Statin Concentration in Prostatic Tissue is Subtype- and Dose-dependent.

OBJECTIVE: To evaluate for the first time, comparative serum and prostate tissue concentrations of lipophilic and hydrophilic statins. METHODS: After reviewing all patients who underwent radical prostatectomy between 1993 and 2019, we selected 80 patients taking atorvastatin (lipophilic) or rosuvastatin (hydrophilic) for cholesterol control and with available banked fresh-frozen tissue from the prostatectomy. Primary endpoint was serum and prostate statin concentration measured by HPLC-mass spectrometry analysis. Serum/prostate statin concentrations were compared between patients on atorvastatin and rosuvastatin, and patients receiving high- and low-dose statin, using the Mann-Whitney U test. RESULTS: In total, 39 patients were taking atorvastatin and 41 were taking rosuvastatin. Thirty-eight and 42 were taking high- and low-dose statin, respectively. Statin concentration was measurable in the prostatic tissue of 15 patients (38.4%) taking atorvastatin (33.3% high-dose vs 42.8% low-dose) compared to 22 (53.6%) taking rosuvastatin (55% high-dose vs 52.3% low-dose). Median tissue concentration of rosuvastatin was greater than atorvastatin (3.98 ng/g vs 0.96 ng/g, P <.001). Dose-dependency was observed: median prostate concentration was higher in those taking high-dose versus low-dose statin for both atorvastatin (1.22 ng/g vs 0.79 ng/g, P = .69) and rosuvastatin (5.21 ng/g vs 1.99 ng/g, P <.001). CONCLUSION: We have shown, for the first time, that lipophilic and hydrophilic statins can be measured in the prostate of patients with prostate cancer and that the concentrations are dependent on dose. Moreover, rosuvastatin, a hydrophilic statin, achieves a 4-fold higher concentration in the prostate.

Single gene mutations and prognosis in limited-stage follicular lymphoma treated with radiation therapy.

Radiotherapy is routinely used for management of limited-stage follicular lymphoma (FL), yet half of patients ultimately relapse. We hypothesized that the presence of specific gene mutations may predict outcomes. We performed targeted sequencing of a 69-gene panel in 117 limited-stage FL patients treated with radiotherapy and identified recurrently mutated genes. CREBBP was most frequently mutated, and mutated CREBBP was associated with inferior progression-free survival, though not after false discovery rate adjustment. This association failed to validate in an independent cohort. We conclude that recurrent gene mutations do not predict outcomes in this setting. Alternative biomarkers may offer better prognostic insight.

Idiopathic secondary azoospermia occurrence in men with oligospermia over time.

PURPOSE: To investigate the occurrence of idiopathic secondary azoospermia (ISA) in men with oligospermia over time and identify risk factors for ISA in this population. METHODS: This was a retrospective cohort study conducted in a university-affiliated male infertility clinic. A total of 1056 oligospermic men (concentration < 15 million/ml (M/ml) and no azoospermia) with at least two SA done between 2000 and 2019 were included. The primary outcome was the occurrence of ISA by oligospermia severity. RESULTS: In the entire cohort, 31 patients (2.9%) eventually became azoospermic with time. The ≤ 1 M/ml extremely severe oligospermia (ESO) group (283 patients) had significantly higher rates of ISA in each time period compared to the 1-5 M/ml severe oligospermia (SO) (310 patients) and 5-15 M/ml mild oligospermia (MO) (463 patients) groups (p < 0.05 for all comparisons), with rates of 21.1% in the ESO, 4.8% in the SO, and 0% in the MO group (p = 0.02) after 3-5 years, reaching 32% after 5 years in the ESO group compared to no cases in the other two groups (p = 0.006). Parameters shown to predict ISA were initial concentration < 1 M/ml (OR 22.12, p < 0.001) and time interval of > 3 and 5 years (OR 4.83 and 6.84, p = 0.009 and < 0.001, respectively), whereas testosterone levels were negatively associated with ISA (OR 0.88, p = 0.03). CONCLUSIONS: Men with ≤ 1 M/ml, especially those with low testosterone levels, have a dramatically increased chance of becoming azoospermic with time. Therefore, sperm banking should be recommended in these cases. Men with a sperm concentration above 1 M/ml have low chances of becoming azoospermic, even after 3 or more years.

Decoding the Prevalent High-Risk Breast Cancers: Demographics, Pathological, Imaging Insights, and Long-Term Outcome.

Objective: To investigate the features and outcomes of breast cancer in high-risk subgroups. Materials and Methods: REB approved an observational study of women diagnosed with breast cancer from 2010 to 2019. Three radiologists, using the BI-RADS lexicon, blindly reviewed mammogram and MRI screenings without a washout period. Consensus was reached with 2 additional reviewers. Inter-rater agreement was measured by Fleiss Kappa. Statistical analysis included Mann-Whitney U, Chi-square tests for cohort analysis, and Kaplan-Meier for survival rates, with a Cox model for comparative analysis using gene mutation as a reference. Results: The study included 140 high-risk women, finding 155 malignant lesions. Significant age differences noted: chest radiation therapy (median age 44, IQR: 37.0-46.2), gene mutation (median age 49, IQR: 39.8-58.0), and familial risk (median age 51, IQR: 44.5-56.0) (P = .007). Gene mutation carriers had smaller (P = .01), higher-grade tumours (P = .002), and more triple-negative ER- (P = .02), PR- (P = .002), and HER2- (P = .02) cases. MRI outperformed mammography in all subgroups. Substantial to near-perfect inter-rater agreement observed. Over 10 years, no deaths occurred in chest radiation group, with no significant survival difference between gene mutation and familial risk groups, HR = 0.93 (95% CI: 0.27, 3.26), P = .92. Conclusion: The study highlights the importance of age and specific tumour characteristics in identifying high-risk breast cancer subgroups. MRI is confirmed as an effective screening tool. Despite the aggressive nature of cancers in gene mutation carriers, early detection is crucial for survival outcomes. These insights, while necessitating further validation with larger studies, advocate for a move toward personalized medical care, strengthening the existing healthcare guidelines.

Somatic Tumor Testing in Prostate Cancer: Experience of a Tertiary Care Center Including Pathologist-Driven Reflex Testing of Localized Tumors at Diagnosis.

Somatic tumor testing in prostate cancer (PCa) can guide treatment options by identifying clinically actionable variants in DNA damage repair genes, including acquired variants not detected using germline testing alone. Guidelines currently recommend performing somatic tumor testing in metastatic PCa, whereas there is no consensus on the role of testing in regional disease, and the optimal testing strategy is only evolving. This study evaluates the frequency, distribution, and pathologic correlates of somatic DNA damage repair mutations in metastatic and localized PCa following the implementation of pathologist-driven reflex testing at diagnosis. A cohort of 516 PCa samples were sequenced using a custom next-generation sequencing panel including homologous recombination repair and mismatch repair genes. Variants were classified based on the Association for Molecular Pathology/American Society of Clinical Oncology/College of American Pathologists guidelines. In total, 183 (35.5%) patients had at least one variant, which is as follows: 72 of 516 (13.9%) patients had at least 1 tier I or tier II variant, whereas 111 of 516 (21.5%) patients had a tier III variant. Tier I/II variant(s) were identified in 27% (12/44) of metastatic biopsy samples and 13% (61/472) of primary samples. Overall, 12% (62/516) of patients had at least 1 tier I/II variant in a homologous recombination repair gene, whereas 2.9% (10/516) had at least 1 tier I/II variant in a mismatch repair gene. The presence of a tier I/II variant was not significantly associated with the grade group (GG) or presence of intraductal/cribriform carcinoma in the primary tumor. Among the 309 reflex-tested hormone-naive primary tumors, tier I/II variants were identified in 10% (31/309) of cases, which is as follows: 9.2% (9/98) GG2; 9% (9/100) GG3; 9.1% (4/44) GG4; and 13.4% (9/67) GG5 cases. Our findings confirm the use of somatic tumor testing in detecting variants of clinical significance in PCa and provide insights that can inform the design of testing strategies. Pathologist-initiated reflex testing streamlines the availability of the results for clinical decision-making; however, pathologic parameters such as GG and the presence of intraductal/cribriform carcinoma may not be reliable to guide patient selection.

Intra-individual changes in sperm parameters and total motile count with time among infertile men.

BACKGROUND: Paternal age association with sperm parameters has been previously studied, demonstrating a decrease in semen volume, sperm motility, and sperm morphology, but not in sperm concentration. However, scarce data exists on the individual intra-personal changes in semen parameters with time. STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To evaluate the changes in semen parameters and total motile count of infertile men over time. MATERIALS AND METHODS: In this retrospective cohort study, infertile men without known risk factors for sperm quality deterioration and at least two semen analyses done > 3 months apart, between 2005 and 2021, were evaluated. Allocation to groups was according to time between first and last semen analyses - 3-12 months, 1-3 years, 3-5 years, and > 5 years. Basic characteristics and first and last semen analyses were compared. The primary outcome was the change in sperm parameters and the secondary outcome was the occurrence of a total motile count < 5 million in men with an initial total motile count > 10 million. RESULTS: A total of 2018 men were included in the study. The median age at first semen analyses was 36.2 (interquartile range: 32.8-40.1) years and the median time between semen analyses was 323 days (range 90-5810 days). The overall trend demonstrated an increase in concentration in the 3-12 months and the 1-3 years groups, whereas volume, motility, and morphology remained similar in these time groups. Semen analyses done more than 5 years apart showed decreased volume (p < 0.05), motility (p < 0.05) morphology (p < 0.05), and steady sperm concentration. Significant declines in TMCs were found over time (p < 0.001), with 18% and 22% of infertile men with an initial total motile count > 10 million dropping to < 5 million after 3 and 5 years, respectively. The factors independently predictive of total motile count < 5 M in the last semen analyses in men with an initial total motile count of > 10 M in a multivariate logistic regression model were baseline volume (odds ratio 0.80, p = 0.03), baseline total motile count (odds ratio 0.98, p = 0.01) and time between semen analyses - 3-5 years (odds ratio 3.79, p < 0.001) and > 5 years (odds ratio 3.49, p = 0.04) DISCUSSION: Our study demonstrates, at the individual level, that while improvement in sperm concentration is observed in the first year and between 1 and 3 years, possibly due to fertility treatments, fertility-related counseling, and lifestyle changes, semen parameters decline with time over 3 years in individuals. Of significance, close to 22% of men with an initial total motile count > 10 million (a range where spontaneous pregnancy is attainable) declined to < 5 million (a range usually indicating a need for in-vitro fertilization/intracytoplasmic sperm injection) over 5 years. This data could contribute to individualized family planning for infertile men regarding the mode and timing of conception and the need for sperm banking, in order to minimize the need for future fertility treatments.

MRI-guided Focused Ultrasound Focal Therapy for Intermediate-Risk Prostate Cancer: Final Results from a 2-year Phase II Clinical Trial.

Background MRI-guided focal therapy (FT) allows for accurate targeting of localized clinically significant prostate cancer (csPCa) while preserving healthy prostate tissue, but the long-term outcomes of this approach require more study. Purpose To assess the 2-year oncological and functional outcomes of men with intermediate-risk prostate cancer (PCa) treated with targeted FT. Materials and Methods In this single-center prospective phase II trial, men with localized unifocal intermediate-risk PCa underwent transrectal MRI-guided focused ultrasound between July 2016 and July 2019. Planned ablation volumes included 10-mm margins when possible. Data regarding adverse events were collected and quality-of-life questionnaires were completed by participants at 6 weeks and at 5, 12, 18, and 24 months after treatment. Multiparametric MRI and targeted and systematic biopsies were performed at 24 months. Ablation volumes were determined by manual contouring of nonperfused volumes on immediate contrast-enhanced images. Generalized estimating equations were used to model trends in quality-of-life measures. Results Treatment was successfully completed in the 44 participants (median age, 67 years; IQR, 62-70 years; 36 patients with grade group [GG] 2; eight patients with GG 3). No major adverse events from treatment were recorded. One participant refused biopsy at 24 months. After 2 years, 39 of 43 participants (91%) had no csPCa at the treatment site and 36 of 43 (84%) had no cancer in the entire gland. No changes in International Index of Erectile Function-15 score or International Prostate Symptom Score were observed during 2-year follow-up (P = .73 and .39, respectively). Conclusion The majority of men treated with MRI-guided focused ultrasound for intermediate risk PCa had negative results for csPCa at biopsy 2 years after treatment. Additionally, there was no significant decline in quality of life per the validated questionnaires. Clinical trial registration no. NCT02968784 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Woodrum in this issue.

Addition of cribriform pattern 4 and intraductal prostatic carcinoma into the CAPRA-S tool improves post-radical prostatectomy patient stratification in a multi-institutional cohort.

AIMS: Pre-surgical risk classification tools for prostate cancer have shown better patient stratification with the addition of cribriform pattern 4 (CC) and intraductal prostatic carcinoma (IDC) identified in biopsies. Here, we analyse the additional prognostic impact of CC/IDC observed in prostatectomies using Cancer of Prostate Risk Assessment post-surgical (CAPRA-S) stratification. METHODS: A retrospective cohort of treatment-naïve radical prostatectomy specimens from three North American academic institutions (2010-2018) was assessed for the presence of CC/IDC. Patients were classified, after calculating the CAPRA-S scores, into low-risk (0-2), intermediate-risk (3-5) and high-risk (6-12) groups. Kaplan-Meier curves were created to estimate biochemical recurrence (BCR)-free survival. Prognostic performance was examined using Harrell's concordance index, and the effects of CC/IDC within each risk group were evaluated using the Cox proportional hazards models. RESULTS: Our cohort included 825 prostatectomies (grade group (GG)1, n=94; GG2, n=475; GG3, n=185; GG4, n=13; GG5, n=58). CC/IDC was present in 341 (41%) prostatectomies. With a median follow-up of 4.2 years (range 2.9-6.4), 166 (20%) patients experienced BCR. The CAPRA-S low-risk, intermediate-risk and high-risk groups comprised 357 (43%), 328 (40%) and 140 (17%) patients, and discriminated for BCR-free survival (p<0.0001). For CAPRA-S scores 3-5, the addition of CC/IDC status improved stratification for BCR (HR 2.27, 95% CI 1.41 to 3.66, p<0.001) and improved the overall c-index (0.689 vs 0.667, analysis of variance p<0.001). CONCLUSION: The addition of CC/IDC into the CAPRA-S classification significantly improved post-radical prostatectomy patient stratification for BCR among the intermediate-risk group (CAPRA-S scores 3-5). The reporting of CC and IDC should be included in future prostate cancer stratification tools for improved outcome prediction.

Intraductal Prostate Cancer Affinity for Lymphatic-Predominant Metastases Through 18F-DCFPyL‒Prostate-Specific Membrane Antigen‒Positron Emission Tomography/CT Scans in Pretreatment Prostate Cancer Patients.

PURPOSE: Intraductal prostate cancer (IDC) is linked to unfavorable oncologic outcomes, marked by distinctive cellular intrinsic pathway changes and intricate immunosuppressive microenvironments that could impact the way cancer spreads. The aim of this study was to determine whether the presence of IDC in prostate biopsy specimens obtained from patients before primary prostate cancer (PCa) treatment is associated with a lymph node metastatic propensity in prostate-specific membrane antigen (PSMA)‒positron emission tomography (PET)/CT. MATERIALS AND METHODS: This was a cross-sectional analysis of all PCa patients undergoing a pretreatment 18F-DCFPyL-PSMA-PET/CT between January 1, 2016, and August 2021 at The Princess Margaret Cancer Centre. Outcomes were presence of any metastasis in the overall cohort, presence of lymphatic vs no metastases, and presence of lymphatic vs bone metastasis among patients who underwent PSMA-PET/CT as PCa primary staging. The associations between IDC presence on the prostate biopsy and the study outcomes were evaluated using univariable and multivariable logistic regression analyses. RESULTS: The cohort consisted of 120 patients. IDC and cribriform pattern were observed in 55 (46%) and 48 (40%) prostate biopsies, respectively. Overall, 52 patients (43%) had evidence of metastasis. Presence of IDC on biopsy was associated with increased odds of overall metastasis (odds ratio: 2.47, 95% CI: 1.09-5.61, P = .03). Of the 52 patients with evidence of metastasis, 41 (79%) had evidence of lymphatic metastasis. Presence of IDC on biopsy was associated with significantly increased odds of lymphatic metastasis vs nonmetastases (odds ratio: 3.03, 95% CI: 1.24-7.40, P = .01). CONCLUSIONS: The identification of IDC morphology in prostate biopsy specimens has been observed to be significantly linked with lymph node metastasis on 18F-DCFPyL-PET/CT imaging in a PCa pretreatment staging setting. We found that presence of IDC in prostate biopsy appears to be a marker for lymph node metastasis on 18F-DCFPyL-PET/CT.

Temporal Trends in Semen Quality, Hormone Levels, and Substance Use Among Infertile Men in Pre- and Post-Cannabis Legalization Eras in Canada.

Background: The Cannabis Act (Bill C-45) was enacted in 2018, to legalize and regulate the use, production, and sale of nonmedical cannabis in Canada. While public health and safety implications of cannabis legalization have yet to be elucidated, the wide availability of cannabis necessitates health care providers to be knowledgeable about therapeutic potential and side effects of use. This study aimed to examine the temporal trends over two decades and the impact of the Cannabis Act in Canada, implemented in October 2018, on substance use, semen parameters, and testosterone levels of infertile men. Methods: We conducted a retrospective cohort study from a prospectively maintained database of a single infertility clinic. Demographic, fertility, and substance use history were correlated with semen and hormone assessments. Temporal trends in cannabis use and semen quality between 2001 and 2021 were investigated and compared between pre-cannabis legalization eras (PRCL) and post-cannabis legalization eras (POCL). Results: Our cohort included 11,630 patients (9411 PRCL and 2230 POCL). Cannabis use increased by 8.4% per year (p<0.001), while alcohol and tobacco consumption declined (0.8% and 1.5% per year, p<0.05 and p=0.004, respectively). Similar trends were noticed in the POCL, with higher rates of cannabis use (22.4% vs. 12.9%, p<0.001) and decreased tobacco and alcohol intake (15.2% vs. 17.7%, p=0.005 and 50.5% vs. 55.2%, p<0.001, respectively) compared to the PRCL group. Semen concentration was lower in the POCL group (24.8±44.8 vs. 28.7±48.3 million/mL, p=0.03). Testosterone did not differ between the cohorts. Comparison between cannabis users (n=1715) and nonusers (n=9924) demonstrated a slight increase in sperm motility (25.9%±15.3% vs. 23.9%±15.0%, p=0.002) and decreased sperm concentration among users (27.6±53.5 vs. 23.9±15.0 million/mL, p=0.03). Conclusion: A nearly 10% rise in cannabis use in the POCL era was observed among men being investigated for infertility. Our data suggest cannabis use may be associated with an increase in testosterone, slightly improved sperm motility, and decreased sperm concentration.

Comparing prostatic artery embolization to surgical and minimally invasive procedures for the treatment of benign prostatic hyperplasia: a systematic review and meta-analysis.

BACKGROUND: To summarize current evidence to report a comparative systematic review and meta-analysis of prostatic artery embolization (PAE) with transurethral resection of the prostate (TURP) and open simple prostatectomy (OSP) for the treatment of benign prostatic hyperplasia (BPH). METHODS: A systematic literature search was performed to identify studies published from inception until August 2021. The search terms used were (prostate embolization OR prostatic embolization) AND (prostatic hyperplasia OR prostatic obstruction) as well as the abbreviations of PAE and BPH. Risk of bias was assessed using the Cochrane Risk of Bias tool for randomized controlled trials (RCTs) and the Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) tool for observational studies. Random-effects meta-analysis was performed using Revman 5.4. RESULTS: Seven studies were included with 810 patients: five RCTs and one observational study compared PAE with TURP, and one observational study compared PAE with OSP. The included studies had considerable risk of bias concerns. TURP and OSP were associated with more statistically significant improvements in urodynamic measures and BPH symptoms compared to PAE. However, PAE seems to significantly improve erectile dysfunction compared to OSP and improve other outcome measures compared to TURP, although not significantly. PAE appeared to reduce adverse events and report more minor complications compared with TURP and OSP, but it is unclear whether PAE is more effective in the long-term. CONCLUSION: PAE is an emerging treatment option for patients with symptomatic BPH who cannot undergo surgery or have undergone failed medical therapy. Overall, PAE groups reported fewer adverse events. Future ongoing and longer-term studies are needed to provide better insight into the benefit of PAE compared to other treatment options.

Reliability and Variability of Ki-67 Digital Image Analysis Methods for Clinical Diagnostics in Breast Cancer.

Ki-67 is a nuclear protein associated with proliferation, and a strong potential biomarker in breast cancer, but is not routinely measured in current clinical management owing to a lack of standardization. Digital image analysis (DIA) is a promising technology that could allow high-throughput analysis and standardization. There is a dearth of data on the clinical reliability as well as intra- and interalgorithmic variability of different DIA methods. In this study, we scored and compared a set of breast cancer cases in which manually counted Ki-67 has already been demonstrated to have prognostic value (n = 278) to 5 DIA methods, namely Aperio ePathology (Lieca Biosystems), Definiens Tissue Studio (Definiens AG), Qupath, an unsupervised immunohistochemical color histogram algorithm, and a deep-learning pipeline piNET. The piNET system achieved high agreement (interclass correlation coefficient: 0.850) and correlation (R = 0.85) with the reference score. The Qupath algorithm exhibited a high degree of reproducibility among all rater instances (interclass correlation coefficient: 0.889). Although piNET performed well against absolute manual counts, none of the tested DIA methods classified common Ki-67 cutoffs with high agreement or reached the clinically relevant Cohen's κ of at least 0.8. The highest agreement achieved was a Cohen's κ statistic of 0.73 for cutoffs 20% and 25% by the piNET system. The main contributors to interalgorithmic variation and poor cutoff characterization included heterogeneous tumor biology, varying algorithm implementation, and setting assignments. It appears that image segmentation is the primary explanation for semiautomated intra-algorithmic variation, which involves significant manual intervention to correct. Automated pipelines, such as piNET, may be crucial in developing robust and reproducible unbiased DIA approaches to accurately quantify Ki-67 for clinical diagnosis in the future.

Limitations of Prostate Biopsy in Detection of Cribriform and Intraductal Prostate Cancer.

BACKGROUND: The presence of cribriform morphology and intraductal carcinoma (IDC) in prostate biopsies and radical prostatectomy specimens is an adverse prognostic feature that can be used to guide treatment decisions. OBJECTIVE: To assess how accurately biopsies can detect cribriform morphology and IDC cancer by examining matched biopsy and prostatectomy samples. DESIGN, SETTING, AND PARTICIPANTS: Patients who underwent radical prostatectomy at The Princess Margaret Cancer Centre between January 2015 and December 2022 and had cribriform morphology and/or IDC in the surgical specimen were included in the study. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We used detection sensitivity to evaluate the level of agreement between biopsy and prostatectomy samples regarding the presence of cribriform morphology and IDC. RESULTS AND LIMITATIONS: Of the 287 men who underwent radical prostatectomy, 241 (84%) had cribriform morphology and 161 (56%) had IDC on final pathology. The sensitivity of prostate biopsy, using radical prostatectomy as the reference, was 42.4% (95% confidence interval [CI] 36-49%) for detection of cribriform morphology and 44.1% (95% CI 36-52%) for detection of IDC. The sensitivity of prostate biopsy for detection of either IDC or cribriform morphology was 52.5% (95% CI 47-58%). Among patients who underwent multiparametric magnetic resonance imaging-guided biopsies, the sensitivity was 54% (95% CI 39-68%) for detection of cribriform morphology and 37% (95% CI 19-58%) for detection of IDC. CONCLUSIONS: Biopsy has low sensitivity for detecting cribriform morphology and IDC. These limitations should be incorporated into clinical decision-making. Biomarkers for better detection of these histological patterns are needed. PATIENT SUMMARY: Prostate biopsy is not an accurate method for detecting two specific types of prostate cancer cells, called cribriform pattern and intraductal prostate cancer, which are associated with unfavorable prognosis.

Addition of Cribriform and Intraductal Carcinoma Presence to Prostate Biopsy Reporting Strengthens Pretreatment Risk Stratification Using CAPRA and NCCN Tools.

BACKGROUND: Pretreatment stratification tools can help in clinical decision making in prostate cancer. To date, none incorporates well-established routinely reported adverse prognostic pathologic features such as intraductal carcinoma of prostate (IDC) or cribriform pattern 4 (CC). OBJECTIVE: To assess the impact of addition of CC and/or IDC on the Cancer of Prostate Risk Assessment (CAPRA) and National Cancer Comprehensive Network (NCCN) tools for predicting biochemical recurrence free survival (BCR-FS) and event-free survival (EFS) across multiple patient cohorts. DESIGN, SETTING, AND PARTICIPANTS: Matched prostate biopsies and radical prostatectomies from institutions in Toronto, Wisconsin and Rotterdam. The presence/absence of CC/IDC was recorded on all biopsies. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relationship to outcome was assessed using Cox proportional hazard models, ANOVA and Harrell's concordance index. RESULTS AND LIMITATIONS: We included 1326 patients (Toronto- 612, Wisconsin- 542, Rotterdam- 172) with median follow up of 4.2 years (IQR 2.9-6.4 years); 306 (23.1%) had CC/IDC on biopsy with 207 (20.9%) BCR and 154 (11.6%) events (metastases/death). Addition of CC/IDC improved stratification in CAPRA scores 3 to 5 for BCR-FS (c-index increase 0.633-0.658, P < .001) and scores 6-10 for EFS (c-index increase 0.653-0.697, P < .001). For NCCN, all risk groups apart from score 1 to 2 showed improvement in BCR-FS (c-index increase 0.599-0.636, P < 0.001) and EFS prediction (c-index increase 0.648-0.697, P < .001). Sub-analysis of grade group (GG) 2 biopsies showed similar findings. The retrospective nature and inclusion of cases only reported by genitourinary pathologists are study limitations. CONCLUSIONS: The clinical benefit of the addition of CC/IDC to both CAPRA and NCCN pretreatment tools was validated in 3 cohorts, including the subset of biopsy GG2 prostate cancer patients. PATIENT SUMMARY: Including additional pathologic features to existing pretreatment, clinical decision making tools improves the ability to predict prostate cancer recurrence, cancer spread and death of disease.

Upfront allogeneic transplantation versus JAK inhibitor therapy for patients with myelofibrosis: a North American collaborative study.

Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF) and is recommended for patients with higher risk disease. However, there is a risk of early mortality, and optimal timing is unknown. JAK inhibitor (JAKi) therapy may offer durable improvement in symptoms, splenomegaly and quality of life. The aim of this multicentre, retrospective observational study was to compare outcomes of patients aged 70 years or below with MF in chronic phase who received upfront JAKi therapy vs. upfront HCT in dynamic international prognostic scoring system (DIPSS)-stratified categories. For the whole study cohort, median overall survival (OS) was longer for patients who received a JAKi vs. upfront HCT, 69 (95% CI 57-89) vs. 42 (95% CI 20-not reached, NR) months, respectively (p = 0.01). In patients with intermediate-2 and high-risk disease, median OS was 55 (95% CI 36-73) months with JAKi vs. 36 (95% CI 20-NR) months for HCT (p = 0.27). An upfront HCT strategy was associated with early mortality and difference in median OS was not observed in any risk group by 5 years of follow-up. Within the limitations of a retrospective observational study, we did not observe any benefit of a universal upfront HCT approach for higher-risk MF.

Long-term outcomes and cost savings of office fulguration of papillary Ta low-grade bladder cancer.

OBJECTIVES: To assess whether office-based fulguration (OF) under local anaesthesia for small, recurrent, pathological Ta low-grade (LG) non-muscle-invasive bladder cancer (NMIBC) is an effective alternative to transurethral resection of bladder tumour (TURBT), avoiding the costs and risks of procedure, and anesthesia. PATIENTS AND METHODS: Of 521 patients with primary TaLG NMIBC, this retrospective study included 270 patients who underwent OF during follow-up for recurrent, small, papillary LG-appearing tumours at a university centre (University Health Network, University of Toronto, Canada). We assessed the cumulative incidence of cancer-specific mortality (CSM) and disease progression (to MIBC or metastases), as well as possible direct cost savings. RESULTS: In the 270 patients with recurrent TaLG NMIBC treated with OF, the mean (sd) age was 64.9 (13.3) years, 70.8% were men, and 60.3% had single tumours. The mean (sd, range) number of OF procedures per patient was 3.1 (3.2, 1-22). The median (interquartile range) follow-up was 10.1 (5.8-16.2) years. Patients also underwent a mean (sd) of 3.6 (3.0) TURBTs during follow-up in case of numerous or bulkier recurrence. In all, 44.4% of patients never received intravesical therapy. The 10-year incidence of CSM and progression were 0% and 3.1% (95% confidence interval 0.8-5.4%), respectively. Direct cost savings in Ontario were estimated at $6994.14 (Canadian dollars) per patient over the study follow-up. CONCLUSIONS: This study supports that properly selected patients with recurrent, apparent TaLG NMIBC can be safely managed with OF under local anaesthesia with occasional TURBT for larger or numerous recurrent tumours, without compromising long-term oncological outcomes. This approach could generate substantial cost-saving to healthcare systems, is patient-friendly, and could be adopted more widely.

Improved sperm DNA fragmentation levels in infertile men following very short abstinence of 3-4 hours.

Background: Limited data exists on possible approaches to improve sperm DNA fragmentation index (DFI) when no identifiable cause is found. The effect of short abstinence on sperm parameters has been extensively studied, but rarely reported on the effect on DFI in infertile men. In this study, we aimed to determine whether a second ejaculate provided after very short abstinence demonstrates lower DFI rates in infertile men. Methods: This prospective cohort study was conducted at Mount Sinai Hospital, Toronto, Canada, a tertiary university affiliated hospital. All men having DFI testing in addition to the standard semen analysis were identified via a prospectively collected database. Infertile men were instructed to provide two semen samples 3-4 hours apart (the first sample was given after 2-5 days of abstinence) to test the effect on DFI levels. Data analysis was performed for the comparison of the change in sperm parameters and DFI between samples and between men with DFI above and under 30%. Results: A total of 52 men provided double ejaculates 3-4 hours apart. In the entire group, DFI decreased from 38.9%±21.4% to 35.1%±21.6% in the second sample (P<0.001). Semen volume was lower on the second sample (2.3±1.4 vs. 1.5±0.9 mL, P<0.001), while the remaining parameters did not change. Forty out of 52 patients (76.9%) had improved DFI (average of 6.0±4.0 percentage points). Change in DFI varied with 22/52 (42.3%) and 7/52 (13.5%) of patients found to have decreases in DFI >5% and >10% in the second ejaculate, respectively. For men with DFI of 30-40%, 64% (7/11) of DFIs reduced to the under 30% range. First DFI value was the only parameter associated with DFI decrease to under 30% in multivariate models [odds ratio (OR), 0.62; 95% confidence interval (CI): 0.39-0.98; P=0.04]. Conclusions: This study identified significant improvements in DFI in infertile men providing a second sample after 3-4 hours. Controlled trials are needed to determine if reproductive outcomes are improved using a second ejaculate for infertile men with high initial sperm DFI values.