Positive Psychosocial Factors and Oxytocin in the Ovarian Tumor Microenvironment.

OBJECTIVE: Clinical ovarian cancer research shows relationships between psychosocial factors and disease-promoting aspects of the stress response (e.g., norepinephrine and cortisol). However, little is known about how psychosocial factors might relate to beneficial hormones in the ovarian tumor microenvironment. Here we examine relationships between psychosocial factors and tumor-associated oxytocin, a hormone linked to survival and antitumor processes in ovarian cancer. METHODS: Patients with ovarian cancer (n = 96) completed assessments of positive psychosocial factors (social support, positive affect, and purpose in life) and distress (perceived stress and depression) at the time of surgery. Levels of oxytocin and interleukin (IL) 6 in ascites fluid were obtained during surgery and analyzed by enzyme-linked immunosorbent assay. Multiple regression analyses adjusting a priori for patient age and disease stage examined associations between psychosocial factors and ascites oxytocin. IL-6 was used as a covariate in secondary analyses to examine the potentially confounding effects of inflammation in these relationships. RESULTS: Higher levels of positive affect (ß = 0.22, p = .034), purpose in life (ß = 0.31, p = .021), and social nurturance (ß = 0.24, p = .024) were all related to higher levels of tumor-associated oxytocin at the time of surgery. In contrast, we found no effects for distress or social attachment. Relationships between oxytocin, purpose in life, and social nurturance were independent of IL-6, whereas positive affect was no longer significant with IL-6 in the model. CONCLUSIONS: Tumor-associated oxytocin may be a previously uninvestigated link in the relationship between psychosocial factors and health in ovarian cancer. Future studies should examine causal mechanisms of relationships observed in this study.

Life stress as a risk factor for sustained anxiety and cortisol dysregulation during the first year of survivorship in ovarian cancer.

BACKGROUND: Patients with ovarian cancer often report elevated anxiety at diagnosis that decreases posttreatment. However, a minority of patients experience sustained anxiety. Few studies have examined risk factors for persistent anxiety or its physiologic sequelae in ovarian cancer. Therefore, the authors investigated associations between prior life events, anxiety, inflammation (plasma levels of interleukin-6), and diurnal cortisol profiles in patients with ovarian cancer during the first year postdiagnosis. METHODS: Participants (n = 337) completed surveys and had blood and salivary sampling prediagnosis, postchemotherapy (6 months), and 12 months after diagnosis. The Life Events and Difficulties Schedule was administered to a patient subset (n = 127) within 1 month of diagnosis. Linear mixed-effects models were used to analyze relations between anxiety and biologic variables over time. Linear regression models assessed whether anxiety trajectories mediated associations between prior stress exposure and biologic variables. Age, chemotherapy at 1 year, and cancer stage were covariates. RESULTS: Decreased anxiety was associated with a more normalized cortisol slope over time (ß = 0.092; P = .047). Early life adversity was related to flatter cortisol slopes over time (ß = -0.763; P = .002); this relation was partially mediated by anxiety trajectory (P = .046). More danger-related events prediagnosis were associated with sustained anxiety (ß = 0.537; P = .019) and flatter cortisol slopes over time (ß = -0.243; P = .047); anxiety partially mediated the relation between danger and cortisol slope (P = .037). Neither anxiety nor prior stress exposure was related to levels of interleukin-6. CONCLUSIONS: Because dysregulated cortisol has been related to fatigue, poorer quality of life, and shorter survival in patients with ovarian cancer, those who have prior life events and chronic anxiety during the first year postdiagnosis may be at risk for more negative outcomes. Cancer 2018. © 2018 American Cancer Society.

Changes in spiritual well-being and psychological outcomes in ovarian cancer survivors.

OBJECTIVE: Because of the poor prognosis of ovarian cancer and concomitant distress, understanding contributors to positive well-being is critical. This study examines spiritual growth as a domain of posttraumatic growth and its contribution to longitudinal emotional outcomes in ovarian cancer. METHODS: Ovarian cancer patients (N = 241) completed measures assessing spirituality (Functional Assessment of Chronic Illness Therapy-Spiritual Well-being-12; subscales: faith, meaning, and peace), depression (Center for Epidemiologic Studies Depression Scale), cancer-specific anxiety (Impact of Event Scale), and total mood disturbance (TMD; Profile of Mood States) prior to surgery and 1-year postsurgery. Stressful life events in the year after diagnosis were measured at 1-year postsurgery. Regressions examined the association between changes in spirituality and depression, anxiety, and TMD at 1-year postsurgery. Additionally, spiritual change was examined as a moderator of the effect of recent life events on mood. RESULTS: Increases in peace were related to lower depression (ß = -.40, P < .001), anxiety (ß = -.20, P = .004), and TMD (ß = -.41, P < .001) at 1 year. Changes in meaning and faith were unrelated to all outcomes. Additionally, changes in peace moderated the effect of stressful life events on depression (ß = -.14, P = .027), anxiety (ß = -.16, P = .05), and TMD (ß = -.17, P = .01), such that those with a high number of life events paired with a decrease in peace experienced the worst psychological outcomes at 1 year. CONCLUSION: These findings suggest that the quality of peace may be the most adaptive facet of spiritual growth in cancer patients. Furthermore, changes in peace appear to moderate the effect of life events on psychological well-being.

Oxytocin in the tumor microenvironment is associated with lower inflammation and longer survival in advanced epithelial ovarian cancer patients.

BACKGROUND: Prior research demonstrates a protective role for oxytocin in ovarian cancer based on its anti-proliferative, anti-migratory, and anti-invasive effects in vitro and in vivo. However, the role of endogenous oxytocin has not been examined in ovarian cancer patients. Oxytocin also has anti-inflammatory properties that have not been examined in cancer. The purpose of this investigation was to examine relationships between endogenous oxytocin, tumor-associated inflammation (interleukin-6), and survival in advanced epithelial ovarian cancer patients. METHODS: Tumor microenvironment (ascites) and plasma oxytocin levels were analyzed via ELISA on extracted samples obtained from 79 patients. In vitro models were used to characterize oxytocin and oxytocin receptor expression in four ovarian cancer cell lines and to investigate direct anti-inflammatory effects of oxytocin on tumor cell secretion of interleukin-6. High and variable levels of oxytocin were observed in ascites, up to 200 times greater than in plasma. Higher levels of ascites oxytocin were associated with lower levels of systemic and tumor-associated interleukin-6, an inflammatory cytokine implicated in ovarian tumor progression. Oxytocin also attenuated interleukin-6 secretion from multiple ovarian tumor cell lines in vitro. Higher levels of ascites oxytocin were associated with a significant survival advantage and statistical mediation analyses suggested this effect was partially mediated by interleukin-6. CONCLUSIONS: These data identify a previously unacknowledged hormone in the ovarian tumor microenvironment and provide initial evidence that oxytocin has protective effects in ovarian cancer via anti-inflammatory mechanisms. Future studies should examine the therapeutic utility of oxytocin.

Diurnal cortisol rhythms, fatigue and psychosocial factors in five-year survivors of ovarian cancer.

Fatigue is a challenge in ovarian cancer survivorship and greatly impacts quality of life. In other cancer populations, fatigue has been associated with abnormal diurnal cortisol patterns. However, little is known about biological and behavioral factors in 5+-year ovarian cancer survivors and potential mechanisms underlying persistent fatigue have not been investigated in this population. Moreover, relationships between neuroendocrine and psychosocial factors in 5+-year ovarian cancer survivors have not been studied. We addressed these issues by examining relationships between diurnal cortisol rhythms, fatigue, life stress, and social support in 30 survivors of ovarian cancer who were assessed at least 5 years (mean=6.20years) following their primary diagnosis. Flatter diurnal cortisol slopes were associated with higher levels of fatigue, suggesting a role for HPA-axis dysregulation in sustained fatigue experienced by survivors. Moreover, greater cumulative lifetime stressor exposure (p=0.023) and stressor severity (p=0.004) were associated with flatter diurnal cortisol slopes, while higher social attachment (p=0.001) was associated with steeper diurnal cortisol slopes. These findings suggest that ovarian cancer survivors with greater lifetime stress exposure or lower social attachment may be at increased risk for circadian rhythm disruption, which in turn is associated with fatigue. Future research should examine relationships of clinical stage and inflammatory cytokines to cortisol rhythms and fatigue in long-term ovarian cancer survivors, as well as investigating the clinical significance of abnormal diurnal cortisol profiles in this population.