David M. Lubaroff

Association of smoking, body mass, and physical activity with risk of prostate cancer in the Iowa 65+ Rural Health Study (United States)

Smoking, obesity, alcohol, and physical activity can modulate theendocrine system, and therefore have been hypothesized to play a role in theetiology of prostate cancer. At baseline in 1982, 80 percent (n = 3,673) ofthe noninstitutionalized persons age 65+ in two rural Iowa (United States)counties were enrolled into the Iowa 65+ Rural Health Study. Follow-up formortality was complete through 1993, and cancer experience was determined bylinkage to the State Health Registry of Iowa cancer database for the years1973-93. We analyzed data on 1,050 men aged 65 to 101 years (mean age 73.5)with a full interview in 1982 and with no documented cancer in the 10 yearsprior to baseline. Through 1993 (8,474 person-years of follow-up), there were71 incident cases of prostate cancer. In a multivariate model, age, cigarettesmoking (relative risk [RR] = 2.9 for currently smoking 20 or more cigarettesper day compared with never smoking; P trend = 0.009), greater body massindex (BMI) (wt/ht 2 ) (RR = 1.7 for BMI > 27.8 kg/m 2 compared with <23.6; P trend = 0.1), and greater level of physical activity (RR = 1.9 forhigh activity level cf inactive; P trend = 0.05) were independent predictorsof prostate cancer, and these associations were stronger for regional ordisseminated disease at diagnosis. Percent change in BMI from age 50 tobaseline was associated positively with risk (P trend = 0.01), and thisassociation appeared to be stronger in heavier men. There were no data ondiet. These findings suggest that smoking, overweight, and weight gain inlater life are risk factors for prostate cancer and support a hormonaletiology; the positive association for physical activity confirms someprevious reports, but remains without a credible biologicmechanism.

Social support and immune function among spouses of cancer patients

This study investigated whether social support was related to immune function among spouses of cancer patients. Effects of depression and negative life events were examined as potential mediators. Results showed evidence of greater immunocompetence on 2 of 3 dynamic measures: natural killer cytotoxicity and proliferation response to phytohemagglutinin among spouses who reported high levels of social support. All six components of social support assessed by the Social Provisions Scale (Cutrona & Russell, 1987) were strongly related to these indices of immune function. No evidence was found for mediation by either life events or depression.

Social Support, Psychological Distress, and Natural Killer Cell Activity in Ovarian Cancer

PURPOSE Psychosocial stress has been related to impaired immunity in cancer patients. However, the extent to which these relationships exist in immune cells in the tumor microenvironment in humans has not been explored. We examined relationships among distress, social support, and natural killer (NK) cell activity in ovarian cancer patients in peripheral-blood mononuclear cells (PBMC), ascitic fluid, and tumor-infiltrating lymphocytes (TIL). PATIENTS AND METHODS Patients awaiting surgery for a pelvic mass suspected of being ovarian cancer completed psychological questionnaires and gave a presurgical sample of peripheral blood. Samples of tumor and ascites were taken during surgery, lymphocytes were then isolated, and NK cytotoxicity and percentage were determined. The final sample, which was confirmed by surgical diagnosis, included 42 patients with epithelial ovarian cancer and 23 patients with benign masses. RESULTS Peripheral NK cell activity was significantly lower among ovarian cancer patients than in patients with benign masses. Among ovarian cancer patients, NK cytotoxicity in TIL was significantly lower than in PBMC or ascitic fluid. Social support was related to higher NK cytotoxicity in PBMC and TIL, adjusting for stage. Distress was related to lower NK cytotoxicity in TIL. A multivariate model indicated independent associations of both distress and social support with NK cell activity in TIL. CONCLUSION Psychosocial factors, such as social support and distress, are associated with changes in the cellular immune response, not only in peripheral blood, but also at the tumor level. These relationships were more robust in TIL. These findings support the presence of stress influences in the tumor microenvironment.

Interleukin-6, Cortisol, and Depressive Symptoms in Ovarian Cancer Patients

PURPOSE Inflammatory processes have been implicated in the pathogenesis of both depression and cancer. Links between depressive symptoms, interleukin-6 (IL-6), and cortisol dysregulation have been demonstrated in cancer patients, but vegetative versus affective components of depression have been minimally examined. The objective of the current study was to examine associations between IL-6, diurnal cortisol rhythms, and facets of depression in epithelial ovarian cancer patients. PATIENTS AND METHODS Patients awaiting surgery for a pelvic mass suspected for ovarian cancer completed questionnaires, collected salivary samples for 3 days presurgery, and gave a presurgical blood sample. Ascites was obtained during surgery. IL-6 was measured by enzyme-linked immunosorbent assay and cortisol by a chemiluminescence immunoassay. The final sample included 112 invasive ovarian cancer patients (86 advanced stage, 26 early stage) and 25 patients with tumors of low malignant potential (LMP). RESULTS Advanced-stage ovarian cancer patients demonstrated elevations in vegetative and affective depressive symptoms, plasma IL-6, and the cortisol area under the curve (AUC) compared with patients with LMP tumors (all P < .05). Among invasive ovarian cancer patients, greater vegetative depression was related to elevated IL-6 in plasma (P = .008) and ascites (P = .024), but affective depression was unrelated to IL-6. Elevations in total depression (P = .026) and vegetative depression (P = .005) were also related to higher evening cortisol levels. Plasma IL-6 was related to greater afternoon and evening cortisol and cortisol AUC (all P values < .005). CONCLUSION These results demonstrate significant relationships between IL-6, cortisol, and vegetative depression, and may have implications for treatment of depression in ovarian cancer patients.

Depression, social support, and beta-adrenergic transcription control in human ovarian cancer.

Motivated by previous indications that beta-adrenergic signaling can regulate tumor cell gene expression in model systems, we sought to determine whether similar dynamics occur in primary human ovarian cancer. DNA microarray analyses of 10 ovarian carcinomas identified 266 human transcripts that were differentially expressed in tumors from patients with elevated biobehavioral risk factors (high depressive symptoms and low social support) relative to grade- and stage-matched tumors from low-risk patients. Promoter-based bioinformatic analyses indicated increased activity of several beta-adrenergically-linked transcription control pathways, including CREB/ATF, NF-kappaB/Rel, STAT, and Ets family transcription factors. Consistent with increased beta-adrenergic signaling, high biobehavioral risk patients also showed increased intra-tumor concentrations of norepinephrine (but no difference in plasma norepinephrine). These data show that genome-wide transcriptional profiles are significantly altered in tumors from patients with high behavioral risk profiles, and they identify beta-adrenergic signal transduction as a likely mediator of those effects.

Biobehavioral influences on matrix metalloproteinase expression in ovarian carcinoma

Purpose: Stromal cells in the tumor microenvironment, such as macrophages, play an active role in tumor growth and angiogenesis. However, little is known about relationships of biobehavioral factors with angiogenic cytokines and matrix metalloproteinases (MMP) produced by stromal cells. This study examined distress, MMPs, and angiogenic cytokines in ovarian cancer patients and in vitro. Experimental Design: Patients suspected of ovarian cancer completed preoperative questionnaires. At surgery, 56 were confirmed to have epithelial ovarian cancer. Tumor samples were analyzed for macrophage (CD68+) and tumor cell levels of MMP-2, MMP-9, and vascular endothelial growth factor. In vitro stimulation of isolated macrophage cells by the stress hormones norepinephrine and cortisol was done to assess effects on MMP-9. Results: Depressed patients showed significant elevations of MMP-9 in CD68+ cells, adjusting for stage (P < 0.0001). Patients with higher levels of current stress (P = 0.01), life stress over the last 6 months (P = 0.004), and general negative affect (P = 0.007) also showed significantly greater MMP-9 in CD68+ cells. In contrast, higher social support was associated with lower levels of MMP-9 (P = 0.023) and vascular endothelial growth factor (P = 0.036) in tumor cells. In vitro analyses showed that macrophage MMP-9 production could be directly enhanced (up to a 2-fold increase) by the stress hormones norepinephrine and cortisol. Conclusions: Ovarian cancer patients with elevated depressive symptoms, chronic stress, and low social support showed elevations in MMP-9 in tumor-associated macrophages. Direct in vitro enhancement of stromal MMP-9 production by stress hormones was also shown. These findings may have implications for patient outcomes in ovarian cancer.

Social isolation is associated with elevated tumor norepinephrine in ovarian carcinoma patients

Noradrenergic pathways have been implicated in growth and progression of ovarian cancer. Intratumoral norepinephrine (NE) has been shown to increase with stress in an animal cancer model, but little is known regarding how tumor NE varies with disease stage and with biobehavioral factors in ovarian cancer patients. This study examined relationships between pre-surgical measures of social support, depressed mood, perceived stress, anxiety, tumor histology and tumor catecholamine (NE and epinephrine [E]) levels among 68 ovarian cancer patients. We also examined whether associations observed between biobehavioral measures and tumor catecholamines extended to other compartments. Higher NE levels were found in advanced stage (p=0.006) and higher grade (p=0.001) tumors. Adjusting for stage, grade, and peri-surgical beta blockers, patients with a perceived lack of social support had significantly higher tumor NE (β=-0.29, p=0.012). A similar trend was seen for social support and ascites NE (adjusting for stage, peri-surgical beta blockers and caffeine: β=-0.50, p=0.075), but not for plasma NE. Other biobehavioral factors were not related to tumor, ascites, or plasma NE (p values >0.21). Tumor E was undetectable in the majority of tumors and thus E was not further analyzed. In summary, these results suggest that tumor NE provides distinct information from circulating plasma concentrations. Tumor NE levels were elevated in relationship to tumor grade and stage. Low subjective social support was associated with elevated intratumoral NE. As beta-adrenergic signaling is related to key biological pathways involved in tumor growth, these findings may have implications for patient outcomes in ovarian cancer.

Immunization with type 5 adenovirus recombinant for a tumor antigen in combination with recombinant canarypox virus (alvac) cytokine gene delivery induces destruction of established prostate tumors

Prostate‐specific antigen (PSA) is expressed by prostate epithelial cells and has a highly restricted tissue distribution. Prostatic malignancies in 95% of patients continue to express PSA, making this antigen a good candidate for targeted immunotherapy. The goals of our studies are to generate a recombinant PSA adenovirus type 5 (Ad5‐PSA) that is safe and effectively activates a PSA‐specific T‐cell response capable of eliminating prostate cancer cells, and to characterize the immunologic basis for this rejection. Here we show that immunization of mice with Ad5‐PSA induced PSA‐specific cellular and humoral immunity that was protective against a subcutaneous challenge with RM11 prostate cancer cells expressing PSA (RM11psa), but not mock‐transfected RM11 tumor cells (RM11neo). Mice immunized with recombinant adenovirus type 5 encoding β‐galactosidase (Ad5‐lacZ) did not generate protective immunity. Antitumor activity was predominantly mediated by CD8+ T lymphocytes. Although Ad5‐PSA immunization prior to RM11psa challenge was protective, Ad5‐PSA immunization alone was not able to control the growth of existing RM11psa tumors. In contrast, established RM11psa tumors ranging in size from 500 to 1,000 mm3 were efficiently eliminated if Ad5‐PSA priming was followed 7 days later by intratumoral injection of recombinant canarypox viruses (ALVAC) encoding interleukin‐12 (IL‐12), IL‐2, and tumor necrosis factor‐α. In this case, antitumor immunity was still dominated by CD8+ T lymphocytes, but natural killer cells became necessary for a maximal response. These data provide information on the effector cell populations in a protective immune response to prostate cancer and demonstrate the utility of an Ad5‐PSA vaccine combined with cytokine gene delivery to eliminate large established tumors that are refractory to other interventional methods.

Effect of verbal self-disclosure on natural killer cell activity: moderating influence of cynical hostility

One objective of the present research was to examine the immunological effects of self-disclosing personal information regarding a traumatic or stressful experience. A second objective was to examine the hypothesis that the effect of self-disclosure on immune function is moderated by individual differences in cynical hostility. Forty-three male college undergraduates, classified as high or low on the Cook-Medley Hostility scale were randomly assigned to either a verbal self-disclosure or a nondisclosure discussion condition. Task-induced change in natural killer (NK) cell activity (i.e., cytotoxicity) served as the dependent variable. As predicted, a significant interaction between discussion condition and hostility was obtained. Among subjects in the self-disclosure condition, high hostility subjects exhibited a significantly greater increase in NK cell cytotoxicity than low hostility subjects. The effect of self-disclosure on NK cell activity is moderated by an individuals level of cynical hostility. The greater short term enhancement in NK cell activity observed for hostile persons is a likely correlate of a more pronounced acute arousal response elicited by the self-disclosure task.

Social Influences on Clinical Outcomes of Patients With Ovarian Cancer

PURPOSE Previous research has demonstrated relationships of social support with disease-related biomarkers in patients with ovarian cancer. However, the clinical relevance of these findings to patient outcomes has not been established. This prospective study examined how social support relates to long-term survival among consecutive patients with ovarian cancer. We focused on two types of social support: social attachment, a type of emotional social support reflecting connections with others, and instrumental social support reflecting the availability of tangible assistance. PATIENTS AND METHODS Patients were prospectively recruited during a presurgical clinic visit and completed surveys before surgery. One hundred sixty-eight patients with histologically confirmed epithelial ovarian cancer were observed from the date of surgery until death or December 2010. Clinical information was obtained from medical records. RESULTS In a Cox regression model, adjusting for disease stage, grade, histology, residual disease, and age, greater social attachment was associated with a lower likelihood of death (hazard ratio [HR], 0.87; 95% CI, 0.77 to 0.98; P = .018). The median survival time for patients with low social attachment categorized on a median split of 15 was 3.35 years (95% CI, 2.56 to 4.15 years). In contrast, by study completion, 59% of patients with high social attachment were still alive after 4.70 years. No significant association was found between instrumental social support and survival, even after adjustment for covariates. CONCLUSION Social attachment is associated with a survival advantage for patients with ovarian cancer. Clinical implications include the importance of screening for deficits in the social environment and consideration of support activities during adjuvant treatment.