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Background Skeletal muscle wasting (SMW) in cancer patients is associated with increased morbidity, mortality, treatment intolerance and discontinuation, and poor quality of life. This is particularly true for patients with pancreatic ductal adenocarcinoma (PDAC), as over 85% experience SMW, which is responsible for ~30% of patient deaths. While the established paradigm to explain SMW posits that muscle catabolism from systemic inflammation and nutritional deficiencies, the cause of death, and the cellular and molecular mechanisms responsible remain to be elucidated. To address this, we investigated the relationship between tumour burden and survival in the KCKO murine PDAC model. Methods Female C57BL/6J mice 6–8 weeks of age underwent orthotopic injection with KCKO‐luc tumour cells. Solid tumour was verified on Day 5, post‐tumour inoculation. In vivo, longitudinal lean mass and tumour burden were assessed via dual‐energy X‐ray absorptiometry and IVIS imaging, respectively, and total body weight was assessed, weekly. Animals were sacrificed at a designated end point of ‘failure to thrive’. After sacrifice, lower limb hind muscles were harvested for histology and RNA extraction. Results We found a strong correlation between primary tumour size and survival (r 2 = 0.83, P

PURPOSE OF REVIEW: Cancer Cachexia is a syndrome of loss of weight and muscle mass that leads to reduced strength, poor physical performance and functional impairment. Muscular fatigue is a distressing syndrome that patients with cachexia suffer from and can impair quality of life. Here we review recent updates in muscular fatigue in cancer cachexia research with a focus on mechanisms, biomarkers, and potential therapies. RECENT FINDINGS: Both in mice and human, research has shown that muscle fatigue can be independent of muscular atrophy and can happen early in cancer development or in pre-cachexia. Inflammatory pathways, mitochondrial dysfunction, and gut microbiota have recently been studied to play an important role in muscle fatigue in pre-clinical models. Exercise can target these pathways and has been studied as a therapeutic intervention to improve muscle fatigue. SUMMARY: Heightened inflammation within muscle, altered muscle function, and muscle fatigue can begin prior to clinical evidence of cachexia, making early recognition and intervention challenging. The emergence of cachexia mouse models and translational and clinical research studying muscle fatigue will hopefully lead to new therapies targeting the underlying mechanisms of cancer cachexia. Exercise will need to be tested in larger randomized studies before entering into daily practice.

A growing body of research suggests that inflammation plays a role in many chemotherapy-related toxicities such as fatigue, anxiety, and neuropathy. Regular exercise can change levels of individual cytokines (e.g., reducing IL-6, increasing IL-10); however, it is not known whether exercise during chemotherapy affects relationships between cytokines (i.e., whether cytokine concentrations change collectively vs. independently). This study assessed how 6 weeks of exercise during chemotherapy affected relationships between changes in concentrations of several cytokines. This is a secondary analysis of a randomized trial studying 6 weeks of moderate-intensity walking and resistance exercise during chemotherapy compared with chemotherapy alone. At pre- and post-intervention, patients provided blood to assess serum concentrations of cytokines IL-1β, IL-6, IL-8, IL-10, and IFN-γ, and receptor sTNFR1. We investigated relationships between cytokines using the correlations between changes in cytokine concentrations from pre- to post-intervention. We obtained complete data from 293 patients (149 randomized to exercise). Exercise strengthened the correlation between concentration changes of IL-10 and IL-6 (r = 0.44 in exercisers vs. 0.11 in controls; p = 0.001). We observed the same pattern for IL-10:IL-1β and IL-10:sTNFR1. Exercise also induced an anti-inflammatory cytokine profile, per reductions in pro-inflammatory IFN-γ (p = 0.044) and perhaps IL-1β (p = 0.099, trend-level significance). Our hypothesis-generating work suggests that regular exercise during 6 weeks of chemotherapy may cause certain cytokine concentrations to change collectively (not independently). This work enhances our understanding of relationships between cytokines and complements traditional analyses of cytokines in isolation. Future work should test for replication and relationships to patient outcomes. Clinical Trials.gov, # NCT00924651, http://www.clinicaltrials.gov .

Progressive skeletal muscle wasting in cancer cachexia involves a process of dysregulated protein synthesis and breakdown. This catabolism may be the result of mal-nutrition, and an upregulation of both pro-inflammatory cytokines and the ubiquitin proteasome pathway (UPP), which can subsequently increase myostatin and activin A release. The skeletal muscle wasting associated with cancer cachexia is clinically significant, it can contribute to treatment toxicity or the premature discontinuation of treatments resulting in increases in morbidity and mortality. Thus, there is a need for further investigation into the pathophysiology of muscle wasting in cancer cachexia to develop effective prophylactic and therapeutic interventions. Several studies have identified a central role for chronic-systemic inflammation in initiating and perpetuating muscle wasting in patients with cancer. Interestingly, while exercise has shown efficacy in improving muscle quality, only recently have investigators begun to assess the impact that exercise has on chronic-systemic inflammation. To put this new information into context with established paradigms, here we review several biological pathways (e.g. dysfunctional inflammatory response, hypothalamus pituitary adrenal axis, and increased myostatin/activin A activity) that may be responsible for the muscle wasting in patients with cancer. Additionally, we discuss the potential impact that exercise has on these pathways in the treatment of cancer-related muscle wasting. Exercise is an attractive intervention for muscle wasting in this population, partially because it disrupts chronic-systemic inflammation mediated catabolism. Most importantly, exercise is a potent stimulator of muscle synthesis, and therefore this therapy may reverse muscle damage caused by cancer cachexia.

Two major health concerns with female high school athletes are: 1) psychosocial wellness, and 2) sports-related injuries. It is also known that these health concerns are much greater for minority students who attend high school in economically depressed cities. While it has been well-established that exercise is an effective intervention for these health concerns, there are no established outcome measures to quantitatively assess athletic performance and injury prevention training interventions in this population. Previously, we have demonstrated the utility of Patient-Reported Outcomes Measurement Information System (PROMIS) as a robust outcome measure following ACL reconstruction. Functional Movement Screening (FMS) has been used as a tool to determine injury risk in female collegiate athletes. Since these tools are broadly available, we completed a research study of urban underrepresented minority and suburban female high school athletes, to assess the feasibility and utility of these tools to measure changes in this population during 10-weeks of athletic training. No adverse events of the training or study were reported. A Kaplan-Meier assessment of the data revealed that there was high student retention throughout the 10 weeks. In addition, we found no difference in weekly attendance between the students that completed the intervention vs. the dropouts (while they were in the program), indicating that the students were highly motivated to attend when possible. While no significant differences were found for fatigue and physical function, the intervention significantly improved anxiety, peer relationships, pain interference, and trended towards significance for depression (p

While cognitive-behavioral therapy for insomnia (CBT-I) has been shown to be efficacious in treating cancer survivors' insomnia, 30-60% of individuals have difficulty adhering to intervention components. Psychosocial predictors of adherence and response to CBT-I, such as social support, have not been examined in intervention studies for cancer survivors.Data from a randomized placebo-controlled 2 x 2 trial of CBT-I and armodafinil (a wakefulness promoting agent) were used to assess adherence. Ninety-six cancer survivors participated in the trial (mean age 56, 86% female, 68% breast cancer).CBT-I and armodafinil were administered over the course of seven weeks, and participants were assessed at baseline, during intervention, postintervention, and at a three-month follow-up. Social support was assessed using a Functional Assessment of Chronic Illness Therapy subscale, insomnia severity was assessed using the Insomnia Severity Index, and adherence was measured based on CBT-I sleep prescriptions.At baseline, social support was negatively correlated with insomnia severity (r = -0.30, p = 0.002) and associations between social support, CBT-I, and insomnia were maintained through the three-month follow-up. Social support was positively associated with adherence to CBT-I during intervention weeks 3, 4, and 5, and with overall intervention adherence. At postintervention, both social support and treatment with CBT-I independently predicted decreased insomnia severity (p0.01) when controlling for baseline insomnia severity.Higher social support is associated with better intervention adherence and improved sleep independent of CBT-I. Additional research is needed to determine whether social support can be leveraged to improve adherence and response to CBT-I.

To (1) explain what yoga is, (2) summarize published literature on the efficacy of yoga for managing cancer treatment-related toxicities, (3) provide clinical recommendations on the use of yoga for oncology professionals, and (4) suggest promising areas for future research. Based on a total of 24 phase II and one phase III clinical trials, low-intensity forms of yoga, specifically gentle hatha and restorative, are feasible, safe, and effective for treating sleep disruption, cancer-related fatigue, cognitive impairment, psychosocial distress, and musculoskeletal symptoms in cancer patients receiving chemotherapy and radiation and cancer survivors. Clinicians should consider prescribing yoga for their patients suffering with these toxicities by referring them to qualified yoga professionals. More definitive phase III clinical trials are needed to confirm these findings and to investigate other types, doses, and delivery modes of yoga for treating cancer-related toxicities in patients and survivors.

Objective To review existing exercise guidelines for cancer patients and survivors for the management of symptom clusters. Data Sources Review of PubMed literature and published exercise guidelines. Conclusion Cancer and its treatments are responsible for a copious number of incapacitating symptoms that markedly impair quality of life. The exercise oncology literature provides consistent support for the safety and efficacy of exercise interventions in managing cancer- and treatment-related symptoms, as well as improving quality of life in cancer patients and survivors. Implications for Nursing Practice Effective management of symptoms enhances recovery, resumption of normal life activities and quality of life for patients and survivors. Exercise is a safe, appropriate, and effective therapeutic option before, during, and after the completion of treatment for alleviating symptoms and symptom clusters.

Although the treatment of cancer is more effective now than ever, patients with cancer still face acute and chronic toxicities such as fatigue, cardiotoxicity, pain, cognitive impairment, and neurotoxicity. In this narrative review, we briefly discuss the use of exercise for toxicity management in patients with cancer, biological mechanisms underlying the toxicities and the effects of exercise, barriers that patients—especially underserved patients—face in adopting and adhering to exercise programs, and new technologies to overcome barriers to exercise. Our conclusions and clinical suggestions are: (1) exercise is safe and effective for treating many toxicities; (2) patients can benefit from a variety of exercise modalities (e.g., walking, cycling, resistance bands, yoga); (3) exercise should be started as soon as possible, even before treatments begin; (4) exercise should be continued as long as possible, as a lifestyle; and (5) barriers to exercise should be identified and addressed, (e.g., continually encouraging patients to exercise, using mobile technology, advocating for safe communities that encourage active lifestyles). Future research should inform definitive clinical guidelines for the use of exercise to ameliorate toxicities from cancer and its treatment.

10119 Background: Chemotherapy (CT) via inflammation and oxidative stress can cause muscle inflammatory injury, mitochondrial damage, and cancer-related fatigue (CRF). Following muscle and mitochondrial damage, various cytoplasmic and mitochondrial components are released into circulation. HLA-DQB1 gene encodes a protein involved in the activation of immune response, and is not expressed in normal muscle cells but is up-regulated under highly inflammatory states. Mitochondrial gene MT-CO2 encodes subunit 2 of complex IV, which plays a critical role in energy metabolism and mitochondrial function. We investigated the (i) influence of an exercise intervention, Exercise for Cancer Patients (EXCAP), on gene expression levels of muscle immune response and mitochondrial damage and (ii) the relationships of these genes with CRF. Methods: In this nationwide, multicenter, phase III RCT conducted through the URCC NCORP Research Base, cancer patients (N = 350; mean age = 55.7) were randomized to 2 groups: (i) CT and (ii) CT plus a 6-week individualized, home-based, aerobic and resistance exercise program (EXCAP). Gene expression and CRF were assessed pre- and post-intervention from whole blood by qPCR and from patient-report by MFSI, respectively. Results: T-tests revealed significant upregulation of peripheral HLA-DQB1 and MT-CO2 mRNA following CT in controls (both p < 0.00001) while there was less up-regulation in exercisers (both p≤0.005). ANCOVA showed a trend for significant differences between controls and exercisers for HLA-DQB1 (9.2% vs 5.4%; p = 0.059) and MT-CO2 (16.3% vs 12.7%; p = 0.061). Pearson correlations revealed that increases in HLA-DQB1 (r = 0.21; p = 0.051) and MT-CO2 (r = 0.19; p = 0.025) were significantly associated with concurrent increase in CRF in controls, but not in exercisers. Conclusions: CT alters muscle immune response and mitochondrial gene expression causing muscle and mitochondrial damage, which may be mediators for CRF. EXCAP is a promising intervention that may reduce both muscle and mitochondrial damage via its positive effects on HLA-DQB1 and MT-CO2. Funding: NCI UGCA189961, R25 CA102618. Clinical trial information: NCT00924651.

10019 Background: Cancer and its treatment frequently impact QoL in patients. In older cancer patients, a small decrement in QoL is associated with significant functional impairment, disability, treatment discontinuation and decreased survival. Little is known about the role of exercise in improving QoL in older cancer patients undergoing active chemotherapy and the mechanistic association between inflammation and QoL. We conducted a secondary analysis of a nationwide phase III RCT to assess the effect of exercise on QoL in older cancer patients. Methods: We included 198 older cancer patients (aged ≥60 years) who were randomized to receive chemotherapy alone (C) or with EXCAP (Exercise for Cancer Patients). EXCAP is a home–based progressive aerobic and resistance training program. We used ANCOVA to evaluate the effect of EXCAP on QoL (measured by the Functional Assessment of Cancer Therapy-General, FACT-G, and -Cognitive Function, FACT-Cog). Baseline values, gender and chemotherapy duration were adjusted. We assessed associations between changes in QoL and changes in inflammatory cytokines. Results: Median age was 66.7 ± 2.3 years, 92% were female and 77% had breast cancer. In terms of chemotherapy, 3-week and 2-week regimens were used for 72% and 28%, respectively. EXCAP group had better social (p=0.02), emotional (p=0.04) and physical (p=0.03) well-being post-intervention than the C group. There was also a positive trend for improvement in functional, cognitive and overall well-being (Table 1). In the EXCAP group, improved social well-being was associated with decreases in the pro-inflammatory cytokine, IL-8 (r=0.30, p=0.03). Conclusions: Our analysis showed that exercise improves QoL in older cancer patients receiving active chemotherapy. Improvement in social well-being may be mediated by reducing inflammation. Physicians should consider incorporating exercise when prescribing chemotherapy for older adults with cancer. Clinical trial information: NCT00924651. [Table: see text]

10095 Background: Over half of patients receiving taxane, platinum, and vinca alkaloid chemotherapy experience chemotherapy-induced peripheral neuropathy (CIPN), which involves numbness and neuropathic pain in the hands and feet. CIPN has no effective treatments partly because its etiology is poorly understood. We theorize that CIPN symptoms are partly caused by impairment of interoceptive brain circuitry, which processes bodily sensations via the posterior insula and anterior cingulate cortex (ACC). We investigated whether CIPN is associated with altered connectivity in interoceptive brain circuitry. Methods: Fifty women with breast cancer (50±9 years) reported CIPN symptoms (CIPN-20) and underwent resting fMRI one or more times: before surgery, one month after completion of chemotherapy, and one year after chemotherapy. We used an a priori seed-based investigation of connectivity between the posterior insula and ACC. We compared connectivity between 31 patients without CIPN symptoms (≤10 CIPN-20-Sensory), 19 patients with CIPN symptoms ( > 10 CIPN-20-Sensory), and 280 healthy adults (174 women, 19.3 years) from another study. Results: Patients with CIPN symptoms had significantly reduced connectivity between the posterior insula and the ACC compared to patients without CIPN symptoms (p = 0.01, d = 0.73). Connectivity between the posterior insula and the ACC was negative in patients with CIPN symptoms but positive in both healthy adults and patients without CIPN symptoms. Conclusions: CIPN is characterized by reduced connectivity in interoceptive brain circuitry. Interoceptive networks may be a target for the development of therapies directed to prevent or treat CIPN. Future work will assess causal relationships between CIPN symptoms and reduced connectivity.

10020 Background: Chemotherapy may lead to systemic muscle damage. Up-regulation of developmental myosin light chain 5 (MYL5) and myosin heavy chain 8 (MYH8) genes is required for normal muscle regeneration in response to damage. However, secretion of MYL5 and MYH8 proteins into the serum suggest degradation of muscle, which, in turn, may lead to cancer-related-fatigue (CRF). In this study, we investigated (1) the effect of an exercise intervention, Exercise for Cancer Patients (EXCAP) on mRNA gene expression and serum protein levels of MYL5 and MYH8 and (2) the association of these novel biomarkers with CRF. Methods: Chemotherapy naïve cancer patients (N = 350; mean age = 55.7) from 39 community oncology practices throughout the U.S. affiliated with the URCC NCORP Research Base participated in this nationwide, multicenter, phase III RCT. Patients were randomized into 2 groups: (1) chemotherapy and (2) chemotherapy plus a 6-week aerobic and resistance exercise prescription-EXCAP. Gene expression and protein levels of MYL5 and MYH8, as well as CRF were assessed pre- and post-intervention from whole blood by qPCR, from serum by Luminex assays, and from patient-report by the Multidimensional Fatigue Symptom Inventory, respectively. Results: T-tests show MYL5, but not MYH8, mRNA levels were significantly up-regulated from pre- to post-intervention in exercisers and controls (all p < 0.01) with no significant group difference. Additionally, MYL5 and MYH8 serum protein levels significantly increased from pre to post in controls (all p < 0.05), but remained stable in exercisers. Significant group differences in these serum proteins (p < 0.01) suggest greater muscle degradation in non-exercisers. Pearson correlations revealed trends suggesting increases in MYL5 and MYH8 serum proteins are associated with increases in CRF (r = 0.09 and r = 0.11, respectively, all p < 0.10). Conclusions: Results suggest EXCAP exercise is protective from chemotherapy-induced muscle damage via its effects on MYL5 and MYH8, and changes in these novel biomarkers may mediate changes in CRF. Further research is needed to confirm these findings. NCI UGCA189961, R25 CA102618. Clinical trial information: NCT00924651.

e16580 Background: Dyspnea and fatigue are two of the most common symptoms reported by patients with advanced cancer. Patients with dyspnea report an inability to complete activities of daily living (ADL) and impaired quality of life (QOL). Exercise has been shown to reduce cancer-related fatigue (CRF); however the relationships between dyspnea, CRF, ADL and QOL are unclear. The purpose of this study is to examine the effect of exercise on dyspnea, CRF, ADL and QOL. Methods: A secondary data analysis was performed on a two-arm randomized controlled trial investigating the influence of exercise on prostate cancer patients treated with hormone (androgen deprivation therapy) and/or radiation therapy. Exercise for Cancer Patients (EXCAP©) is a 6 week home-based program that includes progressive aerobic and resistance band training. Participants were randomly assigned to usual care with EXCAP© or usual care only (UC). Dyspnea, CRF, ADL and QOL were measured using the Multidimensional Fatigue Symptom Inventory (MFSI) and a Clinical Symptom Inventory (SI) at pre- and post-intervention. Results: Participants included 57 sedentary prostate cancer patients, average age 67 ± 8 years. Mean changes in dyspnea showed a positive, association with mean changes in CRF (SI r = .525; p < .01, MFSI r = .327; p = .08) in the EXCAP group but not in the UC group. Dyspnea changes were also positively associated with changes in exercise behavior (r = .590; p < .01), ADL (r = .684; p < .01), and QOL (r = .532; p < .01) in the EXCAP group, no association was found in the UC group. Furthermore, exercisers who reported the greatest improvements in dyspnea also reported greater improvements in CRF = 2.2 (p < .05), ADL = 1.8 (p < .01), and QOL = 2.4 (p = .01). Conclusions: Exercise-induced improvements in dyspnea are associated with improvements in CRF, ADL and QOL in prostate cancer patients. Additional research is needed to further understand these results. NCORP UG1 CA189961, R25 CA102618, DOD PC061518 Clinical trial information: NCT00815672.

10007 Background: Cancer-related fatigue (CRF) is one of the most incapacitating adverse effects of cancer and its treatments. CRF co-occurs with impaired sleep quality in cancer survivors, increasing morbidity and mortality. We have previously shown that yoga significantly lowers CRF and improves sleep quality in survivors. However, it is not clear if the effect of yoga on CRF is mediated by improvements in sleep quality. This study assessed the mediating effects of changes in sleep quality stemming from YOCAS yoga on improvements in CRF. Methods: We conducted a secondary analysis on data collected from a multicenter phase III randomized controlled clinical trial with 2 arms (standard care and standard care + a 4-week YOCAS yoga intervention). 321 cancer patients (96% female; mean age, 54 years; 77% had breast cancer) reported both sleep quality, measured by the Pittsburgh Sleep Quality Index (PSQI), and CRF, evaluated by Multidimensional Fatigue Scale Inventory (MFSI). Causal mediation analyses were used to estimate effects of the changes in global PSQI scores and in each PSQI subscale on the relationship between yoga and CRF. Results: Yoga significantly improved both CRF (p < 0.01) and sleep quality (p < 0.01), compared to standard care, with total reduction in CRF by 6.5 points. Sleep quality significantly mediated the changes in CRF by 1.4 points (p < 0.01) in addition to the direct effect of yoga on CRF reduction (by 5.1 points; p < 0.01), suggesting that 22% (95% CI: 7%-54%) of the reduction in CRF was mediated through improving sleep quality. Among the PSQI subscales, daytime dysfunction had the most mediating effect of yoga on CRF. In this model, yoga directly improved CRF by 4.1 points (p = 0.01) and the mediating effect of yoga on CRF via daytime dysfunction was 2.4 points (p < 0.01), suggesting that 37% (95% CI: 23%-81%) of the improvements in CRF was mediated through decreasing daytime dysfunction. Conclusions: Between 22 and 37% of the improvements in CRF from yoga are due to improvements in sleep quality and reductions in daytime dysfunction. Clinicians should consider prescribing yoga for survivors experiencing CRF in combination with sleep disorders. Funding: NCI UGCA189961, R25 CA102618. Clinical trial information: NCT00397930.