Expression and T cell regulatory action of the PD-1 immune checkpoint in the ovary and fallopian tube.

PROBLEM: Immune cell trafficking and surveillance within the ovary and fallopian tube are thought to impact fertility and also tumorigenesis in those organs. However, little is known of how native cells of the ovary and fallopian tube interact with resident immune cells. Interaction of the Programmed Cell Death Protein-1 (PD-1/PDCD-1/CD279) checkpoint with PD-L1 is associated with downregulated immune response. We have begun to address the question of whether PD-1 ligand or its receptors (PD-L1/-L2) can regulate immune cell function in these tissues of the female reproductive tract. METHOD OF STUDY: PD-1 and ligand protein expression was evaluated in human ovary and fallopian tube specimens, the latter of which included stages of tubal cell transformation and early tumorigenesis. Ovarian expression analysis included the determination of the proteins in human follicular fluid (HFF) specimens collected during in vitro fertilization procedures. Finally, checkpoint bioactivity of HFF was determined by treatment of separately-isolated human T cells and the measurement of interferon gamma (IFNγ). RESULTS: We show that membrane bound and soluble variants of PD-1 and ligands are expressed by permanent constituent cell types of the human ovary and fallopian tube, including granulosa cells and oocytes. PD-1 and soluble ligands were present in HFF at bioactive levels that control T cell PD-1 activation and IFNγ production; full-length checkpoint proteins were found to be highly enriched in HFF exosome fractions. CONCLUSION: The detection of PD-1 checkpoint proteins in the human ovary and fallopian tube suggests that the pathway is involved in immunomodulation during folliculogenesis, the window of ovulation, and subsequent egg and embryo immune-privilege. Immunomodulatory action of receptor and ligands in HFF exosomes is suggestive of an acute checkpoint role during ovulation. This is the first study in the role of PD-1 checkpoint proteins in human tubo-ovarian specimens and the first examination of its potential regulatory action in the contexts of normal and assisted reproduction.

Optimal PSA Threshold for Obtaining MRI-Fusion Biopsy in Biopsy-Naïve Patients.

OBJECTIVE: The study investigates the prostate-specific antigen threshold for adding targeted, software-based, magnetic resonance imaging-ultrasound fusion biopsy during a standard 12-core biopsy in biopsy-naïve patients. It secondarily explores whether the targeted biopsy is necessary in setting of abnormal digital rectal examination. METHODS: 260 patients with suspected localized prostate cancer with no prior biopsy underwent prostate magnetic resonance imaging and were found to have Prostate Imaging Reporting and Data System score ≥ 3 lesion(s). All 260 patients underwent standard 12-core biopsy and targeted biopsy during the same session. Clinically significant cancer was Gleason ≥3 + 4. RESULTS: Percentages of patients with prostate-specific antigen 0-1.99, 2-3.99, 4-4.99, 5-5.99, 6-9.99, and ≥10 were 3.0%, 4.7%, 20.8%, 16.9%, 37.7%, and 16.9%, respectively. Cumulative frequency of clinically significant prostate cancer increased with the addition of targeted biopsy compared with standard biopsy alone across all prostate-specific antigen ranges. The difference in clinically significant cancer detection between targeted plus standard biopsy compared to standard biopsy alone becomes statistically significant at prostate-specific antigen >4.3 (p=0.031). At this threshold, combination biopsy detected 20 clinically significant prostate cancers, while standard detected 14 with 88% sensitivity and 20% specificity. Excluding targeted biopsy in setting of a positive digital rectal exam would save 12.3% magnetic resonance imaging and miss 1.8% clinically significant cancers in our cohort. CONCLUSIONS: In biopsy-naïve patients, at prostate-specific antigen >4.3, there is a significant increase in clinically significant prostate cancer detection when targeted biopsy is added to standard biopsy. Obtaining standard biopsy alone in patients with abnormal digital rectal examinations would miss 1.8% clinically significant cancers in our cohort.

Control of Murine Primordial Follicle Growth Activation by IκB/NFκB Signaling.

The transcription factor NFκB has been associated with the timing of menopause in a large human genome-wide association study. Furthermore, preclinical studies demonstrate that loss of Tumor necrosis factor alpha (Tnfα) or its receptor Tnfr2 slows primordial follicle growth activation (PFGA). Although Tnfα:receptor signaling stimulates NFκB and may mechanistically link these findings, very little is known about NFκB signaling in PFGA. Because signaling downstream of Tnfα/Tnfr2 ligand/receptor interaction has not been interrogated as relates to PFGA, we evaluated the expression of key NFκB signaling proteins in primordial and growing follicles, as well as during ovarian aging. We show that key members of the NFκB pathway, including subunits, activating kinases, and inhibitory proteins, are expressed in the murine ovary. Furthermore, the subunits p65 and p50, and the cytosolic inhibitory proteins IκBα and IκBß, are present in ovarian follicles, including at the primordial stage. Finally, we assessed PFGA in genetically modified mice (AKBI) previously demonstrated to be resistant to inflammatory stress-induced NFκB activation due to overexpression of the NFκB inhibitory protein IκBß. Consistent with the hypothesis that NFκB plays a key role in PFGA, AKBI mice exhibit slower PGFA than wild-type (WT) controls, and their ovaries contain nearly twice the number of primordial follicles as WT both at early and late reproductive ages. These data provide mechanistic insight on the control of PFGA and suggest that targeting NFκB at the level of IκB proteins may be a tractable route to slowing the rate of PFGA in women faced with early ovarian demise.

Current State of Urologic Medical School Education: A Scoping Review.

OBJECTIVE: To review current literature pertaining to the availability and implementation of urology-focused curricula, in an effort to highlight current approaches to urologic education at the medical school level. METHODS: A medical librarian searched PubMed, EMBASE, the Cochrane Library, ERIC, and Scopus for articles focused on undergraduate urology education. Two reviewers adjudicated all retrieved titles. Only those describing interventions in undergraduate medical urology education were included in the review. Data extracted from each article included, but were not limited to: sample size, instructional aim, type of intervention, outcome measurement, significance of results, and strength of evidence. RESULTS: After removal of 1478 duplicate search results, 2425 unique titles remained for adjudication. Title and abstract screening excluded 2311. The remaining 114 articles met inclusion criteria. The articles focused on knowledge-based education (43), urologic curricula (22), clinical skills education (19), surgical skills training (15), and survey of student experiences in urology (15). 73 had been published since January 1, 2010. CONCLUSION: Analysis of the published literature reveals a paucity of articles investigating implementation and outcomes of formal urologic curricula. Most of the literature focuses on acquisition of knowledge concerning narrow urology-related topics. Physicians often receive minimal exposure to formal urologic curricula during their undergraduate years. Appropriate interventions aimed at increasing undergraduate student familiarity with common urologic scenarios are warranted. The results of this study can inform the efforts of urology programs seeking to expand their educational opportunities.

Medium-term results of Oxford phase-3 medial unicompartmental knee arthroplasty.

PURPOSE: To review medium-term results of 49 consecutive patients who underwent Oxford phase-3 medial unicompartmental knee arthroplasty by a single surgeon. METHODS: Records of 28 women (mean age, 71 years) and 21 men (mean age, 68 years) who underwent minimally invasive Oxford phase-3 medial unicompartmental knee arthroplasty by a single surgeon were retrospectively reviewed. The Oxford knee score and visual analogue scale (VAS) scores for pain and satisfaction were assessed at the latest follow-up by an independent observer, as were postoperative radiographs for implant position, osteoarthritic changes in the non-replaced compartments, and radiolucent lines of >2 mm or implant subsidence. The survival rate was calculated using Kaplan-Meier survival analysis. Patient demographics, postoperative alignment (varus/ valgus), Oxford knee scores, and the progression of osteoarthritis in the other compartments were included in a multiple logistic regression (MLR) analysis to identify significant factors affecting the probability of being satisfied (VAS scores for satisfaction of ≤2). RESULTS: The mean follow-up duration was 7.2 years. No patient was lost to follow-up. Two patients with no knee symptoms died (unrelated to surgery) before the 5-year follow-up. The cumulative survival rate at the 9-year follow-up was 91.2% (95% confidence interval, 87.6-94.5%). There were 4 early failures (before 4 years). One patient early in the series developed avascular necrosis of the lateral femoral condyle with an over-corrected tibiofemoral valgus of 12º at 8 months; the other 3 complained of anterior knee pain, without signs of osteoarthritis. All 4 patients underwent revision with total knee arthroplasty. There were 43 patients with more than 5 years of follow-up and without revision of the prosthesis. Patients who were not satisfied (n=6) were more likely to be <65 years old (n=4, adjusted odds ratio [OR], 3.1; MLR p=0.002) and male (n=4; adjusted OR, 2.3; MLR p=0.02). Six of the 43 patients had lucent lines on radiographs, all of which were partial and under the tibial component. Progression of the arthritis in the patellofemoral and/or lateral compartments was worse in 5 patients. CONCLUSION: Careful patient selection and good surgical technique contributed to good outcome. Younger male patients should be counselled regarding the higher chance of limited satisfaction.