BACKGROUND. The question of whether stress poses a risk for cancer progression has been difficult to answer. A randomized clinical trial tested the hypothesis that cancer patients coping with their recent diagnosis but receiving a psychologic intervention would have improved survival compared with patients who were only assessed. METHODS. A total of 227 patients who were surgically treated for regional breast cancer participated. Before beginning adjuvant cancer therapies, patients were assessed with psychologic and behavioral measures and had a health evaluation, and a 60‐mL blood sample was drawn. Patients were randomized to Psychologic Intervention plus assessment or Assessment only study arms. The intervention was psychologist led; conducted in small groups; and included strategies to reduce stress, improve mood, alter health behaviors, and maintain adherence to cancer treatment and care. Earlier articles demonstrated that, compared with the Assessment arm, the Intervention arm improved across all of the latter secondary outcomes. Immunity was also enhanced. RESULTS. After a median of 11 years of follow‐up, disease recurrence was reported to occur in 62 of 212 (29%) women and death was reported for 54 of 227 (24%) women. Using Cox proportional hazards analysis, multivariate comparison of survival was conducted. As predicted, patients in the Intervention arm were found to have a reduced risk of breast cancer recurrence (hazards ratio [HR] of 0.55; P = .034) and death from breast cancer (HR of 0.44; P = .016) compared with patients in the Assessment only arm. Follow‐up analyses also demonstrated that Intervention patients had a reduced risk of death from all causes (HR of 0.51; P = .028). CONCLUSIONS. Psychologic interventions as delivered and studied here can improve survival. Cancer 2008. © 2008 American Cancer Society.
Reactive oxygen species (ROS) appear to play an important role in regulating growth and survival of prostate cancer. However, the sources for ROS production in prostate cancer cells have not been determined. We report that ROS are generated by intact American Type Culture Collection DU 145 cells and by their membranes through a mechanism blocked by NAD(P)H oxidase inhibitors. ROS are critical for growth in these cells, because NAD(P)H oxidase inhibitors and antioxidants blocked proliferation. Components of the human phagocyte NAD(P)H oxidase, p22phox and gp91phox, as well as the Ca2+ concentration-responsive gp91phox homolog NOX5 were demonstrated in DU 145 cells by RT-PCR and sequencing. Although the protein product for p22phox was not detectable, both gp91phox and NOX5 were identified throughout the cell by immunostaining and confocal microscopy and NOX5 immunostaining was enhanced in a perinuclear location, corresponding to enhanced ROS production adjacent to the nuclear membrane imaged by 2',7'-dichlorofluorescin diacetate oxidation. The calcium ionophore ionomycin dramatically stimulated ferricytochrome c reduction in cell media, further supporting the importance of NOX5 for ROS production. Antisense oligonucleotides for NOX5 inhibited ROS production and cell proliferation in DU 145 cells. In contrast, antisense oligonucleotides to p22phox or gp91phox did not impair cell growth. Inhibition of ROS generation with antioxidants or NAD(P)H oxidase inhibitors increased apoptosis in cells. These results indicate that ROS generated by the newly described NOX5 oxidase are essential for prostate cancer growth, possibly by providing trophic intracellular oxidant tone that retards programmed cell death.
The authors investigated the relationship between stress at initial cancer diagnosis and treatment and subsequent quality of life (QoL). Women (n = 112) randomized to the assessment-only arm of a clinical trial were initially assessed after breast cancer diagnosis and surgery and then reassessed at 4 months (during adjuvant treatment) and 12 months (postadjuvant treatment). There were 3 types of stress measured: number of stressful life events (K. A. Matthews et al., 1997), cancer-related traumatic stress symptoms (M. J. Horowitz, N. Wilner, & W. Alvarez, 1979), and perceived global stress (S. Cohen, T. Kamarck, & R. Mermelstein, 1983). Using hierarchical multiple regressions, the authors found that stress predicted both psychological and physical QoL (J. E. Ware, K. K. Snow, & M. Kosinski, 2000) at the follow-ups (all ps < .03). These findings substantiate the relationship between initial stress and later QoL and underscore the need for timely psychological intervention. Keywords stress; quality of life; breast cancerThe impact of a breast cancer diagnosis and its treatment on quality of life (QoL) is well documented (e.g., Ganz et al., 1996;Holzner et al., 2001). Shapiro et al. (2001), in their review of the relationship between QoL and psychosocial variables in breast cancer patients, noted that "the biomedical model of disease, though crucial, does not take into account all of the complex factors involved in cancer … a broader, more integrative framework, which includes psychosocial factors, is needed" (p. 502). The biobehavioral model of cancer stress and disease course offers such a framework (see Andersen, Kiecolt-Glaser, & Glaser, 1994, for a complete discussion). In this conceptual model, cancer diagnosis and cancer treatments are defined as objective, negative events. Although negative events do not always produce stress, data from many studies document severe acute stress at cancer diagnosis and treatment (e.g., Andersen, Anderson, & deProsse, 1989;Epping-Jordan et al., 1999;Maunsell, Brisson, & Deschenes, 1992). Even when stress declines from the peak at diagnosis (Edgar, Rosberger, & Nowlis, 1992), many QoL difficulties remain and new ones may arise during treatment and/or recovery (e.g., psychological distress; relationship, social, and occupational disruption; loss of physical stamina and fatigue; financial problems; Bleiker, Pouwer, van der Ploeg, Leer, & Ader, 2000;Ganz et al., 1996;Holzner et al., 2001). The biobehavioral model postulates that higher initial stress levels (i.e., stress at the time of cancer diagnosis and treatment) can, over time, contribute to lower QoL for cancer patients.To examine the hypothesized longitudinal relationship between stress and QoL, we used stress at initial diagnosis and surgical treatment as a predictor of QoL outcomes as patients received additional difficult treatments (i.e., chemotherapy, radiation) and as they recovered (i.e., when treatments ended and medical follow-up began). As the biobehavioral model does not specify or define stress per se, ...
SummaryObjective-Neuroendocrine-immune models have been proposed to account for the frequent cooccurrence of pain, depression, and fatigue (PDF) among cancer patients.Design-In a cross-sectional observational study of advanced cancer patients (N=104), we test the hypothesis that the PDF cluster covaries with proposed biological mediators: hormones of the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis.Main Outcome Measures-PDF symptoms were measured using the Brief Pain Inventory, Fatigue Severity Index, and the Center for Epidemiological Studies-Depression scales. HPA activation was indicated by plasma levels of cortisol and adrenocorticotropic hormone, and SNS activation was indicated by plasma epinephrine and norepinephrine.Results-Preliminary analyses supported the use of covariance structure modeling to test whether shared variance among hormone levels predicted shared variance among PDF symptoms. Latent variable analysis indicated neuroendocrine levels predicted PDF (standardized β=.23, p=. 039), while controlling for important disease and demographic variables. Conclusion-Previous studies have linked individual symptoms to individual biomarkers.The observed significant paring of the four hormones to the PDF cluster provides the first evidence suggestive of stress hormones as a common mechanism for the co-occurrence of pain, depression, and fatigue symptoms.Keywords symptom clusters; depression; cancer; hypothalamic-pituitary-adrenal axis; sympathetic nervous system Pain, depression and fatigue (PDF) are among the most common and distressing symptoms in advanced breast cancer, and they often occur concurrently (Cleeland, et al., 2003;Miller, Ancoli-Israel, Bower, Capuron, & Irwin, 2008). Their co-occurrence may indicate a common etiological mechanism, and neuroendocrine-immune models have been proposed
Purpose: A clinical trial was designed to test the hypothesis that a psychological intervention could reduce the risk of cancer recurrence. Newly diagnosed regional breast cancer patients (n = 227) were randomized to the intervention-with-assessment or the assessment-only arm. The intervention had positive psychological, social, immune, and health benefits, and after a median of 11 years the intervention arm was found to have reduced the risk of recurrence (hazard ratio, 0.55; P = 0.034). In follow-up, we hypothesized that the intervention arm might also show longer survival after recurrence. If observed, we then would examine potential biobehavioral mechanisms.Experimental Design: All patients were followed; 62 recurred. Survival analyses included all 62. Upon recurrence diagnosis, those available for further biobehavioral study were accrued (n = 41, 23 intervention and 18 assessment). For those 41, psychological, social, adherence, health, and immune (natural killer cell cytotoxicity, T-cell proliferation) data were collected at recurrence diagnosis and 4, 8, and 12 months later.Results: Intent-to-treat analysis revealed reduced risk of death following recurrence for the intervention arm (hazard ratio, 0.41; P = 0.014). Mixed-effects follow-up analyses with biobehavioral data showed that all patients responded with significant psychological distress at recurrence diagnosis, but thereafter only the intervention arm improved (P values < 0.023). Immune indices were significantly higher for the intervention arm at 12 months (P values < 0.017).Conclusions: Hazards analyses augment previous findings in showing improved survival for the intervention arm after recurrence. Follow-up analyses showing biobehavioral advantages for the intervention arm contribute to our understanding of how improved survival was achieved. Clin Cancer Res; 16(12); 3270-8. ©2010 AACR.Meta-analyses suggest that stress-related psychosocial factors (1) and lower health-related quality of life (2) are associated with poorer cancer survival, with a 13% increase in the hazard ratio (HR) in studies of breast cancer patients (1). In 1994 a randomized controlled trial, the Stress and Immunity Breast Cancer Project (SIBCP), was designed to test the hypothesis that newly diagnosed breast cancer patients receiving a psychological intervention would have a reduced risk of recurrence and breast cancer death compared with patients who were only assessed. A conceptual model guided the development of the clinical trial. The Biobehavioral Model of Cancer Stress and Disease Course (3) proposes that psychological stress leads to disruptions in quality of life, health behaviors, and immunity, which in turn contribute to poorer disease outcomes. It was hypothesized that an intervention designed to reduce emotional distress and improve social adjustment, health behaviors, and adherence might also improve immunity and disease course. Analyses showed that positive intervention effects were achieved across the psychological and immune outcomes at 4 months (4)...
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