A nuclear pyruvate dehydrogenase complex is important for the generation of acetyl-CoA and histone acetylation.

DNA transcription, replication, and repair are regulated by histone acetylation, a process that requires the generation of acetyl-coenzyme A (CoA). Here, we show that all the subunits of the mitochondrial pyruvate dehydrogenase complex (PDC) are also present and functional in the nucleus of mammalian cells. We found that knockdown of nuclear PDC in isolated functional nuclei decreased the de novo synthesis of acetyl-CoA and acetylation of core histones. Nuclear PDC levels increased in a cell-cycle-dependent manner and in response to serum, epidermal growth factor, or mitochondrial stress; this was accompanied by a corresponding decrease in mitochondrial PDC levels, suggesting a translocation from the mitochondria to the nucleus. Inhibition of nuclear PDC decreased acetylation of specific lysine residues on histones important for G1-S phase progression and expression of S phase markers. Dynamic translocation of mitochondrial PDC to the nucleus provides a pathway for nuclear acetyl-CoA synthesis required for histone acetylation and epigenetic regulation.

TRIM35 Monoubiquitinates H2B in Cardiac Cells, Implications for Heart Failure.

BACKGROUND: The tumor suppressor and proapoptotic transcription factor P53 is induced (and activated) in several forms of heart failure, including cardiotoxicity and dilated cardiomyopathy; however, the precise mechanism that coordinates its induction with accessibility to its transcriptional promoter sites remains unresolved, especially in the setting of mature terminally differentiated (nonreplicative) cardiomyocytes. METHODS: Male and female control or TRIM35 (tripartite motif containing 35) overexpression adolescent (aged 1-3 months) and adult (aged 4-6 months) transgenic mice were used for all in vivo experiments. Primary adolescent or adult mouse cardiomyocytes were isolated from control or TRIM35 overexpression transgenic mice for all in vitro experiments. Adenovirus or small-interfering RNA was used for all molecular experiments to overexpress or knockdown, respectively, target genes in primary mouse cardiomyocytes. Patient dilated cardiomyopathy or nonfailing left ventricle samples were used for translational and mechanistic insight. Chromatin immunoprecipitation and DNA sequencing or quantitative real-time polymerase chain reaction (qPCR) was used to assess P53 binding to its transcriptional promoter targets, and RNA sequencing was used to identify disease-specific signaling pathways. RESULTS: Here, we show that E3-ubiquitin ligase TRIM35 can directly monoubiquitinate lysine-120 (K120) on histone 2B in postnatal mature cardiomyocytes. This epigenetic modification was sufficient to promote chromatin remodeling, accessibility of P53 to its transcriptional promoter targets, and elongation of its transcribed mRNA. We found that increased P53 transcriptional activity (in cardiomyocyte-specific Trim35 overexpression transgenic mice) was sufficient to initiate heart failure and these molecular findings were recapitulated in nonischemic human LV dilated cardiomyopathy samples. CONCLUSIONS: These findings suggest that TRIM35 and the K120Ub-histone 2B epigenetic modification are molecular features of cardiomyocytes that can collectively predict dilated cardiomyopathy pathogenesis.

Disparities in prostate cancer screening, diagnoses, management, and outcomes between Indigenous and non-Indigenous men in a universal health care system.

BACKGROUND: Indigenous Peoples have higher morbidity rates and lower life expectancies than non-Indigenous Canadians. Identification of disparities between Indigenous and non-Indigenous men regarding prostate cancer (PCa) screening, diagnoses, management, and outcomes was sought. METHODS: An observational cohort of men diagnosed with PCa between June 2014 and October 2022 was studied. Men were prospectively enrolled in the province-wide Alberta Prostate Cancer Research Initiative. The primary outcomes were tumor characteristics (stage, grade, and prostate-specific antigen [PSA]) at diagnosis. Secondary outcomes were PSA testing rates, time from diagnosis to treatment, treatment modality, and metastasis-free, cancer-specific, and overall survivals. RESULTS: Examination of 1,444,974 men for whom aggregate PSA testing data were available was performed. Men in Indigenous communities were less likely to have PSA testing performed than men outside of Indigenous communities (32 vs. 46 PSA tests per 100 men [aged 50-70 years] within 1 year; p < .001). Among 6049 men diagnosed with PCa, Indigenous men had higher risk disease characteristics: a higher proportion of Indigenous men had PSA ≥ 10 ng/mL (48% vs. 30%; p < .01), TNM stage ≥ T2 (65% vs. 47%; p < .01), and Gleason grade group ≥ 2 (79% vs. 64%; p < .01) compared to non-Indigenous men. With a median follow-up of 40 months (interquartile range, 25-65 months), Indigenous men were at higher risk of developing PCa metastases (hazard ratio, 2.3; 95% CI, 1.2-4.2; p < .01) than non-Indigenous men. CONCLUSIONS: Despite receiving care in a universal health care system, Indigenous men were less likely to receive PSA testing and more likely to be diagnosed with aggressive tumors and develop PCa metastases than non-Indigenous men.

Assessing cancer risk in the anterior part of the prostate using micro-ultrasound: validation of a novel distinct protocol.

PURPOSE: To develop and validate a micro-ultrasound risk score that predicts the likelihood of significant prostate cancer in the anterior zone. METHODS: Patients were enrolled from three expert institutions familiar with micro-ultrasound. The study was conducted in two phases. First, the PRI-MUS anterior score was developed by assessing selected prostate videos from patients who subsequently underwent radical prostatectomy. Second, seven urology readers with varying levels of experience in micro-ultrasound examination evaluated prostate loops according to the PRI-MUS anterior score. Each reader watched the videos and recorded the likelihood of the presence of significant cancer in the anterior part of the prostate in a three-point scale. The coherence among the readers was calculated using the Fleiss kappa and the Cronbach alpha. RESULTS: A total of 102 selected prostate scans were used to develop the risk assessment for anterior zone cancer in the prostate. The score comprised three categories: likely, equivocal, and unlikely. The median (IQR) sensitivity, specificity, positive predictive value, and negative predictive value for the seven readers were 72% (68-84), 68% (64-84), 75% (72-81), and 73% (71-80), respectively. The mean SD ROC AUC was 0.75 ± 2%, while the Fleiss kappa and the Cronbach alpha were 0.179 and 0.56, respectively. CONCLUSION: Micro-ultrasound can detect cancerous lesions in the anterior part of the prostate. When combined with the PRI-MUS protocol to assess the peripheral part, it enables an assessment of the entire prostate gland. Pending external validation, the PRI-MUS anterior score developed in this study might be implemented in clinical practice.

Magnetic Resonance Imaging-Guided Biopsy in Active Surveillance of Prostate Cancer.

PURPOSE: The underlying premise of prostate cancer active surveillance (AS) is that cancers likely to metastasize will be recognized and eliminated before cancer-related disease can ensue. Our study was designed to determine the prostate cancer upgrading rate when biopsy guided by magnetic resonance imaging (MRGBx) is used before entry and during AS. MATERIALS AND METHODS: The cohort included 519 men with low- or intermediate-risk prostate cancer who enrolled in prospective studies (NCT00949819 and NCT00102544) between February 2008 and February 2020. Subjects were preliminarily diagnosed with Gleason Grade Group (GG) 1 cancer; AS began when subsequent MRGBx confirmed GG1 or GG2. Participants underwent confirmatory MRGBx (targeted and systematic) followed by surveillance MRGBx approximately every 12 to 24 months. The primary outcome was tumor upgrading to ≥GG3. RESULTS: Upgrading to ≥GG3 was found in 92 men after a median followup of 4.8 years (IQR 3.1-6.5) after confirmatory MRGBx. Upgrade-free probability after 5 years was 0.85 (95% CI 0.81-0.88). Cancer detected in a magnetic resonance imaging lesion at confirmatory MRGBx increased risk of subsequent upgrading during AS (HR 2.8; 95% CI 1.3-6.0), as did presence of GG2 (HR 2.9; 95% CI 1.1-8.2) In men who upgraded ≥GG3 during AS, upgrading was detected by targeted cores only in 27%, systematic cores only in 25% and both in 47%. In 63 men undergoing prostatectomy, upgrading from MRGBx was found in only 5 (8%). CONCLUSIONS: When AS begins and follows with MRGBx (targeted and systematic), upgrading rate (≥GG3) is greater when tumor is initially present within a magnetic resonance imaging lesion or when pathology is GG2 than when these features are absent.

Optimizing Spatial Biopsy Sampling for the Detection of Prostate Cancer.

PURPOSE: The appropriate number of systematic biopsy cores to retrieve during magnetic resonance imaging (MRI)-targeted prostate biopsy is not well defined. We aimed to demonstrate a biopsy sampling approach that reduces required core count while maintaining diagnostic performance. MATERIALS AND METHODS: We collected data from a cohort of 971 men who underwent MRI-ultrasound fusion targeted biopsy for suspected prostate cancer. A regional targeted biopsy (RTB) was evaluated retrospectively; only cores within 2 cm of the margin of a radiologist-defined region of interest were considered part of the RTB. We compared detection rates for clinically significant prostate cancer (csPCa) and cancer upgrading rate on final whole mount pathology after prostatectomy between RTB, combined, MRI-targeted, and systematic biopsy. RESULTS: A total of 16,459 total cores from 971 men were included in the study data sets, of which 1,535 (9%) contained csPCa. The csPCa detection rates for systematic, MRI-targeted, combined, and RTB were 27.0% (262/971), 38.3% (372/971), 44.8% (435/971), and 44.0% (427/971), respectively. Combined biopsy detected significantly more csPCa than systematic and MRI-targeted biopsy (p <0.001 and p=0.004, respectively) but was similar to RTB (p=0.71), which used on average 3.8 (22%) fewer cores per patient. In 102 patients who underwent prostatectomy, there was no significant difference in upgrading rates between RTB and combined biopsy (p=0.84). CONCLUSIONS: A RTB approach can maintain state-of-the-art detection rates while requiring fewer retrieved cores. This result informs decision making about biopsy site selection and total retrieved core count.

Hemigland Cryoablation of Clinically Significant Prostate Cancer: Intermediate-Term Followup via Magnetic Resonance Imaging Guided Biopsy.

PURPOSE: Contemporary biopsy methods were used to determine the success rate of hemigland cryoablation as a primary treatment for prostate cancer. Previous studies, often including men at low risk, have used magnetic resonance imaging guided biopsy to a variable extent. Here, we uniformly used the new diagnostic modality to study all men, each with clinically significant cancer, at baseline and at short and intermediate-term followup. MATERIALS AND METHODS: In an open label trial (NCT03503643) 61 men with unilateral cancer (all clinically significant, ie Grade Group 2 or greater) underwent primary hemigland cryoablation. Subjects were 80% Caucasian, average age 69 years, prostate specific antigen 6.6 ng/ml and prostate volume 38 cc. Biopsy was performed using magnetic resonance imaging/ultrasound fusion prior to treatment and at the followup intervals of near-term (6 months, in 61) and intermediate-term (18 months, in 27). All utilities of fusion biopsy, ie targeting of magnetic resonance imaging visible lesions, template systematic sampling, and in followup, tracking of prior positive sites, were used throughout the study to detect clinically significant cancer, the primary end point. RESULTS: Following treatment 82% of men (50 of 61) had no biopsy detectable clinically significant prostate cancer at 6-month near-term followup and 82% of men (22 of 27) reaching the 18-month intermediate-term remained biopsy negative. Combination of the 3 sampling methods provided maximal cancer detection. During followup a new focus of cancer was found in the contralateral prostate in only 1 of 27 men. No adverse events above Clavien-Dindo grade 2 were encountered. CONCLUSIONS: Hemigland cryoablation, when rigorously evaluated by all utilities of magnetic resonance imaging guided biopsy, appears to eliminate clinically significant cancer in 82% of men, a success rate that endures for at least 18 months.

Risk of Prostate Cancer after a Negative Magnetic Resonance Imaging Guided Biopsy.

PURPOSE: Magnetic resonance imaging guided biopsy which reveals no cancer may impart reassurance beyond that offered by ultrasound guided biopsy. However, followup of men after a negative magnetic resonance imaging guided biopsy has been mostly by prostate specific antigen testing and reports of followup tissue confirmation are few. We investigated the incidence of clinically significant prostate cancer in such men who, because of persistent cancer suspicion, subsequently underwent a repeat magnetic resonance imaging guided biopsy. MATERIALS AND METHODS: Subjects were all men with a negative initial magnetic resonance imaging guided biopsy who underwent at least 1 further magnetic resonance imaging guided biopsy due to continued clinical suspicion of clinically significant prostate cancer (September 2009 to July 2019). Biopsies were magnetic resonance imaging-ultrasound fusion with targeted and systematic cores. Regions of interest from initial magnetic resonance imaging and any new regions of interest at followup magnetic resonance imaging guided biopsy were targeted. The primary end point was detection of clinically significant prostate cancer (Gleason Grade Group 2 or greater). RESULTS: Of 2,716 men 733 had a negative initial magnetic resonance imaging guided biopsy. Study subjects were 73/733 who underwent followup magnetic resonance imaging guided biopsy. Median (IQR) age and prostate specific antigen density were 64 years (59-67) and 0.12 ng/ml/cc (0.08-0.17), respectively. Baseline PI-RADS® scores were 3 or greater in 74%. At followup magnetic resonance imaging guided biopsy (median 2.4 years, IQR 1.3-3.6), 17/73 (23%) were diagnosed with clinically significant prostate cancer. When followup magnetic resonance imaging revealed a lesion (PI-RADS 3 or greater), clinically significant prostate cancer was found in 17/53 (32%). When followup magnetic resonance imaging was negative (PI-RADS less than 3), cancer was not found (0/20) (p <0.01). Overall 54% of men with PI-RADS 5 at followup magnetic resonance imaging guided biopsy were found to have clinically significant prostate cancer. CONCLUSIONS: Men with negative magnetic resonance imaging following an initial negative magnetic resonance imaging guided biopsy are unlikely to harbor clinically significant prostate cancer and may avoid repeat biopsy. However, when lesions are seen on followup magnetic resonance imaging, repeat magnetic resonance imaging guided biopsy is warranted.

Developments in MRI-targeted prostate biopsy.

PURPOSE OF REVIEW: MRI-targeted prostate biopsy may be an attractive alternative to systematic biopsy for diagnosing clinically significant prostate cancer. In this narrative review, we discuss the new developments that have occurred in the advancement of MRI-targeted prostate biopsy, over the past 24 months. RECENT FINDINGS: MRI-targeted biopsy offers enhanced diagnostic accuracy, when compared with the current standard of care of systematic transrectal ultrasound-guided (TRUS) biopsy, by decreasing the overall number of biopsies needed, maintaining or improving significant prostate cancer detection, and reducing the detection of clinically insignificant prostate cancer. The necessity of combining systematic prostate biopsy with MRI-targeted biopsy is still debated. The use of MRI--ultrasound fusion systems for lesion-targeting is promising for optimizing significant cancer detection, but recent evidence suggests that additional cognitive biopsy cores are still useful in detecting additional cancers. SUMMARY: MRI-targeted biopsy in selected men with positive MRI offers a number of benefits over systematic biopsy in all men, and as such, may emerge as the new standard of care for the diagnosis of clinically significant prostate cancer.

Nontransecting Techniques Reduce Sexual Dysfunction after Anastomotic Bulbar Urethroplasty: Results of a Multi-Institutional Comparative Analysis.

PURPOSE: The purpose of this multi-institutional study was to compare outcomes of transecting and nontransecting anastomotic bulbar urethroplasty. MATERIALS AND METHODS: We performed a retrospective, multi-institutional review of the records of 352 patients who underwent transecting or nontransecting anastomotic bulbar urethroplasty performed by 1 of 4 reconstructive urologists from September 2003 to March 2017. Study outcomes were urethroplasty success, defined as urethral patency greater than 16Fr on cystoscopy; de novo sexual dysfunction assessed at 6 months, defined as a 5-point or greater change in the SHIM (Sexual Health Inventory for Men) or a patient reported adverse change; and 90-day complications, defined as Clavien 2 or greater. When appropriate, comparisons were made between the transecting and nontransecting cohorts using the Mantel-Cox test, the t-test or the chi-square test. RESULTS: Of the 352 patients with a mean stricture length of 1.7 cm (range 0.5 to 5) 258 and 94 underwent transecting and nontransecting anastomotic bulbar urethroplasty, respectively. The overall success rate was 94.9% at a mean followup of 64.2 months (range 6 to 170). Of the patients 7.1% experienced a 90-day complication and 11.6% reported sexual dysfunction. When comparing transecting and nontransecting techniques, there was no difference in success (93.8% vs 97.9%, Mantel-Cox test p = 0.18) or postoperative complications (8.1% vs 4.3%, p = 0.25). Patients treated with transecting anastomotic urethroplasty were more likely to report an adverse change in sexual function (14.3% vs 4.3%, p = 0.008). On multivariate analysis only transecting urethroplasty was associated with sexual dysfunction (p = 0.01) while age (p = 0.29), stricture length (p = 0.42), etiology (p = 0.99) and surgeon (p = 0.88) were not. CONCLUSIONS: Anastomotic urethroplasty is a highly effective surgery with relatively minimal associated morbidity. Nontransecting anastomotic urethroplasty compares quite favorably to the transecting technique and likely reduces the risk of associated sexual dysfunction.

Independent Predictors of Stricture Recurrence Following Urethroplasty for Isolated Bulbar Urethral Strictures.

PURPOSE: We evaluated preoperative risk factors associated with stricture recurrence in a large, homogenous series of bulbar urethroplasties. MATERIALS AND METHODS: We analyzed the records of 596 patients who underwent isolated bulbar urethroplasty at a single center from August 2003 to June 2015. Urethroplasty failure was defined as stricture less than 16Fr identified on cystoscopy with a minimum of 12 months of followup. The potential risk factors examined were patient age, stricture etiology, stricture length, diabetes, smoking, obesity, Charlson comorbidity index, previous endoscopic treatment, previous urethroplasty and type of urethroplasty. Univariate and multivariable Cox regression analysis was used to evaluate potential risk factors and associations. RESULTS: Average stricture length was 3.9 cm and mean patient age was 44.4 years. Overall urethral patency was 93.3% and mean followup was 65.4 months (range 12 to 149). Previous endoscopic treatment had failed in 88.1% of patients while previous urethroplasty had failed in 10.7%. On multivariate analysis increased stricture length (HR 1.2, 95% CI 1.1-1.3, p = 0.01), increased patient comorbidity (HR 2.4, 95% CI 1.1-5.3, p = 0.03), obesity (HR 2.9, 95% CI 1.3-6.5, p = 0.01) and infectious strictures (HR 3.7, 95% CI 1.3-10.6, p = 0.02) were associated with stricture recurrence. Previous urethroplasty, the number of failed endoscopic procedures, type of urethroplasty and individual comorbidities such as diabetes, smoking and patient age did not affect the recurrent stricture rate. CONCLUSIONS: Although bulbar urethroplasty has a good stricture-free rate, patients with increased stricture length, increased overall comorbidity, obesity and strictures of infectious etiology are at higher risk for failure. These patients at risk should be counseled accordingly and perhaps be followed more closely after urethroplasty.

Observations and outcomes of urethroplasty for bulbomembranous stenosis after radiation therapy for prostate cancer.

PURPOSE: Bulbomembranous stenosis is a significant complication of radiotherapy for prostate cancer. Our purpose is to report outcomes of urethroplasty for radiation-induced bulbomembranous urethral stenoses. METHODS: Thirty-five patients underwent urethroplasty for refractory radiation-induced bulbomembranous stenoses from January 2004 to November 2013. Patients had a minimum follow-up of 12 months with routine cystoscopy at 6 and 12 months. Primary outcome was urethral patency, and secondary outcomes were 90-day complications, de novo incontinence, de novo erectile dysfunction and bothersome LUTS. Outcomes were compared using Fisher's exact test. RESULTS: Of the 35 patients, 20 and 15 had stenosis related to external beam radiation therapy and brachytherapy, respectively. Mean stricture length was 3.5 cm. Reconstruction was performed using anastomotic urethroplasty in 23 patients (65.7 %), while 12 required tissue transfer as a buccal mucosa graft (20.0 %) or penile island flap (14.3 %). With 50.5 months of follow-up, thirty patients (85.7 %) achieved cystoscopic patency with no significant difference between techniques (p = 0.32). A 90-day complication rate of 31.4 % was observed (all Clavien 1-2) with no difference between techniques (p = 1.00). Adverse change in continence occurred in 25.7 % of patients (13.3 % in those without previous TURP). Postoperatively, persisting storage LUTS occurred in 40.0 and 30.4 % described adverse change in erectile function (exclusively in the anastomotic urethroplasty group). CONCLUSIONS: Reconstruction of radiation-induced bulbomembranous stenosis yields satisfying patency rates. However, radiation-induced urethral stenosis is not an isolated problem as many patients suffer from storage symptoms, erectile dysfunction or incontinence as a consequence of treatment either before or after urethroplasty.

Prostate Cancer Among Black Men in Canada.

Importance: Prostate cancer is a prevalent disease among men worldwide, exhibiting substantial heterogeneity in presentation and outcomes influenced by various factors, including race and ethnicity. Disparities in incidence, stage at diagnosis, and survival rates have been observed between Black men and those of other races and ethnicities. Objective: To compare prostate cancer outcomes between Black men and men with other race (Asian, Hispanic, Indigenous, Middle Eastern, White, Multiracial, and Other) in a universal health care system, with race and ethnicity self-reported. Design, Setting, and Participants: This was a prospective, observational cohort study of men diagnosed with prostate cancer between June 1, 2014, and August 28, 2023, who self-identified race and ethnicity. Participants included men who had been prospectively enrolled in the Alberta Prostate Cancer Research Initiative from the 2 major urology referral centers in Alberta (University of Alberta and University of Calgary). All men with prostate cancer enrolled in the initiative were included. Exposure: Race and ethnicity. Main Outcomes and Measures: The primary outcome was the stage and grade of prostate cancer at diagnosis. Further outcomes included age and prostate-specific antigen level at diagnosis, initial treatment modality, time from diagnosis to initial treatment, and prostate cancer-specific, metastasis-free, and overall survivals. Results: A total of 6534 men were included; 177 (2.7%) were Black, and 6357 (97.3%) had another race or ethnicity. Men who identified as Black were diagnosed with prostate cancer at an earlier age (mean [SD], 62.0 [8.2] compared with 64.6 [7.7] years; P < .001) and had a lower Charlson Comorbidity Index rating (14% compared with 7% ≤ 1; P < .001) compared with men of other races. Men who identified as Black had similar prostate-specific antigen levels at diagnosis, TNM category (74% vs 74% with T1-T2; P = .83) and Gleason Grade Group (34% compared with 35% Gleason Grade Group 1; P = .63). Black men had similar rates of prostate cancer-specific (hazard ratio [HR], 1.10; 95% CI, 0.41-2.97; P = .85), metastasis-free (HR, 0.88; 95% CI, 0.42-1.46; P = .44), and overall (HR, 0.55; 95% CI, 0.25-1.24; P = .15) survival. Conclusions and Relevance: The findings of this cohort study suggest that Black men, despite being diagnosed at a younger age, experience comparable prostate cancer outcomes compared with men of other races.

Value of Incremental Biopsy Cores for Microultrasound Targeted Prostate Biopsies.

OBJECTIVE: To determine the optimal number of cores needed during microultrasound-informed prostate biopsy for the detection of clinically significant prostate cancer (csPCa, defined as Gleason Grade Group ≥2). METHODS: A retrospective review of 1011 consecutive patients between September 2021 and July 2023 at our institution were identified; 536 underwent microultrasound biopsy and 475 underwent magnetic resonance imaging (MRI)/ultrasound (US) targeted biopsy. Lesions were given a Prostate Risk Identification using Microultrasound (PRI-MUS) score, with lesions PRI-MUS ≥3 targeted. MRI lesions were scored with Prostate Imaging-Reporting and Data System (PI-RADS) and lesions PI-RADS ≥3 were targeted. The primary outcome is the detection of csPCa stratified by number of cores. RESULTS: One hundred thirty-eight patients underwent targeted biopsies for microultrasound only lesions, 182 for microultrasound and MRI lesions and 426 underwent MRI/US for MRI lesions. The first targeted core detected 78.0% (46/59), 77.8% (63/81), and 78.8% (216/274) of csPCa for microultrasound, microultrasound+MRI, and MRI/US, respectively. Comparing first to third core, there was not a significant difference in overall detection of csPCa by microultrasound, though MRI/US was significantly different (28.4% vs 36.4% P = .12, 32.5% vs 41.8% P = .06, 42.5% vs 53.9% P < .001 for microultrasound, microultrasound+MRI, and MRI/US, respectively). PI-RADS 3 and PRI-MUS 3 lesions had lower first core detection rates compared to PI-RADS 5 and PRI-MUS 5 lesions (44.4% vs 85.4% P = .01, 65.2% vs 81.4% P = .14, 60% vs 83.1% P = .07 for microultrasound, microultrasound+MRI, and MRI/US, respectively). CONCLUSION: A three-core targeted biopsy per microultrasound lesion improves detection rate of csPCa and should be considered to improve diagnostic accuracy.

Complication rates of ciprofloxacin alone vs. ciprofloxacin plus fosfomycin for transrectal prostate biopsy.

INTRODUCTION: Infectious complications after transrectal prostate biopsy have been increasing, driven in large part, by rates of antibiotic resistance to conventional prophylaxis, such as ciprofloxacin. This study was designed to compare conventional antibiotic prophylaxis (oral ciprofloxacin) with ciprofloxacin and fosfomycin combination therapy prior to biopsy. METHODS: This was a retrospective study looking at men between September 2021 and April 2023, who underwent transrectal prostate biopsy at several institutions in Alberta. The primary outcome was infectious complications within 30 days of prostate biopsy. Secondary outcomes included Clostridium difficile infections, urinary retention, gross hematuria, diarrhea, emergency room (ER ) visits, hospital admissions, and intensive care unit (ICU) admissions. Data was collected on resistance patterns and pathogens isolated in culture. RESULTS: During the study period, 2168 men underwent transrectal prostate biopsy. A total of 1216 men received ciprofloxacin alone and 877 received fosfomycin and ciprofloxacin. Infectious complications were significantly higher in the ciprofloxacin alone group (5.8% vs. 0.5%, p<0.0001). Thirty-day complications (7.2% vs. 2.1%, p<0.0001), 30-day ER visits (7.1% vs. 1.8%, p<0.0001), and 30-day hospitalizations (2.7% vs. 0.7%, p<0.001) were all higher in the ciprofloxacin alone group. The most isolated pathogen was E. coli in 54/60 (90%). Ciprofloxacin resistance in the isolated pathogens was high, with 52/60 (87%) showing resistance to ciprofloxacin and 51/54 (94%) E. coli strains resistant. No difference was seen in retention, C. difficile infections, bleeding, or diarrhea. CONCLUSIONS: The addition of fosfomycin for antibiotic prophylaxis prior to transrectal prostate biopsy was associated with significant improvement in infectious complications and healthcare utilization.

Micro-ultrasound for the detection of clinically significant prostate cancer in biopsy-naive men with negative MRI.

INTRODUCTION: Despite a negative magnetic resonance imaging (MRI), some patients may still harbor clinically significant prostate cancer (csPCa, Gleason grade group ≥2). High-resolution micro-ultrasound (microUS) is a novel imaging technology that could visualize csPCa that is missed by MRI. METHODS: This retrospective review included 1011 consecutive patients biopsied between September 2021 and July 2023 in Alberta, Canada. Among them were 103 biopsy-naive patients with negative MRI (Prostate Imaging Reporting & Data System [PI-RADS] ≤2) undergoing microUS-informed prostate biopsy (n=56) scored using Prostate Risk Identification Using Micro-ultrasound (PRI-MUS) or standard transrectal ultrasound prostate biopsy (n=47). The primary outcome was detection rate of csPCa stratified by biopsy technique and PRI-MUS score. RESULTS: MicroUS biopsy identified csPCa in 14/56 (25%) compared to standard biopsy in 8/47 (17%) (p=0.33). Patients with lesions PRI-MUS ≥3 had csPCa detected at a higher rate compared to patients with PRI-MUS ≤2 (42% vs. 16%, p=0.03). The csPCa detection rate was significantly different comparing patients with prostate-specific antigen (PSA) density <0.15 and PRI-MUS ≤2 compared to patients with PSA density ≥0.15 and PRI-MUS ≥3 (14% vs. 60%, p=0.02). CONCLUSIONS: MicroUS may aid in the detection of csPCa for patients with negative MRI.

Inter-reader Agreement for Prostate Cancer Detection Using Micro-ultrasound: A Multi-institutional Study.

Background and objective: Micro-ultrasound (MUS) uses a high-frequency transducer with superior resolution to conventional ultrasound, which may differentiate prostate cancer from normal tissue and thereby allow targeted biopsy. Preliminary evidence has shown comparable sensitivity to magnetic resonance imaging (MRI), but consistency between users has yet to be described. Our objective was to assess agreement of MUS interpretation across multiple readers. Methods: After institutional review board approval, we prospectively collected MUS images for 57 patients referred for prostate biopsy after multiparametric MRI from 2022 to 2023. MUS images were interpreted by six urologists at four institutions with varying experience (range 2-6 yr). Readers were blinded to MRI results and clinical data. The primary outcome was reader agreement on the locations of suspicious lesions, measured in terms of Light's κ and positive percent agreement (PPA). Reader sensitivity for identification of grade group (GG) ≥2 prostate cancer was a secondary outcome. Key findings and limitations: Analysis revealed a κ value of 0.30 (95% confidence interval [CI] 0.21-0.39). PPA was 33% (95% CI 25-42%). The mean patient-level sensitivity for GG ≥2 cancer was 0.66 ± 0.05 overall and 0.87 ± 0.09 when cases with anterior lesions were excluded. Readers were 12 times more likely to detect higher-grade cancers (GG ≥3), with higher levels of agreement for this subgroup (κ 0.41, PPA 45%). Key limitations include the inability to prospectively biopsy reader-delineated targets and the inability of readers to perform live transducer maneuvers. Conclusions and clinical implications: Inter-reader agreement on the location of suspicious lesions on MUS is lower than rates previously reported for MRI. MUS sensitivity for cancer in the anterior gland is lacking. Patient summary: The ability to find cancer on imaging scans can vary between doctors. We found that there was frequent disagreement on the location of prostate cancer when doctors were using a new high-resolution scan method called micro-ultrasound. This suggests that the performance of micro-ultrasound is not yet consistent enough to replace MRI (magnetic resonance imaging) for diagnosis of prostate cancer.

Evaluation of prostate cancer detection using micro-ultrasound versus MRI through co-registration to whole-mount pathology.

Micro-ultrasound has recently been introduced as a low-cost alternative to multi-parametric MRI for imaging prostate cancer. Early clinical studies have demonstrated promising results; however, robust validation via comparison with whole-mount pathology has yet to be achieved. Due to micro-ultrasound probe design and tissue deformation during scanning, it is difficult to accurately correlate micro-ultrasound imaging planes with ground truth whole-mount pathology slides. In this study, we developed a multi-step methodology to co-register micro-ultrasound and MRI to whole-mount pathology. The three-step process had a registration error of 3.90 ± 0.11 mm and consists of: (1) micro-ultrasound image reconstruction, (2) 3D landmark registration of micro-ultrasound to MRI, and (3) 2D capsule registration of MRI to whole-mount pathology. This process was then used in a preliminary reader study to compare the diagnostic accuracy of micro-ultrasound and MRI in 15 patients who underwent radical prostatectomy for prostate cancer. Micro-ultrasound was found to have equivalent performance to retrospective MRI review for index lesion detection (91.7% vs. 80%), while demonstrating an increased detection of tumor extent (52.5% vs. 36.7%) with similar false positive regions-of-interest (38.3% vs. 40.8%). Prospective MRI review had reduced detection of index lesions (73.3%) and tumor extent (18.9%) but improved false positive regions-of-interest (22.7%) relative to micro-ultrasound and retrospective MRI. Further evaluation is needed with a larger sample size.