Impact of Treatment Modality on Quality of Life Among Uterine Cancer Survivors.

AIMS: Our understanding of the impact of adjuvant therapy on longitudinal quality of life (QoL) following surgery for patients with uterine cancer is limited. The purpose of this study was to compare QoL in patients who have undergone surgery with or without radiation therapy for uterine cancer. MATERIALS AND METHODS: This was a cross-sectional cohort study that examined women treated for uterine cancer at MD Anderson Cancer Center from 2006 to 2017. Participants included those who underwent hysterectomy/bilateral salphingo-oophorectomy alone, with brachytherapy or external beam radiation therapy (EBRT). A non-cancer cohort of women who underwent a hysterectomy/bilateral salphingo-oophorectomy for benign indications was also identified (non-CA). To compare QoL we used the Functional Assessment of Cancer Therapy - Endometrial survey (FACT-En), a validated survey used to assess QoL. The survey has five subscales: physical, social, emotional, functional and an endometrial cancer-specific subscale. Cohorts were compared using ANOVA tests. RESULTS: In total, 309 women responded to the questionnaire (hysterectomy/bilateral salphingo-oophorectomy 64, brachytherapy 77, EBRT 96, non-CA 72). The median time from surgery to survey completion was 6.7 years. The mean total FACT-En score for the entire cohort was 144 [standard deviation 22]. Overall QoL was different between cohorts, with the EBRT cohort reporting the lowest QoL (mean 139.4 [21.6]) and the brachytherapy cohort the highest (150.6 [18.2], P = 0.006). Among patients who had undergone cancer treatment, the EBRT cohort reported the worst endometrial-specific QoL (53.5 [8.6]), while again the brachytherapy group reported the highest score (57.5 [6.1], P = 0.007). CONCLUSIONS: QoL differences in women who have undergone different treatments for uterine cancer may persist years after treatment. In women with endometrial cancer who require adjuvant therapy, brachytherapy does not appear to have any long-term detriments on QoL.

Low CHD5 expression activates the DNA damage response and predicts poor outcome in patients undergoing adjuvant therapy for resected pancreatic cancer.

The DNA damage response (DDR) promotes genome integrity and serves as a cancer barrier in precancerous lesions but paradoxically may promote cancer survival. Genes that activate the DDR when dysregulated could function as useful biomarkers for outcome in cancer patients. Using a siRNA screen in human pancreatic cancer cells, we identified the CHD5 tumor suppressor as a gene, which, when silenced, activates the DDR. We evaluated the relationship of CHD5 expression with DDR activation in human pancreatic cancer cells and the association of CHD5 expression in 80 patients with resected pancreatic adenocarcinoma (PAC) by immunohistochemical analysis with clinical outcome. CHD5 depletion and low CHD5 expression in human pancreatic cancer cells lead to increased H2AX-Ser139 and CHK2-Thr68 phosphorylation and accumulation into nuclear foci. On Kaplan-Meier log-rank survival analysis, patients with low CHD5 expression had a median recurrence-free survival (RFS) of 5.3 vs 15.4 months for patients with high CHD5 expression (P=0.03). In 59 patients receiving adjuvant chemotherapy, low CHD5 expression was associated with decreased RFS (4.5 vs 16.3 months; P=0.001) and overall survival (OS) (7.2 vs 21.6 months; P=0.003). On multivariate Cox regression analysis, low CHD5 expression remained associated with worse OS (HR: 3.187 (95% CI: 1.49-6.81); P=0.003) in patients undergoing adjuvant chemotherapy. Thus, low CHD5 expression activates the DDR and predicts for worse OS in patients with resected PAC receiving adjuvant chemotherapy. Our findings support a model in which dysregulated expression of tumor suppressor genes that induce DDR activation can be utilized as biomarkers for poor outcome.

Tissue expression and plasma concentrations of TNFalpha, IL-1beta, and IL-6 following treadmill exercise in mice.

Exercise can increase plasma inflammatory cytokine concentrations in humans, but tissue responses are not well studied. We examined plasma concentrations and tissue expression of TNFalpha, IL-1beta, and IL-6 following treadmill running in mice. C57B1/6 mice were randomly assigned to: non-exercise control (CON), sacrifice at 0 or 1.5 h after 60 min running (MOD0, MOD 1.5), sacrifice at 0, 1.5, or 3 h after fatiguing running (approximately 3 h) (EX0, EX1.5, EX3), or lipopolysaccharide (25 microg) with no exercise (LPS). Lung, liver, muscle, and brain mRNA expression was analyzed (n = 4-6/group) using reverse transcriptase-rapid polymerase chain reaction (RT-RPCR). Plasma cytokine concentrations were determined (n =4-10/group) by ELISA. Plasma IL-6 was higher in EX1.5, and lung TNFalpha mRNA was higher in EX1.5 and EX3 compared to CON (P < 0.05). No significant increases in plasma cytokine concentrations or tissue cytokine expression were found in other EX groups. LPS significantly increased these cytokine measures in tissues and plasma, with the exception of plasma IL-1beta which was undetectable. The source of the plasma IL-6 following exercise does not appear to be lung, liver, muscle, or brain tissue, and remains to be determined. These data also suggest that tissue level cytokine expression may not necessarily lead to increased plasma cytokine concentrations.

Physical activity in relation to cancer of the colon and rectum in a cohort of male smokers.

We examined the association between occupational and leisure physical activity and colorectal cancer in a cohort of male smokers. Among the 29,133 men aged 50-69 years in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention study,152 colon and 104 rectal cancers were documented during up to 12 years of follow-up. For colon cancer, compared with sedentary workers, men in light occupational activity had a relative risk (RR) of 0.60 [95% confidence interval (CI), 0.34-1.04], whereas those in moderate/heavy activity had an RR of 0.45 (CI, 0.26-0.78; P for trend, 0.003). Subsite analysis revealed a significant association for moderate/heavy occupational activity in the distal colon (RR, 0.21; CI, 0.09-0.51) but not in the proximal colon (RR, 0.87; CI, 0.40-1.92). There was no significant association between leisure activity and colon cancer (active versus sedentary; RR, 0.82; CI, 0.59-1.13); however, the strongest inverse association was found among those most active in both work and leisure (RR, 0.33; CI, 0.16-0.71). For rectal cancer, there were risk reductions for those in light (RR, 0.71; CI, 0.36-1.37) and moderate/heavy occupational activity (RR, 0.50; CI, 0.26-0.97; P for trend, 0.04), and no association for leisure activity. These data provide evidence for a protective role of physical activity in colon and rectal cancer.

Physical activity-related injuries in walkers and runners in the aerobics center longitudinal study.

OBJECTIVE: To examine the association between physical activity-related injuries and participation in walking versus running. DESIGN: Nested case-control study. SETTING: Cooper Clinic Preventive Medicine Center, Dallas. Texas. PARTICIPANTS: 5,327 men and women undergoing exams between 1987 and 1995 and completing follow-up health history questionnaires in 1990 or 1995. Participants were classified as those reporting regular participation in walking or jogging/running at baseline. Those reporting both or neither activity were excluded from the study (n = 1404). Cases (698 men, 169 women) were those reporting physical activity-related injuries requiring physician visits in the previous year on the follow-up questionnaire. Controls (2,358 men, 698 women) were randomly selected from the remaining population. MAIN OUTCOME MEASURES: Logistic regression was used to examine the risk of injury in walkers versus runners and risk of injury by exercise dose while considering age, body mass index, previous injury, and strength training. RESULTS: There was a significantly lower risk of injury for walkers compared with runners in young (<45 years old) (odds ratio [OR] = 0.75, 95% confidence interval [CI] = 0.58-0.97) and older (> or = 45 years) men (OR = 0.64, 95% CI = 0.49-0.82), and a nonsignificantly lower risk among young (OR = 0.73, 95% CI = 0.39-1.37) and older women (OR = 0.72, 95% CI = 0.38-1.35). There was no effect of greater amounts of walking on injuries for either gender; however, there was a higher injury risk associated with running 15-30 min/day (OR = 1.36, 95% CI = 1.07-1.73) and 30+ min/day (OR = 1.52, 95% CI = 1.14-2.04) compared with <15 min/day among men, but not among women. CONCLUSIONS: This low risk of musculoskeletal injury suggests that participation in walking can be safely recommended as a way to improve health and fitness.

Exercise and tumor development in a mouse predisposed to multiple intestinal adenomas.

UNLABELLED: Epidemiological evidence suggests that physical activity may be protective against the development of colon cancer. Potential mechanisms remain largely unexplored due to the paucity of appropriate experimental models. PURPOSE: The purpose of this study was to examine the effect of exercise training on polyp development in an induced mutant mouse strain predisposed to multiple intestinal neoplasia (Min mouse). METHODS: Three-week-old male and female heterozygotes were randomly assigned to control (CON; 10 males, 6 females) or exercise (EX; 11 males, 11 females) groups. In the first week, EX mice were acclimated to treadmill running at 10-18 m x min(-1) for 15-60 min x d(-1). From 4-10 wk of age, mice ran at 18-21 m x min(-1) for 60 min. CON mice sat in Plexiglas lanes suspended above the treadmill for the same time periods. At 10 wk of age, the mice were sacrificed and the intestines removed, opened, and counted for polyps. RESULTS: Skeletal muscle oxidative capacity increased with training as shown by a 64% increase in citrate synthase activity in the gastrocnemius/soleus muscle of EX compared with CON (P = 0.009). There were no significant effects of exercise in the males and females combined on small intestine, colon, or total intestinal polyps (P > 0.05). When analyzed separately, however, there were fewer colon and total polyps in the EX than in the CON males, although the difference was not statistically significant (P = 0.06). CONCLUSIONS: These results suggest that seven weeks of exercise training do not affect the development of intestinal polyps in the Min mouse. Further studies are required to determine if a true sex difference exists or if variations on the current training protocol may affect tumor outcomes.

Immune system activation and fatigue during treadmill running: role of interferon.

UNLABELLED: Extreme fatigue often accompanies infection and other diseases, but the causal mechanisms are unknown. Recent research has focused on various cytokines as potential immune system mediators of fatigue during illness. Interferon-alpha/beta (IFN-alpha/beta) has attracted the most interest in this regard. PURPOSE: The purpose of this research was to study the effect of IFN-alpha/beta on fatigue during treadmill running in mice. METHODS: Mice (male CD-1) were acclimated to treadmill running for 4 d before experimental sessions. In experiment 1 (EXP 1), mice were injected with either polyI:C (pI:C) (5 mg.kg-1 body weight) or saline (CON) 12 or 24 h before the exercise session. These sessions consisted of treadmill running to fatigue (approximately 3 h, 19-24 m.min-1, 5% grade, no shock). In experiment 2 (EXP 2), mice were injected 24 h before exercise with normal rabbit serum (CON), pI:C, or pI:C + anti-IFN-alpha/beta antibody (pI:C + Ab). RESULTS: The results of EXP 1 showed that the plasma IFN-alpha/beta titer was much higher at 24 h than at 12 h after pI:C injection (P < 0.001) and that run time to fatigue was significantly reduced only when the exercise occurred 24 h after injection (P < 0.05). In EXP 2, administration of the anti-IFN-alpha/beta antibody attenuated both the pI:C-induced increase in plasma IFN-alpha/beta (P < 0.001) and the decrease in run time to fatigue (r = -0.81, P < 0.001). CONCLUSIONS: These results suggest that immune system activation by pI:C was associated with early fatigue during prolonged treadmill exercise and that this effect may, at least partially, result from increased IFN-alpha/beta.

Exercise effects on lung tumor metastases and in vitro alveolar macrophage antitumor cytotoxicity.

This study examined the effects of moderate and prolonged exercise on 1) lung tumor metastases and 2) alveolar macrophage antitumor response in vitro. C57B1/6 mice were assigned to either Ex-30 (30-min run), Ex-F (run to fatigue), Ex-F-24 h (run to fatigue 24 h before tumor injection), or Con (rested in lanes above the treadmill). Mice received intravenous injections of syngeneic B16 melanoma cells 30 min postexercise. Lungs were removed 7 or 10 days later, and tumor foci were counted. Ex-F had fewer tumors than either Ex-30 or Con, whereas Ex-F-24 h also showed a strong trend toward fewer tumors. The initial localization of tumor cells in the lungs after injection was not different among groups. For the in vitro experiment, mice were killed immediately after exercise or 8 h later. Alveolar macrophages were removed and cultured in vitro with B16 melanoma cells. The growth of the tumors cultured with macrophages from Ex-F was lower than Con after exercise and, to a lesser extent, 8 h later. In Ex-30, this effect was only found immediately after exercise. The data suggest that prolonged exercise has a protective effect on lung tumor metastases and enhances alveolar macrophage antitumor cytotoxicity.

The role of stress hormones in exercise-induced suppression of alveolar macrophage antiviral function.

We hypothesized that a previously observed exercise-induced suppression of alveolar macrophage antiviral resistance results from increases in corticosterone and/or epinephrine. Mice (CD-1) were run to fatigue on a treadmill (exercise), or placed in Plexiglas lanes above the treadmill (control). The role of corticosterone was assessed by further dividing mice into groups receiving one of the following treatments; sham surgery, adrenalectomy, or adrenalectomy plus corticosterone replacement. Macrophage antiviral function was suppressed in the exercised mice compared to the control mice. However, macrophage antiviral function was not suppressed in the exercised mice that underwent adrenalectomy or adrenalectomy plus corticosterone replacement. We tested whether another adrenal factor (epinephrine) may be involved by dividing mice into exercise and control groups treated with either saline or propranolol. Macrophage antiviral function was again suppressed in the saline-treated exercised mice compared to saline-treated control mice, but no differences were found between the exercised mice receiving propranolol, control mice receiving propranolol, or saline-treated control mice. Isoproterenol, when added to alveolar macrophages in culture, also suppressed antiviral resistance. These findings suggest that decreased macrophage antiviral function following exercise may be due to increased release of adrenal catecholamines.

Exercise, alveolar macrophage function, and susceptibility to respiratory infection.

The effects of exercise on susceptibility to respiratory infection were determined by using a murine model of intranasal challenge with herpes simplex type 1 virus (HSV-1). Two doses of treadmill exercise were assessed: moderate short-term (30 min) exercise and prolonged strenuous exercise to voluntary fatigue (2.5-3.5 h). Morbidity and mortality among exercised and control mice were compared after intranasal challenge with HSV-1. We also assessed the ability of alveolar macrophages to restrict HSV-1 viral replication (intrinsic resistance) among exercise and control groups of mice at several time points postexercise. Exercise to fatigue followed by exposure to viral infection resulted in greater morbidity and mortality than either no exercise or short-term moderate exercise. In addition, antiviral resistance of macrophages obtained from the lungs of both exercised groups was suppressed, albeit for a longer duration in the fatigued group. These data are particularly important in that they identify an exercise-induced decrease in antiviral resistance of a specific component of the immune system within the lungs, in conjunction with increased susceptibility to respiratory infection in vivo. The specific mechanism of decreased antiviral resistance of alveolar macrophages and its role in respiratory infection after exercise remains to be determined.