Neurotrophins and Their Receptors, Novel Therapeutic Targets for Pelvic Pain in Endometriosis, Are Coordinately Regulated by IL-1ß via the JNK Signaling Pathway.

Pelvic pain in women with endometriosis is attributed to neuroinflammation and afferent nociceptor nerves in ectopic and eutopic endometrium. The hypothesis that uterine nociception is activated by IL-1ß, a prominent cytokine in endometriosis, was tested herein. Immunofluorescence histochemistry confirmed the presence of neurons in human endometrial tissue. Expression of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and their receptors in endometrial tissue and cells was validated by immunohistochemistry and Western blotting. Isolated endometrial stromal cells (ESCs) were subjected to dose-response and time-course experiments with IL-1ß and kinase inhibitors to characterize in vitro biomarkers. Neural biomarkers were co-localized in endometrial nerve fibers. NGF, BDNF, and their receptors tropomyosin receptor kinase (Trk) A, TrkB, and p75 neurotrophin receptor were all expressed in primary ESCs. IL-1ß stimulated higher TrkA/B expression in ESCs derived from endometriosis cases (2.8- ± 0.2-fold) than cells from controls (1.5- ± 0.3-fold, t-test, P < 0.01), effects that were mediated via the c-Jun N-terminal kinase (JNK) pathway. BDNF concentrations trended higher in peritoneal fluid of endometriosis cases but were not statistically different from controls (P = 0.16). The results support the hypothesis that NGF and BDNF and their corresponding receptors orchestrate innervation of the endometrium, which is augmented by IL-1ß. We postulate that JNK inhibitors, such as SP600125, have the potential to reduce neuroinflammation in women with endometriosis.

Naturalistic Bladder Filling Reveals Subtypes in Overactive Bladder Syndrome That Differentially Engages Urinary Urgency-Related Brain Circuits: Results From the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN).

PURPOSE: Overactive bladder (OAB) may be attributed to dysfunction in supraspinal brain circuits. Overactive bladder participants enrolled in the LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network) study reported sensations of urinary urgency during a bladder-filling paradigm while undergoing brain functional MRI to map supraspinal dysfunction. MATERIALS AND METHODS: OAB participants and controls (CONs) completed 2 resting-state functional MRI scans following consumption of 350 mL water. Scans were conducted at fuller and emptier bladder states, interleaved with voiding. Urgency ratings (0-10) were assessed. Patterns of urgency during bladder filling were investigated using latent class trajectory models. Clusters of participants encompassing each pattern (ie, subtype) were derived from aggregated groups of OAB and CON independent of diagnosis. RESULTS: Two distinct patterns of urgency trajectories were revealed: first subtype with OAB and CON who were unresponsive to bladder filling (OAB-1 and CON-1) and second highly responsive subtype predominantly containing OAB (OAB-2). OAB-2 participants scored significantly higher on urinary symptoms but not pain or psychosocial measures. Neuroimaging analyses showed change in urgency due to both bladder filling and voided volume related to multiple loci of brain network connectivity in OAB-2, and in some cases, different than OAB-1 and/or CON-1. Sensorimotor to dorsomedial/dorsolateral prefrontal connectivity mediated the relationship between stimulus (voided volume) and percept (urgency) in OAB-2. CONCLUSIONS: Our results reveal different OAB subtypes with latent class trajectory models of urgency ratings during natural bladder filling. Functional MRI revealed differences in pathophysiology between subtypes, namely sensorimotor-prefrontal connectivity is a key locus in OAB patients with higher urinary symptoms.

Plasma proteins and persistent postsurgical pelvic pain among adolescents and young adults with endometriosis.

BACKGROUND: Noninvasive biomarkers that predict surgical treatment response would inform personalized treatments and provide insight into potential biologic pathways underlying endometriosis-associated pain and symptom progression. OBJECTIVE: To use plasma proteins in relation to the persistence of pelvic pain following laparoscopic surgery in predominantly adolescents and young adults with endometriosis using a multiplex aptamer-based proteomics biomarker discovery platform. STUDY DESIGN: We conducted a prospective analysis including 142 participants with laparoscopically-confirmed endometriosis from the Women's Health Study: From Adolescence to Adulthood observational longitudinal cohort with study enrollment from 2012-2018. Biologic samples and patient data were collected with modified World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project tools. In blood collected before laparoscopic ablation or excision of endometriosis, we simultaneously measured 1305 plasma protein levels, including markers for immunity, angiogenesis, and inflammation, using SomaScan. Worsening or persistent postsurgical pelvic pain was defined as having newly developed, persistent (ie, stable), or worsening severity, frequency, or persistent life interference of dysmenorrhea or acyclic pelvic pain at 1-year postsurgery compared with presurgery. We calculated odds ratios and 95% confidence intervals using logistic regression adjusted for age, body mass index, fasting status, and hormone use at blood draw. We applied Ingenuity Pathway Analysis and STRING analysis to identify pathophysiologic pathways and protein interactions. RESULTS: The median age at blood draw was 17 years (interquartile range, 15-19 years), and most participants were White (90%). All had superficial peritoneal lesions only and were treated by excision or ablation. One-year postsurgery, pelvic pain worsened or persisted for 76 (54%) of these participants with endometriosis, whereas pelvic pain improved for 66 (46%). We identified 83 proteins associated with worsening or persistent pelvic pain 1-year postsurgery (nominal P<.05). Compared with those with improved pelvic pain 1-year postsurgery, those with worsening or persistent pelvic pain had higher plasma levels of CD63 antigen (odds ratio, 2.98 [95% confidence interval, 1.44-6.19]) and CD47 (odds ratio, 2.68 [95% confidence interval, 1.28-5.61]), but lower levels of Sonic Hedgehog protein (odds ratio, 0.55 [95% confidence interval, 0.36-0.84]) in presurgical blood. Pathways related to cell migration were up-regulated, and pathways related to angiogenesis were down-regulated in those with worsening or persistent postsurgical pelvic pain compared with those with improved pain. When we examined the change in protein levels from presurgery to postsurgery and its subsequent risk of worsening or persistent postsurgical pain at 1-year follow-up, we observed increasing levels of Sonic Hedgehog protein from presurgery to postsurgery was associated with a 4-fold increase in the risk of postsurgical pain (odds ratio [quartile 4 vs 1], 3.86 [1.04-14.33]). CONCLUSION: Using an aptamer-based proteomics platform, we identified plasma proteins and pathways associated with worsening or persistent pelvic pain postsurgical treatment of endometriosis among adolescents and young adults that may aid in risk stratification of individuals with endometriosis.

Validation of a simple body map to measure widespread pain in urologic chronic pelvic pain syndrome: A MAPP Research Network study.

PURPOSE: In patients with urologic chronic pelvic pain syndrome (UCPPS), the presence of widespread pain appears to identify a distinct phenotype, with a different symptom trajectory and potentially different response to treatment than patients with pelvic pain only. MATERIALS AND METHODS: A 76-site body map was administered four times, at weekly intervals, to 568 male and female UCPPS participants in the MAPP Network protocol. The 76 sites were classified into 13 regions (1 pelvic region and 12 nonpelvic regions). The degree of widespread pain was scored from 0 to 12 based on the number of reported nonpelvic pain regions. This continuous body map score was regressed over other measures of widespread pain, with UCPPS symptom severity, and with psychosocial variables to measure level of association. These models were repeated using an updated body map score (0-12) that incorporated a threshold of pain ≥ 4 at each site. RESULTS: Body map scores showed limited variability over the 4 weekly assessments, indicating that a single baseline assessment was sufficient. The widespread pain score correlated highly with other measures of widespread pain and correlated with worsened UCPPS symptom severity and psychosocial functioning. Incorporating a pain severity threshold ≥4 resulted in only marginal increases in these correlations. CONCLUSIONS: These results support the use of this 13-region body map in the baseline clinical assessment of UCPPS patients. It provides reliable data about the presence of widespread pain and does not require measurement of pain severity, making it relatively simple to use for clinical purposes.

Pelvic myofascial pain is associated with restriction of sexual activity in women with pelvic pain: a cross-sectional study.

Background Dyspareunia and restriction of sexual activity are often reported by patients with chronic pelvic pain, but less is known about which conditions or factors contribute most to these symptoms. Methods This is a cross-sectional study of consecutive new patients who presented to a chronic pelvic pain and endometriosis referral clinic between January 2013 and December 2015. Patients completed a detailed questionnaire prior to their first visit and underwent a comprehensive standardised pelvic examination at their first visit. Patients were grouped according to description of sexual activity as 'normal activity without pain', 'normal activity but painful', 'severely restricted by pain', or 'absent due to pain.' Primary outcome was restriction of sexual activity due to pain. Multinomial logistic regression was performed with 'normal activity without pain' group as reference category and adjusted for age, depression, history of endometriosis, and pelvic myofascial pain. Results Over half of the 187 patients with chronic pelvic pain described severely restricted (n =75, 40.1%) or absent (n =21, 11.2%) sexual activity due to pain. Pelvic myofascial pain was highly prevalent in this population and pelvic myofascial tenderness score was associated with higher odds of sexual activity that was severely restricted by pain (OR 1.05, 95% CI 1.01-1.09, P =0.006) or absent due to pain (OR 1.09, 95% CI 1.04-1.13, P Conclusion Dyspareunia and sexual dysfunction are highly prevalent among patients with chronic pelvic pain, and pelvic myofascial pain is strongly associated with restriction of sexual activity due to pain.

Early and recent exposure to adversity, TLR-4 stimulated inflammation, and diurnal cortisol in women with interstitial cystitis/bladder pain syndrome: A MAPP research network study.

Both early (ELA) and recent life adversity (RLA) have been linked with chronic pain conditions and persistent alterations of neuroendocrine and inflammatory responses. Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a chronic urologic disorder characterized by bladder and/or pelvic pain, and excessive urinary frequency and/or urgency. IC/BPS has been associated with high levels of ELA as well as a distinct inflammatory signature. However, associations between ELA and RLA with inflammatory mechanisms in IC/BPS that might underlie the link between adversity and symptoms have not been examined. Here we investigated ELA and RLA in women with IC/BPS as potential risk factors for inflammatory processes and hypothalamic-pituitaryadrenal (HPA) abnormalities using data from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. Women with IC/BPS and healthy controls (n = 154 and 32, respectively) completed surveys, collected salivary cortisol at awakening and bedtime for 3 days, and gave a blood sample which was analyzed for 7 LPS-stimulated cytokines and chemokines (IL-6, TNFα, IL-1ß, MIP1α, MCP1, IL-8, and IL-10). Two cytokine/chemokine composites were identified using principal components analysis. Patients with greater exposure to RLA or cumulative ELA and RLA of at least moderate severity showed elevated levels of a composite of all cytokines, adjusting for age, body mass index, and study site. Furthermore, there was a trending relationship between ELA and the pro-inflammatory composite score. Nocturnal cortisol and cortisol slope were not associated with ELA, RLA, or inflammation. The present findings support the importance of adverse events in IC/BPS via a biological mechanism and suggest that ELA and RLA should be assessed as risk factors for inflammation as part of a clinical workup for IC/BPS.

Psychosocial predictors of change in sexual activity and sexual function after hysterectomy in women with pelvic pain.

BACKGROUND: Potential impact on sexual function is an often-cited concern for many patients considering hysterectomy. The existing literature indicates that sexual function remains stable to slightly improved for most patients who undergo hysterectomy, but most studies demonstrate a small subset of patients in whom sexual function declines after surgery. Unfortunately, there is a lack of clarity as to surgical, clinical, and psychosocial factors that may influence the likelihood of sexual activity after surgery or the magnitude and direction of change in sexual function. Although psychosocial factors are strongly associated with overall female sexual function, there is minimal data exploring the potential impact of these factors on the change in sexual function after hysterectomy. OBJECTIVE: This study aimed to evaluate the relationship between baseline psychosocial factors and both sexual activity and sexual function at 6 months after hysterectomy. STUDY DESIGN: Patients undergoing hysterectomy for benign, non-obstetric indications were prospectively recruited as part of an observational cohort study evaluating presurgical predictors of posthysterectomy outcomes on pain, quality of life, and sexual function. The Female Sexual Function Index was administered before hysterectomy and 6 months after surgery. Presurgical psychosocial assessments included validated self-reported measures of depression, resilience, relationship satisfaction, emotional support, and social participation. RESULTS: Complete data was available for 193 patients, of whom 149 (77.2%) reported sexual activity at 6 months after hysterectomy. In the binary logistic regression model examining sexual activity at 6 months, older age was associated with a lower likelihood of sexual activity (odds ratio, 0.91; 95% confidence interval, 0.85-0.96; P=.002). Higher relationship satisfaction before surgery was associated with a greater likelihood of sexual activity at 6 months (odds ratio, 1.09; 95% confidence interval, 1.02-1.16; P=.008). As expected, preoperative sexual activity was associated with a greater likelihood of postoperative sexual activity (odds ratio, 9.78; 95% confidence interval, 3.95-24.19, P<.001). Analyses using Female Sexual Function Index scores were limited to patients who were sexually active at both time points (n=132 [68.4%]). The total Female Sexual Function Index score did not change significantly from baseline to 6 months, but there were statistically significant changes in several individual domains of sexual function. Patients reported significant improvement in desire (P=.012), arousal (P=.023), and pain (P<.001) domains. However, significant decreases were reported in orgasm (P<.001) and satisfaction (P<.001) domains. The proportion of patients who met the criteria for sexual dysfunction was quite high (>60%) at both time points, but there was not a statistically significant change in the proportion from baseline to 6 months. In the multivariate linear regression model, there was no relationship between change in sexual function score and any of the variables examined, including age, endometriosis history, pelvic pain severity, or psychosocial measures. CONCLUSION: In this cohort of patients with pelvic pain undergoing hysterectomy for benign indications, both sexual activity and sexual function remained fairly stable after hysterectomy. Higher relationship satisfaction, younger age, and preoperative sexual activity were associated with a greater probability of sexual activity at 6 months after surgery. Psychosocial factors, such as depression, relationship satisfaction, and emotional support, and history of endometriosis were not related to change in sexual function among patients who were sexually active both before hysterectomy and at 6 months after surgery.

Protocol for Biospecimen Collection and Analysis Within the BACPAC Research Program.

The Biospecimen Collection and Processing Working Group of the National Institutes of Health (NIH) HEAL Initiative BACPAC Research Program was charged with identifying molecular biomarkers of interest to chronic low back pain (cLBP). Having identified biomarkers of interest, the Working Group worked with the New York University Grossman School of Medicine, Center for Biospecimen Research and Development-funded by the Early Phase Pain Investigation Clinical Network Data Coordinating Center-to harmonize consortium-wide and site-specific efforts for biospecimen collection and analysis. Biospecimen collected are saliva, blood (whole, plasma, serum), urine, stool, and spine tissue (paraspinal muscle, ligamentum flavum, vertebral bone, facet cartilage, disc endplate, annulus fibrosus, or nucleus pulposus). The omics data acquisition and analyses derived from the biospecimen include genomics and epigenetics from DNA, proteomics from protein, transcriptomics from RNA, and microbiomics from 16S rRNA. These analyses contribute to the overarching goal of BACPAC to phenotype cLBP and will guide future efforts for precision medicine treatment.

An Interventional Response Phenotyping Study in Chronic Low Back Pain: Protocol for a Mechanistic Randomized Controlled Trial.

Evidence-based treatments for chronic low back pain (cLBP) typically work well in only a fraction of patients, and at present there is little guidance regarding what treatment should be used in which patients. Our central hypothesis is that an interventional response phenotyping study can identify individuals with different underlying mechanisms for their pain who thus respond differentially to evidence-based treatments for cLBP. Thus, we will conduct a randomized controlled Sequential, Multiple Assessment, Randomized Trial (SMART) design study in cLBP with the following three aims. Aim 1: Perform an interventional response phenotyping study in a cohort of cLBP patients (n = 400), who will receive a sequence of interventions known to be effective in cLBP. For 4 weeks, all cLBP participants will receive a web-based pain self-management program as part of a run-in period, then individuals who report no or minimal improvement will be randomized to: a) mindfulness-based stress reduction, b) physical therapy and exercise, c) acupressure self-management, and d) duloxetine. After 8 weeks, individuals who remain symptomatic will be re-randomized to a different treatment for an additional 8 weeks. Using those data, we will identify the subsets of participants that respond to each treatment. In Aim 2, we will show that currently available, clinically derived measures, can predict differential responsiveness to the treatments. In Aim 3, a subset of participants will receive deeper phenotyping (n = 160), to identify new experimental measures that predict differential responsiveness to the treatments, as well as to infer mechanisms of action. Deep phenotyping will include functional neuroimaging, quantitative sensory testing, measures of inflammation, and measures of autonomic tone.

Reliability and Validity of Pain and Urinary Symptom Severity Assessment in Urological Chronic Pelvic Pain: A MAPP Network Analysis.

PURPOSE: We assessed the reliability and validity of an efficient severity assessment for pelvic pain and urinary symptoms in urological chronic pelvic pain syndrome, which consists of interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. MATERIALS AND METHODS: A total of 578 patients were assessed using brief, empirically derived self-report scales for pelvic pain severity (PPS) and urinary symptom severity (USS) 4 times during a 1-month period and baseline clinic visit that included urological, pain and illness-impact measures. Mild, moderate and severe categories on each dimension were examined for measurement stability and construct validity. RESULTS: PPS and USS severity categories had adequate reliability and both discriminant validity (differential relationships with specific clinical and self-report measures) and convergent validity (common association with nonurological somatic symptoms). For example, increasing PPS was associated with pelvic tenderness and widespread pelvic pain, whereas USS was associated with urgency during a bladder filling test and increased sensory sensitivity. PPS and USS categories were independently associated with nonurological pain and emotional distress. A descriptive analysis identified higher likelihood characteristics associated with having moderate to severe PPS or USS or both. Lack of sex interactions indicated that the measures are comparable in interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. CONCLUSIONS: Women and men with urological chronic pelvic pain syndrome can be reliably subgrouped using brief self-report measures of mild, moderate or severe pelvic pain and urinary symptoms. Comparisons with a broad range of clinical variables demonstrate the validity and potential clinical utility of these classifications, including use in clinical trials, health services and biological research.

Sexual function after hysterectomy according to surgical indication: a prospective cohort study.

BACKGROUND: Our aims were to describe characteristics of sexual function prior to and 6months following benign hysterectomy in patients with three common surgical indications, and to identify preoperative factors that influence the magnitude and direction of change in sexual function after the procedure. METHODS: This prospective observational cohort study enrolled women (n =80) undergoing hysterectomy for benign indications. Patients were categorised into three groups according to surgical indication: (1) pelvic pain (PP), (2) abnormal uterine bleeding (AUB), and (3) pelvic organ prolapse (POP). Primary outcome was Female Sexual Function Index (FSFI), which patients completed preoperatively and 6months postoperatively. RESULTS: The study included 80 patients, of whom 25.0% (n =20) had surgical indication of PP, 46.3% (n =37) of AUB, and 28.7% (n =23) of POP. PP patients experienced a significant improvement in overall sexual function, as well as orgasm and pain domains following hysterectomy. Significant improvements were not found in AUB and POP patients. In multivariate analysis, lower baseline sexual function (P <0.001), younger age (P =0.013), and pelvic pain<6months (P =0.020) were each independently associated with improvement in sexual function, but surgical indication was not significant. CONCLUSION: Individual patient factors including younger age, lower baseline sexual function, and short duration of pelvic pain are associated with a higher likelihood of improvement in sexual function after hysterectomy. Surgical indication does not appear to be predictive of postoperative sexual function once accounting for other factors.

Altered network architecture of functional brain communities in chronic nociplastic pain.

Neuroimaging has enhanced our understanding of the neural correlates of pain. Yet, how neural circuits interact and contribute to persistent pain remain largely unknown. Here, we investigate the mesoscale organization of the brain through intrinsic functional communities generated from resting state functional MRI data from two independent datasets, a discovery cohort of 43 Fibromyalgia (FM) patients and 20 healthy controls (HC) as well as a replication sample of 34 FM patients and 21 HC. Using normalized mutual information, we found that the global network architecture in chronic pain patients is less stable (more variable). Subsequent analyses of node community assignment revealed the composition of the communities differed between FM and HC. Furthermore, differences in network organization were associated with the changes in the composition of communities between patients with varying levels of clinical pain. Together, this work demonstrates that intrinsic network communities differ substantially between patients with FM and controls. These differences may represent a novel aspect of the pathophysiology of chronic nociplastic pain.

Temporal Relationships between Pain, Mood and Urinary Symptoms in Urological Chronic Pelvic Pain Syndrome: A MAPP Network Study.

PURPOSE: We sought to determine the time-lagged, bidirectional relationships among clinical variables of pelvic pain, urinary symptoms, negative mood, nonpelvic pain and quality of life in men and women with urological chronic pelvic pain syndrome, incorporating interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. MATERIALS AND METHODS: A total of 204 female and 166 male patients were assessed up to 24 times over a 48-week period on the 5 primary outcomes. A lagged autoregressive analysis was applied to determine the directional relationship of one variable to another 2 weeks later, beyond that of the concurrent relationships at each time point and autocorrelations and trends over time. RESULTS: The results show clear evidence for a bidirectional positive relationship between changes in pelvic pain severity and urinary symptom severity. Increases in either variable predicted significant increases in the other 2 weeks later, beyond that explained by their concurrent relationship at each time point. Pelvic pain and to a lesser degree urinary frequency also showed similar bidirectional relationships with negative mood and decreased quality of life. Interestingly, neither pelvic pain or urinary symptom severity showed lagged relationships with nonpelvic pain severity. CONCLUSIONS: Results document for the first time specific short-term positive feedback between pelvic pain and urinary symptoms, and between symptoms of urological chronic pelvic pain syndrome, mood and quality of life. The feedforward aspects of these relationships can facilitate a downward spiral of increased symptoms and worsening psychosocial function, and suggest the need for multifaceted treatments and assessment to address this possibility in individual patients.

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.

Rural residence is related to shorter survival in epithelial ovarian cancer patients.

OBJECTIVE: Rural residence has been related to health disparities and greater mortality risk in cancer patients, including gynecologic cancer patients. Lower survival rates for rural cancer survivors have been attributed to limited access to specialized healthcare, including surgery. Here, we examined whether a rural/urban survival gap existed in ovarian cancer patients receiving surgery at tertiary-care facilities, and potential causes for this gap, including educational attainment. METHODS: Rural and urban patients with high grade invasive ovarian cancer (n = 342) seeking treatment at two midwestern tertiary-care university hospitals were recruited pre-surgery and followed until death or censoring date. Rural/urban residence was categorized using the USDA Rural-Urban Continuum Codes. Stratified Cox proportional hazards regression analyses, with clinical site as strata, adjusting for clinical and demographic covariates, were used to examine the effect of rurality on survival. RESULTS: Despite specialized surgical care, rural cancer survivors showed a higher likelihood of death compared to their urban counterparts, HR = 1.39 (95% CI: 1.04, 1.85) p = 0.026, adjusted for covariates. A rurality by education interaction was observed (p = 0.027), indicating significantly poorer survival in rural vs. urban patients among those with trade school/some college education, adjusted HR = 2.49 (95% CI: 1.44, 4.30), p = 0.001; there was no rurality survival disparity for the other 2 levels of education. CONCLUSIONS: Differences in ovarian cancer survival are impacted by rurality, which is moderated by educational attainment even in patients receiving initial care in tertiary settings. Clinicians should be aware of rurality and education as potential risk factors for adverse outcomes and develop approaches to address these possible risks.

Incidence and predictors of persistent pelvic pain following hysterectomy in women with chronic pelvic pain.

BACKGROUND: Chronic pelvic pain is a debilitating problem that afflicts 15% to 20% of women in the United States. Although more than 200,000 hysterectomies are performed annually for the treatment of chronic pelvic pain, previous studies indicate that 1 in 4 women undergo the discomfort and morbidity of hysterectomy without the relief of pain. The factors that predict treatment failure remain poorly characterized. OBJECTIVE: To describe the incidence of persistent pelvic pain 6 months following hysterectomy in women with chronic pelvic pain and determine whether a simple, self-reported measure of central sensitization is associated with a greater risk of persistent pelvic pain following hysterectomy. STUDY DESIGN: We conducted a prospective, observational cohort study of women undergoing hysterectomy at an academic tertiary care center for a benign indication. Patients with preoperative chronic pelvic pain, defined as average pelvic pain ≥3 on a 0 to 10 numeric rating scale for >3 months before hysterectomy, were included in this analysis. The patients completed validated assessments of pain, anxiety, depression, and centralized pain (using the 2011 Fibromyalgia Survey Criteria, 0-31 points) preoperatively and 6 months after hysterectomy. The demographic information, surgical history, intraoperative findings, and surgical pathology were abstracted from the electronic medical records. Multivariate logistic regression was used to identify the independent predictors of persistent pelvic pain 6 months following hysterectomy, defined as <50% improvement in pelvic pain severity. RESULTS: Among 176 participants with pelvic pain before hysterectomy, 126 (71.6%) were retained at 6 months, and 15 (11.9%) reported persistent pelvic pain. There was no difference in age (P=.46), race (P=.55), average pain severity during menses (P=.68), average overall pelvic pain (P=.10), or pain duration (P=.80) in those with and without persistent pelvic pain. Whereas intraoperative findings of endometriosis (P=.05) and uterine fibroids (P=.03) were associated with a higher incidence of persistent pain on univariate analysis, the surgical route (P=.46), pelvic adhesions (0.51), uterine weight (P=.66), and adenomyosis on histopathology (P=.27) were not related to the risk of persistent pain. Higher preoperative centralized pain scores (P=.01) but not depression (P=.64) or anxiety (P=.45) were more common in women with persistent pelvic pain. Multivariate logistic regression adjusting for age, preoperative pain severity, anxiety, depression, and operative findings of endometriosis and fibroids indicated that every 1-point increase in centralized pain before hysterectomy was associated with a 27% increase in the odds of persistent pelvic pain (odds ratio, 1.27; 95% confidence interval, 1.03-1.57) 6 months after surgery. CONCLUSION: Although the majority of women with chronic pelvic pain report considerable improvement in pain following hysterectomy, higher degrees of centralized pain before hysterectomy is a robust predictor of persistent pelvic pain.

Chronic difficulties are associated with poorer psychosocial functioning in the first year post-diagnosis in epithelial ovarian cancer patients.

OBJECTIVE: Ovarian cancer is characterized by poor prognosis, high levels of distress, disturbed sleep, and compromised quality of life (QOL). Although life stressors have been shown to significantly impact physical and psychological health in cancer populations, no studies have used a high-resolution stress assessment to differentiate effects of acute versus chronic stressors among women with ovarian cancer. We addressed this issue in the present prospective longitudinal study by examining how acute and chronic stress exposure in the year pre-diagnosis relate to depressive symptoms, sleep quality, and QOL over the first year post-diagnosis in women with ovarian cancer. METHODS: One hundred thirty-seven women completed the Life Events and Difficulties Schedule within a month of initial treatment for suspected ovarian cancer. Depressive symptoms, sleep, and QOL were measured pre-treatment, at six months, and one-year post-diagnosis. Mixed models were used to examine associations of acute and chronic stress pre-diagnosis with (a) change in psychosocial outcomes over the first year post-diagnosis and (b) levels of psychosocial outcomes across all time points. RESULTS: Both the number and severity of chronic difficulties (but not acute life events) were related to significantly greater depression, and poorer sleep quality and QOL, across all time-points. In contrast, these stress indices were unrelated to changes in psychosocial functioning over time. CONCLUSIONS: Chronic but not acute stress exposure predicted average levels of depression, sleep, and QOL in the first year post-diagnosis among women with ovarian cancer. Assessing stressors and designing interventions for reducing stress may thus be beneficial for ovarian cancer patients.

Characterizing Pain and Generalized Sensory Sensitivity According to Trauma History Among Patients With Knee Osteoarthritis.

BACKGROUND: Childhood trauma and adversity have been linked to chronic pain and pain sensitivity, particularly centralized pain. Yet, there remain numerous gaps in our understanding of this link. PURPOSE: We explored the association between nonviolent and violent childhood trauma and a component of centralized pain (i.e., generalized sensory sensitivity) and pain sensitivity using self-report measures of centralized pain and quantitative sensory testing (QST). METHODS: Patients scheduled for a total knee arthroplasty (n = 129) completed questionnaires and QST prior to surgery. RESULTS: We found that self-report measures of centralized pain (i.e., widespread pain, somatic awareness, and sensory sensitivity) displayed a graded relationship across trauma groups, with patients with a history of violent trauma reporting the highest scores. Univariable multinomial logistic regression analyses showed that higher sensory sensitivity was associated with increased risk of being in the nonviolent trauma group compared to the no trauma group. Furthermore, higher widespread pain, higher somatic awareness, and higher sensory sensitivity distinguished the violent trauma group from the no trauma group. In multivariable analyses, sensory sensitivity is uniquely distinguished between the violent trauma group and the no trauma group. QST did not distinguish between groups. CONCLUSIONS: The findings highlight the need for future research and interventions that reduce sensory sensitivity for chronic pain patients with a history of violent childhood trauma.

Impact of Fibromyalgia Phenotype in Temporomandibular Disorders.

BACKGROUND: Mounting evidence suggests that central nervous system amplification, similar to that seen in fibromyalgia (FM), contributes to the pain experience in a subset of patients with temporomandibular disorders (TMD). METHODS: In this prospective observational study, patients with TMD completed the 2011 FM survey questionnaire, a surrogate measure of "centralized" pain. The influence of centralized pain on TMD pain, dysfunction, and disability was assessed dichotomously by determining the incidence of FM-positive cases in the sample and by using FM survey scores as a continuous measure of "fibromyalgia-ness" ("FM-ness"). RESULTS: The patients meeting criteria for FM diagnosis (17 of 89) had significantly more disease burden on numerous measures. FM-ness was positively associated with pain at rest, negative mood, tenderness to palpation, perceived jaw functional limitation, and pain-related disability, and it was negatively associated with comfortable pain-free jaw opening. The impact of FM-ness on perceived jaw functional limitation and disability was mediated by levels of spontaneous, ongoing pain in the orofacial region. Importantly, this pattern of findings was still present even in those not meeting the criteria for FM diagnosis. CONCLUSION: Together, these results imply that higher FM-ness increases TMD patient burden by amplifying spontaneous pain and further hampering painless jaw function, even in patients who do not meet criteria for FM diagnosis. These results are highly relevant for the clinical management of TMD, as they imply that targeting the central nervous system in the treatment of patients with TMD with evidence of pain centralization may help ameliorate both pain and jaw dysfunction.

Top down or bottom up? An observational investigation of improvement in fibromyalgia symptoms following hip and knee replacement.

OBJECTIVES: Many patients with osteoarthritis have comorbid symptoms of FM, but it is unknown how these symptoms respond to surgical procedures that address nociceptive input in the periphery, such as total joint replacement. Here we explore differences in clinical characteristics between patients whose FM symptoms do and do not improve following total hip or knee replacement. METHODS: Participants were 150 patients undergoing knee or hip replacement who had a minimum FM survey score of 4 or greater prior to surgery. The top tertile of patients experiencing the most improvement in FM symptoms at month 6 were categorized as 'Improve' (n = 48) while the bottom two tertiles were categorized as 'Worsen/Same' (n = 102). Baseline symptom characteristics were compared between groups, as well as improvement in overall pain severity, surgical pain severity and physical function at 6 months. RESULTS: The Worsen/Same group had higher levels of fatigue, depression and surgical site pain at baseline (all P < 0.05). Additionally, they improved less on overall pain severity and physical functioning 6 months after surgery (both P < 0.05). CONCLUSION: Most patients derive significant benefit in improvement of comorbid FM symptoms following total joint replacement, but a substantial proportion do not. Understanding the neurobiological basis for these different trajectories may help inform clinical judgment and improve patient care.