Publications by authors named "Lee W Jones"

213 Publications

The effects of neoadjuvant chemotherapy and interval debulking surgery on body composition in patients with ovarian cancer.

JCSM Clin Rep 2021 Jan 11;6(1):11-16. Epub 2020 Nov 11.

Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Background: The aim of this study was to quantify changes in body composition during ovarian cancer treatment and relate these changes to rates of complete gross resection (CGR).

Methods: One hundred two patients with stage III or IV ovarian cancer who underwent neoadjuvant chemotherapy (NACT) followed by interval debulking surgery were a part of a prospectively collected database that included computed tomography scans at three time points-diagnosis, following NACT, and following debulking surgery. Skeletal muscle, visceral adipose, and subcutaneous adipose tissue volumes were obtained from a 30-mm volumetric slab beginning at the third lumbar vertebrae.

Results: Following NACT, skeletal muscle volume was significantly reduced (352.5 to 335.0 cm, < 0.001), whereas adiposity was unchanged. Body mass index (BMI) and skeletal muscle volume were significantly lower in patients who achieved CGR ( < 0.05). When these patients were stratified by BMI, the significant association of skeletal muscle to CGR was limited to patients with a BMI < 25 kg/m ( = 0.007).

Conclusion: Skeletal muscle volume was significantly reduced in patients undergoing NACT for ovarian cancer. Non-overweight patients were more likely to achieve CGR if they had lower skeletal muscle volume. Use of volumetric-based measurement for ascertaining body composition should be explored further.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415724PMC
January 2021

Comparing the reporting and conduct quality of exercise and pharmacological randomised controlled trials: a systematic review.

BMJ Open 2021 08 11;11(8):e048218. Epub 2021 Aug 11.

Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA

Objective: Evaluate the quality of exercise randomised controlled trial (RCT) reporting and conduct in clinical populations (ie, adults with or at risk of chronic conditions) and compare with matched pharmacological RCTs.

Design: Systematic review.

Data Sources: Embase (Elsevier), PubMed (NLM) and CINAHL (EBSCO).

Study Selection: RCTs of exercise in clinical populations with matching pharmacological RCTs published in leading clinical, medical and specialist journals with impact factors ≥15.

Review Methods: Overall RCT quality was evaluated by two independent reviewers using three research reporting guidelines (ie, Consolidated Standards of Reporting Trials (CONSORT; pharmacological RCTs)/CONSORT for non-pharmacological treatments; exercise RCTs), CONSORT-Harms, Template for Intervention Description and Replication) and two risk of bias assessment (research conduct) tools (ie, Cochrane Risk of Bias, Jadad Scale). We compared research reporting and conduct quality within exercise RCTs with matched pharmacological RCTs, and examined factors associated with quality in exercise and pharmacological RCTs, separately.

Findings: Forty-eight exercise RCTs (11 658 patients; median sample n=138) and 48 matched pharmacological RCTs were evaluated (18 501 patients; median sample n=160). RCTs were conducted primarily in cardiovascular medicine (43%) or oncology (31%). Overall quality score (composite of all research reporting and conduct quality scores; primary endpoint) for exercise RCTs was 58% (median score 46 of 80; IQR: 39-51) compared with 77% (53 of 68; IQR: 47-58) in the matched pharmacological RCTs (p≤0.001). Individual quality scores for trial reporting and conduct were lower in exercise RCTs compared with matched pharmacological RCTs (p≤0.03). Factors associated with higher overall quality scores for exercise RCTs were journal impact factor (≥25), sample size (≥152) and publication year (≥2013).

Conclusions And Relevance: Research reporting and conduct quality within exercise RCTs is inferior to matched pharmacological RCTs. Suboptimal RCT reporting and conduct impact the fidelity, interpretation, and reproducibility of exercise trials and, ultimately, implementation of exercise in clinical populations.

Prospero Registration Number: CRD42018095033.
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http://dx.doi.org/10.1136/bmjopen-2020-048218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359527PMC
August 2021

Teleguided self-ultrasound scanning for longitudinal monitoring of muscle mass during spaceflight.

iScience 2021 Apr 21;24(4):102344. Epub 2021 Mar 21.

University of Michigan, Ann Arbor, MI 48109, USA.

Loss of muscle mass is a major concern for long duration spaceflight. However, due to the need for specialized equipment, muscle size has only been assessed before and after spaceflight where ~20% loss is observed. Here, we demonstrate the utility of teleguided self-ultrasound scanning (Tele-SUS) to accurately monitor leg muscle size in astronauts during spaceflight. Over an average of 168 ± 57 days of spaceflight, 74 Tele-SUS sessions were performed. There were no significant differences between panoramic ultrasound images obtained by astronauts seven days prior to landing and expert sonographer after flight or between change in muscle size assessed by ultrasound and magnetic resonance imaging. These findings extend the current capabilities of ultrasound imaging to allow self-monitoring of muscle size with remote guidance.
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http://dx.doi.org/10.1016/j.isci.2021.102344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047175PMC
April 2021

Body weight and return to work among survivors of early-stage breast cancer.

ESMO Open 2020 11;5(6):e000908

Prédicteurs moléculaires et nouvelles cibles en oncologie, INSERM Unit 981, Gustave Roussy, Villejuif, France; Medical Oncology, Gustave Roussy, Villejuif, France. Electronic address:

Background: Many breast cancer (BC) survivors are employed at diagnosis and are expected to return to work after treatment. Among them, around 50% are overweight or obese. There are limited data about the impact of body weight on their ability to return to work.

Methods: We used data from CANcer TOxicity (NCT01993498), a prospective, multicentre cohort of women with stage I-III BC. Professionally active women who were ≥5 years younger than retirement age were identified. Multivariable logistic regression models examined associations of body mass index (BMI) at diagnosis and subsequent weight changes with non-return to work 2 years after diagnosis, adjusting for psychosocial, treatment and behavioural characteristics.

Results: Among 1869 women, 689 were overweight or obese. Overall, 398 patients (21.3%) had not returned to work 2 years after diagnosis. Non-return to work was more likely for overweight or obese than underweight or normal weight patients (adjusted OR (aOR) 1.32; 95% CI, 1.01 to 1.75; p=0.045). Weight loss (≥5%) was observed in 15.7% overweight or obese and 8.7% underweight or normal weight patients and was associated with significant increases in physical activity only among overweight or obese patients (mean change, +4.7 metabolic-equivalent-of-task-hour/week; 95% CI +1.9 to +7.5). Overweight or obese patients who lost weight were more likely to return to work compared with those who did not lose weight (aOR of non-return-to-work, 0.48; 95% CI 0.24 to 0.97, p=0.0418), whereas weight loss was associated with increased odds of non-return to work among underweight or normal weight women (aOR 2.07; 95% CI 1.20 to 3.56, p=0.0086) (pBMI×weight changes=0.0002). The continuous trend of weight gain on non-return to work was significant for overweight or obese patients (aOR for one-percent-unit difference, 1.03; 95% CI 1.01 to 1.06, p=0.030).

Conclusions: Excess weight may be a barrier to return to work. Among overweight or obese BC survivors, weight loss was associated with higher rates of return to work, whereas further weight gain was associated with lower likelihood of return to work. Employment outcomes should be evaluated in randomised studies of weight management.
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http://dx.doi.org/10.1136/esmoopen-2020-000908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656950PMC
November 2020

Exercise and immunometabolic regulation in cancer.

Nat Metab 2020 09 14;2(9):849-857. Epub 2020 Sep 14.

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Unhealthful lifestyle factors, such as obesity, disrupt organismal homeostasis and accelerate cancer pathogenesis, partly through metabolic and immunological dysregulation. Exercise is a prototypical strategy that maintains and restores homeostasis at the organismal, tissue, cellular and molecular levels and can prevent or inhibit numerous disease conditions, including cancer. Here, we review unhealthful lifestyle factors that contribute to metabolic and immunological dysregulation and drive tumourigenesis, focusing on patient physiology (host)-tissue-tumour microenvironment interactions. We also discuss how exercise may influence distant tissue microenvironments, thereby improving tissue function through both metabolic and immunospecific pathways. Finally, we consider future directions that merit consideration in basic and clinical translational exercise studies.
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http://dx.doi.org/10.1038/s42255-020-00277-4DOI Listing
September 2020

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

Myocardial infarction accelerates breast cancer via innate immune reprogramming.

Nat Med 2020 09 13;26(9):1452-1458. Epub 2020 Jul 13.

NYU Cardiovascular Research Center, Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, USA.

Disruption of systemic homeostasis by either chronic or acute stressors, such as obesity or surgery, alters cancer pathogenesis. Patients with cancer, particularly those with breast cancer, can be at increased risk of cardiovascular disease due to treatment toxicity and changes in lifestyle behaviors. While elevated risk and incidence of cardiovascular events in breast cancer is well established, whether such events impact cancer pathogenesis is not known. Here we show that myocardial infarction (MI) accelerates breast cancer outgrowth and cancer-specific mortality in mice and humans. In mouse models of breast cancer, MI epigenetically reprogrammed Ly6C monocytes in the bone marrow reservoir to an immunosuppressive phenotype that was maintained at the transcriptional level in monocytes in both the circulation and tumor. In parallel, MI increased circulating Ly6C monocyte levels and recruitment to tumors and depletion of these cells abrogated MI-induced tumor growth. Furthermore, patients with early-stage breast cancer who experienced cardiovascular events after cancer diagnosis had increased risk of recurrence and cancer-specific death. These preclinical and clinical results demonstrate that MI induces alterations in systemic homeostasis, triggering cross-disease communication that accelerates breast cancer.
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http://dx.doi.org/10.1038/s41591-020-0964-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789095PMC
September 2020

Performance Status in Cancer: Not Broken, But Time for an Upgrade?

J Clin Oncol 2020 09 25;38(25):2824-2829. Epub 2020 Jun 25.

Memorial Sloan Kettering Cancer Center, New York, NY.

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http://dx.doi.org/10.1200/JCO.20.00721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460152PMC
September 2020

Changes in weight, physical and psychosocial patient-reported outcomes among obese women receiving treatment for early-stage breast cancer: A nationwide clinical study.

Breast 2020 Aug 11;52:23-32. Epub 2020 Apr 11.

Institut Gustave Roussy, Villejuif, France. Electronic address:

Background: Evidence on how weight loss correlates to health-related quality-of-life (HRQOL) among obese breast cancer (BC) patients is limited. We aimed to evaluate associations between weight changes and HRQOL.

Methods: We included 993 obese women with stage I-II-III BC from CANTO, a multicenter, prospective cohort collecting longitudinal, objectively-assessed anthropometric measures and HRQOL data (NCT01993498). Associations between weight changes (±5% between diagnosis and post-treatment [shortly after completion of surgery, adjuvant chemo- or radiation-therapy]) and patient-reported HRQOL (EORTC QLQ-C30/B23) were comprehensively evaluated. Changes in HRQOL and odds of severely impaired HRQOL were assessed using multivariable generalized estimating equations and logistic regression, respectively.

Results: 14.1% women gained weight, 67.3% remained stable and 18.6% lost weight. Significant decreases in functional status and exacerbation of symptoms were observed overall post-treatment. Compared to gaining weight or remaining stable, obese women who lost weight experienced less of a decline in HRQOL, reporting better physical function (mean change [95%CI] for gain, stability and loss: -12.9 [-16.5,-9.3], -6.9 [-8.2,-5.5] and -6.2 [-8.7,-3.7]; p = 0.006), less dyspnea (+18.9 [+12.3,+25.6], +9.2 [+6.5,+11.9] and +3.2 [-1.0,+7.3]; p = 0.0003), and fewer breast symptoms (+22.1 [+16.8,+27.3], +18.0 [+15.7,+20.3] and +13.4 [+9.0,+17.2]; p = 0.044). Weight loss was also significantly associated with reduced odds of severe pain compared with weight gain (OR [95%CI] = 0.51 [0.31-0.86], p = 0.011) or stability (OR [95%CI] = 0.62 [0.41-0.95], p = 0.029). No associations between weight loss and worsening of other physical or psychosocial parameters were found.

Conclusions: This large contemporary study suggests that weight loss among obese BC patients during early survivorship was associated with better patient-reported outcomes, without evidence of worsened functionality or symptomatology in any domain of HRQOL.
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http://dx.doi.org/10.1016/j.breast.2020.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375600PMC
August 2020

Abnormal body composition is a predictor of adverse outcomes after autologous haematopoietic cell transplantation.

J Cachexia Sarcopenia Muscle 2020 08 25;11(4):962-972. Epub 2020 Mar 25.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.

Background: The number of patients undergoing autologous haematopoietic cell transplant (HCT) is growing, but little is known about the factors that predict adverse outcomes. Low muscle mass and obesity are associated with disability and premature mortality in individuals with non-malignant diseases and may predict outcomes after autologous HCT.

Methods: This was a retrospective cohort study of 320 patients who underwent autologous HCT for Hodgkin or non-Hodgkin lymphoma between 2009 and 2014. Sarcopenia {skeletal muscle index male: <43 cm/m [body mass index (BMI) < 25 kg/m ] or < 53 cm/m [BMI ≥ 25 kg/m ] and female: <41 cm/m [regardless of BMI]) and obesity [total abdominal adiposity ≥450.0 cm (male), ≥396.4 cm (female)] were assessed from single-slice abdominal pre-HCT computed tomography images. Length of hospital stay, first unplanned intensive care unit admission, and 30-day unplanned readmission were evaluated based on body composition using multivariable regression analysis, and mortality was evaluated with Kaplan-Meier analysis and Gray's test.

Results: Median age at HCT was 53.3 years (range, 18.5 to 78.1 years); 26.3% were sarcopenic and an additional 7.8% were sarcopenic obese pre-HCT. Sarcopenic obesity was associated with increased risk of prolonged hospitalization [odds ratio (OR) = 3.6, 95% confidence interval (CI) 1.3-9.8], intensive care unit admission (OR = 4.7, 95% CI 1.5-16.1), and unplanned readmission after HCT (OR = 13.6, 95% CI 2.5-62.8). Patients who were sarcopenic obese also had the highest mortality risk at 1 year [hazard ratio (HR): 3.9, 95% CI 1.1-11.0] and 5 years (HR: 2.5, 95% CI 1.1-5.5), compared with patients with normal body composition. Sarcopenia alone, but not obesity alone, was associated with an increased risk of these outcomes, albeit with a lower magnitude of risk than in patients who were sarcopenic obese.

Conclusions: Sarcopenic obesity was an important predictor of outcomes in patients undergoing autologous HCT. These findings could inform targeted prevention strategies in patients at highest risk of complications after HCT.
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http://dx.doi.org/10.1002/jcsm.12570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432567PMC
August 2020

Association of post-diagnosis cardiorespiratory fitness with cause-specific mortality in cancer.

Eur Heart J Qual Care Clin Outcomes 2020 10;6(4):315-322

Division of Cardiovascular Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.

Aims: The prognostic importance of post-diagnosis assessment of cardiorespiratory fitness (CRF) in cancer patients is not well established. We sought to examine the association between CRF and mortality in cancer patients.

Methods And Results: This was a single-centre cohort analysis of 1632 patients (58% male; 64 ± 12 years) with adult-onset cancer who were clinically referred for exercise treadmill testing a median of 7 [interquartile range (IQR): 3-12] years after primary diagnosis. Cardiorespiratory fitness was defined as peak metabolic equivalents (METs) achieved during standard Bruce protocol and categorized by tertiles. The association between CRF and all-cause and cause-specific mortality was assessed using multivariable Cox proportional hazard models adjusting for important covariates. Median follow-up was 4.6 (IQR: 2.6-7.0) years; a total of 411 deaths (229, 50, and 132 all-cause, cardiovascular (CV), and cancer related, respectively) occurred during this period. Compared with low CRF (range: 1.9-7.6 METs), the adjusted hazard ratio (HR) for all-cause mortality was 0.38 [95% confidence interval (CI): 0.28-0.52] for intermediate CRF (range: 7.7-10.6 METs) and 0.17 (95% CI: 0.11-0.27) for high CRF (range: 10.7-22.0 METs). The corresponding HRs were 0.40 (95% CI: 0.19-0.86) and 0.41 (95% CI: 0.16-1.05) for CV mortality and 0.40 (95% CI: 0.26-0.60) and 0.16 (95% CI: 0.09-0.28) for cancer mortality, respectively. The adjusted risk of all-cause, CV, and cancer mortality decreased by 26%, 14%, and 25%, respectively with each one MET increment in CRF.

Conclusion: Cardiorespiratory fitness is a strong, independent predictor of all-cause, CV, and cancer mortality, even after adjustment for important clinical covariates in patients with certain cancers.
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http://dx.doi.org/10.1093/ehjqcco/qcaa015DOI Listing
October 2020

Physical Activity and Exercise in Lung Cancer Care: Will Promises Be Fulfilled?

Oncologist 2020 03 26;25(3):e555-e569. Epub 2019 Nov 26.

Section of Medical Oncology, Department of Medicine, University of Verona, Italy.

Lung cancer remains the leading cause of cancer-related death worldwide. Affected patients frequently experience debilitating disease-related symptoms, including dyspnea, cough, fatigue, anxiety, depression, insomnia, and pain, despite the progresses achieved in term of treatment efficacy. Physical activity and exercise are nonpharmacological interventions that have been shown to improve fatigue, quality of life, cardiorespiratory fitness, pulmonary function, muscle mass and strength, and psychological status in patients with lung cancer. Moreover, physical fitness levels, especially cardiorespiratory endurance and muscular strength, are demonstrated to be independent predictors of survival. Nevertheless, patients with lung cancer frequently present insufficient levels of physical activity and exercise, and these may contribute to quality of life impairment, reduction in functional capacity with skeletal muscle atrophy or weakness, and worsening of symptoms, particularly dyspnea. The molecular bases underlying the potential impact of exercise on the fitness and treatment outcome of patients with lung cancer are still elusive. Counteracting specific cancer cells' acquired capabilities (hallmarks of cancer), together with preventing treatment-induced adverse events, represent main candidate mechanisms. To date, the potential impact of physical activity and exercise in lung cancer remains to be fully appreciated, and no specific exercise guidelines for patients with lung cancer are available. In this article, we perform an in-depth review of the evidence supporting physical activity and exercise in lung cancer and suggest that integrating this kind of intervention within the framework of a global, multidimensional approach, taking into account also nutritional and psychological aspects, might be the most effective strategy. IMPLICATIONS FOR PRACTICE: Although growing evidence supports the safety and efficacy of exercise in lung cancer, both after surgery and during and after medical treatments, most patients are insufficiently active or sedentary. Engaging in exercise programs is particularly arduous for patients with lung cancer, mainly because of a series of physical and psychosocial disease-related barriers (including the smoking stigma). A continuous collaboration among oncologists and cancer exercise specialists is urgently needed in order to develop tailored programs based on patients' needs, preferences, and physical and psychological status. In this regard, benefit of exercise appears to be potentially enhanced when administered as a multidimensional, comprehensive approach to patients' well-being.
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http://dx.doi.org/10.1634/theoncologist.2019-0463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066706PMC
March 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

Effects of Exercise Therapy Dosing Schedule on Impaired Cardiorespiratory Fitness in Patients With Primary Breast Cancer: A Randomized Controlled Trial.

Circulation 2020 02 17;141(7):560-570. Epub 2020 Feb 17.

Memorial Sloan Kettering Cancer Center, New York, NY (J.M.S., C.T.D., A.F.Y., D.C., C.C., C.C., M.G.M., L.W.J.).

Background: Current exercise guidelines for clinical populations recommend an exercise therapy (ET) prescription of fixed intensity (moderate), duration (40-50 minutes per session), and volume (120-160 min/wk). A critical overarching element of exercise programming that has received minimal attention is dose scheduling. We investigated the tolerability and efficacy of 2 exercise training dose regimens on cardiorespiratory fitness and patient-reported outcomes in patients with posttreatment primary breast cancer.

Methods: Using a parallel-group randomized trial, we randomly allocated 174 postmenopausal patients (2.8 years after adjuvant therapy) with impaired peak oxygen consumption (VOpeak) to 1 of 2 supervised exercise training interventions delivered with a standard linear (LET) (fixed dose intensity per session for 160 min/wk) or nonlinear (NLET) (variable dose intensity per session for ≈120 min/wk) schedule compared with a stretching attention control group for 16 consecutive weeks. Stretching was matched to exercise dosing arms on the basis of location, frequency, duration, and treatment length. The primary end point was change in VOpeak (mL O·kg·min) from baseline to after intervention. Secondary end points were patient-reported outcomes, tolerability, and safety.

Results: No serious adverse events were observed. Mean attendance was 64%, 75%, and 80% for attention control, LET, and NLET, respectively. In intention-to-treat analysis, VOpeak increased 0.6±1.7 mL O·kg·min (=0.05) and 0.8±1.8 mL O·kg·min (=0.07) in LET and NLET, respectively, compared with attention control. Change in VOpeak ranged from -2.7 to 4.1 mL O·kg·min and from -3.6 to 5.1 mL O·kg·min in LET and NLET, respectively. Approximately 40% of patients in both exercise dosing regimens were classified as VOpeak responders (ie, Δ ≥1.32 mL O·kg·min). NLET improved all patient-reported outcomes compared with attention control.

Conclusions: Short-term exercise training, independently of dosing schedule, is associated with modest improvements in cardiorespiratory fitness in patients previously treated for early-stage breast cancer.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01186367.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7032604PMC
February 2020

Exercise reduces immune suppression and breast cancer progression in a preclinical model.

Oncotarget 2020 Jan 28;11(4):452-461. Epub 2020 Jan 28.

Department of Radiation Oncology, Weill Cornell Medical College, Stich Radiation Oncology, New York, NY, USA.

Exercise is associated with favorable changes in circulating immune cells and improved survival in early-stage breast cancer patients, but the mechansims remain to be fully elucidated. Preclinical studies indicate that physical activity started before tumor injection reduces tumor incidence and progression. Here we tested whether exercise has anti-tumor effects in mice with established 4T1 mammary carcinoma, a mouse model of triple negative breast cancer. Exercise slowed tumor progression and reduced the tumor-induced accumulation of myeloid-derived suppressor cells (MDSCs). The reduction in MDSCs was accompanied by a relative increase in natural killer and CD8 T cell activation, suggesting that exercise restores a favorable immune environment. Consistently, exercise improved responses to a combination of programmed cell death protein 1 (PD-1) blockade and focal radiotherapy. These data support further investigations of exercise in breast cancer patients treated with combinations of immunotherapy and cytotoxic agents to improve cancer outcomes.
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http://dx.doi.org/10.18632/oncotarget.27464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996907PMC
January 2020

Long-term Cardiopulmonary Consequences of Treatment-Induced Cardiotoxicity in Survivors of ERBB2-Positive Breast Cancer.

JAMA Cardiol 2020 03;5(3):309-317

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Trastuzumab improves outcomes in patients with ERBB2-positive (formerly HER2) breast cancer but is associated with treatment-induced cardiotoxicity, most commonly manifest by an asymptomatic decline in left ventricular ejection fraction (LVEF). Little is known to date regarding the long-term effects of treatment-induced cardiotoxicity on cardiopulmonary function in patients who survive trastuzumab-treated breast cancer.

Objective: To determine whether treatment-induced cardiotoxicity recovers or is associated with long-term cardiopulmonary dysfunction in survivors of ERBB2-positive breast cancer.

Design, Setting, And Participants: This cross-sectional case-control study enrolled patients with nonmetastatic ERBB2-positive breast cancer after completion of trastuzumab-based therapy (median, 7.0 [interquartile range (IQR), 6.2-8.7] years after therapy) who met 1 of 2 criteria: (1) cardiotoxicity (TOX group) developed during trastuzumab treatment (ie, asymptomatic decrease of LVEF≥10% from baseline to <55% [n = 22]) or (2) no evidence of cardiotoxicity during trastuzumab treatment (NOTOX group [n = 20]). Patients were treated at the Memorial Sloan Kettering Cancer Center. Fifteen healthy control participants (HC group) were also enrolled for comparison purposes. All groups were frequency matched by age strata (<55, 55-64, and ≥65 years). Data were collected from September 9, 2016, to August 10, 2018, and analyzed from November 20, 2018, to August 12, 2019.

Main Outcomes And Measures: Speckle-tracking echocardiography and maximal cardiopulmonary exercise testing were performed to measure indices of left ventricular function (including LVEF and global longitudinal strain [GLS]) and peak oxygen consumption (peak VO2).

Results: A total of 57 participants (median age, 60.8 [IQR, 52.7-65.7] years) were included in the analysis. Overall, 38 of 42 patients with breast cancer (90%) were treated with anthracyclines before trastuzumab. Resting mean (SD) LVEF was significantly lower in the TOX group (56.9% [5.2%]) compared with the NOTOX (62.4% [4.0%]) and HC (65.3% [2.9%]) groups; similar results were found for GLS (TOX group, -17.8% [2.2%]; NOTOX group, -19.8% [2.2%]; HC group, -21.3% [1.8%]) (P < .001). Mean peak VO2 in the TOX group (22.9 [4.4] mL/kg/min) was 15% lower compared with the NOTOX group (27.0 [5.3] mL/kg/min; P = .03) and 25% lower compared with the HC group (30.5 [3.4] mL/ kg/min; P < .001). In patients with breast cancer, GLS was significantly associated with peak VO2 (β coefficient, -0.75; 95% CI, -1.32 to -0.18).

Conclusions And Relevance: Treatment-induced cardiotoxicity appears to be associated with long-term marked impairment of cardiopulmonary function and may contribute to increased risk of late-occurring cardiovascular disease in survivors of ERBB2-positive breast cancer.
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http://dx.doi.org/10.1001/jamacardio.2019.5586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990842PMC
March 2020

Multisystem Toxicity in Cancer: Lessons from NASA's Countermeasures Program.

Cell 2019 11;179(5):1003-1009

Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.

Astronauts and cancer patients are subject to similar multisystem physiological toxicities. Over the past sixty years, NASA developed a state-of-the-art countermeasures program (CMP) to characterize and mitigate the physiological consequences of spaceflight. Here, we propose a NASA-modeled CMP to elucidate and abrogate physiological toxicities in patients with cancer.
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http://dx.doi.org/10.1016/j.cell.2019.10.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380275PMC
November 2019

Pre-Diagnosis Exercise and Cardiovascular Events in Primary Breast Cancer: Women's Health Initiative.

JACC CardioOncol 2019 Sep 24;1(1):41-50. Epub 2019 Sep 24.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Objectives: The purpose of this study was to investigate whether pre-diagnosis exercise reduces the risk of subsequent cardiovascular events (CVEs) in women with primary breast cancer.

Background: Cardiovascular disease (CVD) is the leading nonmalignant cause of death in patients with cancer, and it is the leading cause of death in women with primary breast cancer who are older than 65 years of age.

Methods: Using a prospective design, 4,015 patients with confirmed diagnosis of primary breast cancer enrolled in the Women's Health Initiative (WHI) completed a self-report questionnaire assessing leisure-time physical activity (i.e., exercise) in metabolic equivalent task (MET) hours per week. Age- and multivariable-adjusted Cox proportional hazards models were used to estimate associations between pre-diagnosis exercise and new-onset CVEs (i.e., heart failure [HF], myocardial infarction [MI], angina, coronary revascularization, peripheral arterial disease [PAD], carotid artery disease, transient ischemic attack [TIA], stroke, and cardiovascular death).

Results: Median follow-up was 12.7 years and 8.2 years for cardiovascular disease (CVD) mortality and CVEs, respectively, with 324 CVEs, including 89 MIs, 49 new diagnoses of HF, and 215 CVD deaths. In multivariable analysis, the incidence of composite CVEs decreased across increasing total MET h/week categories (p = 0.016). Compared with <2.5 MET-hours per week, the adjusted hazard ratio (HR) was 0.80 (95% confidence interval [CI]: 0.59 to 1.09) for 2.5 to <8.6 MET h/week; 0.9 (95% CI: 0.64 to 1.17) for 8.6 to <18 MET h/week; and 0.63 (95% CI: 0.45 to 0.88) for ≥18 MET h/week.

Conclusion: Pre-diagnosis exercise exposure is associated with a significant graded reduction in subsequent CVEs in long-term survivors of primary breast cancer.
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http://dx.doi.org/10.1016/j.jaccao.2019.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352124PMC
September 2019

Cardiopulmonary Exercise Testing Following Open Repair for a Proximal Thoracic Aortic Aneurysm or Dissection.

J Cardiopulm Rehabil Prev 2020 03;40(2):108-115

Departments of Internal Medicine, Division of Cardiovascular Medicine (Drs Hornsby, Saberi, Brook, Willer, Eagle, and Rubenfire and Ms Fink) and Cardiac Surgery (Drs Wu, Patel, and Yang), University of Michigan, Michigan Medicine, Ann Arbor; Creighton University School of Medicine, Omaha, Nebraska (Ms Norton); Department of Kinesiology, University of Windsor, Windsor, Ontario, Canada (Dr McGowan); Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, New York (Dr Jones); Departments of Computational Medicine and Bioinformatics and Human Genetics, University of Michigan, Ann Arbor (Dr Willer); and Department of Cardiovascular Diseases, John Ochsner Heart and Vascular Institute, Ochsner Clinical School-The University of Queensland School of Medicine, New Orleans, Louisiana (Dr Lavie).

Purpose: There are limited data on cardiopulmonary exercise testing (CPX) and cardiorespiratory fitness (CRF), following open repair for a proximal thoracic aortic aneurysm or dissection. The aim was to evaluate serious adverse events, abnormal CPX event rate, CRF (peak oxygen uptake, (Equation is included in full-text article.)O2peak), and blood pressure.

Methods: Patients were retrospectively identified from cardiac rehabilitation participation or prospectively enrolled in a research study and grouped by phenotype: (1) bicuspid aortic valve/thoracic aortic aneurysm, (2) tricuspid aortic valve/thoracic aortic aneurysm, and (3) acute type A aortic dissection.

Results: Patients (n = 128) completed a CPX a median of 2.9 mo (interquartile range: 1.8, 3.5) following repair. No serious adverse events were reported, although 3 abnormal exercise tests (2% event rate) were observed. Eighty-one percent of CPX studies were considered peak effort (defined as respiratory exchange ratio of ≥1.05). Median measured (Equation is included in full-text article.)O2peak was <36% predicted normative values (19.2 mL·kgmin vs 29.3 mLkgmin, P < .0001); the most marked impairment in (Equation is included in full-text article.)O2peak was observed in the acute type A aortic dissection group (<40% normative values), which was significantly different from other groups (P < .05). Peak exercise systolic and diastolic blood pressures were 160 mm Hg (144, 172) and 70 mm Hg (62, 80), with no differences noted between groups.

Conclusions: We observed no serious adverse events with an abnormal CPX event rate of only 2% 3 mo following repair for a proximal thoracic aortic aneurysm or dissection. (Equation is included in full-text article.)O2peak was reduced among all patient groups, especially the acute type A aortic dissection group, which may be clinically significant, given the well-established prognostic importance of reduced cardiorespiratory fitness.
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http://dx.doi.org/10.1097/HCR.0000000000000446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048630PMC
March 2020

Randomized trial of weight loss in primary breast cancer: Impact on body composition, circulating biomarkers and tumor characteristics.

Int J Cancer 2020 05 5;146(10):2784-2796. Epub 2019 Sep 5.

O'Neal Comprehensive Cancer Center at UAB, Birmingham, AL.

Obesity adversely impacts overall and cancer-specific survival among breast cancer patients. Preclinical studies demonstrate negative energy balance inhibits cancer progression; however, feasibility and effects in patients are unknown. A two-arm, single-blinded, randomized controlled weight-loss trial was undertaken presurgery among 32 overweight/obese, Stage 0-II breast cancer patients. The attention control arm (AC) received basic nutritional counseling and upper-body progressive resistance training whereas the weight loss intervention (WLI) arm received identical guidance, plus counseling on caloric restriction and aerobic exercise to promote 0.68-0.92 kg/week weight loss. Anthropometrics, body composition, blood and survey data were collected at baseline and presurgery ∼30 days later. Tumor markers (e.g., Ki67) and gene expression were assessed on biopsy and surgical specimens; sera were analyzed for cytokines, growth and metabolic factors. Significant WLI vs. AC differences were seen in baseline-to-follow-up changes in weight (-3.62 vs. -0.52 kg), %body fat (-1.3 vs. 0%), moderate-to-vigorous physical activity (+224 vs. +115 min/week), caloric density (-0.3 vs. 0 kcal/g), serum leptin (-12.3 vs. -4.0 ng/dl) and upregulation of tumor PI3Kinase signaling and cell cycle-apoptosis related genes (CC-ARG; all p-values <0.05). Cytolytic CD56 NK cell expression was positively associated with weight loss; CC-ARG increased with physical activity. Increased tumor (nuclear) TNFα and IL-1β, CX3CL1 and CXCL1 gene expression was observed in the WLI. Tumor Ki67 did not differ between arms. Feasibility benchmarks included 80% accrual, 100% retention, no adverse effects and excellent adherence. Short-term weight loss interventions are feasible; however, mixed effects on tumor biology suggest unclear benefit to presurgical caloric restriction, but possible benefits of physical activity.
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http://dx.doi.org/10.1002/ijc.32637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155016PMC
May 2020

Development of Exercise as Interception Therapy for Cancer: A Review.

JAMA Oncol 2019 Nov;5(11):1620-1627

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Observational data linking physical activity and exercise exposure with reduced risk of either development or progression of cancer have fueled interest in the initiation of large-scale definitive trials to test the association of exercise therapy with disease outcomes. However, several major knowledge gaps impede the rational and optimal design of such trials.

Observations: Critical requirements underpinning the success of several recent contemporary anticancer agents have included adequate demonstration of antitumor activity (in phase 1/2 trials) as well as identification of essential prerequisites (eg, biologically effective dose and predictors of response) permitting optimal design of definitive trials. The existing evidence base investigating exercise as a candidate anticancer preventive or treatment strategy is predominantly confined to observational data, which have several inherent limitations. Consequently, the antitumor activity of exercise remains unclear and, perhaps more important, such data are not sufficient to accurately derive the exercise dose, prescription regimen, or patients most likely to benefit from exercise. In adherence with translational frameworks for lifestyle therapy development, the need for early phase 1/2-equivalent trials to fill current knowledge gaps to optimize the development and potential efficacy of exercise therapy is highlighted.

Conclusions And Relevance: Exercise therapy has significant promise to be an efficacious and cost-effective therapy to improve cancer outcomes, with few toxic effects. Although most nontraditional therapies in cancer prevention and prognosis fail in definitive trials, these failures provide critical lessons for the continued development of exercise as a candidate anticancer therapy.
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http://dx.doi.org/10.1001/jamaoncol.2019.2585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542631PMC
November 2019

Clonal Hematopoiesis: Crossroads of Aging, Cardiovascular Disease, and Cancer: JACC Review Topic of the Week.

J Am Coll Cardiol 2019 07;74(4):567-577

Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

A novel, common, and potent cardiovascular risk factor has recently emerged: clonal hematopoiesis of indeterminate potential (CHIP). CHIP arises from somatic mutations in hematopoietic stem cells that yield clonal progeny of mutant leukocytes in blood. Individuals with CHIP have a doubled risk of coronary heart disease and ischemic stroke, and worsened heart failure outcomes independent of traditional cardiovascular risk factors. The recognition of CHIP as a nontraditional risk factor challenges specialists in hematology/oncology and cardiovascular medicine alike. Should we screen for CHIP? If so, in whom? How should we assess cardiovascular risk in people with CHIP? How should we manage the excess cardiovascular risk in the absence of an evidence base? This review explains CHIP, explores the clinical quandaries, strives to provide reasonable recommendations for the multidisciplinary management of cardiovascular risk in individuals with CHIP, and highlights current knowledge gaps.
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http://dx.doi.org/10.1016/j.jacc.2019.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681657PMC
July 2019

Exercise as a Candidate Antitumor Strategy: A Window into the Future.

Clin Cancer Res 2019 09 21;25(17):5179-5181. Epub 2019 Jun 21.

Memorial Sloan Kettering Cancer Center, New York, New York.

Observational findings suggest exercise is associated with improved outcomes in early-stage breast cancer. However, whether exercise has biological activity in patients with breast cancer has not been investigated. Preoperative window of opportunity studies provide a setting in which to test the short-term effects of novel treatment strategies on validated surrogates..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726555PMC
September 2019

Oncologists' Attitudes and Practice of Addressing Diet, Physical Activity, and Weight Management With Patients With Cancer: Findings of an ASCO Survey of the Oncology Workforce.

J Oncol Pract 2019 06 16;15(6):e520-e528. Epub 2019 May 16.

10 American Cancer Society, Atlanta, GA.

Purpose: Obesity and related factors have been linked to cancer risk and outcomes, but little information exists with regard to oncologists' attention to these issues as a part of clinical care.

Methods: Oncology providers actively caring for patients with cancer in the United States and internationally were asked to complete an online survey about practice patterns and perceptions with regard to obesity and weight management during and after active cancer treatment.

Results: Nine hundred seventy-one practicing oncology providers completed the survey. The majority of respondents indicated a belief that the evidence linking obesity to cancer outcomes was strong and that weight and related factors should be addressed as a part of cancer treatment. The majority of respondents also reported that they frequently assessed body weight and related factors as well as counsel their patients to exercise, consume a healthy diet, and lose weight, if applicable. However, referral to providers and programs to support weight loss and increased physical activity occurred less frequently, and a number of barriers were identified for the incorporation of weight management and physical activity programs in the treatment of patients with cancer.

Conclusion: In a survey of oncology providers, attention to weight management, physical activity, and diet in patients with cancer was high during and after cancer treatment but often did not result in referrals to support lifestyle change. Future work is needed to support education and training of oncology providers to facilitate referrals and overcome barriers to implementation of weight management and physical activity programs for patients with cancer.
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http://dx.doi.org/10.1200/JOP.19.00124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827390PMC
June 2019

Impact of exercise on psychological burden in adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

Cancer 2019 09 8;125(17):3059-3067. Epub 2019 May 8.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Childhood cancer survivors are at risk for adverse psychological outcomes. Whether exercise can attenuate this risk is unknown.

Methods: In total, 6199 participants in the Childhood Cancer Survivor Study (median age, 34.3 years [range, 22.0-54.0 years]; median age at diagnosis, 10.0 years [range, 0-21.0 years]) completed a questionnaire assessing vigorous exercise and medical/psychological conditions. Outcomes were evaluated a median of 7.8 years (range, 0.1-10.0 years) later and were defined as: symptom level above the 90th percentile of population norms for depression, anxiety, or somatization on the Brief Symptom Inventory-18; cancer-related pain; cognitive impairment using a validated self-report neurocognitive questionnaire; or poor health-related quality of life. Log-binomial regression estimated associations between exercise (metabolic equivalent [MET]-hours per week ) and outcomes adjusting for cancer diagnosis, treatment, demographics, and baseline conditions.

Results: The prevalence of depression at follow-up was 11.4% (95% CI, 10.6%-12.3%), anxiety 7.4% (95% CI, 6.7%-8.2%) and somatization 13.9% (95% CI, 13.0%-14.9%). Vigorous exercise was associated with lower prevalence of depression and somatization. The adjusted prevalence ratio for depression was 0.87 (95% CI, 0.72-1.05) for 3 to 6 MET hours per week , 0.76 (95% CI, 0.62-0.94) for 9 to 12 MET-hours per week , and 0.74 (95% CI, 0.58-0.95) for 15 to 21 MET-hours per week . Compared with 0 MET hours per week , 15 to 21 MET-hours per week were associated with an adjusted prevalence ratio of 0.79 (95% CI, 0.62-1.00) for somatization. Vigorous exercise also was associated with less impairment in the physical functioning, general health and vitality (P  < .001), emotional role limitations (P  = .02), and mental health (P  = .02) domains as well as higher cognitive function in the domains of task completion, organization, and working memory (P < .05 for all), but not in the domain of cancer pain.

Conclusions: Vigorous exercise is associated with less psychological burden and cognitive impairment in childhood cancer survivors.
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http://dx.doi.org/10.1002/cncr.32173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690787PMC
September 2019

Cardio-Oncology Rehabilitation to Manage Cardiovascular Outcomes in Cancer Patients and Survivors: A Scientific Statement From the American Heart Association.

Circulation 2019 05;139(21):e997-e1012

Cardiovascular disease is a competing cause of death in patients with cancer with early-stage disease. This elevated cardiovascular disease risk is thought to derive from both the direct effects of cancer therapies and the accumulation of risk factors such as hypertension, weight gain, cigarette smoking, and loss of cardiorespiratory fitness. Effective and viable strategies are needed to mitigate cardiovascular disease risk in this population; a multimodal model such as cardiac rehabilitation may be a potential solution. This statement from the American Heart Association provides an overview of the existing knowledge and rationale for the use of cardiac rehabilitation to provide structured exercise and ancillary services to cancer patients and survivors. This document introduces the concept of cardio-oncology rehabilitation, which includes identification of patients with cancer at high risk for cardiac dysfunction and a description of the cardiac rehabilitation infrastructure needed to address the unique exposures and complications related to cancer care. In this statement, we also discuss the need for future research to fully implement a multimodal model of cardiac rehabilitation for patients with cancer and to determine whether reimbursement of these services is clinically warranted.
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http://dx.doi.org/10.1161/CIR.0000000000000679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603804PMC
May 2019

Impact of Sarcopenia on Adverse Outcomes After Allogeneic Hematopoietic Cell Transplantation.

J Natl Cancer Inst 2019 08;111(8):837-844

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

Background: High intensity treatments such as hematopoietic cell transplantation (HCT) can be curative for patients with hematologic malignancies, but this needs to be balanced by the high risk of nonrelapse mortality (NRM) during the first 2 years after HCT. Sarcopenia (low muscle mass) is associated with physical disability and premature mortality in individuals with nonmalignant diseases and may be a predictor of NRM and poor overall survival in patients undergoing HCT.

Methods: This was a retrospective cohort study of 859 patients with acute leukemia or myelodysplastic syndrome who underwent a first HCT as adults (≥18 years) between 2007 and 2014. Sarcopenia was assessed from pre-HCT abdominal computed tomography scans. Two-year cumulative incidence of NRM was calculated, with relapse/progression considered as a competing risk event. Fine-Gray subdistribution hazard ratio estimates and 95% confidence intervals (CI) were obtained and adjusted for relevant covariates. Kaplan-Meier method was used to examine overall survival. All statistical tests were two-sided.

Results: Median age at HCT was 51 years (range = 18-74 years); 52.5% had a high [≥3] HCT-comorbidity index; 33.7% had sarcopenia pre-HCT. Sarcopenia was an independent predictor of higher NRM risk (hazard ratio = 1.58, 95% CI = 1.16 to 2.16) compared with patients who were not. The 2-year incidence of NRM approached 30% in patients with sarcopenia and high (≥3) HCT-comorbidity index. Patients with sarcopenia had on average a longer hospitalization (37.2 days vs 31.5 days, P < .001) and inferior overall survival at 2 years (55.2%, 95% CI = 49.5% to 61.0% vs 66.9%, 95% CI = 63.0% to 70.8%, P < .001).

Conclusions: Sarcopenia is an important and independent predictor of survival after HCT, with potential additional downstream impacts on health-economic outcomes. This information can be used to facilitate treatment decisions prior to HCT and guide interventions to decrease the risk of treatment-related complications after HCT.
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http://dx.doi.org/10.1093/jnci/djy231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695315PMC
August 2019

Case-control study of heart rate abnormalities across the breast cancer survivorship continuum.

Cancer Med 2019 01 21;8(1):447-454. Epub 2018 Dec 21.

Heart and Vascular Center, Brigham and Women's Hospital, Boston, Massachusetts.

Background: Mechanisms underlying impaired exercise capacity and increased cardiovascular mortality observed in breast cancer (BC) patients remain unclear. The prevalence, functional, and prognostic significance of elevated resting heart rate (HR) and abnormal heart rate recovery (HRR) in breast cancer (BC) requires evaluation.

Methods: In a single-center, retrospective, case-control study of women referred for exercise treadmill testing (ETT), 448 BC patients (62.6 ± 10.0 years) were compared to 448 cancer-free, age-matched controls. Elevated resting HR was defined as HR ≥80 bpm at rest. Abnormal HRR at 1-minute following exercise was defined as ≤12 bpm if active recovery or ≤18 bpm if passive recovery. Association of these parameters with exercise capacity and all-cause mortality was evaluated.

Results: Elevated resting HR (23.7% vs 17.0%, P = 0.013) and abnormal HRR (25.9% vs 20.3%, P = 0.048) were more prevalent in BC cohort than controls. In adjusted analyses, BC patients with elevated resting HR (-0.9 METs (SE 0.3); P = 0.0003) or abnormal HRR (-1.3 METs (SE 0.3); P < 0.0001) had significant reductions in metabolic equivalents (METs) achieved during exercise. Elevated resting HR was not associated with mortality. There was a trend toward increased mortality in BC cohort with abnormal HRR (adjusted hazard ratio 2.06 (95% CI 0.95-4.44, P = 0.07)).

Conclusions: Women across the BC survivorship continuum, referred for ETT, have an increased prevalence of elevated resting HR and abnormal HRR relative to cancer-free, age-matched female controls. These parameters were associated with decreased exercise capacity. Strategies to modulate these abnormalities may help improve functional capacity in this cohort.
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http://dx.doi.org/10.1002/cam4.1916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346251PMC
January 2019

Exercise as Adjunct Therapy in Cancer.

Semin Radiat Oncol 2019 01;29(1):16-24

Departments of Radiation Oncology, Duke University School of Medicine, Durham, NC.. Electronic address:

Data from observational studies indicate that both physical activity as well as exercise (ie, structured physical activity) is associated with reductions in the risk of recurrence and cancer mortality after a diagnosis of certain forms of cancer. Emerging evidence from preclinical studies indicates that physical activity/exercise paradigms regulate intratumoral vascular maturity and perfusion, hypoxia, and metabolism and augments the antitumor immune response. Such responses may, in turn, enhance response to standard anticancer treatments. For instance, exercise improves efficacy of chemotherapeutic agents, and there is rationale to believe that it will also improve radiotherapy response. This review overviews the current preclinical as well as clinical evidence supporting exercise modulation of therapeutic response and postulated biological mechanisms underpinning such effects. We also examine the implications for tumor response to radiation, chemotherapy, and immunotherapy.
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http://dx.doi.org/10.1016/j.semradonc.2018.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656408PMC
January 2019

Exercise inhibits tumor growth and central carbon metabolism in patient-derived xenograft models of colorectal cancer.

Cancer Metab 2018 15;6:14. Epub 2018 Nov 15.

1Division of Medical Oncology, Duke University Medical Center, 3008 Snyderman Building, 905 S. LaSalle St, Durham, NC 27710 USA.

Background: While self-reported exercise is associated with a reduction in the risk of recurrence in colorectal cancer, the molecular mechanisms underpinning this relationship are unknown. Furthermore, the effect of exercise on intratumoral metabolic processes has not been investigated in detail in human cancers. In our current study, we generated six colorectal patient patient-derived xenografts (CRC PDXs) models and treated each PDX to voluntary wheel running (exercise) for 6-8 weeks or no exposure to the wheel (control). A comprehensive metabolomics analysis was then performed on the PDXs to identify exercise induced changes in the tumor that were associated with slower growth.

Results: Tumor growth inhibition was observed in the voluntary wheel running group compared to the control group in three of the six models. A metabolomics analysis first revealed that central carbon metabolism was affected in each model irrespective of treatment. Interestingly, comparison of responsive and resistant models showed that levels of metabolites in nucleotide metabolism, known to be coupled to mitochondrial metabolism, were predictive of response. Furthermore, phosphocreatine levels which are linked to mitochondrial energy demands were associated with inhibition of tumor growth.

Conclusion: Altogether, this study provides evidence that changes to tumor cell mitochondrial metabolism may underlie in part the benefits of exercise.
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http://dx.doi.org/10.1186/s40170-018-0190-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237036PMC
November 2018
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