Improved relapse-free survival on aromatase inhibitors in breast cancer is associated with interaction between oestrogen receptor-α and progesterone receptor-b.

BACKGROUND: Recent pre-clinical studies indicate that activated progesterone receptor (PR) (particularly the PR-B isoform) binds to oestrogen receptor-α (ER) and reprogrammes transcription toward better breast cancer outcomes. We investigated whether ER and PR-B interactions were present in breast tumours and associated with clinical parameters including response to aromatase inhibitors. METHODS: We developed a proximity ligation assay to detect ER and PR-B (ER:PR-B) interactions in formalin-fixed paraffin-embedded tissues. The assay was validated in a cell line and patient-derived breast cancer explants and applied to a cohort of 229 patients with ER-positive and HER2-negative breast cancer with axillary nodal disease. RESULTS: Higher frequency of ER:PR-B interaction correlated with increasing patient age, lower tumour grade and mitotic index. A low frequency of ER:PR-B interaction was associated with higher risk of relapse. In multivariate analysis, ER:PR-B interaction frequency was an independent predictive factor for relapse, whereas PR expression was not. In subset analysis, low frequency of ER:PR-B interaction was predictive of relapse on adjuvant aromatase inhibitor (HR 4.831, p = 0.001), but not on tamoxifen (HR 1.043, p = 0.939). CONCLUSIONS: This study demonstrates that ER:PR-B interactions have utility in predicting patient response to adjuvant AI therapy.

Adapting Disease Prevention Protocols for Human Spaceflight During COVID-19.

BACKGROUND: The National Aeronautics and Space Administration (NASA) Flight Crew Health Stabilization Program (HSP) was historically implemented to minimize infectious disease transmission to astronauts in the immediate prelaunch period. The first ever commercial application and adaptation of the NASA HSP was implemented during the Crew Demo-2 mission in the time of the Coronavirus disease 2019 (COVID-19) pandemic. This article details and discusses the first commercial implementation and adaptation of the HSP prior to the Crew Demo-2 launch.METHODS: This is a retrospective descriptive analysis of the application of NASA disease prevention protocols for human spaceflight during the COVID-19 pandemic. In the context of the pandemic, extra precautions added to the HSP included daily symptom surveys completed by Primary Contacts of the crew, COVID-19 RT-PCR testing, and improved quarantine protocols.RESULTS: Of the 91 SpaceX Primary Contacts who completed a total of 2720 daily symptom surveys prior to launch, 22 individuals (24.2) and 198 surveys (7.3) returned positive for potential symptoms of COVID-19. Two individuals were removed due to symptoms indistinguishable from COVID-19. Through this survey, systematic quarantine, and PCR testing, the Crew Demo-2 mission was successful with no known infectious diseases transmitted.CONCLUSIONS: Overall, the commercial implementation of the NASA Health Stabilization Program by SpaceX with adjustments required during the COVID-19 pandemic was a success, with protocols allowing identification and removal of potentially infectious persons from the program. The principles of the HSP may provide an adequate infectious disease playbook for commercial spaceflight operations going forward.Petersen E, Pattarini JM, Mulcahy RA, Beger SB, Mitchell MR, Hu YD, Middleton KN, Frazier W, Mormann B, Esparza H, Asadi A, Musk ER, Alter G, Nilles E, Menon AS. Adapting disease prevention protocols for human spaceflight during COVID-19. Aerosp Med Hum Perform. 2021; 92(7):597602.

Absent progesterone receptor expression in the lymph node metastases of ER-positive, HER2-negative breast cancer is associated with relapse on tamoxifen.

AIMS: Progesterone receptor (PR) expression is prognostic in early stage breast cancer. There are several reports of discordant expression between primary tumour and axillary lymph node (ALN) metastasis expression of oestrogen receptor (ER) and PR. We sought to determine whether expression of these biomarkers in the synchronous ALN metastases of ER positive (+), HER2 negative (-) breast cancer could provide more accurate prognostic information. METHODS: The retrospective cohort included 229 patients from a single institution with ER+, HER2- breast cancer who had synchronous ALN metastatic disease (2005-2014). PR expression was correlated with relapse-free survival, and subset analysis was performed for patients who received adjuvant tamoxifen or an aromatase inhibitor. RESULTS: One patient had an ER+ primary tumour, which was ER- in the ALN metastasis. 27 (11.3%) were PR- in the primary tumour and 56 (23.6%) in the ALN metastasis. The predominant change was from PR+ in the primary tumour to PR- in the lymph node. Absence of PR expression in the ALN was significantly associated with relapse; however, this was not the case in the primary tumour. In a subset analysis of patients taking adjuvant endocrine therapy, poorer prognosis was limited to those with PR- metastases on tamoxifen (HR=5.203, 95% CI 1.649 to 16.416, p=0.005). No significant prognostic effect of PR- metastases in patients taking aromatase inhibitors was seen (HR=1.519, 95% CI 0.675 to 3.418, p=0.312). CONCLUSIONS: Evaluation of PR expression in ALN metastasis may enable prediction of patients who are less likely to benefit from adjuvant tamoxifen. This study should be replicated in other cohorts.

New perspectives on targeted therapy in ovarian cancer.

Epithelial ovarian cancer remains the most lethal gynecologic malignancy. During the last 15 years, there has been only marginal improvement in 5 year overall survival. These daunting statistics are compounded by the fact that despite all subtypes exhibiting striking heterogeneity, their systemic management remains identical. Although changes to the scheduling and administration of chemotherapy have improved outcomes to a degree, a therapeutic ceiling is being reached with this approach, resulting in a number of trials investigating the efficacy of targeted therapies alongside standard treatment algorithms. Furthermore, there is an urge to develop subtype-specific studies in an attempt to improve outcomes, which currently remain poor. This review summarizes the key studies with antiangiogenic agents, poly(adenosine diphosphate [ADP]-ribose) inhibitors, and epidermal growth factor receptor/human epidermal growth factor receptor family targeting, in addition to folate receptor antagonists and insulin growth factor receptor inhibitors. The efficacy of treatment paradigms used in non-ovarian malignancies for type I tumors is also highlighted, in addition to recent advances in appropriate patient stratification for targeted therapies in epithelial ovarian cancer.

A randomized trial investigating the effect of a brief lifestyle intervention on freshman-year weight gain.

OBJECTIVE: The current study was a randomized controlled trial investigating the effect of an innovative, short-term lifestyle intervention on weight gain in female freshman college students. PARTICIPANTS: Ninety-five freshmen were recruited from a large public university in the United States. METHODS: Participants completed baseline assessments and were randomized to a 5-session, 4-week intervention or wait-list control, with assessments at posttest and 3-month follow-up. RESULTS: The hypothesized time by group interaction was not significant, p = .393; however, trends suggested that control participants maintained baseline weight, whereas intervention participants lost -2.07 kg by posttest but regained 1.05 kg at follow-up. Significantly more intervention participants (47.0%) decreased their daily caloric intake by ≥ 200 kcal compared with control (31.7%), p = .050. CONCLUSION: Brief intervention to prevent weight gain was not effective in this sample. Future studies should investigate lengthening the intervention to enhance effectiveness and increasing recruitment to improve statistical power.

Interleukin-6: an angiogenic target in solid tumours.

During the past decade, incorporating anti-angiogenic agents into the therapeutic management of a myriad of malignancies has in certain cases made a significant impact on survival. However, the development of resistance to these drugs is inevitable and swift disease progression on their cessation often ensues. Hence, there is a drive to devise strategies that aim to enhance response to anti-angiogenic therapies by combining them with other targeted agents that facilitate evasion from resistance. The pleiotropic cytokine, interleukin-6 (IL-6), exerts pro-angiogenic effects in the tumour microenvironment of several solid malignancies and there is emerging evidence that reveals significant relationships between IL-6 signalling and treatment failure with antibodies directed against vascular endothelial growth factor (VEGF). This review summarises the role of IL-6 in pivotal angiogenic processes and preclinical/clinical research to support the future introduction of anti-IL-6 therapies to be utilised either in combination with other anti-angiogenic drugs or as a salvage therapy for patients with diseases that become refractory to these approaches.

Physical activity interventions differentially affect exercise task and barrier self-efficacy: a meta-analysis.

OBJECTIVE: Researchers have yet to establish how interventions to increase physical activity influence specific self-efficacy beliefs. The current study sought to quantify the effect of interventions to increase physical activity among healthy adults on exercise task (EXSE) and barrier self-efficacy (BSE) via meta-analysis. Intervention characteristics associated with self-efficacy and physical activity changes were also identified. METHODS: A systematic database search and manual searches through reference lists of related publications were conducted for articles on randomized, controlled physical activity interventions. Published intervention studies reporting changes in physical activity behavior and either EXSE or BSE in healthy adults were eligible for inclusion. RESULTS: Of the 1,080 studies identified, 20 were included in the meta-analyses. Interventions had a significant effect of g = 0.208, 95% confidence interval (CI) [0.027, 0.388], p < .05, on EXSE; g = 0.128, 95% CI [0.05, 0.20], p < .05 on BSE; and g = 0.335 95% CI [0.196, 0.475], p < .001, on physical activity. Moderator analyses indicated shorter interventions that did not include structured exercise sessions effectively increased EXSE and physical activity, whereas long interventions improved BSE. Interventions that did not provide support increased BSE and physical activity levels. Further, interventions that did not require the use of daily exercise logs improved EXSE and physical activity behavior. CONCLUSION: Interventions designed to increase physical activity differentially influenced EXSE and BSE. EXSE appeared to play a more significant role during exercise adoption, whereas BSE was involved in the maintenance of exercise behavior. Recommendations are offered for the design of future interventions.

Failure to replicate depletion of self-control.

The limited resource or strength model of self-control posits that the use of self-regulatory resources leads to depletion and poorer performance on subsequent self-control tasks. We conducted four studies (two with community samples, two with young adult samples) utilizing a frequently used depletion procedure (crossing out letters protocol) and the two most frequently used dependent measures of self-control (handgrip perseverance and modified Stroop). In each study, participants completed a baseline self-control measure, a depletion or control task (randomized), and then the same measure of self-control a second time. There was no evidence for significant depletion effects in any of these four studies. The null results obtained in four attempts to replicate using strong methodological approaches may indicate that depletion has more limited effects than implied by prior publications. We encourage further efforts to replicate depletion (particularly among community samples) with full disclosure of positive and negative results.

Dietary self-monitoring and long-term success with weight management.

OBJECTIVE: To examine the contributions of frequency, consistency, and comprehensiveness of dietary self-monitoring to long-term weight change. METHODS: Participants included 220 obese women (mean ± SD, age = 59.3 ± 6.1 years; BMI = 36.8 ± 4.9 kg/m(2) ) who achieved a mean weight loss of -10.39 ± 5.28% from baseline during 6 months of behavioral treatment and regained 2.30 ± 7.28% during a 12-month extended-care period. The contributions of cumulative frequency of self-monitoring (total number of food records), consistency across time (number of weeks with ≥3 records), and comprehensiveness of information recorded were examined as predictors of weight regain in a hierarchical linear regression analysis. The mediating role of adherence to daily caloric intake goals was tested using a bootstrapping analysis. RESULTS: The association between high total frequency of self-monitoring and reduced weight regain was moderated by weekly consistency of self-monitoring, P = 0.004; increased frequency produced beneficial effects on weight change only when coupled with high consistency (>3 days/week). There was no impact of comprehensiveness on weight change, P > 0.05. The favorable effect of high frequency/high consistency self-monitoring on weight change was partially mediated by participants' success in meeting daily caloric intake goals (P < 0.001). CONCLUSION: The combination of high frequency plus high consistency of dietary self-monitoring improves long-term success in weight management.

Long-Term Adherence to Health Behavior Change.

The utility of lifestyle-based health promotion interventions is directly impacted by participant adherence to prescribed behavior changes. Unfortunately, poor adherence to behaviors recommended in lifestyle interventions is widespread, particularly over the long-term; thus, the "adherence problem" represents a significant challenge to the effectiveness of these interventions. The current review provides an overview of the adherence problem and describes a theoretical framework through which the factors that impact adherence can be understood. To further understand the difficulties individuals face when adhering to health behavior changes, we focus our discussion on challenges associated with adherence to lifestyle behaviors recommended for weight loss and healthy weight management (i.e., reductions in dietary intake and increases in physical activity). We describe strategies that improve long-term adherence to health behaviors related to healthy weight management, including the provision of extended care, skills training, improving social support, and strategies specific to maintaining changes in dietary intake and physical activity. Finally, we discuss difficulties involved in implementing long-term weight management programs and suggest practical solutions for providers.

Benefits and risks of weight-loss treatment for older, obese women.

BACKGROUND: A key issue in the treatment of obesity in older adults is whether the health benefits of weight loss outweigh the potential risks with respect to musculoskeletal injury. OBJECTIVE: To compare change in weight, improvements in metabolic risk factors, and reported musculoskeletal adverse events in middle-aged (50-59 years) and older (65-74 years), obese women. MATERIALS AND METHODS: Participants completed an initial 6-month lifestyle intervention for weight loss, comprised of weekly group sessions, followed by 12 months of extended care with biweekly contacts. Weight and fasting blood samples were assessed at baseline, month 6, and month 18; data regarding adverse events were collected throughout the duration of the study. RESULTS: Both middle-aged (n = 162) and older (n = 56) women achieved significant weight reductions from baseline to month 6 (10.1 ± 0.68 kg and 9.3 ± 0.76 kg, respectively) and maintained a large proportion of their losses at month 18 (7.6 ± 0.87 kg and 7.6 ± 1.3 kg, respectively); there were no significant differences between the two groups with respect to weight change. Older women further experienced significant reductions in systolic blood pressure, HbA(1c), and C-reactive protein from baseline to month 6 and maintained these improvements at month 18. Despite potential safety concerns, we found that older women were no more likely to experience musculoskeletal adverse events during the intervention as compared with their middle-aged counterparts. CONCLUSION: These results suggest that older, obese women can experience significant health benefits from lifestyle treatment for obesity, including weight loss and improvements in disease risk factors. Further investigation of the impact of weight loss on additional health-related parameters and risks (eg, body composition, muscular strength, physical functioning, and injuries) in older adults is needed.

Effects of prescribing 1,000 versus 1,500 kilocalories per day in the behavioral treatment of obesity: a randomized trial.

OBJECTIVE: Controversy exists regarding the optimal energy prescription to promote successful long-term behavioral management of obesity. Prescribing intake of 1,000 (vs. 1,500) kcal/day may produce larger initial weight reduction, but long-term advantage remains unclear. The effects of prescribing 1,000 versus 1,500 kcal/day on 6- and 12-month weight changes within behavioral treatment of obesity were examined. DESIGN AND METHODS: Participants were 125 obese women (mean ± SD; BMI = 37.84 ± 3.94 kg/m(2) ) randomly assigned goals of 1,000 or 1,500 kcal/day. RESULTS: From months 0 to 6, participants prescribed 1,000 kcal/day lost more weight than those prescribed 1,500 kcal/day (mean ± SE = -10.03 ± 0.92g vs. -6.23 ± 0.94 kg, P = 0.045); however, from months 7 through 12, only the 1,000 kcal/day condition experienced a significant weight regain (1.51 ± 0.77 kg, P = 0.025). Baseline caloric consumption moderated the effect of treatment on regain; participants with baseline intakes ≧2,000 kcal/day who were assigned 1,000 kcal/day were significantly more susceptible to weight regain than those assigned 1,500 kcal/day (P = 0.049). At month 12, a significantly greater percentage of 1,000 kcal/day participants achieved weight reductions of 5% or more than those prescribed 1,500 kcal/day. CONCLUSION: Encouraging obese individuals in behavioral treatment to adhere to a 1,000 kcal/day intake may increase their likelihood of achieving clinically meaningful weight losses.

Successful long-term weight loss maintenance in a rural population.

BACKGROUND: Few investigations of successful long-term weight loss beyond two years have been conducted, and none has examined weight changes in medically underserved rural populations of older adults. The purpose of this study was to assess long-term weight loss maintenance 3.5 years after the completion of an initial six-month lifestyle intervention for obesity among women aged 50-75 years residing in rural communities. METHODS: One hundred and ten obese women with a mean (± standard deviation) age of 60.08 ± 6.17 years and mean body mass index of 36.76 ± 5.10 kg/m(2) completed an in-person assessment during which their weight and adherence to behavioral weight management strategies were evaluated. RESULTS: Participants showed a mean weight reduction of 10.17% ± 5.0% during the initial six- month intervention and regained 6.95% ± 9.44% from the completion of treatment to follow-up assessment 3.5 years later. A substantial proportion of participants (41.80%) were able to maintain weight reductions of 5% or greater from baseline to follow-up. "Successful" participants (those who maintained losses of 5% or greater at follow-up) reported weighing themselves, self-monitoring their intake and calories, planning meals in advance, and choosing lower calorie foods with greater frequency than "unsuccessful" participants (those who lost less than 5%). CONCLUSION: Collectively, these findings indicate that a large proportion of participants were able to maintain clinically significant weight losses for multiple years after treatment, and that self-monitoring was a key component of successful long-term weight management.