Diurnal Cortisol and Survival in Epithelial Ovarian Cancer

IntroductionHypothalamic-pituitary-adrenal (HPA) deregulation is commonly observed in cancer patients, but its clinical significance is not well understood. We prospectively examined the association between HPA activity, tumor-associated inflammation, and survival in ovarian cancer patients prior to treatment.Materials and methodsParticipants were 113 women with ovarian cancer who provided salivary cortisol for three days prior to treatment for calculation of cortisol slope, variability, and night cortisol. Cox proportional hazard regression analyses were used to examine associations between cortisol and survival in models adjusting for disease stage, tumor grade, cytoreduction and age. On a subsample of 41 patients with advanced disease ascites fluid was assayed for levels of interleukin-6 (IL-6) and correlated with cortisol variables.ResultsEach cortisol measure was associated with decreased survival time, adjusting for covariates (all p<.041). A one standard deviation increase in night cortisol was associated with a 46% greater likelihood of death. Patients in the high night cortisol group survived an estimated average of 3.3 years compared to 7.3 years for those in the low night cortisol group. Elevated ascites IL-6 was associated with each cortisol measure (all r>36, all p<.017).DiscussionAbnormal cortisol rhythms assessed prior to treatment are associated with decreased survival in ovarian cancer and increased inflammation in the vicinity of the tumor. HPA abnormalities may reflect poor endogenous control of inflammation, dysregulation caused by tumor-associated inflammation, broad circadian disruption, or some combination of these factors. Nocturnal cortisol may have utility as a non-invasive measure of HPA function and/or disease severity

Depressive symptoms and cortisol variability prior to surgery for suspected endometrial cancer

Endometrial cancer (EC) is the most common type of gynecologic cancer affecting women; however, very little research has examined relationships between psychological factors and hypothalamic-pituitary-adrenal (HPA) axis dysregulation in this population. The current study examined relations between depressive/anxious symptoms and salivary cortisol diurnal rhythm and variability in women undergoing surgery for suspected endometrial cancer. Depressive and anxious symptoms were measured prior to surgery using the Structured Interview Guide for the Hamilton Depression Inventory (SIGH-AD). Saliva was collected four times a day for the three days prior to surgery and then assayed by ELISA to obtain cortisol concentrations. Cortisol slopes and intraindividual variability were then calculated across subjects. Relations between depressive/anxious symptoms and cortisol indices were examined using multilevel modeling and linear regression analyses. Participants were 82 women with nonmetastatic endometrial cancer. Anxious symptoms were not associated with either cortisol slope or intraindividual variability, and depressive symptoms were unrelated to cortisol slope. However, after controlling for presence of poorer prognosis cancer subtypes, greater depressive symptoms (excluding symptoms possibly/definitely due to health/treatment factors) in the week preceding surgery were significantly related to greater cortisol intraindividual variability (β=.214; p<.05). These results suggest that depressive symptoms prior to surgery for suspected endometrial cancer are related to greater cortisol intraindividual variability, which is suggestive of more erratic HPA axis arousal. Future research should examine whether mood symptoms may be associated with compromised health outcomes via erratic HPA axis arousal in this population

Paraneoplastic thrombocytosis in ovarian cancer

&lt;p&gt;Background: The mechanisms of paraneoplastic thrombocytosis in ovarian cancer and the role that platelets play in abetting cancer growth are unclear.&lt;/p&gt; &lt;p&gt;Methods: We analyzed clinical data on 619 patients with epithelial ovarian cancer to test associations between platelet counts and disease outcome. Human samples and mouse models of epithelial ovarian cancer were used to explore the underlying mechanisms of paraneoplastic thrombocytosis. The effects of platelets on tumor growth and angiogenesis were ascertained.&lt;/p&gt; &lt;p&gt;Results: Thrombocytosis was significantly associated with advanced disease and shortened survival. Plasma levels of thrombopoietin and interleukin-6 were significantly elevated in patients who had thrombocytosis as compared with those who did not. In mouse models, increased hepatic thrombopoietin synthesis in response to tumor-derived interleukin-6 was an underlying mechanism of paraneoplastic thrombocytosis. Tumorderived interleukin-6 and hepatic thrombopoietin were also linked to thrombocytosis in patients. Silencing thrombopoietin and interleukin-6 abrogated thrombocytosis in tumor-bearing mice. Anti–interleukin-6 antibody treatment significantly reduced platelet counts in tumor-bearing mice and in patients with epithelial ovarian cancer. In addition, neutralizing interleukin-6 significantly enhanced the therapeutic efficacy of paclitaxel in mouse models of epithelial ovarian cancer. The use of an antiplatelet antibody to halve platelet counts in tumor-bearing mice significantly reduced tumor growth and angiogenesis.&lt;/p&gt; &lt;p&gt;Conclusions: These findings support the existence of a paracrine circuit wherein increased production of thrombopoietic cytokines in tumor and host tissue leads to paraneoplastic thrombocytosis, which fuels tumor growth. We speculate that countering paraneoplastic thrombocytosis either directly or indirectly by targeting these cytokines may have therapeutic potential. &lt;/p&gt

Focal Adhesion Kinase Silencing Augments Docetaxel-Mediated Apoptosis in Ovarian Cancer Cells

Docetaxel causes cell death through induction of apoptosis; however, cell death characteristics for docetaxel have not yet been fully elucidated. We examined the role of focal adhesion kinase (FAK) cleavage in docetaxel-mediated apoptosis

Cortisol and inflammatory processes in ovarian cancer patients following primary treatment: Relationships with depression, fatigue, and disability

a b s t r a c t Elevations in the pro-inflammatory cytokine interleukin-6 (IL-6) and alterations in the anti-inflammatory hormone cortisol have been reported in a variety of cancers. IL-6 has prognostic significance in ovarian cancer and cortisol has been associated with fatigue, disability, and vegetative depression in ovarian cancer patients prior to surgery. Ovarian cancer patients undergoing primary treatment completed psychological self-report measures and collected salivary cortisol and plasma IL-6 prior to surgery, at 6 months, and at 1 year. Patients included in this study had completed chemotherapy and had no evidence of disease recurrence. At 6 months, patients showed significant reductions in nocturnal cortisol secretion, plasma IL-6, and a more normalized diurnal cortisol rhythm, changes that were maintained at 1 year. The reductions in IL-6 and nocturnal cortisol were associated with declines in self-reported fatigue, vegetative depression, and disability. These findings suggest that primary treatment for ovarian cancer reduces the inflammatory response. Moreover, patients who have not developed recurrent disease by 1 year appear to maintain more normalized levels of cortisol and IL-6. Improvement in fatigue and vegetative depression is associated with the normalization of IL-6 and cortisol, a pattern which may be relevant for improvements in overall quality of life for ovarian cancer patients

Differential Platelet Levels Affect Response to Taxane-Based Therapy in Ovarian Cancer

We hypothesized that platelet levels during therapy could serve as a biomarker for response to therapy and that manipulation of platelet levels could impact responsiveness to chemotherapy

Host Factors and Cancer Progression: Biobehavioral Signaling Pathways and Interventions

Whereas evidence for the role of psychosocial factors in cancer initiation has been equivocal, support continues to grow for links between psychological factors such as stress, depression, and social isolation and progression of cancer. In vitro, in vivo, and clinical studies show that stress- related processes can impact pathways implicated in cancer progression, including immuno-regulation, angiogenesis, and invasion. Contributions of systemic factors, such as stress hormones to the crosstalk between tumor and stromal cells, appear to be critical in modulating downstream signaling pathways with important implications for disease progression. Inflammatory pathways may also be implicated in fatigue and other factors related to quality of life. Although substantial evidence supports a positive effect of psychosocial interventions on quality of life in cancer, the clinical evidence for efficacy of stress-modulating psychosocial interventions in slowing cancer progression remains inconclusive, and the biobehavioral mechanisms that might explain such effects are still being established. This article reviews research findings to date and outlines future avenues of research in this area

Biobehavioral Pathways and Cancer Progression: Insights for Improving Well-Being and Cancer Outcomes

The relationship between psychosocial factors and cancer has intrigued people for centuries. In the last several decades there has been an expansion of mechanistic research that has revealed insights regarding how stress activates neuroendocrine stress-response systems to impact cancer progression. Here, we review emerging mechanistic findings on key pathways implicated in the effect of stress on cancer progression, including the cellular immune response, inflammation, angiogenesis, and metastasis, with a primary focus on the mediating role of the sympathetic nervous system. We discuss converging findings from preclinical and clinical cancer research that describe these pathways and research that reveals how these stress pathways may be targeted via pharmacological and mind-body based interventions. While further research is required, the body of work reviewed here highlights the need for and feasibility of an integrated approach to target stress pathways in cancer patients to achieve comprehensive cancer treatment

Internet-Based Group Intervention for Ovarian Cancer Survivors: Feasibility and Preliminary Results

Development of psychosocial group interventions for ovarian cancer survivors has been limited. Drawing from elements of cognitive-behavioral stress management (CBSM), mindfulness-based stress reduction (MBSR), and acceptance and commitment therapy (ACT), we developed and conducted preliminary testing of an Internet-based group intervention tailored specifically to meet the needs of ovarian cancer survivors. The Internet-based platform facilitated home delivery of the psychosocial intervention to a group of cancer survivors for whom attending face-to-face programs could be difficult given their physical limitations and the small number of ovarian cancer survivors at any one treatment site. The aim of this study was to develop, optimize, and assess the usability, acceptability, feasibility, and preliminary intended effects of an Internet-based group stress management intervention for ovarian cancer survivors delivered via a tablet or laptop. In total, 9 ovarian cancer survivors provided feedback during usability testing. Subsequently, 19 survivors participated in 5 waves of field testing of the 10-week group intervention led by 2 psychologists. The group met weekly for 2 hours via an Internet-based videoconference platform. Structured interviews and weekly evaluations were used to elicit feedback on the website and intervention content. Before and after the intervention, measures of mood, quality of life (QOL), perceived stress, sleep, and social support were administered. Paired t tests were used to examine changes in psychosocial measures over time. Usability results indicated that participants (n=9) performed basic tablet functions quickly with no errors and performed website functions easily with a low frequency of errors. In the field trial (n=19), across 5 groups, the 10-week intervention was well attended. Perceived stress (P=.03) and ovarian cancer-specific QOL (P=.01) both improved significantly during the course of the intervention. Trends toward decreased distress (P=.18) and greater physical (P=.05) and functional well-being (P=.06) were also observed. Qualitative interviews revealed that the most common obstacles participants experienced were technical issues and the time commitment for practicing the techniques taught in the program. Participants reported that the intervention helped them to overcome a sense of isolation and that they appreciated the ability to participate at home. An Internet-based group intervention tailored specifically for ovarian cancer survivors is highly usable and acceptable with moderate levels of feasibility. Preliminary psychosocial outcomes indicate decreases in perceived stress and improvements in ovarian cancer-specific QOL following the intervention. A randomized clinical trial is needed to demonstrate the efficacy of this promising intervention for ovarian cancer survivors