychometric properties evaluated include item and subscale characteristics (including correlation analysis), reliability (estimated using Cronbach’s α), validity (by independent sample t test), responsiveness (using mixed models with repeated measures), and clinically meaningful changes using both anchor-based and distribution-based methods.ResultsOne hundred and seventy-two patients completed the FACT-Bl questionnaire at baseline. Many individual items had floor or ceiling effects indicative of minimal symptoms and high functioning. The psychometric properties of the existing established scales were assessed and found to range from acceptable to very good. Internal consistency (most Cronbach’s α coefficients range 0.66–0.85) and stability (test–retest reliability) generally exceeded standards for good reliability (most estimated intraclass correlations [ICCs] exceeded 0.70, although ICCs for some items [e.g. emotional well-being, ICC 0.58; social well-being, ICC 0.66] were lower than 0.70). Evidence for known-group validity of relevant FACT-Bl subscales and total score was demonstrated by significant differences between groups defined by baseline tumour burden and quality of life scores (difference of FACT-Bl total between low/high tumour burden groups 11.72 (p = 0.001); difference between low/high QoL scores groups 30.51 (p < 0.0001)). The FACT-Bl subscale and total scores were responsive to changes in bladder cancer symptom severity. Clinically meaningful changes in FACT-Bl scores were estimated.ConclusionsResults support the use of the FACT-Bl within this patient population in future clinical research.

Purpose Pancreatic cancer and its treatments impact patients’ symptoms, functioning, and quality of life. Content-valid patient-reported outcome (PRO) instruments are required to assess outcomes in clinical trials. This study aimed to: (a) conceptualise the patient experience of pancreatic cancer; (b) identify relevant PRO instruments; (c) review the content validity of mapped instruments to guide PRO measurement in clinical trials. Methods Qualitative literature and interviews with clinicians and patients were analysed thematically to develop a conceptual model of patient experience. PRO instruments were reviewed against the conceptual model to identify gaps in measurement. Cognitive debriefing explored PRO conceptual relevance and patients’ understanding. Results Patients in the USA ( N  = 24, aged 35–84) and six clinicians (from US and Europe) were interviewed. Pre-diagnosis, pain was the most frequently reported symptom ( N  = 21). Treatments included surgery, radiation, chemotherapy, and immunotherapy. Surgery was associated with acute pain and gastrointestinal symptoms. Chemotherapy/chemoradiation side effects were cyclical and included fatigue/tiredness ( N  = 21), appetite loss ( N  = 15), bowel problems ( N  = 15), and nausea/vomiting ( N  = 15). Patients’ functioning and well-being were impaired. The literature review identified 49 PRO measures; the EORTC QLQ-C30/PAN26 were used most frequently and mapped with interview concepts. Patients found the EORTC QLQ-C30/PAN26 to be understandable and relevant; neuropathic side effects were suggested additions. Conclusions This is the first study to develop a conceptual model of patients’ experience of metastatic/recurrent pancreatic cancer and explore the content validity of the EORTC QLQ-C30/PAN26 following therapeutic advances. The EORTC QLQ-C30/PAN26 appears conceptually relevant; additional items to assess neuropathic side effects are recommended. A recall period should be stated throughout to standardise responses.

Objectives There has been limited success in achieving integration of patient-reported outcomes (PROs) in clinical trials. We describe how stakeholders envision a solution to this challenge. Methods Stakeholders from academia, industry, non-profits, insurers, clinicians, and the Food and Drug Administration convened at a Think Tank meeting funded by the Duke Clinical Research Institute to discuss the challenges of incorporating PROs into clinical trials and how to address those challenges. Using examples from cardiovascular trials, this article describes a potential path forward with a focus on applications in the United States. Results Think Tank members identified one key challenge: a common understanding of the level of evidence that is necessary to support patient-reported outcome measures (PROMs) in trials. Think Tank participants discussed the possibility of creating general evidentiary standards depending upon contextual factors, but such guidelines could not be feasibly developed because many contextual factors are at play. The attendees posited that a more informative approach to PROM evidentiary standards would be to develop validity arguments akin to courtroom briefs, which would emphasize a compelling rationale (interpretation/use argument) to support a PROM within a specific context. Participants envisioned a future in which validity arguments would be publicly available via a repository, which would be indexed by contextual factors, clinical populations, and types of claims. Conclusions A publicly available repository would help stakeholders better understand what a community believes constitutes compelling support for a specific PROM in a trial. Our proposed strategy is expected to facilitate the incorporation of PROMs into cardiovascular clinical trials and trials in general.

Limited data are available on acne treatment patterns, expectations, and satisfaction in the adult female subpopulation, particularly among different racial and ethnic groups. Describe acne treatment patterns and expectations in adult females of different racial/ethnic groups and analyze and explore their potential effects on medication compliance and treatment satisfaction. A cross-sectional, Web-based survey was administered to US females (25-45 years) with facial acne (≥25 visible lesions). Data collected included sociodemographics, self-reported clinical characteristics, acne treatment use, and treatment expectations and satisfaction. Three hundred twelve subjects completed the survey (mean age, 35.3±5.9 years), comprising black (30.8%), Hispanic (17.6%), Asian/other (17.3%), and white (34.3%). More than half of the subjects in each racial group recently used an acne treatment or procedure (black, 63.5%; Hispanic, 54.5%; Asian/other, 66.7%; white, 66.4%). Treatment use was predominantly over-the-counter (OTC) (47.4%) versus prescription medications (16.6%). OTC use was highest in white subjects (black, 42.7%; Hispanic, 34.5%; Asian/other, 44.4%; white, 59.8%; P<0.05). The most frequently used OTC treatments in all racial/ethnic groups were salicylic acid (SA) (34.3%) and benzoyl peroxide (BP) (32.1%). Overall, compliance with acne medications was highest in white versus black (57.0±32.4 vs 42.7±33.5 days, P>0.05), Hispanic (57.0±32.4 vs 43.2±32.9 days, P>0.05), and Asian/other (57.0±32.4 vs 46.9±37.2 days, P>0.05) subjects. Most subjects expected OTC (73.7%) and prescription (74.7%) treatments to work quickly. Fewer than half of the subjects were satisfied with OTC treatment (BP, 47.0%; SA, 43.0%), often due to skin dryness (BP, 26.3%; SA, 44.3%) and flakiness (BP, 12.3%; SA, 31.1%). No statistically significant differences were observed among racial/ethnic groups in their level of satisfaction with OTC or prescription acne treatments. Racial/ethnic differences were observed in acne treatment patterns in adult females, while treatment expectations were similar. Results indicate that treatment patterns and expectations may impact treatment satisfaction and medication compliance.

Immigration to the United States has increased significantly over the past three decades. As a result, immigrants now constitute about 12% of the total U.S. population. In the same way, the population of children in immigrant families in the United States (including immigrant children and U.S.-born children of adult immigrants) has also increased considerably. The proportion of children residing in a home with at least one foreign-born parent rose from 12.1% in 1990 to 18.1% in 2000 and 22% in 2007. Yet, the health and health behaviors of this fast-growing population of children in immigrant families remain insufficiently understood. Additional research is needed to adequately understand the psychological, physical, and emotional needs of children in immigrant families, identify the barriers to resources that they experience, and examine the underlying mechanisms through which various aspects of immigrant integration affect the physical and psychological well-being of immigrant children. This dissertation focuses on adolescents with one or more immigrant parents. The thesis consists of three studies that examine the disparities in physical and mental health status and health care access and utilization between adolescents and young adults in immigrant and non-immigrant families. In the first study, I examine the differences in the trajectories of self-reported physical health from age 12 to 32 among non-Hispanic Whites, non-Hispanic Blacks, Asians, and Hispanics in immigrant and non-immigrant families. Further, I assess the effect of assimilation on the self-reported health trajectories of adolescents and young adults age 12 to 32 with immigrant or non-immigrant parents from the four racial/ethnic backgrounds mentioned. The second study determines whether the trends in the receipt of routine physical exams from age 12 to 32 differ for those in immigrant and non-immigrant families. Also, the role of factors associated with health care access and utilization on the trajectories of routine physical examination is evaluated. Finally, the third study examines the immigrant generational differences in depressive symptoms among adolescents and notes how person, family, and neighborhood factors explain the association between depressive symptoms and generational status. In all the three studies, I analyze the National Longitudinal Study of Adolescent Health (Add Health) data using hierarchical or multilevel modeling techniques. The results of the first study are that an advantage in the trajectory of self-reported health exists for those in immigrant families from age 12 to 32 regardless of race/ethnicity and adjusting for socioeconomic characteristics, demographic factors, acculturation, and spatial assimilation does not fully explain the health advantage. The second study results show immigrant families are less likely to receive timely routine physical exams between the ages of 12 and 22 compared to those in non-immigrant families. However, from age 23 to 32 those in immigrant families are more likely to receive routine physical exam compared to those in non-immigrant families among Blacks, Asians, and Hispanics. High income, health insurance, having a usual source of health care, and a high parental education enhance the probability of routine physical exam over time. In the third study, first generation adolescents report higher average depressive symptoms than third generation adolescents while second generation adolescents do not differ significantly from third generation adolescents regarding average depressive symptoms reported. Also, greater proportions of first and second generation adolescents reside in neighborhoods characterized by high concentrated disadvantage, high immigrant concentration, and low residential stability. Results from the third study also indicate that person and family factors account for generation differences in depressive symptoms while neighborhood factors contribute substantially to racial/ethnic disparities in depressive symptoms among adolescents. Taken as a whole, the three studies in the dissertation have added to the existing knowledge on the health status and health care access and utilization of adolescents and young adults in immigrant families as well as the role of person, family, and neighborhood factors in shaping these health outcomes using a nationally representative longitudinal data set and multi-level modeling approaches.