Upgrading of Grade Group 1 Prostate Cancer at Prostatectomy: Germline Risk Factors in a Prospective Cohort.

BACKGROUND: Localized prostate tumors show significant spatial heterogeneity, with regions of high-grade disease adjacent to lower-grade disease. Consequently, prostate cancer biopsies are prone to sampling bias, potentially leading to underestimation of tumor grade. To study the clinical, epidemiologic and molecular hallmarks of this phenomenon, we conducted a prospective study of grade upgrading: differences in detected prostate cancer grade between biopsy and surgery. METHODS: We established a prospective, multi-institutional cohort of men with Grade Group 1 (GG1) prostate cancer on biopsy who underwent radical prostatectomy. Upgrading was defined as detection of GG2+ in the resected tumor. Germline DNA from 192 subjects was subjected to whole-genome sequencing to quantify ancestry, pathogenic variants in DNA damage response genes and polygenic risk. RESULTS: Of 285 men, 67% upgraded at surgery. PSA density and percent of cancer in pre-prostatectomy positive biopsy cores were significantly associated with upgrading. No assessed genetic risk factor was predictive of upgrading, including polygenic risk scores for prostate cancer diagnosis. CONCLUSIONS: In a cohort of low-grade prostate cancer patients, a majority upgraded at radical prostatectomy. PSA density and percent of cancer in pre-prostatectomy positive biopsy cores portended the presence of higher-grade disease, while germline genetics was not informative in this setting. Patients with low-risk prostate cancer, but elevated PSA density or percent cancer in positive biopsy cores, may benefit from repeat biopsy, additional imaging or other approaches to complement active surveillance. IMPACT: Further risk stratification of patients with low-risk prostate cancer may provide useful context for active surveillance decision-making.

Assessing sociodemographic and regional disparities in Oncotype DX Genomic Prostate Score uptake.

BACKGROUND: The Oncotype DX Genomic Prostate Score (ODX-GPS) is a gene expression assay that predicts disease aggressiveness. The objective of this study was to identify sociodemographic and regional factors associated with ODX-GPS uptake. METHODS: Data from Surveillance Epidemiology and End Results registries on men with localized prostate cancer with a Gleason score of 3 + 3 or 3 + 4, PSA ≤20 ng/mL, and stage T1c to T2c disease from 2013 through 2017 were linked with ODX-GPS data. Census-tract level neighborhood socioeconomic status (nSES) quintiles were constructed using a composite socioeconomic score. Multivariable logistic regression was used to estimate the associations of ODX-GPS uptake with age at diagnosis, race and ethnicity, nSES, geographic region, insurance type, and marital status, accounting for National Comprehensive Cancer Network risk group, year of diagnosis, and clustering by census tract. RESULTS: Among 111,434 eligible men, 5.5% had ODX-GPS test uptake. Of these, 78.3% were non-Hispanic White, 9.6% were Black, 6.7% were Hispanic, and 3.6% were Asian American. Black men had the lowest odds of ODX-GPS uptake (odds ratio, 0.70; 95% confidence interval [CI], 0.63-0.76). Those in the highest versus lowest quintile of nSES were 1.64 times more likely (95% CI, 1.38-2.94) to have ODX-GPS uptake. The odds of ODX-GPS uptake were statistically significantly higher among men residing in the Northeast, West, and Midwest compared to the South. CONCLUSIONS: Disparities in ODX-GPS uptake by race, ethnicity, nSES, and geographical region were identified. Concerted efforts should be made to ensure that this clinical test is equitably available.

Increased alertness and moderate ingroup cohesion in bonobos' response to outgroup cues.

In a number of species, including humans, perceived outgroup threat can promote ingroup cohesion. However, the distribution and selection history of this association across species with varied intergroup relations remains unclear. Using a sample of 8 captive groups (N = 43 individuals), we here tested whether bonobos, like chimpanzees, show more affiliative ingroup behaviour following perception of outgroup cues (unfamiliar male long-distance vocalisations). We used comparable methods to our previous study of captive chimpanzees, and found that, although weaker, there was an association for more frequent social grooming in response to the outgroup condition than the control condition, alongside more alert posture and increased self-directed behaviour. This provides preliminary evidence for an ancestral origin to the proximate association between outgroup cues and ingroup cohesion, at least prior to the Pan-Homo split, and suggests the presence of intergroup competition in our last common ancestor.

Incidence and Pitfalls of Adipose Tissue Encountered in Prostatic Transurethral Resections and Related Specimens.

While the presence of adipose tissue and its involvement by prostatic cancer (extraprostatic extension) is well-recognized in prostate biopsies, adipose tissue in transurethral resections of the prostate (TURP) is largely unexplored. Herein, 200 consecutive TURPs and related specimens were reviewed, including a separate 3-year analysis of specimens containing prostatic cancer, with the following data collected: presence of fat, presence of cancer within fat, and quantity of fat. For specimens with both fat and prostatic cancer, specimen weight and tumor volume were recorded. Within the 200 consecutive TURPs and related specimens, adipose tissue was identified in 20%; 55% had 2.5 mm of adipose tissue; the number of fragments with adipose tissue ranged from 1 to 14. No correlation between specimen weight and measured extent of adipose tissue or number of fragments with adipose tissue was identified. Of all the specimens with prostatic cancer, 15/56 (27%) involved adipose tissue, with two specimens with large cancer volume (>90%) demonstrating extensive involvement of adipose tissue. Adipose tissue is frequently present within TURP and related specimens with variability in extent. The etiology behind encountering adipose tissue is uncertain, and it could represent resection into peri-prostatic fat, intraprostatic fat, or bladder neck fat sampling. Although encountering adipose tissue involved by cancer in TURP and related specimens may imply extraprostatic extension (pT3a), further studies are needed to corroborate these findings as well as to determine if these should be included in reported synoptics.

Plasma concentration of thrombopoietin in dogs with immune thrombocytopenia.

BACKGROUND: Immune thrombocytopenia (ITP) is a common cause of severe thrombocytopenia in dogs. The pathogenesis of nonassociative, primary ITP (pITP) appears complex, with ill-defined thrombopoietic response. OBJECTIVES: Develop an immunoassay to measure plasma canine thrombopoietin (TPO) concentration and characterize TPO concentrations in dogs with pITP. ANIMALS: Forty-one healthy dogs, 8 dogs in an induced ITP model (3 control, 5 ITP), and 58 pITP dogs. METHODS: Recombinant canine TPO (rcTPO) was purchased and its identity confirmed by mass spectrometry. Monoclonal antibodies were raised to rcTPO and used to configure a sandwich ELISA using streptavidin-biotin detection. Assay performance, coefficients of variability, and healthy dog plasma TPO reference interval (RI) were determined, followed by assay of ITP samples. RESULTS: Assay dynamic range was 15 pg/mL (lower limit of detection) to 1000 pg/mL TPO, with limit of quantitation of 62 pg/mL. Plasma TPO RI was 0 to 158 pg/mL, with plasma TPO <62 pg/mL for 35/41 healthy dogs. All dogs with induced ITP developed marked increases in plasma TPO concentration. Peak values ranged from 515 to >6000 pg/mL. In contrast, only 2/58 pITP dogs had TPO values above RI. CONCLUSIONS AND CLINICAL IMPORTANCE: Plasma TPO concentration is paradoxically low at diagnosis for most dogs with pITP. This finding suggests that ineffective thrombopoiesis contributes to thrombocytopenia in pITP dogs and supports evaluating TPO receptor agonist treatment as used for pITP in humans. The TPO assay provides a new tool to study thrombopoiesis in pITP and other thrombocytopenic syndromes in dogs.

Oxytocin homogenizes horse group organization.

The oxytocinergic system has been suggested to make up an important part of the endocrine basis of group cohesion. However, controlled studies in open-group settings have not been performed. We here investigated the impact of exogenous intranasal oxytocin on the group-level social organization of 5 groups of horses (N = 58; 12 mares and 46 geldings) through GPS tracking and social network analysis. We find oxytocin flattened social differentiation across levels. Most strikingly, oxytocin did not simply reinforce existing bonds but selectively shifted social preferences toward homogenization - individuals and pairs who otherwise rarely associated spent more time close together, while individuals and pairs with the highest baseline association instead spent more time further apart. This resulted in a more distributed structure and lower clustering coefficient at the network level. These effects reinforce and extend oxytocin's role in collective behavior, social organization, and the evolution of group-based sociality across taxa.

Critical Consciousness and Sex Positivity: Opinions on Race Play within Alternate Sexuality Communities.

Race play, the act of making explicit overtures to race, racial differences, or political racial dynamics within the context of a kink or BDSM (bondage dominance/submission, sadism/masochism) can be a contentious topic among scholars and members of alternative sexuality communities. In the current study, we explored how individuals' ideologies about race and sex are associated with their opinions of race play. Two-hundred thirty-four participants recruited through sex-positive and BDSM community spaces between January and June of 2021 completed measures of color-blind racial ideology and sexual comfort as assessments of critical consciousness and sex-positive values. Additionally, participants provided open-ended responses to a description of race play. Mixed-methods analyses using k-means clusters and crosstabs approaches indicated that the interaction of critical consciousness and sex positive attitudes influenced participants' views on race play. Among those with strong sex-positive attitudes, those who denied institutional racism were more likely to provide unequivocal support for race play while those who acknowledged institutional racism were more likely to emphasize the nuance of balancing personal sexual freedom with the implications of race for practitioners as well as spectators. Additional research is needed to further determine whether racial group membership has an impact on opinions toward race play.

Proposal for an optimised definition of adverse pathology (unfavourable histology) that predicts metastatic risk in prostatic adenocarcinoma independent of grade group and pathological stage.

AIMS: Histological grading of prostate cancer is a powerful prognostic tool, but current criteria for grade assignment are not fully optimised. Our goal was to develop and test a simplified histological grading model, based heavily on large cribriform/intraductal carcinoma, with optimised sensitivity for predicting metastatic potential. METHODS AND RESULTS: Two separate non-overlapping cohorts were identified: a 419-patient post-radical prostatectomy cohort with long term clinical follow-up and a 209-patient post-radical prostatectomy cohort in which all patients had pathologically confirmed metastatic disease. All prostatectomies were re-reviewed for high-risk histological patterns of carcinoma termed 'unfavourable histology'. Unfavourable histology is defined by any classic Gleason pattern 5 component, any large cribriform morphology (> 0.25 mm) or intraductal carcinoma, complex intraluminal papillary architecture, grade 3 stromogenic carcinoma and complex anastomosing cord-like growth. For the outcome cohort, Kaplan-Meier analysis compared biochemical recurrence, metastasis and death between subjects with favourable and unfavourable histology, stratified by pathological stage and grade group. Multivariable Cox proportional hazards models evaluated adding unfavourable histology to the Memorial Sloan Kettering Cancer Center (MSKCC) post-prostatectomy nomogram and stratification by percentage of unfavourable histology. At 15 years unfavourable histology predicted biochemical recurrence, with sensitivity of 93% and specificity of 88%, metastatic disease at 100 and 48% and death at 100 and 46%. Grade group 2 prostate cancers with unfavourable histology were associated with metastasis independent of pathological stage, while those without had no risk. Histological models for prediction of metastasis based on only large cribriform/intraductal carcinoma or increasing diameter of cribriform size improved specificity, but with lower sensitivity. Multivariable Cox proportional hazards models demonstrated that unfavourable histology significantly improved discriminatory power of the MSKCC post-prostatectomy nomogram for biochemical failure (likelihood ratio test P < 0.001). In the retrospective review of a separate RP cohort in which all patients had confirmed metastatic disease, none had unequivocal favourable histology. CONCLUSIONS: Unfavourable histology at radical prostatectomy is associated with metastatic risk, predicted adverse outcomes better than current grading and staging systems and improved the MSKCC post-prostatectomy nomogram. Most importantly, unfavourable histology stratified grade group 2 prostate cancers into those with and without metastatic potential, independent of stage. While unfavourable histology is driven predominantly by large cribriform/intraductal carcinoma, the recognition and inclusion of other specific architectural patterns add to the sensitivity for predicting metastatic disease. Moreover, a simplified dichotomous model improves communication and could increase implementation.

Major incident preparedness in a post pandemic world: A survey of anaesthetists.

The COVID-19 pandemic profoundly changed anaesthetic and critical care departments across the UK and fulfilled the definition of a major incident for an extended period of time. It is regularly highlighted that individual and organisational readiness for major incident is inconsistent, as is support in the aftermath. Post-pandemic rates of anxiety and PTSD in healthcare staff have significantly increased, but we still have no embedded method of helping to prevent it. Clinical debriefing is an emerging tool with proven improved psychological outcomes for staff following an adverse event. We surveyed 354 anaesthetists of a range of grades and experiences prior to attending a webinar centred on major incident organisation, human factors and clinical debrief. While 73.8% knew where to access their hospital's major incident plan, only 16.8% had been trained in any form of clinical debrief. Only 29% had ever received any formal training in major incident management. It seems that the occurrence of major incidents is no longer a 'once in a career' event. The inconsistencies in training and preparedness shown in our survey highlight opportunities for our workforce to be more agile and subsequently better supported for the future.

Long-Term Outcomes in Patients Using Protocol-Directed Active Surveillance for Prostate Cancer.

Importance: Outcomes from protocol-directed active surveillance for favorable-risk prostate cancers are needed to support decision-making. Objective: To characterize the long-term oncological outcomes of patients receiving active surveillance in a multicenter, protocol-directed cohort. Design, Setting, and Participants: The Canary Prostate Active Surveillance Study (PASS) is a prospective cohort study initiated in 2008. A cohort of 2155 men with favorable-risk prostate cancer and no prior treatment were enrolled at 10 North American centers through August 2022. Exposure: Active surveillance for prostate cancer. Main Outcomes and Measures: Cumulative incidence of biopsy grade reclassification, treatment, metastasis, prostate cancer mortality, overall mortality, and recurrence after treatment in patients treated after the first or subsequent surveillance biopsies. Results: Among 2155 patients with localized prostate cancer, the median follow-up was 7.2 years, median age was 63 years, 83% were White, 7% were Black, 90% were diagnosed with grade group 1 cancer, and median prostate-specific antigen (PSA) was 5.2 ng/mL. Ten years after diagnosis, the incidence of biopsy grade reclassification and treatment were 43% (95% CI, 40%-45%) and 49% (95% CI, 47%-52%), respectively. There were 425 and 396 patients treated after confirmatory or subsequent surveillance biopsies (median of 1.5 and 4.6 years after diagnosis, respectively) and the 5-year rates of recurrence were 11% (95% CI, 7%-15%) and 8% (95% CI, 5%-11%), respectively. Progression to metastatic cancer occurred in 21 participants and there were 3 prostate cancer-related deaths. The estimated rates of metastasis or prostate cancer-specific mortality at 10 years after diagnosis were 1.4% (95% CI, 0.7%-2%) and 0.1% (95% CI, 0%-0.4%), respectively; overall mortality in the same time period was 5.1% (95% CI, 3.8%-6.4%). Conclusions and Relevance: In this study, 10 years after diagnosis, 49% of men remained free of progression or treatment, less than 2% developed metastatic disease, and less than 1% died of their disease. Later progression and treatment during surveillance were not associated with worse outcomes. These results demonstrate active surveillance as an effective management strategy for patients diagnosed with favorable-risk prostate cancer.

Mortality Risks Associated with Depression in Men with Prostate Cancer.

BACKGROUND: Men diagnosed with prostate cancer (PC) have an increased risk of depression; however, it is unclear to what extent depression affects long-term survival. A better understanding of such effects is needed to improve long-term care and outcomes for men with PC. OBJECTIVE: To determine the associations between major depression and mortality in a national cohort of men with PC. DESIGN, SETTING, AND PARTICIPANTS: A national cohort study was conducted of all 180 189 men diagnosed with PC in Sweden during 1998-2017. Subsequent diagnoses of major depression were ascertained from nationwide outpatient and inpatient records through 2018. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Deaths were identified from nationwide records through 2018. Cox regression was used to compute hazard ratios (HRs) for all-cause mortality associated with major depression, adjusting for sociodemographic factors and comorbidities. Subanalyses assessed differences by PC treatment during 2005-2017. PC-specific mortality was examined using competing risks models. RESULTS AND LIMITATIONS: In 1.3 million person-years of follow-up, 16 134 (9%) men with PC were diagnosed with major depression and 65 643 (36%) men died. After adjusting for sociodemographic factors and comorbidities, major depression was associated with significantly higher all-cause mortality in men with high-risk PC (HR, 1.50; 95% confidence interval [CI], 1.44-1.55) or low- or intermediate-risk PC (1.64; 1.56-1.71). These risks were elevated regardless of PC treatment or age at PC diagnosis, except for youngest men (<55 yr) in whom the risks were nonsignificant. Major depression was also associated with increased PC-specific mortality in men with either high-risk PC (HR, 1.35; 95% CI, 1.28-1.43) or low- or intermediate-risk PC (1.42; 1.27-1.59). This study was limited to Sweden and will need replication in other countries when feasible. CONCLUSIONS: In this national cohort of men with PC, major depression was associated with ∼50% higher all-cause mortality. Men with PC need timely detection and treatment of depression to support their long-term outcomes and survival. PATIENT SUMMARY: In this report, we examined the effects of depression on survival in men with prostate cancer. We found that among all men with prostate cancer, those who developed depression had a 50% higher risk of dying than those without depression. Men with prostate cancer need close monitoring for the detection and treatment of depression to improve their long-term health outcomes.

AZGP1 deficiency promotes angiogenesis in prostate cancer.

BACKGROUND: Loss of AZGP1 expression is a biomarker associated with progression to castration resistance, development of metastasis, and poor disease-specific survival in prostate cancer. However, high expression of AZGP1 cells in prostate cancer has been reported to increase proliferation and invasion. The exact role of AZGP1 in prostate cancer progression remains elusive. METHOD: AZGP1 knockout and overexpressing prostate cancer cells were generated using a lentiviral system. The effects of AZGP1 under- or over-expression in prostate cancer cells were evaluated by in vitro cell proliferation, migration, and invasion assays. Heterozygous AZGP1± mice were obtained from European Mouse Mutant Archive (EMMA), and prostate tissues from homozygous knockout male mice were collected at 2, 6 and 10 months for histological analysis. In vivo xenografts generated from AZGP1 under- or over-expressing prostate cancer cells were used to determine the role of AZGP1 in prostate cancer tumor growth, and subsequent proteomics analysis was conducted to elucidate the mechanisms of AZGP1 action in prostate cancer progression. AZGP1 expression and microvessel density were measured in human prostate cancer samples on a tissue microarray of 215 independent patient samples. RESULT: Neither the knockout nor overexpression of AZGP1 exhibited significant effects on prostate cancer cell proliferation, clonal growth, migration, or invasion in vitro. The prostates of AZGP1-/- mice initially appeared to have grossly normal morphology; however, we observed fibrosis in the periglandular stroma and higher blood vessel density in the mouse prostate by 6 months. In PC3 and DU145 mouse xenografts, over-expression of AZGP1 did not affect tumor growth. Instead, these tumors displayed decreased microvessel density compared to xenografts derived from PC3 and DU145 control cells, suggesting that AZGP1 functions to inhibit angiogenesis in prostate cancer. Proteomics profiling further indicated that, compared to control xenografts, AZGP1 overexpressing PC3 xenografts are enriched with angiogenesis pathway proteins, including YWHAZ, EPHA2, SERPINE1, and PDCD6, MMP9, GPX1, HSPB1, COL18A1, RNH1, and ANXA1. In vitro functional studies show that AZGP1 inhibits human umbilical vein endothelial cell proliferation, migration, tubular formation and branching. Additionally, tumor microarray analysis shows that AZGP1 expression is negatively correlated with blood vessel density in human prostate cancer tissues. CONCLUSION: AZGP1 is a negative regulator of angiogenesis, such that loss of AZGP1 promotes angiogenesis in prostate cancer. AZGP1 likely exerts heterotypical effects on cells in the tumor microenvironment, such as stromal and endothelial cells. This study sheds light on the anti-angiogenic characteristics of AZGP1 in the prostate and provides a rationale to target AZGP1 to inhibit prostate cancer progression.

Critical evaluation of artificial intelligence as a digital twin of pathologists for prostate cancer pathology.

Prostate cancer pathology plays a crucial role in clinical management but is time-consuming. Artificial intelligence (AI) shows promise in detecting prostate cancer and grading patterns. We tested an AI-based digital twin of a pathologist, vPatho, on 2603 histological images of prostate tissue stained with hematoxylin and eosin. We analyzed various factors influencing tumor grade discordance between the vPatho system and six human pathologists. Our results demonstrated that vPatho achieved comparable performance in prostate cancer detection and tumor volume estimation, as reported in the literature. The concordance levels between vPatho and human pathologists were examined. Notably, moderate to substantial agreement was observed in identifying complementary histological features such as ductal, cribriform, nerve, blood vessel, and lymphocyte infiltration. However, concordance in tumor grading decreased when applied to prostatectomy specimens (κ = 0.44) compared to biopsy cores (κ = 0.70). Adjusting the decision threshold for the secondary Gleason pattern from 5 to 10% improved the concordance level between pathologists and vPatho for tumor grading on prostatectomy specimens (κ from 0.44 to 0.64). Potential causes of grade discordance included the vertical extent of tumors toward the prostate boundary and the proportions of slides with prostate cancer. Gleason pattern 4 was particularly associated with this population. Notably, the grade according to vPatho was not specific to any of the six pathologists involved in routine clinical grading. In conclusion, our study highlights the potential utility of AI in developing a digital twin for a pathologist. This approach can help uncover limitations in AI adoption and the practical application of the current grading system for prostate cancer pathology.

RAPHIA: A deep learning pipeline for the registration of MRI and whole-mount histopathology images of the prostate.

Image registration can map the ground truth extent of prostate cancer from histopathology images onto MRI, facilitating the development of machine learning methods for early prostate cancer detection. Here, we present RAdiology PatHology Image Alignment (RAPHIA), an end-to-end pipeline for efficient and accurate registration of MRI and histopathology images. RAPHIA automates several time-consuming manual steps in existing approaches including prostate segmentation, estimation of the rotation angle and horizontal flipping in histopathology images, and estimation of MRI-histopathology slice correspondences. By utilizing deep learning registration networks, RAPHIA substantially reduces computational time. Furthermore, RAPHIA obviates the need for a multimodal image similarity metric by transferring histopathology image representations to MRI image representations and vice versa. With the assistance of RAPHIA, novice users achieved expert-level performance, and their mean error in estimating histopathology rotation angle was reduced by 51% (12 degrees vs 8 degrees), their mean accuracy of estimating histopathology flipping was increased by 5% (95.3% vs 100%), and their mean error in estimating MRI-histopathology slice correspondences was reduced by 45% (1.12 slices vs 0.62 slices). When compared to a recent conventional registration approach and a deep learning registration approach, RAPHIA achieved better mapping of histopathology cancer labels, with an improved mean Dice coefficient of cancer regions outlined on MRI and the deformed histopathology (0.44 vs 0.48 vs 0.50), and a reduced mean per-case processing time (51 vs 11 vs 4.5 min). The improved performance by RAPHIA allows efficient processing of large datasets for the development of machine learning models for prostate cancer detection on MRI. Our code is publicly available at: https://github.com/pimed/RAPHIA.

68Ga-RM2 PET-MRI versus MRI alone for evaluation of patients with biochemical recurrence of prostate cancer: a single-centre, single-arm, phase 2/3 imaging trial.

BACKGROUND: National Comprehensive Cancer Network guidelines include prostate-specific membrane antigen (PSMA)-targeted PET for detection of biochemical recurrence of prostate cancer. However, targeting a single tumour characteristic might not be sufficient to reflect the full extent of disease. Gastrin releasing peptide receptors (GRPR) have been shown to be overexpressed in prostate cancer. In this study, we aimed to evaluate the diagnostic performance of the GRPR-targeting radiopharmaceutical 68Ga-RM2 in patients with biochemical recurrence of prostate cancer. METHODS: This single-centre, single-arm, phase 2/3 trial was done at Stanford University (USA). Adult patients (aged ≥18 years) with biochemical recurrence of prostate cancer, a Karnofsky performance status of 50 or higher, increasing prostate-specific antigen concentration 0·2 ng/mL or more after prostatectomy or 2 ng/mL or more above nadir after radiotherapy, and non-contributory conventional imaging (negative CT or MRI, and bone scan) were eligible. All participants underwent 68Ga-RM2 PET-MRI. The primary outcome was the proportion of patients with PET-positive findings on 68Ga-RM2 PET-MRI compared with MRI alone after initial therapy, at a per-patient and per-lesion level. The primary outcome would be considered met if at least 30% of patients had one or more lesions detected by 68Ga-RM2 PET-MRI and the detection by 68Ga-RM2 PET-MRI was significantly greater than for MRI. Each PET scan was interpreted by three independent masked readers using a standardised evaluation criteria. This study is registered with ClinicalTrials.gov, NCT02624518, and is complete. FINDINGS: Between Dec 12, 2015, and July 27, 2021, 209 men were screened for eligibility, of whom 100 were included in analyses. Median follow-up was 49·3 months (IQR 36·7-59·2). The primary endpoint was met; 68Ga-RM2 PET-MRI was positive in 69 (69%) patients and MRI alone was positive in 40 (40%) patients (p<0·0001). In the per-lesion analysis 68Ga-RM2 PET-MRI showed significantly higher detection rates than MRI alone (143 vs 96 lesions; p<0·0001). No grade 1 or worse events were reported. INTERPRETATION: 68Ga-RM2 PET-MRI showed better diagnostic performance than MRI alone in patients with biochemical recurrence of prostate cancer. Further prospective comparative studies with PSMA-targeted PET are needed to gain a better understanding of GRPR and PSMA expression patterns in these patients. FUNDING: The US Department of Defense.

The Effects of Clopidogrel Duration on Carotid Artery In-Stent Restenosis.

BACKGROUND: There are limited data supporting a specific duration for dual antiplatelet therapy in carotid artery stenting (CAS), and most clinical evidence is derived from studies involving coronary interventions. As a result, the appropriate duration of dual antiplatelet therapy after CAS is yet to be determined. We aimed to elucidate whether the duration of dual antiplatelet therapy played a role in the rate of carotid in-stent restenosis. METHODS: A retrospective analysis of all patients who underwent CAS at our institution over a 20-year period (1996-2016) was performed (n = 279). Patients who did not complete their follow-up duplex studies or were not discharged on clopidogrel were excluded from the study. Patients were separated into short-term (<6 weeks, n = 159) and long-term (>6 weeks, n = 112) clopidogrel users based on duration of therapy. We defined clinically significant in-stent restenosis as >50% restenosis (peak systolic velocity = 224 cm/s) in symptomatic patients and >80% restenosis (peak systolic velocity = 325 cm/s) in asymptomatic patients status-post prior CAS based on published velocity criteria. Rates of in-stent restenosis at 1-year, 2-year, and 5-year intervals were analyzed between the 2 groups using chi-squared analysis. RESULTS: Demographic information was largely similar between the 2 groups; however, short-term clopidogrel users were more likely to have a history of atrial fibrillation (9.43% vs. 1.68%, P = 0.008) and were less likely to have a history of coronary artery bypass graft (16.35% vs. 29.41%, P = 0.009), diabetes (33.34% vs. 49.58%, P = 0.006), and coronary artery disease (50.31% vs. 63.03%, P = 0.035). All patients were on long-term aspirin therapy. There was no significant difference between overall rates of in-stent restenosis between the short-term and long-term clopidogrel users (5.03% vs. 9.24%, P = 0.168) within 5 years of the index procedure. Similar results were observed when these groups were evaluated at 1-year (5.61% vs. 3%, P = 0.321), 2-year (2.02% vs. 6.59%, P = 0.072), and 5-year (2.24% vs. 3.57%, P = 0.635) follow-up. CONCLUSIONS: No statistically significant difference was observed in the rate of in-stent restenosis after CAS between short-term and long-term clopidogrel therapy. Patients in whom there is no other indication for longer duration clopidogrel therapy may be considered for shorter duration course of dual antiplatelet therapy following CAS.

Identification and characterization of intact glycopeptides in human urine.

Glycoproteins in urine have the potential to provide a rich class of informative molecules for studying human health and disease. Despite this promise, the urine glycoproteome has been largely uncharacterized. Here, we present the analysis of glycoproteins in human urine using LC-MS/MS-based intact glycopeptide analysis, providing both the identification of protein glycosites and characterization of the glycan composition at specific glycosites. Gene enrichment analysis reveals differences in biological processes, cellular components, and molecular functions in the urine glycoproteome versus the urine proteome, as well as differences based on the major glycan class observed on proteins. Meta-heterogeneity of glycosylation is examined on proteins to determine the variation in glycosylation across multiple sites of a given protein with specific examples of individual sites differing from the glycosylation trends in the overall protein. Taken together, this dataset represents a potentially valuable resource as a baseline characterization of glycoproteins in human urine for future urine glycoproteomics studies.

UCHL1 is a potential molecular indicator and therapeutic target for neuroendocrine carcinomas.

Neuroendocrine carcinomas, such as neuroendocrine prostate cancer and small-cell lung cancer, commonly have a poor prognosis and limited therapeutic options. We report that ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, is elevated in tissues and plasma from patients with neuroendocrine carcinomas. Loss of UCHL1 decreases tumor growth and inhibits metastasis of these malignancies. UCHL1 maintains neuroendocrine differentiation and promotes cancer progression by regulating nucleoporin, POM121, and p53. UCHL1 binds, deubiquitinates, and stabilizes POM121 to regulate POM121-associated nuclear transport of E2F1 and c-MYC. Treatment with the UCHL1 inhibitor LDN-57444 slows tumor growth and metastasis across neuroendocrine carcinomas. The combination of UCHL1 inhibitors with cisplatin, the standard of care used for neuroendocrine carcinomas, significantly delays tumor growth in pre-clinical settings. Our study reveals mechanisms of UCHL1 function in regulating the progression of neuroendocrine carcinomas and identifies UCHL1 as a therapeutic target and potential molecular indicator for diagnosing and monitoring treatment responses in these malignancies.