Nociceptin/Orphanin FQ Opioid Peptide-Receptor Expression in the Endometriosis-Associated Nerve Fibers-Possible Treatment Option?

Endometriosis (EM) is a chronic inflammatory disease affecting millions of women worldwide. Chronic pelvic pain is one of the main problems of this condition, leading to quality-of-life impairment. Currently, available treatment options are not able to treat these women accurately. A better understanding of the pain mechanisms would be beneficial to integrate additional therapeutic management strategies, especially specific analgesic options. To understand pain in more detail, nociceptin/orphanin FQ peptide (NOP) receptor expression was analyzed in EM-associated nerve fibers (NFs) for the first time. Laparoscopically excised peritoneal samples from 94 symptomatic women (73 with EM and 21 controls) were immunohistochemically stained for NOP, protein gene product 9.5 (PGP9.5), substance P (SP), calcitonin gene-related peptide (CGRP), tyrosine hydroxylase (TH), and vasoactive intestinal peptide (VIP). Peritoneal NFs of EM patients and healthy controls were positive for NOP and often colocalized with SP-, CGRP-, TH-, and VIP-positive nerve fibers, suggesting that NOP is expressed in sensory and autonomic nerve fibers. In addition, NOP expression was increased in EM associate NF. Our findings highlight the potential of NOP agonists, particularly in chronic EM-associated pain syndromes and deserve further study, as the efficacy of NOP-selective agonists in clinical trials.

Nivolumab plus ipilimumab, with or without enzalutamide, in AR-V7-expressing metastatic castration-resistant prostate cancer: A phase-2 nonrandomized clinical trial.

BACKGROUND: AR-V7-positive metastatic prostate cancer is a lethal phenotype with few treatment options and poor survival. METHODS: The two-cohort nonrandomized Phase 2 study of combined immune checkpoint blockade for AR-V7-expressing metastatic castration-resistant prostate cancer (STARVE-PC) evaluated nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg), without (Cohort 1) or with (Cohort 2) the anti-androgen enzalutamide. Co-primary endpoints were safety and prostate-specific antigen (PSA) response rate. Secondary endpoints included time-to-PSA-progression-free survival (PSA-PFS), time-to-clinical/radiographic-PFS, objective response rate (ORR), PFS lasting greater than 24 weeks, and overall survival (OS). RESULTS: Thirty patients were treated with ipilimumab plus nivolumab (N = 15, Cohort 1, previously reported), or ipilimumab plus nivolumab and enzalutamide (N = 15, Cohort 2) in patients previously progressing on enzalutamide monotherapy. PSA response rate was 2/15 (13%) in cohort 1 and 0/15 in cohort 2, ORR was 2/8 (25%) in Cohort 1 and 0/9 in Cohort 2 in those with measureable disease, median PSA-PFS was 3.0 (95% confidence interval [CI]: 2.1-NR) in cohort 1 and 2.7 (95% CI: 2.1-5.9) months in cohort 2, and median PFS was 3.7 (95% CI: 2.8-7.5) in cohort 1 and 2.9 (95% CI: 1.3-5.8) months in cohort 2. Three of 15 patients in cohort 1 (20%, 95% CI: 7.1%-45.2%) and 4/15 patients (26.7%, 95% CI: 10.5%-52.4%) in cohort 2 achieved a durable PFS lasting greater than 24 weeks. Median OS was 8.2 (95% CI: 5.5-10.4) in cohort 1 and 14.2 (95% CI: 8.5-NA) months in cohort 2. Efficacy results were not statistically different between cohorts. Grade-3/4 adverse events occurred in 7/15 cohort 1 patients (46%) and 8/15 cohort 2 patients (53%). Combined cohort (N = 30) baseline alkaline phosphatase and cytokine analysis suggested improved OS for patients with lower alkaline phosphatase (hazards ratio [HR], 0.30; 95% CI: 0.11-0.82), lower circulating interleukin-7 (IL-7) (HR, 0.24; 95% Cl: 0.06-0.93) and IL-6 (HR, 0.13; 95% Cl: 0.03-0.52) levels, and higher circulating IL-17 (HR, 4.53; 95% CI: 1.47-13.93) levels. There was a trend towards improved outcomes in men with low sPD-L1 serum levels. CONCLUSION: Nivolumab plus ipilimumab demonstrated only modest activity in patients with AR-V7-expressing prostate cancer, and was not sufficient to justify further exploration in unselected patients. Stratification by baseline alkaline phosphatase and cytokines (IL-6, -7, and -17) may be prognostic for outcomes to immunotherapy.

Willingness to Discuss Clinical Trials Among Black vs White Men With Prostate Cancer.

IMPORTANCE: Black individuals are underrepresented in cancer clinical trials. OBJECTIVE: To examine whether Black and White men with prostate cancer differ in their willingness to discuss clinical trials with their physicians and, if so, whether patient-level barriers statistically mediate racial differences. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional survey study used baseline data from Partnering Around Cancer Clinical Trials, a randomized clinical trial to increase Black individuals' enrollment in prostate cancer clinical trials. Data were collected from 2016 through 2019 at 2 National Cancer Institute-designated comprehensive cancer centers; participants were Black and White men with intermediate-risk to high-risk prostate cancer. In mediation analysis, path models regressed willingness onto race and each potential mediator, simultaneously including direct paths from race to each mediator. Significant indirect effect sizes served as evidence for mediation. EXPOSURES: Race was the primary exposure. Potential mediators included age, education, household income, perceived economic burden, pain/physical limitation, health literacy, general trust in physicians, and group-based medical suspicion. MAIN OUTCOMES AND MEASURES: The primary outcome was the answer to a single question: "If you were offered a cancer clinical trial, would you be willing to hear more information about it?" RESULTS: A total of 205 participants were included (92 Black men and 113 White men), with a mean (range) age of 65.7 (45-89) years; 32% had a high school education or lower, and 27.5% had a household income of less than $40 000. Most (88.3%) reported being definitely or probably willing to discuss trials, but White participants were more likely to endorse this highest category of willingness than Black participants (82% vs 64%; χ22 = 8.81; P = .01). Compared with White participants, Black participants were younger (F1,182 = 8.67; P < .001), less educated (F1,182 = 22.79; P < .001), with lower income (F1,182 = 79.59; P < .001), greater perceived economic burden (F1,182 = 42.46; P < .001), lower health literacy (F1,184 = 9.84; P = .002), and greater group-based medical suspicion (F1,184 = 21.48; P < .001). Only group-based medical suspicion significantly mediated the association between race and willingness to discuss trials (indirect effect, -0.22; P = .002). CONCLUSIONS AND RELEVANCE: In this study of men with prostate cancer, most participants were willing to discuss trials, but Black men were significantly less willing than White men. Black men were more likely to believe that members of their racial group should be suspicious of the health care system, and this belief was associated with lower willingness to discuss trials. Addressing medical mistrust may improve equity in clinical research.

Unpacking Trial Offers and Low Accrual Rates: A Qualitative Analysis of Clinic Visits With Physicians and Patients Potentially Eligible for a Prostate Cancer Clinical Trial.

PURPOSE: Cancer clinical trial accrual rates are low, and information about contributing factors is needed. We examined video-recorded clinical interactions to identify circumstances under which patients potentially eligible for a trial at a major cancer center were offered a trial. METHODS: We conducted a qualitative directed content analysis of 62 recorded interactions with physicians (n = 13) and patients with intermediate- or high-risk prostate cancer (n = 43). Patients were screened and potentially eligible for a trial. We observed and coded the interactions in 3 steps: (1) classification of all interactions as explicit offer, offer pending, trial discussed/not offered, or trial not discussed; (2) in interactions with no explicit offer, classification of whether the cancer had progressed; (3) in interactions classified as progression but no trial offered, identification of factors discussed that may explain the lack of an offer. RESULTS: Of the 62 interactions, 29% were classified as explicit offer, 12% as offer pending, 18% as trial discussed/not offered, and 39% as trial not discussed. Of those with no offer, 57% included information that the cancer had not progressed. In 68% of the remaining interactions with patients whose cancer had progressed but did not receive an offer, reasons for the lack of offer were identified, but in 32%, no explanation was provided. CONCLUSION: Even in optimal circumstances, few patients were offered a trial, often because their cancer had not progressed. Findings support professional recommendations to broaden trial inclusion criteria. Findings suggest accrual rates should reflect the proportion of eligible patients who enroll.

Pain and distress in advanced dementia: choosing the right tools for the job.

OBJECTIVE: There is a concern that pain is under-recognized in dementia. However, there may be other causes of distress. We wished to evaluate the utility of a distress tool and a pain tool. METHODS: Nursing home residents with advanced dementia were observed using pain (Pain Assessment in Advanced Dementia scale (PAINAD)) and distress (Disability Distress Assessment Tool (DisDAT)) assessment tools. Those in pain were treated. Reassessment occurred at one and three months. RESULTS: From 79 participants, 13 were assessed as being in pain. Psychosocial factors explained the behaviour of a false positive group. Both tools showed a significant decrease in pain following intervention (p = 0.008). Behaviours were similar in both groups. CONCLUSIONS: Both tools are useful. However, the pain tool also picks up distress, which is not caused by pain. It could potentially lead to false ascriptions of pain. The distress tool picks up a broader array of signs, which may be useful both in practice and in research.

The utility of PAINAD in assessing pain in a UK population with severe dementia.

OBJECTIVE: Studies suggest that pain is under-recognized and under-treated in those with severe dementia. Identifying pain is the first step in its effective management. Few studies have investigated the utility of behavioural pain tools in those with advanced dementia. METHODS: Participants were nursing home residents with advanced dementia who were observed on three occasions using a pain assessment tool (PAINAD). Following further assessment, an appropriate management plan was formulated for those thought to be in pain. Participants who scored above the cutoff (two) on the PAINAD scale, but were felt not to be in pain, formed the false positive group. The pain and false positive groups were reassessed at 1 and 3 months. RESULTS: Seventy-nine participants completed the study, with 39 participants scoring above two on the PAINAD. Of these, only 13 were assessed as being in pain. The other 26 participants who scored above the cutoff on PAINAD were not felt to be in pain. Instead, their behaviour had a psychosocial explanation, often to do with a lack of understanding as to what was happening to them. The sensitivity of PAINAD was 92%. In those with pain, a significant decrease was demonstrated in the PAINAD scores on intervention following treatment for pain (p=0.008). CONCLUSIONS: PAINAD is a sensitive tool for detecting pain in people with advanced dementia, but has a high false positive rate, frequently detecting psychosocial distress rather than pain. PAINAD can be used to assess whether pain management strategies have been successful.

Extending palliative care to patients with dementia.

Palliative care should be available to all with a life-limiting illness, including those with dementia. This article examines the palliative needs of those with dementia and how these needs might be met.