Publications by authors named "Melinda L Irwin"

115 Publications

Randomized trial of weight loss on circulating ghrelin levels among breast cancer survivors.

NPJ Breast Cancer 2021 May 11;7(1):49. Epub 2021 May 11.

Yale University School of Public Health, New Haven, CT, USA.

Obesity among breast cancer survivors is associated with increased risk for recurrence and mortality. The hormone ghrelin plays a role in initiating appetite and thus regulating body weight. This study aims to determine the effect of a lifestyle intervention on ghrelin levels in breast cancer survivors with a body mass index (BMI) ≥ 25 kg/m. The Lifestyle, Exercise, and Nutrition (LEAN) study was a 6-month randomized trial, examining the effectiveness of a weight loss intervention versus usual care in 151 breast cancer survivors with BMI ≥ 25 kg/m. Ghrelin was measured in fasting baseline and 6-month blood samples. Baseline associations between ghrelin, body composition, and blood biomarkers were examined. Six-month change in ghrelin was compared between study arms. Ghrelin measurements were available for 149 women. At baseline, ghrelin was correlated with age (r = 0.28, p < 0.001) and inversely correlated with weight (r = -0.18, p = 0.03), lean body mass (r = -0.18, p = 0.02), and leptin (r = -0.18, p = 0.03). Over 6 months, ghrelin increased by 144 pg/mL (7.2%) in the intervention and decreased by 466 pg/mL (32.5%) in the usual care (p = 0.07). Among all women, greater weight loss was associated with an increase in ghrelin (p = 0.01). These findings indicate that weight loss, achieved through a lifestyle intervention, is associated with higher ghrelin levels in breast cancer survivors which may be informative for developing sustainable weight loss programming for this population. Future research should investigate the long term impacts of lifestyle interventions on ghrelin levels in the context of weight maintenance and weight regain.
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http://dx.doi.org/10.1038/s41523-021-00260-6DOI Listing
May 2021

Pre- and post-diagnosis leisure time physical activity and survival following diagnosis with ovarian cancer.

Int J Cancer 2021 May 8. Epub 2021 May 8.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Little is known about the influence of pre- and post-diagnosis physical activity on ovarian cancer survival. We investigated this association in two large cohorts, the Nurses' Health Study (NHS) and NHSII. Analyses included 1461 women with confirmed invasive, epithelial ovarian cancer and data on physical activity. Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for ovarian cancer-specific mortality. Ovarian cancer-specific mortality was not associated with physical activity reported 1-8 years before diagnosis overall (≥7.5 vs. <1.5 MET-hours/week, HR=0.96), for high-grade serous/ poorly differentiated tumors, or non-serous/ low-grade serous tumors (P-heterogeneity=0.45). An inverse association was observed for activity 1-4 years after diagnosis (≥7.5 vs. <1.5 MET-hours/week, HR=0.67, 95%CI: 0.48-0.94), with similar results by histotype (P-heterogeneity=0.53). Women who decreased their activity from ≥7.5 MET-hours/week 1-8 years before diagnosis to <7.5 MET-hours/week 1-4 years after diagnosis, compared with those with <7.5 MET-hours/week across periods, had a 49% increased risk of death (HR=1.49, 95%CI: 1.07-2.08). Physical activity after, but not before, ovarian cancer diagnosis was associated with better prognosis.
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http://dx.doi.org/10.1002/ijc.33676DOI Listing
May 2021

Association of epigenetic age acceleration with risk factors, survival, and quality of life in patients with head and neck cancer.

Int J Radiat Oncol Biol Phys 2021 Apr 18. Epub 2021 Apr 18.

Emory University School of Nursing.

Purpose: Epigenetic age acceleration (EAA) is robustly linked with mortality and morbidity. This study examined risk factors of EAA and its association with overall survival (OS), progression-free survival (PFS), and quality of life (QOL) in patients with head and neck cancer (HNC) receiving radiotherapy.

Methods And Materials: Patients without distant metastasis were enrolled and followed before and end of radiotherapy, and 6-months and 12-months post-radiotherapy. EAA was calculated with DNAmPhenoAge at all four times. Risk factors included demographics, lifestyle, clinical characteristics, treatment-related symptoms, and blood biomarkers. Survival data were collected until August 2020; QOL was measured using Functional Assessment of Cancer Therapy-HNC.

Results: Increased comorbidity, HPV-unrelated, and severer treatment-related symptoms were associated with higher EAA (p=0.03 to <0.001). A non-linear association (quadratic) between body mass index (BMI) and EAA was observed: decreased BMI (when BMI<35,p=0.04) or increased BMI (when BMI≥35,p=0.01), was linked to higher EAA. Increased EAA (per year) was associated with worse OS (hazard ratio (HR)=1.11,95% CI=[1.03,1.18],p=0.004; HR=1.10,95% CI=[1.01,1.19], p=0.02, for EAA at 6-months and 12-months post-treatment, respectively), PFS (HR=1.10, 95% CI=[1.02,1.19], p=0.02; HR=1.14, 95% CI=[1.06,1.23], p<0.001; HR=1.08,95% CI=[1.02,1.14], p=0.01, for EAA before, end, and 6-months post-radiotherapy, respectively), and QOL over time (β=-0.61,p=0.001). An average of 3.25-3.33 years of age acceleration across time, which was responsible for 33% to 44% higher HRs of OS and PFS, was observed in those who died or developed recurrences compared to those who did not (all p<0.001).

Conclusion: Compared to demographic and lifestyle factors, clinical characteristics were more likely to contribute to faster biological aging in patients with HNC. Acceleration in epigenetic age resulted in more aggressive adverse events including OS and PFS. EAA could be considered as a marker for cancer outcomes, and decelerating aging could improve survival and QOL.
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http://dx.doi.org/10.1016/j.ijrobp.2021.04.002DOI Listing
April 2021

"Randomized trial of physical activity on quality of life and lung cancer biomarkers in patients with advanced stage lung cancer: a pilot study".

BMC Cancer 2021 Apr 1;21(1):352. Epub 2021 Apr 1.

Department of Chronic Disease Epidemiology, Yale University School of Public Health, New Haven, USA.

Background: Lung cancer survivors need more options to improve quality of life (QoL). It is unclear to what extent patients with advanced stage disease are willing to participate in home-based physical activity (PA) and if these interventions improve QoL. The goal of our study was to determine interest in participating in our 3-month home-based walking regimen in patients with advanced stage lung cancer. We used a randomized design to evaluate for potential benefit in PA and patient-reported outcomes.

Methods: We performed an open-label, 1:1 randomized trial in 40 patients with stage III/IV non-small cell lung cancer (NSCLC) evaluating enrollment rate, PA, QoL, dyspnea, depression, and biomarkers. Compared to usual care (UC), the intervention group (IG) received an accelerometer, in-person teaching session, and gain-framed text messages for 12 weeks.

Results: We enrolled 56% (40/71) of eligible patients. Participants were on average 65 years and enrolled 1.9 years from diagnosis. Most patients were women (75%), and receiving treatment (85%) for stage IV (73%) adenocarcinoma (83%). A minority of patients were employed part-time or full time (38%). Both groups reported low baseline PA (IG mean 37 (Standard deviation (SD) 46) vs UC 59 (SD 56) minutes/week; p = 0.25). The IG increased PA more than UC (mean change IG + 123 (SD 212) vs UC + 35 (SD 103) minutes/week; p = 0.051)). Step count in the IG was not statistically different between baseline (4707 step/day), week 6 (5605; p = 0.16), and week 12 (4606 steps/day; p = 0.87). The intervention improved EORTC role functioning domain (17 points; p = 0.022) with borderline improvement in dyspnea (- 13 points; p = 0.051) compared to UC. In patients with two blood samples (25%), we observed a significant increase in soluble PD-1 (219.8 (SD 54.5) pg/mL; p < 0.001).

Conclusions: Our pilot trial using a 3-month, home-based, mobile health intervention enrolled over half of eligible patients with stage III and IV NSCLC. The intervention increased PA, and may improve several aspects of QoL. We also identified potential biomarker changes relevant to lung cancer biology. Future research should use a larger sample to examine the effect of exercise on cancer biomarkers, which may mediate the association between PA and QoL.

Clinical Trial Registration: Clinicaltrials.gov ( NCT03352245 ).
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http://dx.doi.org/10.1186/s12885-021-08084-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015735PMC
April 2021

Randomized trial of exercise on depressive symptomatology and brain derived neurotrophic factor (BDNF) in ovarian cancer survivors: The Women's Activity and Lifestyle Study in Connecticut (WALC).

Gynecol Oncol 2021 May 26;161(2):587-594. Epub 2021 Mar 26.

Yale School of Public Health, New Haven, CT, United States of America; Yale Cancer Center, New Haven, CT, United States of America.

Objectives: Depression is one of the most prevalent mental disorders, and rates are higher among cancer survivors than the general population, and higher in ovarian cancer patients compared to cohorts of other cancer survivors. Physical activity has been associated with lower depressive symptoms in cancer survivors, yet no trial has examined this association in women with ovarian cancer. We examined the effect of exercise on depression symptomatology and serum brain derived neurotrophin factor (BDNF) which has been associated with depression, in women with ovarian cancer.

Methods: We conducted a 6-month home-based randomized trial of exercise vs. attention-control (AC) in 144 ovarian cancer survivors. Depressive symptomatology was measured via the Center for Epidemiologic Studies Depression Scale (CES-D). Serum total and free BDNF was measured at baseline and 6-months. Student's t-statistic and mixed-model repeated measures analysis was used to evaluate six-month change between arms in CES-D scores and BDNF.

Results: Women were 57.3 ± 8.6 (mean ± SD) years old, 1.7 ± 1.0 years post-diagnosis with a baseline CES-D score of 11.79 ± 10.21. The majority (55%) were diagnosed with stage III/IV ovarian cancer. CES-D scores decreased in the exercise arm by 2.7 points (95% CI: -4.4, -0.9) or a 21% decrease compared to a 0.3 point decrease (-2.2, 1.5) (3% decrease) in the AC arm (P = 0.05). There was no difference in change in total or free BDNF between the exercise and AC arms.

Conclusions: Ovarian cancer survivors are able to exercise at recommended levels, and exercise was associated with a significant reduction in depressive symptomatology.
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http://dx.doi.org/10.1016/j.ygyno.2021.02.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085084PMC
May 2021

Examining the effect of obesity-associated gene variants on breast cancer survivors in a randomized weight loss intervention.

Breast Cancer Res Treat 2021 Mar 6. Epub 2021 Mar 6.

Yale School of Public Health, MPH, 55 Church Street, Suite 801, New Haven, CT, 06510, USA.

Purpose: Our study examined whether common variants of obesity-associated genes FTO, MC4R, BDNF, and CREB1 moderated the effects of a lifestyle intervention on weight change among breast cancer survivors.

Methods: 151 breast cancer survivors with a body mass index ≥ 25 kg/m were randomly assigned to a 6-month weight loss intervention or usual care group. Genotyping of FTO rs9939609, MC4R rs6567160, BDNF rs11030104, CREB1 rs17203016 was performed. Linear mixed models were used including the main effects of genotype (assuming a dominant genetic model), treatment arm on weight and percent body fat changes, and genotype by treatment interaction variable. All statistical tests were evaluated against a Bonferroni-corrected alpha of 0.0125.

Results: Women in the intervention group achieved significantly greater weight loss than the usual care group (5.9% vs 0.4%, p < 0.001), regardless of genotype. Changes in weight and percent body fat did not differ significantly between carriers of the FTO rs9939609, MC4R rs6567160, BDNF rs11030104, and CREB1 rs17203016 risk alleles compared to non-carriers (p-interaction > 0.0125 for each single-nucleotide polymorphisms).

Conclusions: Women who are genetically predisposed to obesity and recently diagnosed with breast cancer may achieve significant and clinically meaningful weight loss through healthy eating and exercise.

Clinical Trial Registration: NCT02863887 (Date of Registration: August 11, 2016); NCT02110641 (Date of Registration: April 10, 2014).
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http://dx.doi.org/10.1007/s10549-021-06151-5DOI Listing
March 2021

A randomized trial of physical activity for cognitive functioning in breast cancer survivors: Rationale and study design of I Can! Improving Cognition After Cancer.

Contemp Clin Trials 2021 Mar 24;102:106289. Epub 2021 Jan 24.

UC San Diego Moores Cancer Center, UC San Diego, La Jolla, CA, USA.

Introduction: Difficulties with cognition are extremely common among breast cancer survivors and can significantly impact quality of life, daily functioning, and ability to return to work. One promising intervention is increasing physical activity, as it has been effective in improving cognition in non-cancer populations. Few physical activity intervention trials with cognition outcomes have included cancer survivors. This project builds upon our previous work indicating that increased physical activity can improve objectively measured processing speed and self-reported cognition among breast cancer survivors.

Methods: The I Can! study will examine whether a physical activity intervention improves cognition among 250 post-treatment breast cancer survivors (Stages I-III, <5 years post-treatment) who are reporting cognitive difficulties. This 2-arm randomized controlled trial comparing a 6-month physical activity intervention (Exercise Group) to a health & wellness attention-comparison condition (Health & Wellness Group) will examine intervention effects on cognition (at 3 and 6 months) and maintenance of effects at 12 months. The primary aim is to investigate the impact of exercise on objectively measured processing speed and self-reported cognition. Secondary aims are to investigate maintenance of cognitive changes and examine candidate biological mechanisms and psychological mediators.

Conclusion: The I Can! study will contribute to the scientific, public health, and survivorship intervention literature by providing new information on the impact of physical activity for cognitive impairment in breast cancer survivors. Findings from this study will inform guidelines for physical activity to improve the lives of millions of breast cancer survivors.
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http://dx.doi.org/10.1016/j.cct.2021.106289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009833PMC
March 2021

Racial/Ethnic Disparities in Screening for and Awareness of High Cholesterol Among Pregnant Women Receiving Prenatal Care.

J Am Heart Assoc 2021 Jan 21;10(1):e017415. Epub 2020 Dec 21.

Division of Cardiology University of Pennsylvania Perelman School of Medicine Philadelphia PA.

Background Atherosclerotic cardiovascular disease remains a leading cause of morbidity and mortality among women, with younger women being disproportionately affected by traditional cardiovascular risk factors such as dyslipidemia. Despite recommendations for lipid screening in early adulthood and the risks associated with maternal dyslipidemia during pregnancy, many younger women lack access to and utilization of early screening. Accordingly, our objective was to assess the prevalence of and disparities in lipid screening and awareness of high cholesterol as an atherosclerotic cardiovascular disease risk factor among pregnant women receiving prenatal care. Methods and Results We invited 234 pregnant women receiving prenatal care at 1 of 3 clinics affiliated with the University of Pennsylvania Health System to complete our survey. A total of 200 pregnant women (86% response rate) completed the survey. Overall, 59% of pregnant women (mean age 32.2 [±5.7] years) self-reported a previous lipid screening and 79% of women were aware of high cholesterol as an atherosclerotic cardiovascular disease risk factor. Stratified by racial/ethnic subgroups, non-Hispanic Black women were less likely to report a prior screening (43% versus 67%, =0.022) and had lower levels of awareness (66% versus 92%, <0.001) compared with non-Hispanic White women. Non-Hispanic Black women were more likely to see an obstetrician/gynecologist for their usual source of non-pregnancy care compared with non-Hispanic White women (18% versus 5%, =0.043). Those seeing an obstetrician/gynecologist for usual care were less likely to report a prior lipid screening compared with those seeing a primary care physician (29% versus 63%, =0.007). Conclusions Significant racial/ethnic disparities persist in lipid screening and risk factor awareness among pregnant women. Prenatal care may represent an opportunity to enhance access to and uptake of screening among younger women and reduce variations in accessing preventive care services.
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http://dx.doi.org/10.1161/JAHA.120.017415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955491PMC
January 2021

Association of relative dose intensity with BMI and pathologic complete response in patients treated with neoadjuvant chemotherapy for breast cancer.

Breast Cancer Res Treat 2021 Feb 30;186(1):191-197. Epub 2020 Oct 30.

Yale Cancer Center, New Haven, CT, USA.

Purpose: Previous work found that lower BMI is associated with a pathologic complete response (pCR) following neoadjuvant chemotherapy for breast cancer. Relative dose intensity (RDI) of chemotherapy is an important marker of treatment tolerability. We hypothesized that patients with low BMI would have higher RDI than patients with high BMI, explaining the mechanism for the association between BMI and pCR.

Methods: We conducted a retrospective study of women treated with neoadjuvant chemotherapy for stage I-III breast cancer at Yale New Haven Hospital-Smilow Cancer Hospital. We reviewed medical records to determine tumor characteristics, chemotherapy doses, and reasons for dose reductions or delays. The treatment RDI was calculated using published methods. Chi-squared analyses were conducted to determine the associations between RDI and BMI and between RDI and pCR.

Results: Our cohort (n = 237) had an average age of 53 years (SD 13) and mean BMI of 29.5 kg/m (SD 7.0). Fifty-eight patients (24%) received <85% RDI, and 61% of patients experienced at least one dose reduction or delay. BMI was not associated with RDI (p = 0.71), and RDI was not associated with pCR (p = 0.31); however, fewer dose delays was associated with pCR (p = 0.02). The most common reasons for dose reduction or delays were neuropathy, myelosuppression, and personal reasons.

Conclusions: Nearly one quarter of our cohort had RDI <85%. Although RDI overall was not associated with pCR, having fewer dose delays was associated with pCR. Our results highlight a need for improved patient adherence to and tolerability of neoadjuvant chemotherapy to minimize treatment delays.
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http://dx.doi.org/10.1007/s10549-020-05994-8DOI Listing
February 2021

Effect of Exercise or Metformin on Biomarkers of Inflammation in Breast and Colorectal Cancer: A Randomized Trial.

Cancer Prev Res (Phila) 2020 12 28;13(12):1055-1062. Epub 2020 Aug 28.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Observational studies report that physical activity and metformin are associated with improved clinical outcome in patients with cancer. Inflammation is one biological mechanism hypothesized to mediate these associations. In this phase II, multicenter, 2 × 2 factorial trial, 139 patients with breast and colorectal cancer who completed standard therapy were randomized to one of four treatment groups for 12 weeks: exercise alone, metformin alone, exercise and metformin, or control. Inflammation outcomes included high-sensitivity C-reactive protein (hs-CRP), soluble tumor necrosis factor alpha receptor two (sTNFαR2), and IL6. The primary modeling strategy evaluated the trial product estimand that was quantified using a generalized linear mixed model. Compared with control, exercise alone reduced hs-CRP [-30.2%; 95% confidence interval (CI), -50.3, -1.0] and IL6 (-30.9%; 95% CI, -47.3, -9.5) but did not change sTNFαR2 (1.0%; 95% CI, -10.4, 13.9). Compared with control, metformin alone did not change hs-CRP (-13.9%; 95% CI, -40.0, 23.4), sTNFαR2 (-10.4%; 95% CI, -21.3, 2.0), or IL6 (-22.9%; 95% CI, -42.3, 2.0). Compared with control, exercise and metformin reduced sTNFαR2 (-13.1%; 95% CI, -22.9, -1.0) and IL6 (-38.7%; 95% CI, -52.3, -18.9) but did not change hs-CRP (-20.5%; 95% CI, -44.0, 12.7). The combination of exercise and metformin was not synergistic for hs-CRP, sTNFαR2, or IL6. In survivors of breast and colorectal cancer with low baseline physical activity and without type 2 diabetes, exercise and metformin reduced measures of inflammation that are associated with cancer recurrence and mortality.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718298PMC
December 2020

Skin carotenoids are inversely associated with adiposity in breast cancer survivors.

Nutr Res 2020 07 24;79:77-86. Epub 2020 May 24.

Yale School of Public Health, 60 College St, New Haven, CT 06511; Yale Cancer Center, PO Box 208028, New Haven, CT 06519. Electronic address:

Carotenoids are antioxidants which may mitigate some of the adverse effects of obesity, a condition associated with poor outcomes in breast cancer patients. We hypothesized that baseline skin carotenoids would be inversely associated with adiposity in breast cancer survivors and would increase with weight loss. Skin carotenoid score (SCS) was assessed by resonance Raman spectroscopy in breast cancer survivors (body mass index ≥25 kg/m) enrolled in a 6-month randomized controlled weight loss trial (n = 47). Measurements included total body fat using dual-energy X-ray absorptiometry, height, weight, waist and hip circumference, dietary intake, and serum biomarkers. Associations between SCS, adiposity measures, and serum biomarkers were assessed at baseline, as was the change in SCS from baseline to 6 months, in the intervention and usual care groups. At baseline, SCS was inversely correlated with all adiposity measures (P ≤ .05). In multivariate analyses, baseline percent body fat had the strongest association with baseline SCS (partial R= 0.20). Baseline SCS was significantly inversely associated with log C-reactive protein levels (regression coefficient β ± SE: -0.051± 0.019; P = .011) and log leptin (β ± SE: -0.019± 0.009; P = .046), but the associations were no longer significant after adjustment for adiposity. Over the 6-month study, the intervention group had a 17.6% increase in SCS compared to a 1.5% decrease in the usual care group (P = .28). In our study of overweight and obese breast cancer survivors, dual-energy X-ray absorptiometry-measured body fat explained a large portion of the variation in skin carotenoids at baseline, suggesting a stronger association than that previously seen in studies using less accurate measures of adiposity.
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http://dx.doi.org/10.1016/j.nutres.2020.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409553PMC
July 2020

Randomized Phase II Trial of Exercise, Metformin, or Both on Metabolic Biomarkers in Colorectal and Breast Cancer Survivors.

JNCI Cancer Spectr 2020 Feb 20;4(1):pkz096. Epub 2019 Nov 20.

See the Notes section for the full list of authors' affiliations.

Background: Observational data support inverse relationships between exercise or metformin use and disease outcomes in colorectal and breast cancer survivors, although the mechanisms underlying these associations are not well understood.

Methods: In a phase II trial, stage I-III colorectal and breast cancer survivors who completed standard therapy were randomly assigned to structured exercise or metformin or both or neither for 12 weeks. The primary outcome was change in fasting insulin levels; secondary outcomes included changes in other blood-based energetic biomarkers and anthropometric measurements. Analyses used linear mixed models.

Results: In total, 139 patients were randomly assigned; 91 (65%) completed follow-up assessments. Fasting insulin levels statistically significantly decreased in all three intervention arms (-2.47 μU/mL combination arm, -0.08 μU/mL exercise only, -1.16 μU/mL metformin only, + 2.79 μU/mL control arm). Compared with the control arm, all groups experienced statistically significant weight loss between baseline and 12 weeks (-1.8% combination arm, -0.22% exercise only, -1.0% metformin only, +1.55% control). The combination arm also experienced statistically significant improvements in the homeostatic model assessment for insulin resistance (-30.6% combination arm, +61.2% control) and leptin (-42.2% combination arm, -0.8% control), compared with the control arm. The interventions did not change insulin-like growth factor-1 or insulin-like growth factor binding protein-3 measurements as compared with the control arm. Tolerance to metformin limited compliance (approximately 50% of the participants took at least 75% of the planned dosages in both treatment arms).

Conclusions: The combination of exercise and metformin statistically significantly improved insulin and associated metabolic markers, as compared to the control arm, with potential greater effect than either exercise or metformin alone though power limited formal synergy testing. Larger efforts are warranted to determine if such a combined modality intervention can improve outcomes in colorectal and breast cancer survivors.
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http://dx.doi.org/10.1093/jncics/pkz096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025659PMC
February 2020

Transdisciplinary Research in Energetics and Cancer early career investigator training program: first year results.

Transl Behav Med 2021 Mar;11(2):549-562

Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA.

Energy imbalance increases cancer burden by increasing cancer risk and mortality. Training early career investigators on conducting impactful energy balance and cancer research is needed. We developed a Transdisciplinary Research in Energetics and Cancer (TREC) Training Program for early career investigators. This analysis examined program satisfaction, knowledge gained, publications, and awards among Year 1 participants (i.e., fellows). The program consists of an in-person course, followed by 1 year of mentorship. Faculty and fellows completed precourse and postcourse surveys. Following the mentorship period, we surveyed fellows for TREC-related research productivity, including publications and grant funding attributed to the program. Twenty fellows were accepted into the program: 3 basic, 7 clinical, and 10 population scientists. Sixteen fellows were junior faculty and four were postdoctoral fellows. The course included ~50 lectures, small group sessions, and faculty-fellow sessions. 96.7% of attendees rated the course in the highest categories of "good/very good." Knowledge significantly improved in 37 of 39 research competencies (94.8%). In the 18 months following the course, fellows published 25 manuscripts, with 3 published in journals with impact factor ≥10. Nineteen grants were funded to TREC fellows (i.e., 7 National Institutes of Health awards, 2 American Cancer Society [ACS] awards, and 10 foundation/pilot awards), and 7 fellows received career promotions. The program's impact will be defined by the degree to which TREC fellows produce discoveries that could improve the health of populations at risk for and/or surviving cancer. Upon the conclusion of our fifth year in 2021, we will publicly disseminate the program material.
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http://dx.doi.org/10.1093/tbm/ibaa009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963289PMC
March 2021

Risk factors for hepatocellular carcinoma (HCC) in the northeast of the United States: results of a case-control study.

Cancer Causes Control 2020 Apr 14;31(4):321-332. Epub 2020 Feb 14.

Epidemiology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.

Purpose: HCC incidence has been continuously rising in the US for the past 30 years. To understand the increase in HCC risk, we conducted a case-control study in Connecticut, New Jersey and part of New York City.

Methods: Through rapid case ascertainment and random digit dialing, we recruited 673 incident HCC patients and 1,166 controls. Information on demographic and anthropometric characteristics, lifestyle factors, medical and family cancer histories, were ascertained through telephone interviews using a structured questionnaire. Saliva specimens were collected for testing hepatitis C virus (HCV) antibodies. Unconditional logistic regression models were utilized to calculate odds ratio (OR) and 95% confidence interval (CI) to determine HCC associations with risk factors.

Results: The study confirmed that HCV infection and obesity were important risk factors for HCC, ORs 110 (95% CI 59.2-204) and 2.13 (95% CI 1.52-3.00), respectively. High BMI and HCV infection had synergy in association with elevated HCC risk. Patients both obese and infected with HCV had HCC detected on average nearly 10 years earlier than those with neither factor. Diabetes, cigarette smoking and heavy alcohol intake were all associated with increased risk of HCC, whereas aspirin and other NSAID use were associated with reduced risk. HCC cases tended to attain less education, with lower household incomes, unmarried, and to have had more sexual partners than the controls.

Conclusions: Individuals at risk of HCC in the US comprise a unique population with low socioeconomic status and unhealthy lifestyle choices. Given the multifactorial nature, a comprehensive approach is needed in HCC prevention.
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http://dx.doi.org/10.1007/s10552-020-01277-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136513PMC
April 2020

Moderators of Exercise Effects on Cancer-related Fatigue: A Meta-analysis of Individual Patient Data.

Med Sci Sports Exerc 2020 02;52(2):303-314

Netherlands Cancer Institute, Amsterdam, THE NETHERLANDS.

Purpose: Fatigue is a common and potentially disabling symptom in patients with cancer. It can often be effectively reduced by exercise. Yet, effects of exercise interventions might differ across subgroups. We conducted a meta-analysis using individual patient data of randomized controlled trials (RCT) to investigate moderators of exercise intervention effects on cancer-related fatigue.

Methods: We used individual patient data from 31 exercise RCT worldwide, representing 4366 patients, of whom 3846 had complete fatigue data. We performed a one-step individual patient data meta-analysis, using linear mixed-effect models to analyze the effects of exercise interventions on fatigue (z score) and to identify demographic, clinical, intervention- and exercise-related moderators. Models were adjusted for baseline fatigue and included a random intercept on study level to account for clustering of patients within studies. We identified potential moderators by testing their interaction with group allocation, using a likelihood ratio test.

Results: Exercise interventions had statistically significant beneficial effects on fatigue (β = -0.17; 95% confidence interval [CI], -0.22 to -0.12). There was no evidence of moderation by demographic or clinical characteristics. Supervised exercise interventions had significantly larger effects on fatigue than unsupervised exercise interventions (βdifference = -0.18; 95% CI -0.28 to -0.08). Supervised interventions with a duration ≤12 wk showed larger effects on fatigue (β = -0.29; 95% CI, -0.39 to -0.20) than supervised interventions with a longer duration.

Conclusions: In this individual patient data meta-analysis, we found statistically significant beneficial effects of exercise interventions on fatigue, irrespective of demographic and clinical characteristics. These findings support a role for exercise, preferably supervised exercise interventions, in clinical practice. Reasons for differential effects in duration require further exploration.
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http://dx.doi.org/10.1249/MSS.0000000000002154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962544PMC
February 2020

Association between pre-diagnosis BMI, physical activity, pathologic complete response, and chemotherapy completion in women treated with neoadjuvant chemotherapy for breast cancer.

Breast Cancer 2019 Nov 22;26(6):719-728. Epub 2019 May 22.

Yale University School of Medicine, 300 George St, Suite 120, New Haven, CT, 06511, USA.

Purpose: Physical activity and lower BMI have shown benefit for breast cancer survival, but the association between these factors, pathologic complete response (pCR), and chemotherapy completion is not clear. We evaluated whether BMI and physical activity are associated with pCR and chemotherapy completion during neoadjuvant breast cancer treatment.

Methods: We conducted a retrospective case-control study of women given neoadjuvant chemotherapy for stage I-III breast cancer between 2010 and 2016. A medical record review provided pCR, chemotherapy completion, and patient characteristics. A telephone survey assessed physical activity 1 year before diagnosis. Unconditional logistic regression models identified factors associated with pCR and chemotherapy completion.

Results: In our cohort (n = 243), the average age was 52.9 years (SD 13.0) and mean BMI was 29.5 kg/m (SD 7.0). Seventy-five (31%) patients had pCR and 168 (69%) had residual disease. Patients with pCR had lower mean BMI than those with residual disease (28.2 (SD) vs. 30.1 (SD), P = 0.04). Exercise was associated with completion of chemotherapy (OR 7.6, 95% CI 1.4-41.2, P = 0.02).

Conclusions: Pathologic complete response was associated with lower BMI; chemotherapy completion was associated with exercising at CDC-recommended levels prior to breast cancer diagnosis.
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http://dx.doi.org/10.1007/s12282-019-00974-3DOI Listing
November 2019

Impact of a Pre-Operative Exercise Intervention on Breast Cancer Proliferation and Gene Expression: Results from the Pre-Operative Health and Body (PreHAB) Study.

Clin Cancer Res 2019 Sep 24;25(17):5398-5406. Epub 2019 Apr 24.

Yale School of Public Health, New Haven, Connecticut.

Purpose: Exercise after breast cancer diagnosis is associated with lower cancer-specific mortality, but the biological mechanisms through which exercise impacts breast cancer are not fully understood. The Pre-Operative Health and Body (PreHAB) Study was a randomized window-of-opportunity trial designed to test the impact of exercise on Ki-67, gene expression, and other biomarkers in women with breast cancer.

Experimental Design: Inactive women with newly diagnosed breast cancer were randomized to an exercise intervention or mind-body control group, and participated in the study between enrollment and surgery (mean 29.3 days). Tumor and serum were collected at baseline and surgery.

Results: Forty-nine women were randomized (27 exercise, 22 control). At baseline, mean age was 52.6, body mass index was 30.2 kg/m, and exercise was 49 minutes/week. Exercise participants significantly increased exercise versus controls (203 vs. 23 minutes/week, < 0.0001). There were no differences in changes of expression of Ki-67, insulin receptor, and cleaved caspase-3 in exercise participants versus controls. KEGG pathway analysis demonstrated significant upregulation of 18 unique pathways between the baseline biopsy and surgical excision in exercise participants and none in control participants ( < 0.1). Top-ranked pathways included several implicated in immunity and inflammation. Exploratory analysis of tumor immune infiltrates demonstrated a trend toward a decrease in FOXP3 cells in exercise versus control participants over the intervention period ( = 0.08).

Conclusions: A window-of-opportunity exercise intervention did not impact proliferation but led to alterations in gene expression in breast tumors, suggesting that exercise may have a direct effect on breast cancer..
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3143DOI Listing
September 2019

Endocrine-related quality of life in a randomized trial of exercise on aromatase inhibitor-induced arthralgias in breast cancer survivors.

Cancer 2019 07 6;125(13):2262-2271. Epub 2019 Mar 6.

Yale School of Public Health, New Haven, Connecticut.

Background: The objective of this study was to evaluate the role of a 12-month exercise intervention on endocrine-related quality of life (QOL) and overall QOL among breast cancer survivors with aromatase inhibitor (AI)-induced arthralgia in the Hormones and Physical Exercise (HOPE) Study.

Methods: This was a randomized controlled trial of 121 breast cancer survivors who were currently receiving AIs and experiencing at least mild arthralgia. QOL was assessed using the Functional Assessment of Cancer Therapy (FACT) questionnaires and the 36-Item Short Form Survey (SF-36) at baseline, 6 months, and 12 months. Participants were randomized to either a 1-year gym-based, supervised exercise intervention group (150 minutes of aerobic exercise and 2 strength-training sessions each week) or a usual care group. Effects of the intervention on QOL were assessed using mixed-model, repeated-measures analysis.

Results: At 12 months, the exercise group had greater improvement in the overall QOL measures as well as the breast cancer-specific (scores, 2.2 vs 0.7; P = .02), endocrine-specific (scores, 5.6 vs 1.6; P < .001), and fatigue-specific (score, 5.8 vs 0.5; P < .001) subscales compared with the usual care group. The results indicated a stronger effect at 12 months versus 6 months after the intervention.

Conclusions: Combined aerobic and resistance exercise, such as treadmill walking and strength training, improved endocrine-related and overall QOL among breast cancer survivors who were experiencing adverse side effects from AIs. Because adverse side effects associated with AI use are quite common and this is the main reason for treatment discontinuation, this nonpharmacologic intervention could benefit many breast cancer survivors and increase successful adherence to AIs in breast cancer treatment.
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http://dx.doi.org/10.1002/cncr.32051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731173PMC
July 2019

Targeting Exercise Interventions to Patients With Cancer in Need: An Individual Patient Data Meta-Analysis.

J Natl Cancer Inst 2018 11;110(11):1190-1200

School of Medicine & Public Health (ELJ) and Priority Research Centre for Physical Activity and Nutrition (RCP), The University of Newcastle, Callaghan, NSW, Australia.

Background: Exercise effects in cancer patients often appear modest, possibly because interventions rarely target patients most in need. This study investigated the moderator effects of baseline values on the exercise outcomes of fatigue, aerobic fitness, muscle strength, quality of life (QoL), and self-reported physical function (PF) in cancer patients during and post-treatment.

Methods: Individual patient data from 34 randomized exercise trials (n = 4519) were pooled. Linear mixed-effect models were used to study moderator effects of baseline values on exercise intervention outcomes and to determine whether these moderator effects differed by intervention timing (during vs post-treatment). All statistical tests were two-sided.

Results: Moderator effects of baseline fatigue and PF were consistent across intervention timing, with greater effects in patients with worse fatigue (Pinteraction = .05) and worse PF (Pinteraction = .003). Moderator effects of baseline aerobic fitness, muscle strength, and QoL differed by intervention timing. During treatment, effects on aerobic fitness were greater for patients with better baseline aerobic fitness (Pinteraction = .002). Post-treatment, effects on upper (Pinteraction < .001) and lower (Pinteraction = .01) body muscle strength and QoL (Pinteraction < .001) were greater in patients with worse baseline values.

Conclusion: Although exercise should be encouraged for most cancer patients during and post-treatments, targeting specific subgroups may be especially beneficial and cost effective. For fatigue and PF, interventions during and post-treatment should target patients with high fatigue and low PF. During treatment, patients experience benefit for muscle strength and QoL regardless of baseline values; however, only patients with low baseline values benefit post-treatment. For aerobic fitness, patients with low baseline values do not appear to benefit from exercise during treatment.
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http://dx.doi.org/10.1093/jnci/djy161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454466PMC
November 2018

Randomized controlled trial of weight loss versus usual care on telomere length in women with breast cancer: the lifestyle, exercise, and nutrition (LEAN) study.

Breast Cancer Res Treat 2018 Nov 30;172(1):105-112. Epub 2018 Jul 30.

Yale Cancer Center, Yale University School of Medicine, 333 Cedar St, PO Box 208032, New Haven, CT, 06520-8032, USA.

Purpose: Some studies suggest that telomere shortening may be associated with increased breast cancer risk and mortality. Obesity is also associated with increased breast cancer risk and mortality. Few studies have examined changes in telomere length in overweight or obese breast cancer survivors. The purpose of our study was to examine the effect of a 6-month diet- and exercise-induced weight loss intervention versus usual care on telomere length in breast cancer survivors.

Methods: 151 breast cancer survivors with body mass index (BMI) ≥ 25 kg/m were randomly assigned to a 6-month weight loss intervention (n = 93) or to usual care (n = 58). Fasting blood samples, height, weight, physical activity, and diet were measured at baseline and 6-months. Relative telomere length (RTL) was measured by quantitative-polymerase chain reaction (qPCR) done on buffy coat-extracted genomic DNA. Mean baseline to 6-month changes were compared between groups (intention-to-treat) using generalized estimating equations.

Results: Complete telomere data were available in 125 participants. Women were 58 ± 8 years, with BMI 33.0 ± 6.2 kg/m and were 2.9 ± 2.5 years from diagnosis; 90% were non-Hispanic white, and 76% had stage 0/I breast cancer. After 6 months, women randomized to weight loss had 3% telomere lengthening compared to 5% shortening in the usual care group (p = 0.12). Among women with stage 0/I, the intervention group experienced 7% telomere lengthening compared to 8% shortening in the usual care group (p = 0.01). No intervention effect was observed in women with stage II/III breast cancer.

Conclusion: Our findings suggest a weight loss intervention in stage 0 and 1 breast cancer survivors may lead to telomere lengthening, compared to a shortening in their usual care counterparts.
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http://dx.doi.org/10.1007/s10549-018-4895-7DOI Listing
November 2018

Randomized Trial of Exercise on Quality of Life in Women With Ovarian Cancer: Women's Activity and Lifestyle Study in Connecticut (WALC).

J Natl Cancer Inst 2017 12;109(12)

Yale Cancer Center, New Haven, CT.

Background: Ovarian cancer survivors experience a wide range of treatment side effects that can negatively affect health-related quality of life (HRQOL). Physical activity has been shown to improve HRQOL and cancer-related fatigue (CRF) for other cancer survivors; however, no large randomized controlled trial (RCT) has been conducted for ovarian cancer.

Methods: This study examined the impact of a six-month RCT of exercise vs attention control on change in HRQOL (Short Form Health Survey-36) and CRF (Functional Assessment of Cancer Therapy-Fatigue Scale) in ovarian cancer survivors. Women (n = 144) were randomly assigned to study arms between May 1, 2010, and March 20, 2014. All statistical tests were two-sided.

Results: A total of 74 women were randomly assigned to exercise and 70 to attention control. A total of 113 (78.5%) of the participants completed the six-month assessment. Adherence to the exercise intervention was excellent (166.0±66.1 minutes/week in the exercise arm). At six months, women in the exercise arm had improved physical HRQOL (SF-36 Physical Component Summary Score) compared with the control arm, 1.8 (SD = 1.1) vs -2.0 (SD = 1.2) , respectively (group difference = 3.7, SD = 1.2, 95% confidence interval [CI] = 0.7 to 6.8, P = .02). No group differences were seen for change in mental HRQOL. There was a statistically significant improvement in the fatigue score (Functional Assessment of Cancer Therapy-Fatigue) for exercisers (4.0, SD = 1.1, 95% CI = 1.8 to 6.2, P < .001) but not for controls (1.2, SD = 1.2, 95% CI = -1.1 to 3.5, P = .31), with a between-group difference of 2.8 (SD = 1.5, 95% CI = -0.2 to 5.7, P = .06).

Conclusions: We found a six-month home-based, telephone-delivered exercise intervention of primarily brisk walking to be associated with improved physical HRQOL in women with ovarian cancer. Given that higher HRQOL and exercise have both been associated with overall survival in women diagnosed with ovarian cancer, oncologists and primary care providers should recommend and refer women diagnosed with ovarian cancer to clinic- or community-based exercise programs.
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http://dx.doi.org/10.1093/jnci/djx072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515522PMC
December 2017

Exercise and weight loss interventions and miRNA expression in women with breast cancer.

Breast Cancer Res Treat 2018 Jul 6;170(1):55-67. Epub 2018 Mar 6.

Yale School of Public Health, New Haven, CT, 06510, USA.

Purpose: Obesity and weight gain are associated with comorbidities including a higher risk of tumor recurrence and cancer-related deaths among breast cancer (BC) survivors; however, the underlying mechanisms linking obesity and cancer are poorly understood. Given the lack of clinically validated BC biomarkers, obesity and weight-loss studies utilize serum biomarkers as the intermediary outcomes of tumor recurrence. Studies have indicated microRNAs (miRNA)s are reliable biomarkers for cancer. We hypothesized that miRNA expression correlates with obesity and weight loss amongst BC survivors. This would yield insight into the biological pathways by which this association occurs, enabling more precise development of therapeutics.

Patients And Methods: We correlated baseline body mass index (BMI) with serum miRNA expression in 121 BC survivors enrolled in the Hormones and Physical Exercise (HOPE) trial. We then analyzed expression of the 35 most abundant miRNAs from HOPE in a six-month randomized controlled weight-loss trial (Lifestyle, Exercise, and Nutrition; LEAN) in 100 BC survivors. Ingenuity pathway analysis (IPA) software was used to identify biological pathway targets of the BMI-associated and intervention-responsive miRNAs using predictive biomarkers.

Results: Pearson correlations in HOPE identified eight miRNAs associated with BMI, including miR-191-5p (r = - 0.22, p = 0.016) and miR-122-5p (r = 0.25, p = 0.0048). In the LEAN validation study, levels of miR-191-5p significantly increased during the six-month intervention (p = 0.082). Ingenuity Pathway Analysis identified "Estrogen-mediated S-phase entry" (HOPE p = 0.003; LEAN p < 0.001) and "Molecular mechanisms of cancer" (HOPE p = 0.02; LEAN p < 0.001) as the top canonical pathways that significantly correlated with BMI-associated and intervention-responsive miRNAs and contain obesity and cancer-relevant genes including the E2F family of transcription factors and CCND1, which have been implicated in sporadic BC.

Conclusion: While the association between obesity and BC recurrence and mortality has been demonstrated in the literature, mechanisms underlying the link between weight gain and cancer are unclear. Using two independent clinical trials, we identified novel miRNAs associative to BMI and weight loss that contribute to the development of cancer. Predictive modeling of miRNA targets identified multiple canonical pathways associated with cancer, highlighting potential mechanisms explaining the link between BMI and increased cancer risk.
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http://dx.doi.org/10.1007/s10549-018-4738-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444907PMC
July 2018

Lymphedema in ovarian cancer survivors: Assessing diagnostic methods and the effects of physical activity.

Cancer 2018 05 13;124(9):1929-1937. Epub 2018 Feb 13.

Yale School of Public Health, New Haven, Connecticut.

Background: Lymphedema is a poorly understood side effect of gynecologic cancer treatment. This study was designed to determine the prevalence of lower limb lymphedema (LLL) in a sample of ovarian cancer survivors via 3 different diagnostic methods and to assess the effect of a randomized exercise intervention.

Methods: Physically inactive ovarian cancer survivors (n = 95) were enrolled in a 6-month randomized trial of exercise (primarily brisk walking) versus attention control. LLL was measured at baseline and 6-month visits via a self-report questionnaire, optoelectronic perometry, and an evaluation by a certified lymphedema specialist.

Results: LLL prevalence ranged from 21% to 38% according to the diagnostic method, and there was substantial agreement between the self-report questionnaire and the lymphedema specialist evaluation (κ = 0.61). There was no agreement between the evaluation with optoelectronic perometry and the specialist evaluation. With LLL defined by any method, the baseline prevalence was 38% in both groups. At 6 months, both groups experienced a decreased LLL prevalence: 28% in the exercise group and 35% in the control group. There was no difference in the change in lymphedema prevalence between the 2 groups (P = .64). Body mass index was a significant predictor of LLL.

Conclusions: With a potential prevalence of LLL as high as 40%, further evaluation of diagnostic methods is required to better characterize this side effect of ovarian cancer treatment. No adverse effect of exercise on LLL was found. Further research is strongly needed to evaluate predictors of LLL and the effects of exercise on LLL in order to develop effective physical activity recommendations for women with ovarian cancer. Cancer 2018;124:1929-37. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31239DOI Listing
May 2018

Design and rationale of the Cardiovascular Health and Text Messaging (CHAT) Study and the CHAT-Diabetes Mellitus (CHAT-DM) Study: two randomised controlled trials of text messaging to improve secondary prevention for coronary heart disease and diabetes.

BMJ Open 2017 12 21;7(12):e018302. Epub 2017 Dec 21.

China Oxford Centre for International Health Research, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Introduction: Mobile health interventions have the potential to promote risk factor management and lifestyle modification, and are a particularly attractive approach for scaling across healthcare systems with limited resources. We are conducting two randomised trials to evaluate the efficacy of text message-based health messages in improving secondary coronary heart disease (CHD) prevention among patients with or without diabetes.

Methods And Analysis: The Cardiovascular Health And Text Messaging (CHAT) Study and the CHAT-Diabetes Mellitus (CHAT-DM) Study are multicentre, single-blind, randomised controlled trials of text messaging versus standard treatment with 6 months of follow-up conducted in 37 hospitals throughout 17 provinces in China. The intervention group receives six text messages per week which target blood pressure control, medication adherence, physical activity, smoking cessation (when appropriate), glucose monitoring and lifestyle recommendations including diet (in CHAT-DM). The text messages were developed based on behavioural change techniques, using models such as the information-motivation-behavioural skills model, goal setting and provision of social support. A total sample size of 800 patients would be adequate for CHAT Study and sample size of 500 patients would be adequate for the CHAT-DM Study. In CHAT, the primary outcome is the change in systolic blood pressure (SBP) at 6 months. Secondary outcomes include a change in proportion of patients achieving a SBP <140 mm Hg, low-density lipoprotein cholesterol (LDL-C), physical activity, medication adherence, body mass index (BMI) and smoking cessation. In CHAT-DM, the primary outcome is the change in glycaemic haemoglobin (HbA) at 6 months. Secondary outcomes include a change in the proportion of patients achieving HbA<7%, fasting blood glucose, SBP, LDL-C, BMI, physical activity and medication adherence.

Ethics And Dissemination: The central ethics committee at the China National Center for Cardiovascular Disease and the Yale University Institutional Review Board approved the CHAT and CHAT-DM studies. Results will be disseminated via usual scientific forums including peer-reviewed publications.

Trial Registration Number: CHAT (NCT02888769) and CHAT-DM (NCT02883842); Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2017-018302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778311PMC
December 2017

Weight management and physical activity throughout the cancer care continuum.

CA Cancer J Clin 2018 01 22;68(1):64-89. Epub 2017 Nov 22.

Chief Medical Advisor, Bipartisan Policy Center, Washington, DC.

Mounting evidence suggests that weight management and physical activity (PA) improve overall health and well being, and reduce the risk of morbidity and mortality among cancer survivors. Although many opportunities exist to include weight management and PA in routine cancer care, several barriers remain. This review summarizes key topics addressed in a recent National Academies of Science, Engineering, and Medicine workshop entitled, "Incorporating Weight Management and Physical Activity Throughout the Cancer Care Continuum." Discussions related to body weight and PA among cancer survivors included: 1) current knowledge and gaps related to health outcomes; 2) effective intervention approaches; 3) addressing the needs of diverse populations of cancer survivors; 4) opportunities and challenges of workforce, care coordination, and technologies for program implementation; 5) models of care; and 6) program coverage. While more discoveries are still needed for the provision of optimal weight-management and PA programs for cancer survivors, obesity and inactivity currently jeopardize their overall health and quality of life. Actionable future directions are presented for research; practice and policy changes required to assure the availability of effective, affordable, and feasible weight management; and PA services for all cancer survivors as a part of their routine cancer care. CA Cancer J Clin 2018;68:64-89. © 2017 American Cancer Society.
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http://dx.doi.org/10.3322/caac.21441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766382PMC
January 2018

Changes in diet quality in a randomized weight loss trial in breast cancer survivors: the lifestyle, exercise, and nutrition (LEAN) study.

NPJ Breast Cancer 2016 24;2:16026. Epub 2016 Aug 24.

Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.

Obesity is associated with increased breast cancer recurrence and mortality. Though some post-diagnosis weight loss interventions have achieved weight loss outcomes, it is unclear whether they also improve diet quality. In the Lifestyle, Exercise, and Nutrition (LEAN) study, overweight or obese breast cancer survivors were randomized to either usual care group (=33) or the 6-month lifestyle intervention (=67). Dietary intake was assessed at baseline and 6 months using a validated food frequency questionnaire, and overall diet quality was calculated using the Healthy Eating Index (HEI)-2010 (range 0-100). Intervention effects on diet were evaluated with generalized linear models. Among the 81 participants (51 intervention, 30 usual care) with dietary data, the mean baseline HEI score was 70.5 (s.d.=8.8) and was improved at 6 months (intervention group=6.8 point increase vs usual care=3.1, =0.09). Intervention group participants achieved greater reductions in percent of energy from total fat (-4.2% vs -1.2%; =0.013) and saturated fat (-2.2% vs -1.1%; =0.003), and greater increases in fiber (4.8 g per 1000 kcal vs 1.3 g per 1000 kcal; =0.007) and fruit (0.5 servings vs 0.0 servings; =0.006) intake. Intervention group participants who lost ⩾5% body weight (=27) demonstrated significantly greater improvements in HEI score (10.4 vs 2.8) than those who lost <5% (=23). The intervention increased fruit and fiber intake and decreased percent energy from fat, and those with greater weight loss achieved greater increases in overall diet quality. These findings support the ability of a weight loss intervention to improve diet among breast cancer survivors.
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http://dx.doi.org/10.1038/npjbcancer.2016.26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515327PMC
August 2016

Nutritional metabolomics and breast cancer risk in a prospective study.

Am J Clin Nutr 2017 Aug 28;106(2):637-649. Epub 2017 Jun 28.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.

The epidemiologic evidence for associations between dietary factors and breast cancer is weak and etiologic mechanisms are often unclear. Exploring the role of dietary biomarkers with metabolomics can potentially facilitate objective dietary characterization, mitigate errors related to self-reported diet, agnostically test metabolic pathways, and identify mechanistic mediators. The aim of this study was to evaluate associations of diet-related metabolites with the risk of breast cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We examined prediagnostic serum concentrations of diet-related metabolites in a nested case-control study in 621 postmenopausal invasive breast cancer cases and 621 matched controls in the multicenter PLCO cohort. We calculated partial Pearson correlations between 617 metabolites and 55 foods, food groups, and vitamin supplements on the basis of the 2015 Dietary Guidelines for Americans and derived from a 137-item self-administered food-frequency questionnaire. Diet-related metabolites (correlation < 1.47 × 10) were evaluated in breast cancer analyses. ORs for the 90th compared with the 10th percentile were calculated by using conditional logistic regression, with body mass index, physical inactivity, other breast cancer risk factors, and caloric intake controlled for (false discovery rate <0.2). Of 113 diet-related metabolites, 3 were associated with overall breast cancer risk (621 cases): caprate (10:0), a saturated fatty acid (OR: 1.77; 95% CI = 1.28, 2.43); γ-carboxyethyl hydrochroman (γ-CEHC), a vitamin E (γ-tocopherol) derivative (OR: 1.64; 95% CI: 1.18, 2.28); and 4-androsten-3β,17β-diol-monosulfate (1), an androgen (OR: 1.61; 95% CI: 1.20, 2.16). Nineteen metabolites were significantly associated with estrogen receptor (ER)-positive (ER) breast cancer (418 cases): 12 alcohol-associated metabolites, including 7 androgens and α-hydroxyisovalerate (OR: 2.23; 95% CI: 1.50, 3.32); 3 vitamin E (tocopherol) derivatives (e.g., γ-CEHC; OR: 1.80; 95% CI: 1.20, 2.70); butter-associated caprate (10:0) (OR: 1.81; 95% CI: 1.23, 2.67); and fried food-associated 2-hydroxyoctanoate (OR: 1.46; 95% CI: 1.03, 2.07). No metabolites were significantly associated with ER-negative breast cancer (144 cases). Prediagnostic serum concentrations of metabolites related to alcohol, vitamin E, and animal fats were moderately strongly associated with ER breast cancer risk. Our findings show how nutritional metabolomics might identify diet-related exposures that modulate cancer risk. This trial was registered at clinicaltrials.gov as NCT00339495.
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http://dx.doi.org/10.3945/ajcn.116.150912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5525118PMC
August 2017

Correlates of overweight and obesity in 5529 adolescents with type 1 diabetes: The T1D Exchange Clinic Registry.

Diabetes Res Clin Pract 2017 Apr 4;126:68-78. Epub 2017 Feb 4.

School of Nursing, Yale University, West Haven, CT, United States.

Aims: To describe the prevalence of overweight and obesity in adolescents with type 1 diabetes (T1D) and to examine the associations among socio-demographic, clinical, and self-management factors by weight status.

Methods: We analyzed baseline data obtained from 5529 adolescents with T1D (mean age=15.4±1.4years, 51.8% male, 77.9% white, mean HbA1c=8.7±1.8%; 72mmol/mol) from the T1D Exchange Clinic Registry. We examined correlates of weight status using multinomial logistic regression analyses.

Results: Overweight (22.9%) and obesity (13.1%) were prevalent in the overall sample and was highest among girls (40.8%) and adolescents of Hispanic/Latino race/ethnicity (46.1%). Female gender, older age, annual household income <$35,000 (vs. ≥$200,000), high school parental educational attainment (vs. ≥graduate degree), lower HbA1c, longer duration of T1D, higher amount of insulin, and a recent visit with an allied healthcare provider were independently and significantly associated with higher odds of overweight or obesity. Adolescents who self-rated their health as fair/poor (vs. excellent) had the highest odds of obesity (OR 3.92, 95% CI 2.53-6.06).

Conclusions: Overweight/obesity is prevalent among adolescents with T1D, especially among girls and those of diverse race/ethnicity. Some of these factors may be amenable to remediation and point to subgroups that can benefit from obesity prevention and management efforts.
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http://dx.doi.org/10.1016/j.diabres.2017.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5401652PMC
April 2017

Post-diagnosis body mass index and mortality among women diagnosed with endometrial cancer: Results from the Women's Health Initiative.

PLoS One 2017 2;12(2):e0171250. Epub 2017 Feb 2.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States of America.

Higher body mass index (BMI) measured before endometrial cancer diagnosis has been associated with greater risk of developing endometrial cancer and higher mortality, but the association between BMI measured after diagnosis and mortality risk is unclear. We identified 467 women (91 deaths) in the Women's Health Initiative (WHI) with information on BMI measured after diagnosis and used Cox proportional hazards regression to generate hazard ratios (HR) and 95% confidence intervals (CI) for all-cause mortality. Comparing BMI 35+ with <25 kg/m2, we observed no association with all-cause mortality (HR = 1.02, 95% CI 0.55-1.91). Our study does not support the hypothesis that higher BMI after endometrial cancer diagnosis is associated with poorer survival.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0171250PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5289573PMC
August 2017

Identifying biomarkers of dietary patterns by using metabolomics.

Am J Clin Nutr 2017 02 28;105(2):450-465. Epub 2016 Dec 28.

Division of Cancer Epidemiology and Genetics and.

Background: Healthy dietary patterns that conform to national dietary guidelines are related to lower chronic disease incidence and longer life span. However, the precise mechanisms involved are unclear. Identifying biomarkers of dietary patterns may provide tools to validate diet quality measurement and determine underlying metabolic pathways influenced by diet quality.

Objective: The objective of this study was to examine the correlation of 4 diet quality indexes [the Healthy Eating Index (HEI) 2010, the Alternate Mediterranean Diet Score (aMED), the WHO Healthy Diet Indicator (HDI), and the Baltic Sea Diet (BSD)] with serum metabolites.

Design: We evaluated dietary patterns and metabolites in male Finnish smokers (n = 1336) from 5 nested case-control studies within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort. Participants completed a validated food-frequency questionnaire and provided a fasting serum sample before study randomization (1985-1988). Metabolites were measured with the use of mass spectrometry. We analyzed cross-sectional partial correlations of 1316 metabolites with 4 diet quality indexes, adjusting for age, body mass index, smoking, energy intake, education, and physical activity. We pooled estimates across studies with the use of fixed-effects meta-analysis with Bonferroni correction for multiple comparisons, and conducted metabolic pathway analyses.

Results: The HEI-2010, aMED, HDI, and BSD were associated with 23, 46, 23, and 33 metabolites, respectively (17, 21, 11, and 10 metabolites, respectively, were chemically identified; r-range: -0.30 to 0.20; P = 6 × 10 to 8 × 10). Food-based diet indexes (HEI-2010, aMED, and BSD) were associated with metabolites correlated with most components used to score adherence (e.g., fruit, vegetables, whole grains, fish, and unsaturated fat). HDI correlated with metabolites related to polyunsaturated fat and fiber components, but not other macro- or micronutrients (e.g., percentages of protein and cholesterol). The lysolipid and food and plant xenobiotic pathways were most strongly associated with diet quality.

Conclusions: Diet quality, measured by healthy diet indexes, is associated with serum metabolites, with the specific metabolite profile of each diet index related to the diet components used to score adherence. This trial was registered at clinicaltrials.gov as NCT00342992.
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http://dx.doi.org/10.3945/ajcn.116.144501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5267308PMC
February 2017