Eric Neri

Decrease in Depression Symptoms Is Associated With Longer Survival in Patients With Metastatic Breast Cancer: A Secondary Analysis

PURPOSE Numerous studies have examined the comorbidity of depression with cancer, and some have indicated that depression may be associated with cancer progression or survival. However, few studies have assessed whether changes in depression symptoms are associated with survival. METHODS In a secondary analysis of a randomized trial of supportive-expressive group therapy, 125 women with metastatic breast cancer (MBC) completed a depression symptom measure (Center for Epidemiologic Studies-Depression Scale [CES-D]) at baseline and were randomly assigned to a treatment group or to a control group that received educational materials. At baseline and three follow-up points, 101 of 125 women completed a depression symptom measure. We used these data in a Cox proportional hazards analysis to examine whether decreasing depression symptoms over the first year of the study (the length of the intervention) would be associated with longer survival. RESULTS Median survival time was 53.6 months for women with decreasing CES-D scores over 1 year and 25.1 months for women with increasing CES-D scores. There was a significant effect of change in CES-D over the first year on survival out to 14 years (P = .007) but no significant interaction between treatment condition and CES-D change on survival. Neither demographic nor medical variables explained this association. CONCLUSION Decreasing depression symptoms over the first year were associated with longer subsequent survival for women with MBC in this sample. Further research is necessary to confirm this hypothesis in other samples, and causation cannot be assumed based on this analysis.

Stress-induced redistribution of immune cells—From barracks to boulevards to battlefields: A tale of three hormones – Curt Richter Award Winner

BACKGROUND The surveillance and effector functions of the immune system are critically dependent on the appropriate distribution of immune cells in the body. An acute or short-term stress response induces a rapid and significant redistribution of immune cells among different body compartments. Stress-induced leukocyte redistribution may be a fundamental survival response that directs leukocyte subpopulations to specific target organs during stress, and significantly enhances the speed, efficacy and regulation of an immune response. Immune responses are generally enhanced in compartments (e.g., skin) that are enriched with leukocytes, and suppressed in compartments that are depleted of leukocytes during/following stress. The experiments described here were designed to elucidate the: (1) Time-course, trajectory, and subpopulation-specificity of stress-induced mobilization and trafficking of blood leukocytes. (2) Individual and combined actions of the principal stress hormones, norepinephrine (NE), epinephrine (EPI), and corticosterone (CORT), in mediating mobilization or trafficking of specific leukocyte subpopulations. (3) Effects of stress/stress hormones on adhesion molecule, L-selectin (CD62L), expression by each subpopulation to assess its adhesion/functional/maturation status. METHODS Male Sprague Dawley rats were stressed (short-term restraint, 2-120 min), or adrenalectomized and injected with vehicle (VEH), NE, EPI, CORT, or their combinations, and blood was collected for measurement of hormones and flow cytometric quantification of leukocyte subpopulations. RESULTS Acute stress induced an early increase/mobilization of neutrophils, lymphocytes, helper T cells (Th), cytolytic T cells (CTL), and B cells into the blood, followed by a decrease/trafficking of all cell types out of the blood, except neutrophil numbers that continued to increase. CD62L expression was increased on neutrophils, decreased on Th, CTL, and natural killer (NK) cells, and showed a biphasic decrease on monocytes & B cells, suggesting that CD62L is involved in mediating the redistribution effects of stress. Additionally, we observed significant differences in the direction, magnitude, and subpopulation specificity of the effects of each hormone: NE increased leukocyte numbers, most notably CD62L⁻/⁺ neutrophils and CD62L⁻ B cells. EPI increased monocyte and neutrophil numbers, most notably CD62L⁻/⁺ neutrophils and CD62L⁻ monocytes, but decreased lymphocyte numbers with CD62L⁻/⁺ CTL and CD62L⁺ B cells being especially sensitive. CORT decreased monocyte, lymphocyte, Th, CTL, and B cell numbers with CD62L⁻ and CD62L⁺ cells being equally affected. Thus, naïve (CD62L⁺) vs. memory (CD62L⁻) T cells, classical (CD62L⁺) vs. non-classical (CD62L⁻) monocytes, and similarly distinct functional subsets of other leukocyte populations are differentially mobilized into the blood and trafficked to tissues by stress hormones. CONCLUSION Stress hormones orchestrate a large-scale redistribution of immune cells in the body. NE and EPI mobilize immune cells into the bloodstream, and EPI and CORT induce traffic out of the blood possibly to tissue surveillance pathways, lymphoid tissues, and sites of ongoing or de novo immune activation. Immune cell subpopulations appear to show differential sensitivities and redistribution responses to each hormone depending on the type of leukocyte (neutrophil, monocyte or lymphocyte) and its maturation/functional characteristics (e.g., non-classical/resident or classical/inflammatory monocyte, naïve or central/effector memory T cell). Thus, stress hormones could be administered simultaneously or sequentially to induce specific leukocyte subpopulations to be mobilized into the blood, or to traffic from blood to tissues. Stress- or stress hormone-mediated changes in immune cell distribution could be clinically harnessed to: (1) Direct leukocytes to sites of vaccination, wound healing, infection, or cancer and thereby enhance protective immunity. (2) Reduce leukocyte traffic to sites of inflammatory/autoimmune reactions. (3) Sequester immune cells in relatively protected compartments to minimize exposure to cytotoxic treatments like radiation or localized chemotherapy. (4) Measure biological resistance/sensitivity to stress hormones in vivo. In keeping with the guidelines for Richter Award manuscripts, in addition to original data we also present a model and synthesis of findings in the context of the literature on the effects of short-term stress on immune cell distribution and function.

Depression and stress reactivity in metastatic breast cancer

Objective: Cancer-related distress due to the psychological and physical challenges of metastatic breast cancer (MBC) may result in symptoms of depression, which negatively affects quality and may influence quantity of life. This study investigated how depression affects MBC stress reactivity, including autonomic (ANS) and hypothalamic–pituitary–adrenal (HPA) axis function. Method: Forty-five nondepressed and 45 depressed patients with MBC underwent a modified Trier Social Stress Test (TSST) while affect, cardiovascular, respiratory, and cortisol responses were measured. Results: At study entry, depressed compared with nondepressed patients had significantly lower log cortisol waking rise levels (p = .005) but no other HPA differences. Positive affect (p = .025) and high-frequency heart-rate variability (lnHF) (p = .002) were significantly lower at TSST baseline in depressed patients. In response to the TSST, depressed patients reported significantly lower positive (p = .050) and greater negative affect (p = .037) and had significantly reduced lnHF (p = .031). In secondary analyses, at TSST baseline both low-frequency (lnLF) (p = .002) and very-low-frequency (lnVLF) (p = .0001) heart rate variability were significantly lower in the depressed group. In secondary analyses during the TSST, those who were depressed had significantly lower lnVLF (p = .008) and did not increase aortic impedance reactivity as much as did the nondepressed during the stressor (p = .005). Conclusion: Depression in patients with MBC was associated with alterations in autonomic regulation, particularly reductions in respiratory sinus arrhythmia, a measure of cardiac vagal control, at baseline and during the TSST. In addition, depression was associated with blunted HPA response to awakening. Both MBC groups had relative cortisol hyporesponsiveness to acute stress. ANS = autonomic nervous system; BMI = body mass index; BP = blood pressure; BRC = baroreflex control of heart rate; CO = cardiac output; CVD = cardiovascular disease; DBP = diastolic blood pressure; ECG = electrocardiogram; HDL = high-density lipoprotein; HPA axis = hypothalamic–pituitary–adrenal axis; HR = heart rate; HRSD = Hamilton Rating Scale of Depression; HRV = heart rate variability; ICG = impedance cardiogram; lnHF = natural log of high-frequency HRV; lnLF = natural log of low-frequency HRV; lnVLF = natural log of very low frequency HRV; LDL = low-density lipoprotein; MBC = metastatic breast cancer; MDD = major depressive disorder; ND = nondepressed; PANAS = Positive and Negative Affect Schedule; pCO2 = partial pressure of carbon dioxide; PEP = preejection period; RR interval = time between two consecutive R waves of the ECG; RSA = respiratory sinus arrhythmia; RSATF = transfer function respiratory sinus arrhythmia; SBP = systolic blood pressure; SNRI = serotonin–norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TSST = Trier Social Stress Test; VLDL = very-low-density lipoprotein.

Cancer supportive care, improving the quality of life for cancer patients. A program evaluation report

Goals of workAs medical care for cancer has become more specialized in diagnosis, treatment has become more technical and fragmented. In order to help cancer patients and their families, we developed a coordinated program called the Stanford Cancer Supportive Care Program (SCSCP) at the Center for Integrative Medicine at Stanford Hospital and Clinics. The Stanford Cancer Supportive Care Program was initiated in 1999 to provide support for cancer patients, addressing the need for improved physical and emotional well-being and quality of life. This paper is a program evaluation report.Patients and methodsThe number of patient visits grew from 421 in 1999 to 6319 in 2002. This paper describes the utilization of the SCSCP program as assessed by 398 patient visit evaluations during a 9-week period, January 2002 to March 2002. During this time we collected attendance records with demographic data and anonymous questionnaires evaluating each program. Patients were asked to evaluate how the program helped them regarding increase of energy, reduction in stress, restful sleep, pain reduction, sense of hopefulness, and empowerment.Main resultsOver 90% of the patients using the SCSCP felt there was benefit to the program. Programs were chosen based on a needs assessment by oncologists, nurse managers, social workers, and patients. Massage, yoga, and qigong classes had the highest number of participants. Qualitative data showed benefit for each program offered.ConclusionsThis evaluation of a free cancer supportive care program initiated in a hospital outpatient setting provides initial evidence of patient satisfaction and improvement in quality of life.

Effects of supportive-expressive group therapy on pain in women with metastatic breast cancer.

OBJECTIVE To examine whether a group intervention including hypnosis can reduce cancer pain and trait hypnotizability would moderate these effects. DESIGN This randomized clinical trial examined the effects of group therapy with hypnosis (supportive-expressive group therapy) plus education compared to an education-only control condition on pain over 12 months among 124 women with metastatic breast cancer. MAIN OUTCOME MEASURES Pain and suffering, frequency of pain, and degree of constant pain were assessed at baseline and 4-month intervals. Those in the treatment group also reported on their experiences using the hypnosis exercises. RESULTS Intention-to-treat analyses indicated that the intervention resulted in significantly less increase in the intensity of pain and suffering over time, compared to the education-only group, but had no significant effects on the frequency of pain episodes or amount of constant pain, and there was no interaction of the intervention with hypnotizability. Within the intervention group, highly hypnotizable participants, compared to those less hypnotizable, reported greater benefits from hypnosis, employed self-hypnosis more often outside of group, and used it to manage other symptoms in addition to pain. CONCLUSION These results augment the growing literature supporting the use of hypnosis as an adjunctive treatment for medical patients experiencing pain.

Psychophysiological and Cortisol Responses to Psychological Stress in Depressed and Nondepressed Older Men and Women With Elevated Cardiovascular Disease Risk

Objective: The objective of this study was to compare psychophysiological and cortisol reactions to psychological stress in older depressed and nondepressed patients at risk for cardiovascular disease (CVD). Methods: Forty-eight depressed participants and 20 controls with elevated cardiovascular risk factors underwent a psychological stress test during which cardiovascular variables were measured. Salivary cortisol was collected after each test segment. Traditional (e.g., lipids) and atypical (e.g., C-reactive protein) CVD risk factors were also obtained. Results: At baseline, the groups did not differ on lipid levels, flow-mediated vasodilation, body mass index, or asymmetric dimethylarginine. However, the depressed patients had significantly higher C-reactive protein levels. Contrary to our hypothesis, there were no differences in baseline cortisol levels or diurnal cortisol slopes, but depressed patients showed significantly lower cortisol levels during the stress test (p = .03) and less cortisol response to stress. Compared with nondepressed subjects, depressed subjects also showed lower levels of respiratory sinus arrhythmia (RSATF) during the stress test (p = .02). Conclusions: In this sample, older depressed subjects with elevated risk for CVD exhibited a hypocortisol response to acute stress. This impaired cortisol response might contribute to chronic inflammation (as reflected in the elevated C-reactive proteins in depressed patients) and in other ways increase CVD risk. The reduced RSATF activity may also increase CVD risk in depressed patients through impaired autonomic nervous system response to cardiophysiological demands. ACTH = adrenocorticotropic hormone; ADH = antidiuretic hormone; ADMA = asymmetric dimethylarginine; ANS = autonomic nervous system; BMI = body mass index; BP = blood pressure; BRC = baroreflex control; CAD = coronary artery disease; CBT = cognitive behavioral therapy; CHD = coronary heart disease; CO = cardiac output; CON = nondepressed control; CPM = cycles per minute; CVD = cardiovascular disease; DBP = diastolic blood pressure; DISH = Depression Interview and Structured Hamilton; ECG = electrocardiogram; FMVD = flow-mediated vasodilation; HDL = high-density lipoprotein; HPA = hypothalamic–pituitary–adrenal axis; HR = heart rate; HRSD = Hamilton Rating Scale of Depression; HRV = heart rate variability; LDL = low-density lipoprotein; MDD = major depressive disorder; MI = myocardial infarction; NO = nitric oxide; PANAS = Positive and Negative Affect Schedule; pCO2 = partial pressure of carbon dioxide; PEP = preejection period; PSS = Perceived Stress Scale; RSA = respiratory sinus arrhythmia; RSATF = transfer function respiratory sinus arrhythmia; SBP = systolic blood pressure; SVR = systemic vascular resistance; TSST = Trier Social Stress Test; VLDL = very-low-density lipoprotein.

Actigraphy-measured sleep disruption as a predictor of survival among women with advanced breast cancer.

BACKGROUND Poor sleep, prevalent among cancer survivors, is associated with disrupted hormonal circadian rhythms and poor quality of life. Using a prospective research design, this study aimed to clarify the relationship between objective measures of sleep efficiency and sleep disruption with survival among women with advanced breast cancer. METHOD We examined sleep quality and duration via wrist-worn actigraphy and sleep diaries for 3 days among 97 women in whom advanced breast cancer was diagnosed (age = 54.6 ± 9.8 years). Sleep efficiency was operationalized using actigraphy as the ratio of total sleep time to total sleep time plus wake after sleep onset. RESULTS As hypothesized, better sleep efficiency was found to predict a significant reduction in overall mortality (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.94-0.98; P < 0.001) at median 6 y follow-up. This relationship remained significant (HR, 0.94; 95% CI, 0.91-0.97; P < 0.001) even after adjusting for other known prognostic factors (age, estrogen receptor status, cancer treatment, metastatic spread, cortisol levels, and depression). Secondary hypotheses were also supported (after adjusting for baseline prognostic factors) showing that less wake after sleep onset (HR, 0.41; 95% CI, 0.25-0.67; P < 0.001), fewer wake episodes, (HR, 0.93; 95% CI, 0.88-0.98; P = 0.007); and shorter wake episode duration (HR, 0.29; 95% CI, 0.14-0.58; P < 0.001) also contributed to reductions in overall mortality. CONCLUSIONS These findings show that better sleep efficiency and less sleep disruption are significant independent prognostic factors in women with advanced breast cancer. Further research is needed to determine whether treating sleep disruption with cognitive behavioral and/or pharmacologic therapy could improve survival in women with advanced breast cancer.

Screening for distress, the 6th vital sign: common problems in cancer outpatients over one year in usual care: associations with marital status, sex, and age

BackgroundVery few studies examine the longitudinal prevalence of problems and the awareness or use of clinical programs by patients who report these problems. Of the studies that examine age, gender and marital status as predictors of a range of patient outcomes, none examines the interactions between these demographic variables. This study examined the typical trajectory of common practical and psychosocial problems endorsed over 12 months in a usual-care sample of cancer outpatients. Specifically, we examined whether marital status, sex, age, and their interactions predicted these trajectories. We did not actively triage or refer patients in this study in order to examine the natural course of problem reports.MethodsPatients completed baseline screening (N = 1196 of 1707 approached) and the sample included more men (N = 696) than women (N = 498), average age 61.1 years. The most common diagnoses were gastrointestinal (27.1%), prostate (19.2%), skin (11.1%) and gynecological (9.2%). Among other measures, patients completed a Common Problem Checklist and Psychosocial Resources Use questions at baseline, 3, 6, and 12 months using paper and pencil surveys.ResultsResults indicated that patients reported psychosocial problems more often than practical and both decreased significantly over time. Younger single patients reported more practical problems than those in committed relationships. Younger patients and women of all ages reported more psychosocial problems. Among a number of interesting interactions, for practical problems, single older patients improved more; whereas among married people, younger patients improved more. For psychosocial problems we found that older female patients improved more than younger females, but among males, it was younger patients who improved more. Young single men and women reported the most past-and future-use of services.ConclusionsYounger women are particularly vulnerable to experiencing practical and psychosocial problems when diagnosed with cancer, but being married protects these younger women. Marriage appeared to buffer reports of both practical and psychosocial problems, and led to less awareness and use of services. Unexpectedly, young men reported the highest use of psychosocial services. This study informs clinical program development with information on these risk groups.

High-Anxious Individuals Show Increased Chronic Stress Burden, Decreased Protective Immunity, and Increased Cancer Progression in a Mouse Model of Squamous Cell Carcinoma

In spite of widespread anecdotal and scientific evidence much remains to be understood about the long-suspected connection between psychological factors and susceptibility to cancer. The skin is the most common site of cancer, accounting for nearly half of all cancers in the US, with approximately 2–3 million cases of non-melanoma cancers occurring each year worldwide. We hypothesized that a high-anxious, stress-prone behavioral phenotype would result in a higher chronic stress burden, lower protective-immunity, and increased progression of the immuno-responsive skin cancer, squamous cell carcinoma. SKH1 mice were phenotyped as high- or low-anxious at baseline, and subsequently exposed to ultraviolet-B light (1 minimal erythemal dose (MED), 3 times/week, 10-weeks). The significant strengths of this cancer model are that it uses a normal, immunocompetent, outbred strain, without surgery/injection of exogenous tumor cells/cell lines, and produces lesions that resemble human tumors. Tumors were counted weekly (primary outcome), and tissues collected during early and late phases of tumor development. Chemokine/cytokine gene-expression was quantified by PCR, tumor-infiltrating helper (Th), cytolytic (CTL), and regulatory (Treg) T cells by immunohistochemistry, lymph node T and B cells by flow cytometry, adrenal and plasma corticosterone and tissue vascular-endothelial-growth-factor (VEGF) by ELISA. High-anxious mice showed a higher tumor burden during all phases of tumor development. They also showed: higher corticosterone levels (indicating greater chronic stress burden), increased CCL22 expression and Treg infiltration (increased tumor-recruited immuno-suppression), lower CTACK/CCL27, IL-12, and IFN-γ gene-expression and lower numbers of tumor infiltrating Th and CTLs (suppressed protective immunity), and higher VEGF concentrations (increased tumor angiogenesis/invasion/metastasis). These results suggest that the deleterious effects of high trait anxiety could be: exacerbated by life-stressors, accentuated by the stress of cancer diagnosis/treatment, and mediate increased tumor progression and/or metastasis. Therefore, it may be beneficial to investigate the use of chemotherapy-compatible anxiolytic treatments immediately following cancer diagnosis, and during cancer treatment/survivorship.

Shame, guilt, and posttraumatic stress disorder in adult survivors of childhood sexual abuse at risk for human immunodeficiency virus: outcomes of a randomized clinical trial of group psychotherapy treatment.

This study evaluated the effectiveness of group psychotherapy in reducing levels of shame and guilt in adult survivors of childhood sexual abuse at risk for HIV, and whether such reductions would mediate the effects of treatment on posttraumatic stress disorder (PTSD) symptoms. One hundred sixty-six women were randomized into 3 conditions: a trauma-focused group, a present-focused group, and a waitlist group. Women received 6 months of treatment and were assessed at pretreatment (T1), immediately posttreatment (T2), and 6 months posttreatment (T3). Both treatment conditions resulted in reduced shame and guilt. The treatment effect on PTSD symptoms was mediated by changes in shame, but it was not associated with changes in guilt. These findings suggest that, when treating childhood sexual abuse survivors’ PTSD, it is important to address the negative self-appraisals, such as shame, that commonly accompany such symptoms.