Deciphering radiological stable disease to immune checkpoint inhibitors.

BACKGROUND: 'Stable disease (SD)' as per RECIST is a common but ambiguous outcome in patients receiving immune checkpoint inhibitors (ICIs). This study aimed to characterize SD and identify the subset of patients with SD who are benefiting from treatment. Understanding SD would facilitate drug development and improve precision in correlative research. PATIENTS AND METHODS: A systematic review was carried out to characterize SD in ICI trials. SD and objective response were compared to proliferation index using The Cancer Genome Atlas gene expression data. To identify a subgroup of SD with outcomes mirroring responders, we examined a discovery cohort of non-small-cell lung cancer (NSCLC). Serial cutpoints of two variables, % best overall response and progression-free survival (PFS), were tested to define a subgroup of patients with SD with similar survival as responders. Results were then tested in external validation cohorts. RESULTS: Among trials of ICIs (59 studies, 14 280 patients), SD ranged from 16% to 42% in different tumor types and was associated with disease-specific proliferation index (ρ = -0.75, P = 0.03), a proxy of tumor kinetics, rather than relative response to ICIs. In a discovery cohort of NSCLC [1220 patients, 313 (26%) with SD to ICIs], PFS ranged widely in SD (0.2-49 months, median 4.9 months). The subset with PFS >6 months and no tumor growth mirrored partial response (PR) minor (overall survival hazard ratio 1.0) and was proposed as the definition of SD responder. This definition was confirmed in two validation cohorts from trials of NSCLC treated with durvalumab and found to apply in tumor types treated with immunotherapy in which depth and duration of benefit were correlated. CONCLUSIONS: RECIST-defined SD to immunotherapy is common, heterogeneous, and may largely reflect tumor growth rate rather than ICI response. In patients with NSCLC and SD to ICIs, PFS >6 months and no tumor growth may be considered 'SD responders'. This definition may improve the efficiency of and insight derivable from clinical and translational research.

Effectiveness of Live Health Professional-Led Group eHealth Interventions for Adult Mental Health: Systematic Review of Randomized Controlled Trials.

BACKGROUND: The COVID-19 pandemic has had adverse impacts on mental health and substance use worldwide. Systematic reviews suggest eHealth interventions can be effective at addressing these problems. However, strong positive eHealth outcomes are often tied to the intensity of web-based therapist guidance, which has time and cost implications that can make the population scale-up of more effective interventions difficult. A way to offset cost while maintaining the intensity of therapist guidance is to offer eHealth programs to groups rather than more standard one-on-one formats. OBJECTIVE: This systematic review aims to assess experimental evidence for the effectiveness of live health professional-led group eHealth interventions on mental health, substance use, or bereavement among community-dwelling adults. Within the articles selected for our primary aim, we also seek to examine the impact of interventions that encourage physical activity compared with those that do not. METHODS: Overall, 4 databases (MEDLINE, CINAHL, PsycINFO, and the Cochrane Library) were searched in July 2020. Eligible studies were randomized controlled trials (RCTs) of eHealth interventions led by health professionals and delivered entirely to adult groups by videoconference, teleconference, or webchat. Eligible studies reported mental health, substance use, or bereavement as primary outcomes. The results were examined by outcome, eHealth platform, and intervention length. Postintervention data were used to calculate effect size by study. The findings were summarized using the Synthesis Without Meta-Analysis guidelines. Risk of bias was assessed using the Cochrane Collaboration Tool. RESULTS: Of the 4099 identified studies, 21 (0.51%) RCTs representing 20 interventions met the inclusion criteria. These studies examined mental health outcomes among 2438 participants (sample size range: 47-361 participants per study) across 7 countries. When effect sizes were pooled, live health professional-led group eHealth interventions had a medium effect on reducing anxiety compared with inactive (Cohen d=0.57) or active control (Cohen d=0.48), a medium to small effect on reducing depression compared with inactive (Cohen d=0.61) or active control (Cohen d=0.21), and mixed effects on mental distress and coping. Interventions led by videoconference, and those that provided 8-12 hours of live health professional-led group contact had more robust effects on adult mental health. Risk of bias was high in 91% (19/21) of the studies. Heterogeneity across interventions was significant, resulting in low to very low quality of evidence. No eligible RCT was found that examined substance use, bereavement, or physical activity. CONCLUSIONS: Live eHealth group interventions led by health professionals can foster moderate improvements in anxiety and moderate to small improvements in depression among community-based adults, particularly those delivered by videoconference and those providing 8-12 hours of synchronous engagement. TRIAL REGISTRATION: PROSPERO CRD42020187551; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=187551. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s13643-020-01479-3.

IgE blockade with omalizumab reduces pruritus related to immune checkpoint inhibitors and anti-HER2 therapies.

BACKGROUND: Immunoglobulin E (IgE) blockade with omalizumab has demonstrated clinical benefit in pruritus-associated dermatoses (e.g. atopic dermatitis, bullous pemphigoid, urticaria). In oncology, pruritus-associated cutaneous adverse events (paCAEs) are frequent with immune checkpoint inhibitors (CPIs) and targeted anti-human epidermal growth factor receptor 2 (HER2) therapies. Thus, we sought to evaluate the efficacy and safety of IgE blockade with omalizumab in cancer patients with refractory paCAEs related to CPIs and anti-HER2 agents. PATIENTS AND METHODS: Patients included in this multicenter retrospective analysis received monthly subcutaneous injections of omalizumab for CPI or anti-HER2 therapy-related grade 2/3 pruritus that was refractory to topical corticosteroids plus at least one additional systemic intervention. To assess clinical response to omalizumab, we used the Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was defined as reduction in the severity of paCAEs to grade 1/0. RESULTS: A total of 34 patients (50% female, median age 67.5 years) received omalizumab for cancer therapy-related paCAEs (71% CPIs; 29% anti-HER2). All had solid tumors (29% breast, 29% genitourinary, 15% lung, 26% other), and most (n = 18, 64%) presented with an urticarial phenotype. In total 28 of 34 (82%) patients responded to omalizumab. The proportion of patients receiving oral corticosteroids as supportive treatment for management of paCAEs decreased with IgE blockade, from 50% to 9% (P < 0.001). Ten of 32 (31%) patients had interruption of oncologic therapy due to skin toxicity; four of six (67%) were successfully rechallenged following omalizumab. There were no reports of anaphylaxis or hypersensitivity reactions related to omalizumab. CONCLUSIONS: IgE blockade with omalizumab demonstrated clinical efficacy and was well tolerated in cancer patients with pruritus related to CPIs and anti-HER2 therapies.

Stand When You Can: development and pilot testing of an intervention to reduce sedentary time in assisted living.

BACKGROUND: Prolonged daily sedentary time is associated with increased risk of cardiometabolic diseases, impaired physical function, and mortality. Older adults are more sedentary than any other age group and those in assisted living residences accumulate more sedentary time as they often have little need to engage in light-intensity or standing activities such as cleaning or meal preparation. This "low movement" environment can hasten functional decline. Thus, the purpose of this study was to develop a multi-level intervention to reduce and interrupt sedentary time within assisted living residences and conduct a pilot study to determine if the intervention is feasible and if further testing is warranted. METHODS: "Stand When You Can" (SWYC) was developed using a Social Ecological framework based on a review of literature and consultation with residents and staff at assisted living residences. After development, a six-week pilot study was conducted in two different residences with 10 older adults (82.2 ± 8.7 years). Before and after the 6 weeks, ActivPAL™ inclinometers were used to measure daily movement behaviours and self-report questionnaires assessed time spent in different sedentary behaviours and quality of life. Physical function was assessed using the Short Physical Performance Battery. Paired sample t-tests examined pre-post differences for pooled data and individual sites. At the end of the pilot study, feedback on the intervention was gathered from both residents and staff to examine feasibility. RESULTS: There was a trend towards a decrease in self-reported sitting time (142 min/day; p = 0.09), although device-measured sedentary time did not change significantly. Participants with lower physical function at baseline showed clinically meaningful improvements in physical function after the 6 weeks (p = 0.04, Cohen's d = 0.89). There was no change in quality of life. Residents and staff reported that the intervention strategies were acceptable and practical. CONCLUSION: This study suggests that a multi-level intervention for reducing prolonged sedentary time is feasible for implementation at assisted living residences. The intervention could potentially help delay functional decline among older adults when they transition to a supportive living environment. Longer and larger trials to test the efficacy of SWYC are necessary. TRIAL REGISTRATION: Name of Clinical Trial Registry: clinicaltrials.gov Trial Registration number: NCT04458896 . Date of registration: July 8, 2020. (Retrospectively registered).

[Effect of humor training on stress, cheerfulness and depression in patients with coronary artery disease and refractory angina pectoris]. / Effekt von Humortraining auf Stress, Heiterkeit und Depression bei Patienten mit koronarer Herzkrankheit und therapierefraktärer Angina pectoris.

BACKGROUND: Angina pectoris refractory to conventional medical treatment is a common phenomenon in patients with stable coronary artery disease (CAD). Many of these patients suffer from depression and generate substantial costs in the healthcare system. Therefore, the development of new therapeutic concepts is of particular importance. This study investigated whether professional, structured humor training has a positive effect on the symptoms of patients with treatment refractory angina pectoris. METHODS: Between 2013 and 2014 a total of 35 patients with stable CAD were included. Enrolment was possible if patients suffered from treatment refractory angina pectoris (Canadian Cardiovascular Society, CCS grades II-IV) despite optimal antianginal medication and exhaustion of options for myocardial revascularization. Previously, 25.8% of the patients had had a myocardial infarction. In this study, a professional humor coaching was conducted with a duration of 7 weeks. In order to evaluate the effects of the coaching, the following examinations were performed before and after the intervention: exercise stress test (treadmill), hair segment cortisol analysis, Beck Depression Inventory (BDI), the Trier Inventory for the Assessment of Chronic Stress (TICS) and the State-Trait-Cheerfulness Inventory (STCI). RESULTS: Out of the 35 initially recruited patients 31 completed the study. The mean age was 65.5 years and 94.5% were female. There was a significant improvement in cheerfulness (STCI, pre 23.3 ± 5.4, post 27.5 ± 5, p = 0,03). This effect was even stronger in a subgroup analysis in which only female patients were included (pre 23.6 ± 5.5, post 27.7 ± 4.6, p = 0.003). The results of the BDI showed a remarkable improvement in the pre-post analysis (pre 14.6 ± 8.1, post 11.0 ± 6.5, p = 0.064). Analyzing only the female patients, this difference became significant (pre 13.1 ± 6.4, post 9.9 ± 4.6 p = 0,037). The hair segment investigations showed that patients who had a higher cortisol level in the beginning (>25. percentile, n = 22) showed a significant reduction of the cortisol concentration (pre 6.54 pg/mg, 3.78-12.12 pg/mg, post 3.65 pg/mg, 2.82-7.68 pg/mg, p = 0.029). CONCLUSION: Patients with refractory angina pectoris and stable CAD benefit from a professional humor coaching. This effect was shown in a) a significant decrease in cortisol concentrations in the hair segment analysis, b) an improvement in cheerfulness in the STCI and c) a significant difference in the BDI between pre-post values.

Trauma-informed interventions versus control for cancer-risk behaviours among adults: rationale and design for a randomized trial.

BACKGROUND: Tobacco use, alcohol use, and sugar-sweetened beverage consumption are each associated with increased cancer-risk. Psychological trauma is a common experience and a key driver of these behaviours among adults. The primary aim of this study is to evaluate the effect of trauma-informed yoga, drumming, and psychoeducation compared to control on tobacco use, alcohol use, and sugar-sweetened beverage consumption among community-based adults. Secondary aims are to evaluate the effect of these interventions compared to control on psychological and physiological stress symptomology, social connection, and coping behaviour. METHODS: Recruitment for this single-blinded randomized trial began in April 2019 in the Faculty of Health Sciences at the University of Lethbridge. Adults who consumed tobacco, alcohol, or sugar-sweetened beverages in the past month and live in Lethbridge, Alberta are being recruited using ads placed in public spaces. Participants are randomly allocated to a 12-session group yoga class, 12-session group drumming class, a 12-session psychoeducation class, or control. Participants attend an appointment in-person to fill out an online questionnaire package, provide a saliva sample, and complete physical measures pre-intervention, and 1-month and 6-months post-intervention. DISCUSSION: This study provides a unique opportunity to compare the impacts of two trauma-informed body-based interventions to psychoeducation and control for cancer-risk behaviour among community-based adults. The findings can be used to develop trauma-informed group interventions to reduce cancer-risk behaviour in general populations. Results are expected in 2022. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov ISRCTN15583681 on 22 August 2019 (retrospectively registered).

A randomized phase II trial of CRLX101 in combination with bevacizumab versus standard of care in patients with advanced renal cell carcinoma.

BACKGROUND: Nanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle-drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1α and 2α. In a phase Ib/2 trial, CRLX101 + bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101 + bevacizumab versus standard of care (SOC) in refractory mRCC. PATIENTS AND METHODS: Patients with mRCC and 2-3 prior lines of therapy were randomized 1 : 1 to CRLX101 + bevacizumab versus SOC, defined as investigator's choice of any approved regimen not previously received. The primary end point was progression-free survival (PFS) by blinded independent radiological review in patients with clear cell mRCC. Secondary end points included overall survival, objective response rate and safety. RESULTS: In total, 111 patients were randomized and received ≥1 dose of drug (CRLX101 + bevacizumab, 55; SOC, 56). Within the SOC arm, patients received single-agent bevacizumab (19), axitinib (18), everolimus (7), pazopanib (4), sorafenib (4), sunitinib (2), or temsirolimus (2). In the clear cell population, the median PFS on the CRLX101 + bevacizumab and SOC arms was 3.7 months (95% confidence interval, 2.0-4.3) and 3.9 months (95% confidence interval 2.2-5.4), respectively (stratified log-rank P = 0.831). The objective response rate by IRR was 5% with CRLX101 + bevacizumab versus 14% with SOC (Mantel-Haenszel test, P = 0.836). Consistent with previous studies, the CRLX101 + bevacizumab combination was generally well tolerated, and no new safety signal was identified. CONCLUSIONS: Despite promising efficacy data on the earlier phase Ib/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101 + bevacizumab combination when compared with approved agents in patients with heavily pretreated clear cell mRCC. Further development in this disease is not planned. CLINICAL TRIAL IDENTIFICATION: NCT02187302 (NIH).

Replacing sedentary time with sleep, light, or moderate-to-vigorous physical activity: effects on self-regulation and executive functioning.

Recent attention has highlighted the importance of reducing sedentary time for maintaining health and quality of life. However, it is unclear how changing sedentary behavior may influence executive functions and self-regulatory strategy use, which are vital for the long-term maintenance of a health behavior regimen. The purpose of this cross-sectional study is to examine the estimated self-regulatory and executive functioning effects of substituting 30 min of sedentary behavior with 30 min of light activity, moderate-to-vigorous physical activity (MVPA), or sleep in a sample of older adults. This study reports baseline data collected from low-active healthy older adults (N = 247, mean age 65.4 ± 4.6 years) recruited to participate in a 6 month randomized controlled exercise trial examining the effects of various modes of exercise on brain health and function. Each participant completed assessments of physical activity self-regulatory strategy use (i.e., self-monitoring, goal-setting, social support, reinforcement, time management, and relapse prevention) and executive functioning. Physical activity and sedentary behaviors were measured using accelerometers during waking hours for seven consecutive days at each time point. Isotemporal substitution analyses were conducted to examine the effect on self-regulation and executive functioning should an individual substitute sedentary time with light activity, MVPA, or sleep. The substitution of sedentary time with both sleep and MVPA influenced both self-regulatory strategy use and executive functioning. Sleep was associated with greater self-monitoring (B = .23, p = .02), goal-setting (B = .32, p < .01), and social support (B = .18, p = .01) behaviors. Substitution of sedentary time with MVPA was associated with higher accuracy on 2-item (B = .03, p = .01) and 3-item (B = .02, p = .04) spatial working memory tasks, and with faster reaction times on single (B = -23.12, p = .03) and mixed-repeated task-switching blocks (B = -27.06, p = .04). Substitution of sedentary time with sleep was associated with marginally faster reaction time on mixed-repeated task-switching blocks (B = -12.20, p = .07) and faster reaction time on mixed-switch blocks (B = 17.21, p = .05), as well as reduced global reaction time switch cost (B = -16.86, p = .01). Substitution for light intensity physical activity did not produce significant effects. By replacing sedentary time with sleep and MVPA, individuals may bolster several important domains of self-regulatory behavior and executive functioning. This has important implications for the design of long-lasting health behavior interventions. Trial Registration clinicaltrials.gov identifier NCT00438347.

[Public Health as an Applied, Multidisciplinary Subject: Is Research-Based Learning the Answer to Challenges in Learning and Teaching?] / Public Health als anwendungsorientiertes Fach und Multidisziplin ­ "Forschendes Lernen" als Antwort auf die Herausforderungen für Lehren und Lernen?

Public health education aims at enabling students to deal with complex health-related challenges using appropriate methods based on sound theoretical understanding. Virtually all health-related problems in science and practice require the involvement of different disciplines. However, the necessary interdisciplinarity is only partly reflected in the curricula of public health courses. Also theories, methods, health topics, and their application are often taught side-by-side and not together. For students, it can become an insurmountable challenge to integrate the different disciplines ("horizontal integration") and theories, methods, health topics, and their application ("vertical integration"). This situation is specific for education in public health but is representative for other interdisciplinary fields as well. Several approaches are available to achieve the horizontal integration of different disciplines and vertical integration of theories, methods, health topics, and their application. A curriculum that is structured by topics, rather than disciplines might be more successful in integrating different disciplines. Vertical integration can be achieved by research-based learning. Research-based learning places a student-led research project at the centre of teaching. Students choose a topic and a research question, raise their own questions for theories and methods and will hopefully cross the seeming chasm between science and practice. Challenges of research-based learning are enhanced demands on students, teachers and curriculum design.

Safety and clinical activity of vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitors after programmed cell death 1 inhibitor treatment in patients with metastatic clear cell renal cell carcinoma.

BACKGROUND: Emerging agents blocking the programmed cell death 1 (PD-1) pathway show activity in metastatic clear cell renal cell carcinoma (mRCC). The aim of this study was to evaluate the efficacy and safety of vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-tyrosine kinase inhibitor (TKI) therapy after PD-1 inhibition. PATIENTS AND METHODS: Patients with mRCC treated with anti-PD-1 antibody (aPD-1) monotherapy or in combination (with VEGFR-TKI or ipilimumab) that subsequently received VEGFR-TKI were retrospectively reviewed. The efficacy end points were objective response rate (ORR) and progression-free survival (PFS) stratified by the type of prior PD-1 regimen. Safety by the type and PD-1 exposure was also evaluated. RESULTS: Seventy patients were included. Forty-nine patients received prior therapy with immune checkpoint inhibitors (CPIs) alone and 21 had combination therapy of aPD-1 and VEGFR-TKI. Overall, ORR to VEGFR-TKI after PD-1 inhibition was 28% (19/68) and the median PFS was 6.4 months (mo) (4.3-9.5). ORR to VEGFR-TKI after aPD-1 in combination with VEGFR-TKI was lower than that in patients treated with VEGFR-TKI after CPI alone (ORR 10% versus 36%, P = 0.039). In the multivariable analysis, patients treated with prior CPI alone were more likely to achieve an objective response than those treated with aPD-1 in combination with VEGFR-TKI (OR = 5.38; 95% CI 1.12-26.0, P = 0.03). There was a trend toward numerically longer median PFS in the VEGFR-TKI after the CPI alone group, 8.4 mo (3.2-12.4) compared with 5.5 mo (2.9-8.3) for those who had VEGFR-TKI after aPD-1 in combination with VEGFR-TKI (P = 0.15). The most common adverse events (AEs) were asthenia, hypertension, and diarrhea. CONCLUSIONS: The efficacy and safety of VEGFR-TKIs after PD-1 inhibition were demonstrated in this retrospective study. The response rate was lower and the median progression-free survival was shorter in those patients who received prior PD-1 in combination with VEGFR-TKI. PD-1 exposure does not seem to significantly influence the safety of subsequent VEGFR-TKI treatment.

White matter integrity, hippocampal volume, and cognitive performance of a world-famous nonagenarian track-and-field athlete.

Physical activity (PA) and cardiorespiratory fitness (CRF) are associated with successful brain and cognitive aging. However, little is known about the effects of PA, CRF, and exercise on the brain in the oldest-old. Here we examined white matter (WM) integrity, measured as fractional anisotropy (FA) and WM hyperintensity (WMH) burden, and hippocampal (HIPP) volume of Olga Kotelko (1919-2014). Olga began training for competitions at age of 77 and as of June 2014 held over 30 world records in her age category in track-and-field. We found that Olga's WMH burden was larger and the HIPP was smaller than in the reference sample (58 healthy low-active women 60-78 years old), and her FA was consistently lower in the regions overlapping with WMH. Olga's FA in many normal-appearing WM regions, however, did not differ or was greater than in the reference sample. In particular, FA in her genu corpus callosum was higher than any FA value observed in the reference sample. We speculate that her relatively high FA may be related to both successful aging and the beneficial effects of exercise in old age. In addition, Olga had lower scores on memory, reasoning and speed tasks than the younger reference sample, but outperformed typical adults of age 90-95 on speed and memory. Together, our findings open the possibility of old-age benefits of increasing PA on WM microstructure and cognition despite age-related increase in WMH burden and HIPP shrinkage, and add to the still scarce neuroimaging data of the healthy oldest-old (>90 years) adults.

Cigarette smoke-induced disruption of pulmonary barrier and bacterial translocation drive tumor-associated inflammation and growth.

Microorganisms have an important role in tumorgenesis by the induction of inflammation and by a direct impact on tumor cells. Chronic obstructive pulmonary disease (COPD) is associated with an increased risk for lung cancer and microbial colonization. We asked whether bacterial pathogens act as tumor promoters during CS-induced pulmonary inflammation. In a metastatic lung cancer (LC) model, Lewis lung carcinoma (LLC) cells were injected in mice to initiate the growth of tumors in the lung. Exposure to the combination of cigarette smoke (CS) and nontypeable Haemophilus influenzae (NTHi) synergistically increased metastatic growth. Lung levels of albumin and LDH, translocation of bacterial factors into tumor tissue, tumor inflammation, and tumor proliferation were significantly increased in mice exposed to CS in combination with NTHi. Bacterial pathogens increased the proliferation of cultured LLC cells and human cancer cell lines. Metastatic growth induced by the exposure to CS in combination with NTHi was reduced in mice deficient for IL-17. Our data provide evidence that CS-induced loss of pulmonary barrier integrity allows bacterial factors to translocate into tumor tissue and to regulate tumor-associated inflammation and tumor proliferation. Translocation of bacterial factors in tumor tissue links CS-induced inflammation with tumor proliferation.

Treatment outcome with mTOR inhibitors for metastatic renal cell carcinoma with nonclear and sarcomatoid histologies.

BACKGROUND: The clinical trials that reported benefit of the rapalogs temsirolimus and everolimus in advanced renal cell carcinoma (RCC) were primarily conducted in patients with clear-cell histology (ccRCC). We assessed outcome with these mammalian target of rapamicin (mTOR) inhibitors in two subsets of kidney cancer: sarcomatoid variant ccRCC and nonclear-cell RCC. PATIENTS AND METHODS: Baseline clinical features, information on prior treatment, and histologic subtypes were collected for patients previously treated with rapalogs for metastatic RCC of either nonclear phenotype or ccRCC with sarcomatoid features. Outcome was assessed centrally by a dedicated research radiologist for determination of tumor response, progression-free survival (PFS), and overall survival (OS). RESULTS: Eighty-five patients received temsirolimus (n = 59) or everolimus (n = 26). Nonclear-cell phenotypes included papillary (n = 14), chromophobe (n = 9), collecting duct (n = 4), translocation-associated (n = 3), and unclassified (n = 32) RCC. Twenty-three patients had clear-cell histology with sarcomatoid features. The response rate in assessable patients (n = 82) was 7% (all partial responses); 49% of patients achieved stable disease, and 44% had progressive disease as their best response. Tumor shrinkage was observed in 26 patients (32%). Median PFS and OS were 2.9 and 8.7 months, respectively. Nine patients (11%) were treated for ≥1 year, including cases of papillary (n = 3), chromophobe (n = 2), unclassified (n = 3) RCC, and ccRCC with sarcomatoid features (n = 1). No tumor shrinkages were observed for patients with collecting duct or translocation-associated RCC. CONCLUSIONS: A subset of patients with nonclear-cell and sarcomatoid variant ccRCC subtypes benefit from mTOR inhibitors, but most have poor outcome. Histologic subtype does not appear to be helpful in selecting patients for rapalog therapy. Future efforts should include the identification of predictive tissue biomarkers.

Bacterial phenylalanine and phenylacetate catabolic pathway revealed.

Aromatic compounds constitute the second most abundant class of organic substrates and environmental pollutants, a substantial part of which (e.g., phenylalanine or styrene) is metabolized by bacteria via phenylacetate. Surprisingly, the bacterial catabolism of phenylalanine and phenylacetate remained an unsolved problem. Although a phenylacetate metabolic gene cluster had been identified, the underlying biochemistry remained largely unknown. Here we elucidate the catabolic pathway functioning in 16% of all bacteria whose genome has been sequenced, including Escherichia coli and Pseudomonas putida. This strategy is exceptional in several aspects. Intermediates are processed as CoA thioesters, and the aromatic ring of phenylacetyl-CoA becomes activated to a ring 1,2-epoxide by a distinct multicomponent oxygenase. The reactive nonaromatic epoxide is isomerized to a seven-member O-heterocyclic enol ether, an oxepin. This isomerization is followed by hydrolytic ring cleavage and beta-oxidation steps, leading to acetyl-CoA and succinyl-CoA. This widespread paradigm differs significantly from the established chemistry of aerobic aromatic catabolism, thus widening our view of how organisms exploit such inert substrates. It provides insight into the natural remediation of man-made environmental contaminants such as styrene. Furthermore, this pathway occurs in various pathogens, where its reactive early intermediates may contribute to virulence.

CT-angiography prior to DIEP flap breast reconstruction: a systematic review and meta-analysis.

BACKGROUND: Preoperative CT-angiography (CTA) has shown to reduce operative time in deep inferior epigastric perforator (DIEP) flap breast reconstruction compared to Doppler ultrasonography (US). Although decreased flap loss has been suggested, statistical significant reduction remains indeterminate. The purpose of this review is to evaluate flap loss after preoperative CTA and Doppler US in DIEP-flap breast reconstruction. METHODS: A systematic literature search was performed in MEDLINE, EMBASE, and Cochrane libraries. All articles comparing CTA to Doppler US were selected and critically appraised; data on flap loss were extracted. RESULTS: From 678 studies, eight were selected for appraisal. Six case-control studies were included in the final analysis. Pooled analysis showed CTA resulted in a significant reduction in partial necrosis (odds ratio/OR 0.15; 95% confidence interval/CI 0.07-0.32, P < 0.0001) and decreased flap loss (OR 0.28; 95% CI 0.10-0.79, P = 0.02). CONCLUSIONS: Studies included in this meta-analysis have several limitations. However, most studies find a large clinical advantage of CTA over Doppler US, which reaches statistical significance when combined. As results show that CTA prior to DIEP flap breast reconstruction offers significant clinical benefits, we suggest the routine use of preoperative CTA.

Changes in physical activity, sedentary behavior, and self-reported cognitive function in cancer survivors before and during the COVID-19 pandemic: A cross-sectional study.

BACKGROUND: Physical activity (PA) and reductions in sedentary behavior (SED) may mitigate cancer-related cognitive impairment. The purpose of this study was to examine (a) the associations between changes in PA, SED, and cognitive function in cancer survivors before and during the coronavirus disease 2019 (COVID-19) pandemic; and (b) clinical subgroups that moderate this association. METHODS: A cross-sectional survey was administered online to adult cancer survivors globally between July and November of 2020. This was a secondary analysis of a cross-sectional survey examining changes in self-reported PA and quality of life in cancer survivors before and during the COVID-19 pandemic. Self-reported Questionnaires assessed moderate-to-vigorous PA (MVPA) using the modified Godin Leisure Time Exercise Questionnaire, cognitive function using the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) scale, and SED using the Domain-specific Sitting Time questionnaire. Cancer survivors were classified into no change in behavior, desirable change (i.e., increase MVPA to meet PA guidelines or decrease SED by ≥60 min/day), and undesirable change (i.e., decrease MVPA to <150 min/week or increase SED by ≥60 min/day). Analysis of covariance examined differences in FACT-Cog scores across the activity change categories. Planned contrasts compared differences in FACT-Cog scores between cancer survivors with (a) no meaningful change vs. any change, and (b) a desirable change vs. an undesirable change. RESULTS: There were no significant differences in FACT-Cog scores across activity-change categories in the full sample of cancer survivors (n = 371; age = 48.6 ± 15.3 years (mean ± SD)). However, cancer survivors who were diagnosed ≥5 years ago (t(160) = -2.15, p = 0.03) or who received treatment ≥5 years ago (t(102) = -2.23, p = 0.03) and who had a desirable change in activity reported better perceived cognitive abilities than those who had an undesirable change. CONCLUSION: PA promotion efforts should consider reducing SED in addition to maintaining MVPA in long-term cancer survivors to mitigate cancer-related cognitive impairment during the COVID-19 pandemic.

The importance of collaboration between medical and exercise professionals in addressing patient physical inactivity.

Physical activity has declined further during the coronavirus disease 2019 (COVID-19) pandemic. Physicians are at the front lines of proactively educating and promoting physical activity to patients; however, physicians do not feel confident and face numerous barriers in prescribing exercise to patients. Exercise referral schemes, comprising collaborations with qualified exercise professionals, represent a fruitful option for supporting physicians hoping to promote physical activity to more patients. Herein, we provide practical suggestions for establishing and creating a successful referral scheme. Ultimately, exercise referral schemes offer an alternative to help physician burnout and mitigate patient physical inactivity during and beyond the COVID-19 pandemic.

Differential adipose tissue inflammatory state in obese nondiabetic Zucker fatty rats compared to obese diabetic zucker diabetic fatty rats.

Adipose tissue (AT) inflammation is linked to the pathogenesis of diabetes in obesity. Here, we compare the AT inflammatory state of 2 animal models of obesity and obesity plus diabetes, respectively. Obese nondiabetic ZF rats exhibited a trend towards increased proportions of CD11b positive cells in the adipose tissue stroma vascular fraction suggesting a state of increased AT inflammation compared to their lean littermates, but no alterations in systemic inflammatory parameters. In contrast, obese diabetic ZDF rats exhibited systemic as well as local AT inflammation with elevated levels of circulating Regulated upon Activation, Normal T-cell Expressed and Secreted Protein (Rantes), interleukin 1ß (IL-1ß) and monocyte chemotactic protein 1 (MCP-1), and an increased infiltration of adipose tissue CD11b positive cells. Our data provide a novel phenotypic characterisation of 2 common metabolic animal models and suggest an association of obesity with local inflammation in adipose tissue, and an association of diabetes with local inflammation in adipose tissue plus systemic inflammation. AT inflammation in obesity might therefore initiate a process that above a certain limits finally results in systemic inflammation and diabetes.

Sleep Quality and the Importance Women Place on Healthy Eating Interact to Influence Psychological Resilience.

Objectives: The impact women's daily habits may have on psychological resilience is not well understood. This cross-sectional analysis examined: (1) the impact of sleep quality on resilience, and (2) whether this association was modified by the importance women place on healthy eating. Methods: We collected data from 64 women (aged 18-67 years). The Pittsburgh Sleep Quality Index and Connor-Davidson Resilience Scale-10 assessed sleep quality and resilience, respectively, with lower scores indicating reduced resilience. One item assessed attitudes towards healthy eating. Linear regression models and 95% confidence intervals examined associations adjusted for age and income. Results: Reduced sleep quality was associated with a decreased resilience score (B=0.55, 95% CI: -1.06, -0.04, p=.04) when adjusted for age and income. After stratification, sleep quality and resilience were not associated among women who indicated healthy eating was very important. Among women who indicated healthy eating was less than very important, reduced sleep quality was associated with decreased psychological resilience (B=0.85, 95% CI: -1.55, -0.15, p=.02). Conclusions: Poor sleep quality was associated with reduced resilience among women. Placing a strong emphasis on healthy eating helped buffer the impact of poor sleep quality on women's psychological resilience.

Tetraspanin CD151 is a novel prognostic marker in poor outcome endometrial cancer.

BACKGROUND: Type II cancers account for 10% of endometrial cancers but 50% of recurrence. Response rates to chemotherapy at recurrence are poor and better prognostic markers are needed to guide therapy. CD151 is a small transmembrane protein that regulates cell migration and facilitates cancer metastasis. High CD151 expression confers poor prognosis in breast, pancreatic and colorectal cancer. The prognostic significance of tetraspanin CD151 expression in poor outcome endometrial cancers was evaluated, along with oestrogen receptor (ER), progesterone receptor (PR), p53, human epidermal growth factor receptor -2 (HER-2), and CD 151 staining compared with α6ß1, α3ß1 integrins, and E-cadherin. METHODS: Tissue microarray constructed from 156 poor outcome endometrial cancers, tested with immunohistochemistry and staining correlated with clinicopathological data were used. A total of 131 data sets were complete for analysis. RESULTS: Expression of CD151 was significantly higher in uterine papillary serous and clear cell carcinoma than in grade 3 endometrioid carcinoma, sarcoma or carcinosarcoma (P<0.001). In univariate analysis, age, stage, histology type and CD151 were significant for both recurrence free (RFS) and disease specific survival (DSS). In multivariate analyses, CD151 was significant for RFS and DSS (P=0.036 and 0.033, respectively) in triple negative (ER, PR and HER-2 negative) tumours (88/131). The HER-2, p53, ER and PR were not prognostic for survival. There was strong concordance of CD151 with E-cadherin (98%), but not with α6ß1 (35%), α3ß1 staining (60%). CONCLUSION: The CD151 is a novel marker in type 2 cancers that can guide therapeutic decisions. CD151 may have an important role in tumourigenesis in some histology types.