Treatment with pembrolizumab in programmed death ligand 1-positive recurrent glioblastoma: Results from the multicohort phase 1 KEYNOTE-028 trial.

BACKGROUND: Current treatments for recurrent glioblastoma offer limited benefit. The authors report the antitumor activity and safety of the anti-programmed death 1 (anti-PD-1) immunotherapy, pembrolizumab, in programmed death ligand 1 (PD-L1)-positive, recurrent glioblastoma. METHODS: Adult patients with PD-L1-positive tumors were enrolled in the recurrent glioblastoma cohort of the multicohort, phase 1b KEYNOTE-028 study (ClinicalTrials.gov identifier, NCT02054806) and received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years. The primary endpoint was investigator-assessed overall response rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Archival tumor samples were assessed for PD-L1 expression levels (prospectively) and T-cell-inflamed gene expression profile score (retrospectively). RESULTS: After a median follow-up of 14 months (range, 2-55 months) among the 26 enrolled patients, the overall response rate was 8% (95% CI, 1%-26%). Two partial responses, lasting 8.3 and 22.8 months, occurred. Progression-free survival (median, 2.8 months; 95% CI, 1.9-8.1 months) rate at 6 months was 37.7%, and the overall survival (median, 13.1 months; 95% CI, 8.0-26.6 months) rate at 12 months was 58%. Correlation of therapeutic benefit to level of PD-L1 expression, gene expression profile score, or baseline steroid use could not be established. Treatment-related adverse events occurred in 19 patients (73%), and 5 patients experienced grade 3 or 4 events (there were no grade 5 events). Immune-mediated adverse events and infusion reactions occurred in 7 patients (27%). CONCLUSIONS: Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with manageable toxicity in this small, signal-finding, recurrent glioblastoma cohort. Future studies evaluating rationally designed pembrolizumab combination regimens may improve outcomes in patients with recurrent glioblastoma.

An eye toward the future: Pressing questions for our discipline in today's academic and research climate.

This paper seeks to open a dialogue concerning the current trend in hiring non-nurse faculty (NNF) to tenure track positions in schools/colleges of nursing. The evolution of non-nurses as faculty, including a review of contemporary papers in affecting this trend, is offered. Three means of involving non-nurses in advancing our discipline are presented. The impact of the growing trend of NNF is discussed relative to the integrity of our discipline and effects on education. We conclude by suggesting a manner of proceeding and raise questions for furthering dialogue.

Consumers' experience with and attitudes toward direct-to-consumer prescription drug promotion: a nationally representative survey.

The way consumers get and seek health information reflects the current information landscape. To gather updated insights on consumer experiences with and attitudes towards direct-to-consumer (DTC) promotion of prescription drugs, we conducted a nationally representative survey of 1,744 US adults using a mail-push-to-web methodology with paper nonresponse follow-up. Results showed high exposure and indifferent attitudes to DTC promotion. Respondents reported DTC promotion has prompted action, particularly searches for more information, increased use of online resources, and some reported that they refused to take or stopped taking a prescription drug because they saw or heard about the drug's side effects.

Pembrolizumab monotherapy in Japanese patients with advanced ovarian cancer: Subgroup analysis from the KEYNOTE-100.

Interim results from the two-cohort, phase 2 KEYNOTE-100 study (NCT02674061) of 376 patients with previously treated advanced recurrent ovarian cancer (ROC) showed that pembrolizumab monotherapy was associated with an objective response rate (ORR) of 8.0% (95% CI, 5.4-11.2). We present outcomes for the Japanese patients (n = 21) enrolled in KEYNOTE-100. Patients with epithelial ROC had received either 1-3 prior chemotherapy lines and had platinum-free interval or treatment-free interval (PFI; TFI) of 3-12 months (cohort A) or 4-6 prior chemotherapy lines and had PFI/TFI of ≥3 months (cohort B). All patients received pembrolizumab 200 mg every 3 weeks as monotherapy for 2 years or until progression, death, unacceptable toxicity or consent withdrawal. Primary objectives were ORR per RECIST v1.1 for each cohort and higher programmed death ligand-1 (PD-L1) tumor expression. The relationship between PD-L1 expression (measured as combined positive score [CPS]) and ORR was assessed. Twenty-one Japanese patients (cohort A, n = 19; cohort B, n = 2) were treated. The median (range) age was 57 (37-78) years; 19 (90.5%) patients had ECOG status of 0 and 16 (76.2%) patients had stage III-IV disease. ORR was 19.0% (95% CI, 5.4-41.9) and seemed to increase with increasing PD-L1 expression. A total of 13 (61.9%) patients had treatment-related adverse events (TRAE), and 5 (23.8%) had grade 3-4 TRAE. There were no treatment-related deaths in this subpopulation. Pembrolizumab monotherapy was associated with antitumor activity in Japanese patients with ROC, with no new safety signals identified in this subpopulation. The data suggested a trend toward higher PD-L1 expression among some patients with higher ORR.

Pembrolizumab for the treatment of programmed death-ligand 1-positive advanced carcinoid or pancreatic neuroendocrine tumors: Results from the KEYNOTE-028 study.

BACKGROUND: Despite a protracted disease course and multiple available therapies, patients with well-differentiated neuroendocrine tumors (NETs) inevitably experience disease progression. Programmed death-ligand 1 (PD-L1) has been associated with NET progression and prognosis. The multicohort, phase 1 KEYNOTE-028 study (ClinicalTrials.gov identifier NCT02054806) evaluated the activity and safety of the anti-programmed cell death protein 1 immunotherapy pembrolizumab in patients with well-differentiated or moderately-differentiated NETs. METHODS: Patients with PD-L1-positive, locally advanced or metastatic carcinoid or well-differentiated or moderately-differentiated pancreatic NETs (pNETs) were enrolled into separate cohorts and received pembrolizumab at a dose of 10 mg/kg every 2 weeks for up to 2 years. The objective response rate was the primary endpoint (as per Response Evaluation Criteria in Solid Tumors version 1.1, by investigator review). Safety was a secondary endpoint. RESULTS: Of 170 and 106 patients, respectively, who had evaluable samples among those screened for the carcinoid and pNET cohorts, 21% and 25%, respectively, had PD-L1-positive tumors; of these, 25 and 16 patients, respectively, were eligible and treated. The median follow-up was 20 months (range, 2-35 months) and 21 months (range, 5-32 months), respectively. The objective response rate was 12.0% (95% CI, 2.5%-31.2%) and 6.3% (95% CI, 0.2%-30.2%), respectively; 3 partial responses occurred among the carcinoid cohort and 1 among the pNET cohort. The median duration of response in the carcinoid cohort was 9.2 months (range, 6.9-11.1 months), and was not reached in the pNET cohort. No complete responses occurred. Treatment-related adverse events occurred in 68% and 69% of patients, respectively, most often diarrhea (7 patients in the carcinoid cohort and 4 patients in the pNET cohort) and fatigue (6 patients in each cohort). Hypothyroidism was the most common immune-mediated adverse event (5 patients in the carcinoid cohort and 2 patients in the pNET cohort). CONCLUSIONS: Pembrolizumab demonstrated antitumor activity in a subset of patients with NETs and was well-tolerated.

Consumer understanding of the scope of FDA's prescription drug regulatory oversight: A nationally representative survey.

PURPOSE: Misperceptions of how the US Food and Drug Administration (FDA) regulates prescription drugs may affect how consumers assess the safety and efficacy of prescription drugs. The study objective was to survey the public on their knowledge of FDA oversight regarding prescription drug approval and advertising. METHODS: In 2017, we conducted a nationally representative mail-push-to-web survey with 1,744 US adults. RESULTS: Although most respondents (86%) knew that FDA approves prescription drugs, we found misperceptions about what that approval means. In addition, few respondents understood FDA oversight of prescription drug advertising, with approximately half of respondents reporting that they did not know whether FDA approved these ads or components of the ads, and several mis-reporting that FDA approves these ads (31%) or components of the ads (22%-41%). CONCLUSIONS: Enhanced collaboration and communication with the public by key stakeholders in this space could increase public understanding of the roles and responsibilities of FDA.

The influence of identity on the prevalence and persistence of disordered eating and weight control behaviors in Mexican American college women.

Disordered eating behaviors are prevalent in Mexican-American college-enrolled women and contribute to compromised physical and psychological health. Although disordered eating behaviors are multi-determined, few studies have examined individual difference factors that contribute to disordered eating behaviors in Mexican women beyond acculturation. Evidence suggests that individual differences in the constellation of identities may be an important factor influencing the disordered eating behaviors. We hypothesized that individual differences in the collection of identities (self-schemas) increases susceptibility to defining oneself as fat (fat self-schema) and contribute to disordered eating behaviors over time in Mexican American college women. A 12-month longitudinal design was used to measure the level of disordered eating behaviors at 5 points over 12 months in 477 Mexican American women. Identity properties (i.e., positive self-schemas, negative self-schemas, fat self-schema) were measured at baseline. Controlling for relevant covariates, latent growth curve models showed that Mexican American women with few positive and many negative self-schemas were more likely to define themselves as fat, which in turn, predicted purging and fasting/restricting behaviors across the year. However, identity properties were not predictive of binge eating and excessive exercise episodes. Interventions focused on development of positive self-schemas that reflect areas of interest and competence and the revision of negative self-schemas may protect against purging and fasting/restricting in Mexican American college-enrolled women.

Maternal and child dietary intake: The role of maternal healthy-eater self-schema.

BACKGROUND: Mothers play a key role in shaping the dietary intake of their young children through their own dietary intake and the foods they make available at home. Therefore, understanding the mechanisms underlying maternal food choices is crucial. Cognitions about the self as a healthy eater, referred to as healthy-eater self-schema (HESS), predict dietary intake in diverse samples, but the linkage has not been investigated in mothers and their feeding behaviors. This study examined the relationship between a maternal HESS, maternal and child intake of fruits, vegetables, saturated fat, and added sugar, and home food availability. METHODS: A cross-sectional, descriptive design was used with mothers and their 2-5 year old children (N = 124 dyads). Kendzierski's Healthy-Eater Self-Schema questionnaire was used to measure HESS. Block Food Frequency Screeners were used to measure diets (mother and child) and the Home Environment Survey was used to measure home availability of fruits/vegetables and fats/sweets. Multiple regression and multiple mediation analyses were performed. RESULTS: Maternal HESS was positively associated with maternal intake of fruits and vegetables, and negatively associated with intake of added sugar. Maternal HESS was not directly associated with child dietary intake, but was indirectly associated with child intake of fruits, vegetables, and added sugar through maternal intake of the same foods. Home food availability was not significantly associated with HESS. CONCLUSION: This study found that a mother's HESS was positively associated with her diet, which was subsequently associated with aspects of her child's diet. Interventions to foster development of HESS in mothers may be an effective means to promote healthy dietary intake in mothers and their young children.

Self-schema as a non-drinker: a protective resource against heavy drinking in Mexican-American college women.

Alcohol use is considered less acceptable for women than men in the Mexican culture. However, recent studies of Mexican-American (MA) women show that prevalence and rates of alcohol use are escalating, particularly in those with high acculturation to Western standards. Building on recent studies that demonstrated that drinking-related identities (self-schemas) are important predictors of alcohol use in college populations, this secondary data analysis investigated the association between acculturation, MA cultural values, and acculturative stress, drinking-related self-schemas and heavy drinking over time in college-enrolled MA women. Data were drawn from a 12-month longitudinal study of self-schemas and health-risk behaviors in 477 college-enrolled MA women. Drinking-related self-schemas, acculturation, MA cultural values and acculturative stress were measured at baseline, and heavy drinking was measured at baseline, 3, 6, 9 and 12 months. Thirty-six percent of women had a non-drinker self-schema but only 3% had a drinker self-schema. Higher spirituality was protective against heavy drinking, and this effect can be partially explained by presence of a non-drinker self-schema. Interventions that emphasize the personal relevance of being a non-drinker and support the importance of spirituality may help to prevent heavy drinking in MA college women.

Relationships between early alcohol experiences, drinker self-schema, and drinking and smoking in college students.

BACKGROUND: Drinking and smoking commonly co-occur in undergraduate students. Although an identity as a drinker is a known predictor of alcohol use and alcohol problems, and early evidence suggests that it also predicts smoking, the role of these behaviors in the development of an identity as a drinker is unknown. In this study, the authors conceptualized a drinker identity as an enduring memory structure referred to as a self-schema and conducted a preliminary investigation of the relationships between early drinking experiences, drinker self-schema, and alcohol and tobacco use in undergraduate students. METHODS: Three-hundred thirty undergraduates who reported current alcohol and tobacco use were recruited for an online survey study. Frequency of alcohol and tobacco use in the past 30 days, drinker self-schema, and early experiences with alcohol were measured. RESULTS: Structural equation modeling showed that parental alcohol problems were associated with early onset of drinking. Early onset of drinking and high school friends' drinking were associated with more alcohol use and alcohol-related problems in high school. Alcohol problems during high school were associated with high drinker self-schema scores, which were associated with high frequency of alcohol and tobacco use during college. The indirect effects through the drinker self-schema were significant. CONCLUSIONS: Although cross-sectional, this preliminary examination supports theoretical predictions that early alcohol experiences may contribute to development of the drinker self-schema, which, as expected, was positively associated with alcohol and tobacco use in college. Longitudinal studies that track the unfolding of drinking behavior and the contextual factors that are associated with it in the development of the drinker self-schema are essential to confirming the theoretical model. If supported, implications for intervention at different developmental stages to prevent early onset of drinking, limit adolescent alcohol use, and modify the development of a drinker self-schema may mitigate undergraduate drinking and smoking.

Effects of drinker self-schema on drinking- and smoking-related information processing and behaviors.

BACKGROUND: Co-occurrence of drinking and smoking is prevalent in undergraduate students. A drinker self-schema-cognition about the self as the drinker-is a common identity in undergraduates and a well-known predictor of drinking behaviors. Given that smoking commonly occurs in the context of drinking, a drinker self-schema may be a cognitive mechanism to motivate co-occurring alcohol and tobacco use (i.e., cross-substance facilitation hypothesis). This study was to determine whether the drinker self-schema influences the processing of drinking- and smoking-related information and facilitates the co-occurrence of alcohol and tobacco use in undergraduate students who drink and smoke but do not self-identify as smokers. METHODS: This study was the second phase of a 2-phase study. Of the 330 who completed phase 1 (online survey), 99 completed the phase 2 study. Phase 2 was an in-person session that included a computerized information processing task to measure endorsements and response latencies for drinking- and smoking-related attributes, and a computerized Timeline Followback that was used to measure 90-day alcohol- and tobacco-use behaviors. The 5-item drinker self-schema scale, administered in phase 1, was used to measure the strength of the drinker self-schema. RESULTS: A higher drinker self-schema score was associated with more endorsements of positive attributes for drinking and smoking, fewer endorsements of negative attributes for smoking, faster processing of agreements with positive alcohol-use-related attributes, higher levels of drinking and smoking, and more days of co-occurring alcohol and tobacco use. CONCLUSIONS: Findings provide preliminary evidence to support the cross-substance facilitation hypothesis that the drinker self-schema facilitates the processing of not only drinking-related but also smoking-related stimuli and behaviors. Undergraduates who have higher drinker self-schema scores may be vulnerable to co-occurring alcohol and tobacco use.

Pharmacokinetics and pharmacodynamics of everolimus in patients with renal angiomyolipoma and tuberous sclerosis complex or lymphangioleiomyomatosis.

AIMS: The purpose was to determine the exposure-response relationship of everolimus in patients with angiomyolipoma from the EXIST-2 trial and to analyze the correlation between exposure and plasma concentrations of angiogenic biomarkers in these patients. METHODS: One hundred and eighteen patients with angiomyolipoma associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (sLAM) were randomly assigned 2 : 1 to receive everolimus 10 mg (n = 79) or placebo (n = 39) once daily. Blood samples for determining everolimus concentration were collected at weeks 2, 4, 12, 24 and 48 during double-blind treatment. Plasma samples for biomarker analysis were collected at baseline and weeks 4, 12, 24, 36, 48 and at the end of treatment. Concentrations of eight angiogenic biomarkers associated with tumour growth were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Peak and trough concentrations of everolimus in blood remained stable over time and similar to those reported in other indications. Substantial pharmacodynamic effects were observed in the everolimus, but not placebo, arm for three biomarkers: After 24 weeks of treatment, reduction of vascular endothelial growth factor D (VEGF-D) and collagen type IV (COL-IV) (mean fold-changes with 95% confidence intervals [CI] were 0.36 [0.33, 0.40], and 0.54 [0.51, 0.57], respectively, P < 0.001 for both), along with increased VEGF-A (mean fold-change of 1.59 [1.39, 1.80], P < 0.001), were seen. Furthermore, baseline VEGF-D and COL-IV levels were associated with angiomyolipoma size at baseline and with angiomyolipoma response to everolimus. CONCLUSIONS: These findings suggest that plasma angiogenic markers may provide an objective measure of patient response to everolimus.

Rosalie Wolf Memorial Lecture: A logic model to measure the impacts of World Elder Abuse Awareness Day.

This commentary discusses the need to evaluate the impact of World Elder Abuse Awareness Day activities, the elder abuse field's most sustained public awareness initiative. A logic model is proposed with measures for short-term, medium-term, and long-term outcomes for community-based programs.

Prospective effects of possible selves on alcohol consumption in adolescents.

Possible selves, cognitions about the self that reflect hopes, fears, and expectations for the future, are reliable predictors of health risk behaviors but have not been explored as predictors of adolescents' alcohol use. In a secondary analysis of data from 137 adolescents, we examined the influence of possible selves assessed in eighth grade on alcohol consumption (yes/no and level of use) in ninth grade. Having a most important feared possible self related to academics in eighth grade predicted alcohol abstinence in ninth grade. Among those who reported alcohol use, having many hoped-for possible selves and a most important hoped-for possible self related to academics in eighth grade predicted lower level of alcohol consumption in ninth grade. Interventions that foster the personal relevance and importance of academics and lead to the development of hoped-for possible selves may reduce adolescents' alcohol consumption.

Expected Problem Drinker Possible Self: Predictor of Alcohol Problems and Tobacco Use in Adolescents.

BACKGROUND: Alcohol and tobacco use commonly co-occur in adolescents. According to the cross-substance facilitation of information processing hypothesis, cognitive structures related to one substance increase use of another related substance through enhanced cognitive processing. In this study, the authors test this hypothesis by determining whether a problem drinker "possible self" in 8th grade predicts alcohol and tobacco use in 9th grade. METHODS: A secondary data analysis of a 12-month longitudinal dataset was conducted. The outcome variables were alcohol consumption, alcohol problems, and tobacco use in 9th grade. The main predictor of interest was presence of an expected problem drinker possible self in 8th grade. Zero-inflated gamma regression, zero-inflated negative binomial regression, and logistic regression were used. RESULTS: Among 137 adolescents, controlling for known family, parent, and peer determinants, and corresponding 8th grade behavior, having an expected problem drinker possible self in 8th grade predicted alcohol problems, but not level of alcohol consumption in 9th grade. Moreover, the expected problem drinker possible self in 8th grade predicted tobacco use in 9th grade, controlling for known determinants and concurrent alcohol problems. CONCLUSIONS: Findings provide support for the cross-substance facilitation hypothesis, suggesting that interventions designed to modify the expected problem drinker possible self may reduce not only adolescent alcohol use but also tobacco use. Further studies are needed to determine whether smoking content is embedded in a drinking cognition or 2 separate but related drinking and smoking cognitions account for the association between alcohol and tobacco use.

The effect of everolimus on renal angiomyolipoma in patients with tuberous sclerosis complex being treated for subependymal giant cell astrocytoma: subgroup results from the randomized, placebo-controlled, Phase 3 trial EXIST-1.

BACKGROUND: Tuberous sclerosis complex (TSC) is characterized by benign tumours in multiple organs, including the brain, kidneys, skin, lungs and heart. Our objective was to evaluate everolimus, an mTOR inhibitor, in the treatment of angiomyolipoma in patients with subependymal giant cell astrocytoma (SEGA) associated with TSC. METHODS: EXamining everolimus In a Study of Tuberous Sclerosis Complex-1 (NCT00789828), a prospective, double-blind, randomized, placebo-controlled, Phase 3 study, examined everolimus in treating SEGA associated with TSC. Patients with serial SEGA growth from pre-baseline to baseline scans were randomly assigned (2:1) to receive 4.5 mg/m(2)/day everolimus (target blood trough: 5-15 ng/mL; n = 78) or placebo (n = 39). Angiomyolipoma response rates were analysed in patients (n = 44) with target baseline angiomyolipoma lesions (≥1 angiomyolipoma; longest diameter ≥1.0 cm). An angiomyolipoma response rate, defined as the proportion of patients with confirmed angiomyolipoma response, was assessed by kidney CT or MRI screening at baseline, at 12, 24 and 48 weeks and annually. RESULTS: Angiomyolipoma response rates were 53.3% (16/30) and 0% (0/14) for everolimus- and placebo-treated patients, respectively. Angiomyolipoma reductions ≥50% in the sum of volumes of all target lesions were seen only in everolimus-treated patients (56.5, 78.3 and 80.0%) compared with placebo-treated patients (0% at each time point) at Weeks 12, 24 and 48, respectively. Greater percentages of everolimus-treated patients had angiomyolipoma reductions ≥30% at these same time points (82.6, 100 and 100% versus 8.3, 18.2 and 16.7% for everolimus versus placebo, respectively). CONCLUSIONS: Everolimus showed efficacy in reducing angiomyolipoma lesion volume in patients with SEGA associated with TSC.The trial is registered with ClinicalTrials.gov, number NCT00789828; http://clinicaltrials.gov/ct2/show/NCT00789828?term=EXIST-1&rank=1.

World elder abuse awareness day: the concept, the reality, and the promise.

This commentary traces the origins and evolution of the World Elder Abuse Awareness Day (WEAAD) initiative and provides recommendations for increasing WEAAD's impact as a catalyst for a coordinated movement within the United States.

An unexplored ethical issue in clinical research: disclosure of individual findings in the Creando Posibilidades [Creating Possibilities] study.

Individual disclosure refers to the presumptive ethical responsibility of an investigator to communicate to a study participant information that was collected as a part of a research study protocol and is specific to the individual. Currently, there are no federal regulatory guidelines specifying the conditions and management of disclosure of health-related individual-specific information. In this report, the authors discuss the challenges associated with individual disclosure in the context of a longitudinal descriptive study. Arguments favoring disclosure and those challenging disclosure as a general ethical duty are presented. Finally, strategies for addressing individual disclosure are discussed using a research exemplar in which risk behaviors related to health outcomes were measured.

A randomized clinical trial of an identity intervention programme for women with eating disorders.

OBJECTIVE: Findings of a randomized trial of an identity intervention programme (IIP) designed to build new positive self-schemas that are separate from other conceptions of the self in memory as the means to promote improved health in women diagnosed with eating disorders are reported. METHOD: After baseline data collection, women with anorexia nervosa or bulimia nervosa were randomly assigned to IIP (n = 34) or supportive psychotherapy (SPI) (n = 35) and followed at 1, 6, and 12 months post-intervention. RESULTS: The IIP and supportive psychotherapy were equally effective in reducing eating disorder symptoms at 1 month post-intervention, and changes were stable through the 12-month follow-up period. The IIP tended to be more effective in fostering development of positive self-schemas, and the increase was stable over time. Regardless of baseline level, an increase in the number of positive self-schemas between pre-intervention and 1-month post-intervention predicted a decrease in desire for thinness and an increase in psychological well-being and functional health over the same period. DISCUSSION: A cognitive behavioural intervention that focuses on increasing the number of positive self-schemas may be central to improving emotional health in women with anorexia nervosa and bulimia nervosa.