Exploratory Analysis of Associations Between Whole Blood Mitochondrial Gene Expression and Cancer-Related Fatigue Among Breast Cancer Survivors.

BACKGROUND: Cancer-related fatigue is a prevalent, debilitating, and persistent condition. Mitochondrial dysfunction is a putative contributor to cancer-related fatigue, but relationships between mitochondrial function and cancer-related fatigue are not well understood. OBJECTIVES: We investigated the relationships between mitochondrial DNA (mtDNA) gene expression and cancer-related fatigue, as well as the effects of fish and soybean oil supplementation on these relationships. METHODS: A secondary analysis was performed on data from a randomized controlled trial of breast cancer survivors 4-36 months posttreatment with moderate-severe cancer-related fatigue. Participants were randomized to take 6 g fish oil, 6 g soybean oil, or 3 g each daily for 6 weeks. At pre- and postintervention, participants completed the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire and provided whole blood for assessment of mtDNA gene expression. The expression of 12 protein-encoding genes was reduced to a single dimension using principal component analysis for use in regression analysis. Relationships between mtDNA expression and cancer-related fatigue were assessed using linear regression. RESULTS: Among 68 participants, cancer-related fatigue improved and expression of all mtDNA genes decreased over 6 weeks with no effect of treatment group on either outcome. Participants with lower baseline mtDNA gene expression had greater improvements in cancer-related fatigue. No significant associations were observed between mtDNA gene expression and cancer-related fatigue at baseline or changes in mtDNA gene expression and changes in cancer-related fatigue. DISCUSSION: Data from this exploratory study add to the growing literature that mitochondrial dysfunction may contribute to the etiology and pathophysiology of cancer-related fatigue.

Longitudinal study of inflammatory, behavioral, clinical, and psychosocial risk factors for chemotherapy-induced peripheral neuropathy.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect of taxane and platinum chemotherapy for breast cancer. Clinicians cannot accurately predict CIPN severity partly because its pathophysiology is poorly understood. Although inflammation may play a role in CIPN, there are limited human studies. Here, we identified the strongest predictors of CIPN using variables measured before taxane- or platinum-based chemotherapy, including serum inflammatory markers. METHODS: 116 sedentary women with breast cancer (mean age 55 years) rated (1) numbness and tingling and (2) hot/coldness in hands/feet on 0-10 scales before and after 6 weeks of taxane- or platinum-based chemotherapy. A sub-study was added to collect cytokine data in the final 55 patients. We examined all linear models to predict CIPN severity at 6 weeks using pre-chemotherapy assessments of inflammatory, behavioral, clinical, and psychosocial factors. The final model was selected via goodness of fit. RESULTS: The strongest pre-chemotherapy predictors of numbness and tingling were worse fatigue/anxiety/depression (explaining 27% of variance), older age (9%), and baseline neuropathy (5%). The strongest predictors of hot/coldness in hands/feet were worse baseline neuropathy (11%) and fatigue/anxiety/depression (6%). Inflammation was a risk for CIPN, per more pro-inflammatory IFN-γ (12%) and IL-1ß (6%) and less anti-inflammatory IL-10 (6%) predicting numbness/tingling and more IFN-γ (17%) and less IL-10 (9%) predicting hot/coldness in hands/feet. CONCLUSIONS: The strongest pre-chemotherapy predictors of CIPN included worse fatigue/anxiety/depression and baseline neuropathy. A pro-inflammatory state also predicted CIPN. Because this is an exploratory study, these results suggest specific outcomes (e.g., IL-1ß) and effect size estimates for designing replication and extension studies. CLINICAL TRIAL REGISTRATION: NCT00924651.

Association Between Pretreatment Sleep Disturbance and Radiation Therapy-Induced Pain in 573 Women With Breast Cancer.

CONTEXT: Pain can be a debilitating side effect of radiation therapy (RT). Data from the general population have shown that sleep disturbance can influence pain incidence and severity; however, less is known about this relationship in patients with breast cancer receiving RT. OBJECTIVES: This secondary analysis examined the association of pretreatment moderate/severe levels of sleep disturbance with subsequent RT-induced pain after adjusting for pre-RT pain. METHODS: We report on 573 female patients with breast cancer undergoing RT from a previously completed Phase II clinical trial for radiation dermatitis. Sleep disturbance, total pain, and pain subdomains-sensory pain, affective pain, and perceived pain intensity were assessed at pre-RT and post-RT. At pre-RT, patients were dichotomized into two groups: those with moderate/severe sleep disturbance (N = 85) vs. those with no/mild sleep disturbance (control; N = 488). RESULTS: At pre-RT, women with moderate/severe sleep disturbance were younger, less likely to be married, more likely to have had mastectomy and chemotherapy, and more likely to have depression/anxiety disorder and fatigue than the control group (all Ps < 0.05). Generalized estimating equations model, after controlling for pre-RT pain and other covariates (e.g., trial treatment condition and covariates that were significantly correlated with post-RT pain), showed that women with moderate/severe sleep disturbance at pre-RT vs. control group had significantly higher mean post-RT total pain as well as sensory, affective, and perceived pain (effect size = 0.62, 0.60, 0.69, and 0.52, respectively; all Ps < 0.05). CONCLUSION: These findings suggest that moderate/severe disturbed sleep before RT is associated with increased pain from pre-to-post-RT in patients with breast cancer.

Effects of High-Dose Vitamin D Supplementation on Phase Angle and Physical Function in Patients with Prostate Cancer on ADT.

PURPOSE: Androgen deprivation therapy (ADT) is commonly used to treat patients with advanced prostate cancer but is associated with functional decline. Bioelectrical impedance analysis (BIA)-derived phase angle may reflect frailty and functional decline in cancer patients. High-dose vitamin D supplementation may improve phase angle values and physical function. METHODS: We conducted an exploratory analysis from a phase II randomized controlled trial investigating the efficacy of high-dose vitamin D supplementation in prostate cancer patients (age ≥ 60 yrs). Fifty-nine patients were randomized to high-dose vitamin D (600 IU/day plus 50,000 IU/week) or low-dose: RDA for vitamin D (600 IU/day plus placebo weekly) for 24 weeks. Phase angle was measured by BIA. Physical function measures included handgrip strength, 6-minute walk test, Short Performance Physical Battery and leg extension. All testing was completed at baseline, week 12 and week 24. RESULTS: Phase angle values were wider over the entire study in the high-dose vitamin D arm indicating healthier muscle cells. The low-dose vitamin D arm had phase angle values consistent with frailty cutoffs in older men (<5.7°). CONCLUSION: Patients in the high-dose vitamin D arm experienced wider phase angle values over the course of the study which may indicate less frailty. ClinicalTrials.gov ID: NCT02064946.

Excess Body Weight and Cancer-Related Fatigue, Systemic Inflammation, and Serum Lipids in Breast Cancer Survivors.

BACKGROUND: Cancer-related fatigue (CRF) is a common side effect impacting breast cancer survivors. Research points to a relationship between obesity and CRF in breast cancer survivors related to elevated systemic inflammation and metabolic alterations. METHODS: This cross-sectional study examined the relationship of obesity to CRF, inflammatory markers and serum lipids through a secondary analysis of a nationwide randomized controlled trial. Breast cancer survivors with CRF were categorized based on BMI category. Symptoms of CRF, inflammatory markers and serum fatty acids were assessed among groups. RESULTS: There were 105 breast cancer survivors in the analysis. BMI was positively associated with CRF based on MFSI General (p = 0.020; 95% C.I. 0.024, 0.273) and MFSI Physical (p = 0.013; 95% C.I. 0.035, 0.298) subscales. TNF-α (p = 0.007; 95% C.I. 0.007, 0.044), and IL-6 (p = 0.020; 95% C.I. 0.006, 0.073) were elevated in the obese. Monounsaturated fatty acid levels (p = 0.047; 95% C.I. 0.000, 0.053) and the omega-6 to omega-3 fatty acid ratio were associated with obesity (p = 0.047; 95% C.I. 0.002, 0.322). CONCLUSIONS: Obese breast cancer survivors had greater levels of CRF, inflammatory markers and certain fatty acids. Inflammatory markers and fatty acids were not found to have any mediating or positive association with CRF variables in this analysis. NCT02352779.

Longitudinal assessment of the impact of higher body mass index on cancer-related fatigue in patients with breast cancer receiving chemotherapy.

PURPOSE: To assess the impact of obesity on cancer-related fatigue (CRF) in patients with breast cancer, through a secondary analysis of a large, longitudinal, nationwide study of breast cancer patients beginning chemotherapy. METHODS: All patients (N = 565; aged 53 ± 10.6) with breast cancer completed the multidimensional fatigue symptom inventory and the symptom inventory to measure CRF symptoms at baseline, post-chemotherapy, and 6 months post-chemotherapy. Height and weight at baseline were used to categorize subjects based on body mass index (BMI): obese (≥ 30.0 kg/m2; n = 294), overweight (25.0-29.9 kg/m2; n = 146), and normal weight (18.5-24.9 kg/m2; n = 125). Multivariate regression models evaluated the relationship of obesity level to CRF over time, controlling for age, menopausal status, race, Karnofsky Performance Status, cancer stage, radiation, and exercise status. RESULTS: At baseline, the obese had significantly higher CRF symptoms than the normal weight subjects for both the Multidimensional fatigue symptom inventory (MFSI) total (obese = 11.2 vs normal weight = 6.3; p = 0.03) and Symptom Inventory (SI) (obese = 3.5 vs normal weight = 2.9; p = 0.03). Significantly higher SI fatigue scores persisted at post-chemotherapy for the obese (obese = 5.0 vs normal weight = 4.4; p = 0.02). At 6 months post-chemotherapy, the obese patients still had significantly higher SI fatigue scores (obese = 3.5 vs normal weight = 3.0; p = 0.05). CONCLUSION: Obese patients suffered greater CRF from pre-chemotherapy through 6 months post-chemotherapy. Recommendations for weight loss or weight maintenance may impact CRF levels in obese breast cancer patients before and after chemotherapy.

Influence of Yoga on Cancer-Related Fatigue and on Mediational Relationships Between Changes in Sleep and Cancer-Related Fatigue: A Nationwide, Multicenter Randomized Controlled Trial of Yoga in Cancer Survivors.

BACKGROUND: Cancer-related fatigue (CRF) often co-occurs with sleep disturbance and is one of the most pervasive toxicities resulting from cancer and its treatment. We and other investigators have previously reported that yoga therapy can improve sleep quality in cancer patients and survivors. No nationwide multicenter phase III randomized controlled trial (RCT) has investigated whether yoga therapy improves CRF or whether improvements in sleep mediate the effect of yoga on CRF. We examined the effect of a standardized, 4-week, yoga therapy program (Yoga for Cancer Survivors [YOCAS]) on CRF and whether YOCAS-induced changes in sleep mediated changes in CRF among survivors. STUDY DESIGN AND METHODS: Four hundred ten cancer survivors were recruited to a nationwide multicenter phase III RCT comparing the effect of YOCAS to standard survivorship care on CRF and examining the mediating effects of changes in sleep, stemming from yoga, on changes in CRF. CRF was assessed by the Multidimensional Fatigue Symptom Inventory. Sleep was assessed via the Pittsburgh Sleep Quality Index. Between- and within-group intervention effects on CRF were assessed by analysis of covariance and 2-tailed t test, respectively. Path analysis was used to evaluate mediation. RESULTS: YOCAS participants demonstrated significantly greater improvements in CRF compared with participants in standard survivorship care at post-intervention ( P < .01). Improvements in overall sleep quality and reductions in daytime dysfunction (eg, excessive napping) resulting from yoga significantly mediated the effect of yoga on CRF (22% and 37%, respectively, both P < .01). CONCLUSIONS: YOCAS is effective for treating CRF among cancer survivors; 22% to 37% of the improvements in CRF from yoga therapy result from improvements in sleep quality and daytime dysfunction. Oncologists should consider prescribing yoga to cancer survivors for treating CRF and sleep disturbance.

Multicenter Randomized Controlled Trial of Omega-3 Fatty Acids Versus Omega-6 Fatty Acids for the Control of Cancer-Related Fatigue Among Breast Cancer Survivors.

BACKGROUND: Cancer-related fatigue (CRF) is a common side effect of adjuvant therapy and becomes a chronic problem for approximately one-third of survivors. Omega-3 polyunsaturated fatty acids (O3-PUFA) demonstrated preliminary antifatigue effects in previous research, but have not been investigated in fatigued cancer survivors. METHODS: Breast cancer survivors 4-36 months posttreatment with a CRF score of 4 or more of 10 using the symptom inventory (SI) were randomly assigned to O3-PUFA (fish oil, 6 g/d), omega-6 PUFA (O6-PUFA; soybean oil, 6 g/d), or a low-dose combination of O3-/O6-PUFA (3 g/d O3-PUFA and O6-PUFA) for 6 weeks. CRF was assessed by the SI (screening question), the Brief Fatigue Inventory, and the Multidimensional Fatigue Symptom Index. Protein and mRNA levels of inflammatory and antioxidant biomarkers, along with fatty acid and lipid levels, were assessed at baseline and week 6. Statistical tests were two-sided. RESULTS: A total of 108 breast cancer survivors consented; 97 subjects were randomly assigned and 81 completed the trial. The SI CRF score decreased by 2.51 points at week 6 with O6-PUFA and by 0.93 points with O3-PUFA, with statistically significant between-group difference (effect size = -0.86, P < .01). Similar changes were observed for the Brief Fatigue Inventory and Multidimensional Fatigue Symptom Index but were not statistically significant. Stratified analyses showed the largest benefit was observed in those with severe baseline CRF (≥7). Compared with O3-PUFA, O6-PUFA supplementation statistically significantly decreased proinflammatory markers in the TNF-α signaling pathway. CONCLUSION: Contrary to our original hypothesis, O6-PUFA statistically significantly reduced CRF compared with O3-PUFA. Further research is needed to confirm these findings and to elucidate mechanisms of action.

Nutritional Interventions for Treating Cancer-Related Fatigue: A Qualitative Review.

Cancer-related fatigue (CRF) is a debilitating syndrome that persists for many cancer survivors for years after treatment. Symptoms include early and persistent fatigue, functional decline, depression, and cognitive difficulties. Inflammation, assessed using pro-inflammatory biomarkers, is increased in cancer survivors with fatigue and treatments for fatigue are often aimed at reducing inflammation. Additionally, cancer and its treatment lead to nutritional complications, changes in body composition, and nutritional deficiencies that potentially weaken the cancer survivor and impact CRF. We conducted a qualitative review of clinical trials that assessed nutritional interventions for preventing and treating CRF. Further studies were examined that used nutritional interventions to address inflammation and fatigue, due to the dearth of nutrition research directly related to CRF. Dietary intake prior to, during, and after cancer treatment appears to affect fatigue levels. Increased protein intake may help preserve lean mass and body composition. Dietary patterns that reduce inflammation, such as the Mediterranean diet and other plant-based diets, appear tolerable to cancer survivors and may reduce fatigue. Supplementation with ginseng, ginger, or probiotics may improve cancer survivors' energy levels. Nutritional interventions, alone or in combination with other interventions should be considered as therapy for fatigue in cancer survivors.

Aging human body: changes in bone, muscle and body fat with consequent changes in nutrient intake.

Aging affects almost all physiological processes, but changes in body composition and body phenotype are most observable. In this review, we focus on these changes, including loss of bone and muscle and increase in body fat or redistribution of the latter, possibly leading to osteosarcopenic obesity syndrome. We also address low-grade chronic inflammation, prevalent in aging adults and a cause of many disorders including those associated with body composition. Changes in dietary intake and nutritional requirements of older individuals, that all may lead to some disturbances on tissue and organ levels, are discussed as well. Finally, we discuss the hormonal changes in the aging body, considering each of the tissues, bone, muscle and fat as separate endocrine organs, but yet in the continuous interface and communication with each other. Although there are still many unanswered questions in this field, this review will enable the readers to better understand the aging human body and measures needing to be implemented toward reducing impaired health and disability in older individuals.

Osteosarcopenic obesity in women: impact, prevalence, and management challenges.

Osteosarcopenic obesity syndrome (OSO) has recently been identified as a condition encompassing osteopenia/osteoporosis, sarcopenia and obesity. OSO is especially deleterious in older adults (even if they are not obese by conventional measures), due to age-related redistribution of fat and its infiltration into bone and muscle. Osteoporosis and bone fractures in elderly increase the risk of sarcopenia, which, through decreased mobility, increases the risk of more falls and fractures, creating a vicious cycle. Obesity plays a dual role: to a certain extent, it promotes bone and muscle gains through mechanical loading; in contrast, increased adiposity is also a source of pro-inflammatory cytokines and other endocrine factors that impair bone and muscle. As the elderly population increases, changes in lifestyle to delay the onset of OSO, or prevent OSO, are warranted. Among these changes, dietary patterns and physical activity modifications are the first ones to be implemented. The typical Western diet (and lifestyle) promotes several chronic diseases including OSO, by facilitating a pro-inflammatory state, largely via the imbalance in omega-6/omega-3 fatty acid ratio and low-fiber and high-processed food consumption. Nutritional modifications to prevent and/or alleviate the OSO syndrome include adequate intake of protein, calcium, magnesium and vitamin D and increasing consumptions of foods containing omega-3 polyunsaturated fatty acids and fiber. Certain types of physical activity, often decreased in overweight/obese women and in elderly, might preserve bone and muscle, as well as help in reducing body fat accrual and fat infiltration. Habitual daily activities and some alternative modes of exercise may be more appropriate for older adults and play a crucial role in preventing bone and muscle loss and maintaining optimal weight. In conclusion, older adults who suffer from OSO syndrome may benefit from combined efforts to improve diet and physical activity, and such recommendations should be fostered as part of public health programs.

Osteosarcopenic Obesity Syndrome: What Is It and How Can It Be Identified and Diagnosed?

Conditions related to body composition and aging, such as osteopenic obesity, sarcopenia/sarcopenic obesity, and the newly termed osteosarcopenic obesity (triad of bone muscle and adipose tissue impairment), are beginning to gain recognition. However there is still a lack of definitive diagnostic criteria for these conditions. Little is known about the long-term impact of these combined conditions of osteoporosis, sarcopenia, and obesity in older adults. Many may go undiagnosed and progress untreated. Therefore, the objective of this research is to create diagnostic criteria for osteosarcopenic obesity in older women. The proposed diagnostic criteria are based on two types of assessments: physical, via body composition measurements, and functional, via physical performance measures. Body composition measurements such as T-scores for bone mineral density, appendicular lean mass for sarcopenia, and percent body fat could all be obtained via dual energy X-ray absorptiometry. Physical performance tests: handgrip strength, one-leg stance, walking speed, and sit-to-stand could be assessed with minimal equipment. A score could then be obtained to measure functional decline in the older adult. For diagnosing osteosarcopenic obesity and other conditions related to bone loss and muscle loss combined with obesity, a combination of measures may more adequately improve the assessment process.

The Microbiome and Osteosarcopenic Obesity in Older Individuals in Long-Term Care Facilities.

Increasing evidence points to a role of altered microbiota on inflammation, obesity, and other chronic conditions. This commentary addresses the connection between osteosarcopenic obesity syndrome, an impairment in bone, muscle, and adipose tissues that occurs concurrently, with the altered microbiota in elderly individuals, particularly those living in long-term care facilities. As elderly move to long-term care facilities, they experience changes in gut bacteria that might exasperate the underlying conditions such as osteosarcopenic obesity. These individuals have exponentially higher osteoporotic fracture rates and immobility impairments compared to independently living individuals. However, there is very limited research on this topic and more insight is needed on the impact of probiotic treatment and diet in older individuals, especially those with chronic conditions related to aging, such as osteosarcopenic obesity.

Interrelationship among muscle, fat, and bone: connecting the dots on cellular, hormonal, and whole body levels.

While sarcopenia and sarcopenic obesity have been recognized in the last decade, a combined concept to include decreased muscle mass and strength, as well as decreased bone mass with coexistence of adiposity is discussed here. We introduce a new term, osteopenic obesity, and operationalize its meaning within the context of osteopenia and obesity. Next, we consolidate osteopenic obesity with the already existing and more familiar term, sarcopenic obesity, and delineate the resulting combined condition assigning it the term osteosarcopenic obesity. Identification and possible diagnosis of each condition are discussed, as well as the interactions of muscle, fat and bone tissues on cellular level, considering their endocrine features. Special emphasis is placed on the mesenchymal stem cell commitment into osteoblastogenic, adipogenic and myogenic lineages and causes of its deregulation. Based on the presented evidence and as expounded within the text, it is reasonable to say that under certain conditions, osteoporosis and sarcopenia could be the obesity of bone and muscle, respectively, with the term osteosarcopenic obesity as an encompassment for all.