Andrew Schrepf

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

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.

Sleep disturbance, cytokines, and fatigue in women with ovarian cancer.

Pro-inflammatory cytokines, such as interleukin-6 (IL-6), have been implicated in the underlying processes contributing to sleep regulation and fatigue. Despite evidence for sleep difficulties, fatigue, and elevations in IL-6 among women with ovarian cancer, the association between these symptoms and IL-6 has not been investigated. To address this knowledge gap, we examined relationships between sleep disturbance, fatigue, and plasma IL-6 in 136 women with ovarian cancer prior to surgery. These relationships were also examined in 63 of these women who were disease-free and not receiving chemotherapy one year post-diagnosis. At both time-points, higher levels of IL-6 were significantly associated with sleep disturbances (p<0.05), controlling for potentially confounding biological and psychosocial covariates. Higher IL-6 was significantly associated with fatigue prior to surgery (p<0.05); however, when sleep disturbance was included in the model, the relationship was no longer significant. IL-6 was not significantly associated with fatigue at one year. Changes in sleep over time were significantly associated with percent change in IL-6 from pre-surgery to one year, adjusting for covariates (p<0.05). These findings support a direct association of IL-6 with sleep disturbances in this population, whereas the relationship between IL-6 and fatigue prior to surgery may be mediated by poor sleep. As this study is the first to examine cytokine contributions to sleep and fatigue in ovarian cancer, further research is warranted to clarify the role of biological correlates of sleep and fatigue in this population.

Sleep disturbance, distress, and quality of life in ovarian cancer patients during the first year after diagnosis

Sleep disturbance is a common clinical complaint of oncology patients and contributes to substantial morbidity. However, because most sleep studies have been cross‐sectional, associations between sleep quality and distress in patients with ovarian cancer over time remain unclear. This prospective longitudinal study examined rates of sleep disturbance; contributions of depression, anxiety, and medication use in sleep disturbance; and associations between sleep quality and quality of life (QOL) during the first year after diagnosis among women with ovarian cancer.

Diurnal cortisol and survival in epithelial ovarian cancer

Introduction Hypothalamic-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 Methods Participants 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. Results Each 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). Discussion Abnormal 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.

Inflammation and inflammatory control in interstitial cystitis/bladder pain syndrome: Associations with painful symptoms.

Summary Inflammatory dysregulation marks interstitial cystitis/bladder pain syndrome. Inflammatory responses in peripheral blood mononuclear cells following Toll‐like receptor 4 stimulation predict the magnitude of painful symptoms. ABSTRACT Toll‐like receptors (TLR) are known to play a role in chronic pain, from animal models and limited research in humans, but their role in interstitial cystitis/bladder pain syndrome (IC/BPS) is unknown. Similarly, alterations of the hypothalamic–pituitary–adrenal axis have been reported in some pain conditions. Our objectives were to identify inflammatory processes that might distinguish individuals with IC/BPS from healthy controls (HC) and to examine their associations with IC/BPS symptoms. Female participants (58 IC/BPS patients and 28 HCs) completed pain and urinary symptom questionnaires and collected saliva for cortisol as part of the Multidisciplinary Approach to Pelvic Pain study. Inflammatory cytokines were assayed in plasma, and in TLR‐2− and TLR‐4–stimulated peripheral blood mononuclear cells. Controlling for BMI and negative affect, between‐group differences were analyzed by general linear models, and relationships between symptoms and inflammatory variables were analyzed by regression. Compared to HCs, IC/BPS patients had higher levels of plasma interleukin‐6 (P = .040), greater interleukin‐1&bgr; responsive to TLR‐2 stimulation (P = .040), and flatter diurnal cortisol slopes (P = .010), indicating inflammatory dysregulation. In IC/BPS patients, inflammation after TLR‐4 stimulation was associated with multiple symptoms, including genitourinary pain (P = .010), sexual pain (P = .002), and marginally with urinary symptoms (P = .068). Genitourinary pain severity (P = .008), frequency (P = .001), and pain with intercourse (P = .002) were strongly associated with TLR‐4 inflammatory response. TLR‐4 appears to play a central role in painful symptoms of IC/BPS patients, which may be linked to poor endogenous inflammatory control. These findings may help to identify new mechanisms in IC/BPS and lead to new therapeutic approaches.

Endogenous opioidergic dysregulation of pain in fibromyalgia: a PET and fMRI study.

Abstract Endogenous opioid system dysfunction potentially contributes to chronic pain in fibromyalgia (FM), but it is unknown if this dysfunction is related to established neurobiological markers of hyperalgesia. We previously reported that µ-opioid receptor (MOR) availability was reduced in patients with FM as compared with healthy controls in several pain-processing brain regions. In the present study, we compared pain-evoked functional magnetic resonance imaging with endogenous MOR binding and clinical pain ratings in female opioid-naive patients with FM (n = 18) using whole-brain analyses and regions of interest from our previous research. Within antinociceptive brain regions, including the dorsolateral prefrontal cortex (r = 0.81, P < 0.001) and multiple regions of the anterior cingulate cortex (all r > 0.67; all P < 0.02), reduced MOR availability was associated with decreased pain-evoked neural activity. Additionally, reduced MOR availability was associated with lower brain activation in the nucleus accumbens (r = 0.47, P = 0.050). In many of these regions, pain-evoked activity and MOR binding potential were also associated with lower clinical affective pain ratings. These findings are the first to link endogenous opioid system tone to regional pain-evoked brain activity in a clinical pain population. Our data suggest that dysregulation of the endogenous opioid system in FM could lead to less excitation in antinociceptive brain regions by incoming noxious stimulation, resulting in the hyperalgesia and allodynia commonly observed in this population. We propose a conceptual model of affective pain dysregulation in FM.

Toll-like Receptor 4 and comorbid pain in Interstitial Cystitis/Bladder Pain Syndrome: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain research network study

BACKGROUND Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a condition characterized by pelvic pain and urinary symptoms. Some IC/BPS patients have pain confined to the pelvic region, while others suffer widespread pain. Inflammatory processes have previously been linked to pelvic pain in IC/BPS, but their association with widespread pain in IC/BPS has not been characterized. METHODS Sixty-six women meeting criteria for IC/BPS completed self-report measures of pain as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP), collected 3days of saliva for cortisol assays, and provided blood samples. Peripheral blood mononuclear cells (PBMCs) were stimulated with Toll-like Receptor (TLR) 2 and 4 agonists and cytokines were measured in supernatant; IL-6 was also measured in plasma. Associations between inflammatory variables and the likelihood of endorsing extra-pelvic pain, or the presence of a comorbid syndrome, were tested by logistic regression and General Linear Models, respectively. A subset of patients (n=32) completed Quantitative Sensory Testing. RESULTS A one standard deviation increase in TLR-4 inflammatory response was associated with a 1.59 greater likelihood of endorsing extra-pelvic pain (p=.019). Participants with comorbid syndromes also had higher inflammatory responses to TLR-4 stimulation in PBMCs (p=.016). Lower pressure pain thresholds were marginally associated with higher TLR-4 inflammatory responses (p=.062), and significantly associated with higher IL-6 in plasma (p=.031). CONCLUSIONS TLR-4 inflammatory responses in PBMCs are a marker of widespread pain in IC/BPS, and should be explored in other conditions characterized by medically unexplained pain.

From Childhood Trauma to Elevated C-Reactive Protein in Adulthood: The Role of Anxiety and Emotional Eating

Objective Childhood trauma is known to be related to inflammatory processes in adulthood, but underlying psychological/behavioral mechanisms have not been fully characterized. To investigate associations between childhood trauma and inflammation (indexed by C-reactive protein [CRP]), we used a structural equation modeling approach on a subsample of the Midlife in the United States biomarker project. Methods Participants included 687 men and women without history of cancer, diabetes, cardiovascular disease, or stroke who completed a physical examination and extensive questionnaires and provided blood. To test for sex differences, we held as many parameters invariant across sexes as possible while still retaining good model fit. Results Tests of direct and indirect effects revealed that childhood trauma was significantly associated with elevated CRP, via elevated body mass index (BMI; p < .001). This relationship was mediated by a broad latent measure of distress, which was associated with using food as a coping mechanism. Men and women differed in reported levels of physical abuse, sexual abuse, and physical neglect. Compared with men, women showed a stronger association between BMI and CRP, whereas men had a stronger association between use of food to cope and elevated BMI. Conclusions Our results are consistent with a model in which childhood trauma is associated with elevated CRP, a relationship associated with stress reactivity and compensatory emotional eating. Men and women may experience trauma in qualitatively distinct patterns but share many vulnerabilities, which can lead to elevated health risks. Emotional eating may be an important target for intervention in this population.

Pain Mechanisms and Centralized Pain in Temporomandibular Disorders.

Until recently, most clinicians and scientists believed that the experience of pain is perceptually proportional to the amount of incoming peripheral nociceptive drive due to injury or inflammation in the area perceived to be painful. However, many cases of chronic pain have defied this logic, leaving clinicians perplexed as to how patients are experiencing pain with no obvious signs of injury in the periphery. Conversely, there are patients who have a peripheral injury and/or inflammation but little or no pain. What makes some individuals experience intense pain with minimal peripheral nociceptive stimulation and others experience minimal pain with serious injury? It is increasingly well accepted in the scientific community that pain can be generated and maintained or, through other mechanisms, suppressed by changes in the central nervous system, creating a complete mismatch between peripheral nociceptive drive and perceived pain. In fact, there is no known chronic pain condition where the observed extent of peripheral damage reproducibly engenders the same level of pain across individuals. Temporomandibular disorders (TMDs) are no exception. This review focuses on the idea that TMD patients range on a continuum—from those whose pain is generated peripherally to those whose pain is centralized (i.e., generated, exacerbated, and/or maintained by central nervous system mechanisms). This article uses other centralized chronic pain conditions as a guide, and it suggests that the mechanistic variability in TMD pain etiology has prevented us from adequately treating many individuals who are diagnosed with the condition. As the field moves forward, it will be imperative to understand each person’s pain from its own mechanistic standpoint, which will enable clinicians to deliver personalized medicine to TMD patients and eventually provide relief in even the most recalcitrant cases.

Pre-treatment effects of peripheral tumors on brain and behavior: neuroinflammatory mechanisms in humans and rodents.

Cancer patients suffer high levels of affective and cognitive disturbances, which have been attributed to diagnosis-related distress, impairment of quality of life, and side effects of primary treatment. An inflammatory microenvironment is also a feature of the vast majority of solid tumors. However, the ability of tumor-associated biological processes to affect the central nervous system (CNS) has only recently been explored in the context of symptoms of depression and cognitive disturbances. In this review, we summarize the burgeoning evidence from rodent cancer models that solid tumors alter neurobiological pathways and subsequent behavioral processes with relevance to affective and cognitive disturbances reported in human cancer populations. We consider, in parallel, the evidence from human clinical cancer research demonstrating that affective and cognitive disturbances are common in some malignancies prior to diagnosis and treatment. We further consider the underlying neurobiological pathways, including altered neuroinflammation, tryptophan metabolism, prostaglandin synthesis and associated neuroanatomical changes, that are most strongly implicated in the rodent literature and supported by analogous evidence from human cancer populations. We focus on the implications of these findings for behavioral researchers and clinicians, with particular emphasis on methodological issues and areas of future research.