Evaluating Leukocyte Telomere Length and Myeloid-Derived Suppressor Cells as Biomarkers for Prostate Cancer.

BACKGROUND: Leukocyte telomere length (LTL) and myeloid-derived suppressor cells (MDSC) are associated with aging and the development and progression of cancer. However, the exact nature of this relationship remains unclear. Our study aimed to investigate the potential of LTL and MDSC as diagnostic biomarkers for prostate cancer while also seeking to deepen our understanding of the relationship of these potential biomarkers to each other. METHODS: Our study involved patients undergoing a prostate biopsy. We analyzed the relative LTL in genomic DNA obtained from peripheral blood leukocytes as well as the percentage of MDSC and their subtypes in peripheral blood mononuclear cells (PBMC). Our evaluation focused on examining the relationship between LTL and MDSC and pathological diagnoses as well as investigating the correlation between LTL and MDSC levels. RESULTS: In our study of 102 participants, 56 were pathologically diagnosed with localized prostate cancer (cancer group), while 46 tested negative (control group). The cancer group exhibited significantly shorter LTL in comparison to the control group (p = 0.024). Additionally, the cancer group showed a tendency towards a higher percentage of monocytic MDSC (M-MDSC), although this difference did not reach statistical significance (p = 0.056). Our multivariate logistic regression analysis revealed that patients with shorter LTL and higher percentages of M-MDSC had a 2.98-fold (95% CI = 1.001-8.869, p = 0.049) and 3.03-fold (95% CI = 1.152-7.977, p = 0.025) increased risk of prostate cancer diagnosis, respectively. There was also a significant negative correlation between LTL and M-MDSC. (r = -0.347, p < 0.001). CONCLUSIONS: Our research has established a correlation between LTL and MDSC in patients undergoing biopsy for prostate cancer. Notably, we observed that individuals with localized prostate cancer tend to have shorter LTL and a higher percentage of M-MDSC prior to their diagnosis. These findings suggest that LTL and M-MDSC could potentially serve as adjunctive biomarkers for the early diagnosis of prostate cancer.

Long-Term Effects of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Predictors of Treatment Response and Safety over 6 Years of Continuous Therapy.

Tolvaptan, an oral vasopressin V2 receptor antagonist, reduces renal volume expansion and loss of renal function in patients with autosomal dominant polycystic kidney disease (ADPKD). Data for predictive factors indicating patients more likely to benefit from long-term tolvaptan are lacking. Data were retrospectively collected from 55 patients on tolvaptan for 6 years. Changes in renal function, progression of renal dysfunction (estimated glomerular filtration rate [eGFR], 1-year change in eGFR [ΔeGFR/year]), and renal volume (total kidney volume [TKV], percentage 1-year change in TKV [ΔTKV%/year]) were evaluated at 3-years pre-tolvaptan, at baseline, and at 6 years. In 76.4% of patients, ΔeGFR/year improved at 6 years. The average 6-year ΔeGFR/year (range) minus baseline ΔeGFR/year: 3.024 (-8.77-20.58 mL/min/1.73 m2). The increase in TKV was reduced for the first 3 years. A higher BMI was associated with less of an improvement in ΔeGFR (p = 0.027), and family history was associated with more of an improvement in ΔeGFR (p = 0.044). Hypernatremia was generally mild; 3 patients had moderate-to-severe hyponatremia due to prolonged, excessive water intake in response to water diuresis-a side effect of tolvaptan. Family history of ADPKD and baseline BMI were contributing factors for ΔeGFR/year improvement on tolvaptan. Hyponatremia should be monitored with long-term tolvaptan administration.

The Detection and Negative Reversion of Circulating Tumor Cells as Prognostic Biomarkers for Metastatic Castration-Resistant Prostate Cancer with Bone Metastases Treated by Enzalutamide.

Enzalutamide is a second-generation androgen receptor inhibitor that increases overall survival (OS) rates in patients with metastatic castration-resistant prostate cancer (mCRPC). This study evaluates the efficacy of circulating tumor cell (CTC) status as a prognostic biomarker following enzalutamide administration. A retrospective subgroup analysis and prognostic survey were conducted on 43 patients with mCRPC and bone metastases treated in Juntendo University-affiliated hospitals from 2015 to 2022. Patients were treated with 160 mg enzalutamide daily. CTC analyses on blood samples were performed regularly before and every three months after treatment. The relationship between the patients' clinical factors and the OS rate was analyzed using the log-rank test; the median OS was 37 months. Patients with no detected CTCs at baseline showed significantly longer OS than those with detectable CTCs at baseline. Furthermore, patients demonstrating negative reversion of CTCs during enzalutamide treatment had significantly longer OS than patients with CTC-positivity. Two biomarkers-higher hemoglobin at baseline and achieving negative reversion of CTCs-were significantly associated with prolonged OS. This study suggests that patients achieving CTC-negative reversion during treatment for mCRPC with bone metastases exhibit improved long-term OS. Chronological measurement of CTC status might be clinically useful in the treatment of mCRPC.

Management of Male Fertility in Hypogonadal Patients on Testosterone Replacement Therapy.

Testosterone is crucial in regulating several body functions in men, including metabolic, sexual, and cardiovascular functions, bone and muscle mass, and mental health. Therefore, optimizing testosterone levels in men is an important step to maintaining a healthy body and mind, especially as we age. However, traditional testosterone replacement therapy has been shown to lead to male infertility, caused by negative feedback in the hypothalamic-pituitary-gonadal (HPG) axis. Recent advances in research have led to the discovery of many new methods of administration, which can have more or less suppressive effects on the HPG axis. Also, the usage of ancillary medications instead of or after testosterone administration might help maintain fertility in hypogonadal patients. The goal of this narrative review is to summarize the newest methods for optimizing fertility parameters in patients undergoing treatment for hypogonadism and to provide the necessary information for healthcare providers to make the right treatment choices.

The impact of serum testosterone level to reflect age-related multi-organ functions.

The aim of this study is to examine the correlation between aging, serum total testosterone and biomarkers of multiple organ functions in men. The participants consisted of 12,547 outpatients, whose serum testosterone level was measured. A multiple regression analysis was conducted to determine whether biomarkers including hemoglobin (Hb), hematocrit (Hct), luteinizing hormone (LH), follicle stimulating hormone (FSH), alkaline phosphatase (ALP), albumin (ALB), creatinine (Cre), aspartate aminotransferase (AST), alanine aminotransferase (ALT), glucose (Glu), C-reactive protein (CRP), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) values were associated with serum total testosterone concentration. Significant correlations (p < 0.05) were found between total testosterone and Hb, Hct, LH, FSH, ALP, ALB, TG, HDL-C, AST, ALT, Glu, and CRP. In addition, significant correlations (p < 0.05) were found between Hb, Hct, LH, FSH, ALP, ALB, TG and HDL-C associated with [age × testosterone]. This large-scale study provided new insights into correlations between serum testosterone and biomarkers associated with age-related diseases, suggesting that testosterone is especially important for maintaining homeostasis in aging males. Thus, hypogonadism in elderly patients may be associated with multiple organ dysfunctions.

Body composition and testosterone in men: a Mendelian randomization study.

Background: Testosterone is an essential sex hormone that plays a vital role in the overall health and development of males. It is well known that obesity decreases testosterone levels, but it is difficult to determine the causal relationship between body composition and testosterone. Methods: To investigate potential causal associations between body composition and testosterone levels by a first time application of Mendelian randomization methods. Exposure variables in men included body composition (fat mass, fat-free mass, and body mass index). In addition to whole body fat and fat-free mass, we examined fat and fat-free mass for each body part (e.g., trunk, left arm, right arm, left leg and right leg) as exposures. Instrumental variables were defined using genome-wide association study data from the UK Biobank. Outcome variables in men included testosterone levels (total testosterone [TT], bioavailable testosterone [BT], and sex hormone-binding globulin [SHBG]). A one-sample Mendelian randomization analysis of inverse-variance weighted and weighted median was performed. Results: The number of genetic instruments for the 13 exposure traits related to body composition ranged from 156 to 540. Genetically predicted whole body fat mass was negatively associated with TT (ß=-0.24, P=5.2×10-33), BT (ß=-0.18, P=5.8×10-20) and SHBG (ß=-0.06, P=8.0×10-9). Genetically predicted whole body fat-free mass was negatively associated with BT (ß=-0.04, P=2.1×10-4), but not with TT and SHBG, after multiple testing corrections. When comparing the causal effect on testosterone levels, there was a consistent trend that the effect of fat mass was more potent than that of fat-free mass. There were no differences between body parts. Conclusion: These results show that reducing fat mass may increase testosterone levels.

Small cell bladder carcinoma treated with nivolumab as adjuvant maintenance therapy.

We report using the programmed death-1 immune checkpoint inhibitor (ICI) antibody, nivolumab, as part of a multimodal treatment strategy in small cell bladder carcinoma (SCBC). The patient presented with gross haematuria and was diagnosed with urothelial carcinoma with SCBC. He received neoadjuvant chemotherapy (NAC; carboplatin plus etoposide) according to the small cell lung cancer regimen. After three cycles of NAC, there was no progression of local disease, and a robot-assisted radical cystectomy with ileal conduit was conducted. Post surgery, the patient was treated with nivolumab (240 mg) every 2 weeks as a maintenance therapy after adjuvant cisplatin plus etoposide therapy. After more than 1.5 years post surgery, no tumour recurrence or metastases are present. The patient was treated with nivolumab, which was curative after radical cystectomy. Further research is required to elucidate the potential role of ICIs in SCBC.

T-Cell Receptor Repertoire as a Predictor of Immune-Related Adverse Events in Renal Cell Carcinoma.

Immune checkpoint inhibitors (ICIs) are effective in treating renal cell carcinoma (RCC) but can also cause immune-related adverse events (irAEs). The relationship between irAEs and the T-cell receptor (TCR) repertoire in RCC patients treated with ICIs remains unclear. We analyzed the relationship between the severity and diversity of irAEs and the TCR repertoire in RCC patients who received dual checkpoint inhibitors (ipilimumab + nivolumab). The TCRß (TRB) repertoires were characterized in peripheral blood samples from six patients with RCC before the initiation of ICI therapy. The diversity and clonality of the TCR repertoire were compared between patients with grade 2 and grade 3 irAEs. The median proportion of top 10 unique reads in the TCR repertoire was significantly higher in grade 3 compared with grade 2 irAEs in RCC patients receiving immune checkpoint inhibitors (grade 2: 0.196%; grade 3: 0.346%; p = 0.0038). We provide insight into the relationship between TCR repertoire and irAEs in RCC patients treated with ICIs. TCR repertoire clonality may be associated with the development of irAEs in RCC patients.

Successful wound closure using fibrin glue for intractable neobladder-urethral anastomosis leakage after radical cystectomy and neobladder reconstruction.

Introduction: Complications of cystectomy and neobladder reconstruction such as anastomotic leakage have been reported. It is a common complication; however, most cases improve conservatively. The use of fibrin glue for fistulas has been reported, but no reports have shown its effectiveness for urinary tract anastomotic leakage. We experienced a case of intractable neobladder-urethral anastomosis leakage after radical cystectomy and neobladder reconstruction, which was effectively managed using fibrin glue. Case presentation: A 70-year-old man underwent radical cystectomy and ileal neobladder reconstruction for invasive bladder cancer with urothelial carcinoma. After surgery, the urethral catheter fell off and the anastomotic leakage did not improve by adjusting the position of the urethral catheter and percutaneous nephrostomy. We closed the intractable neobladder-urethral anastomotic leakage by injecting fibrin glue and the leakage completely disappeared. Conclusion: Injecting fibrin glue into anastomotic site can be effective in severe neobladder-urethral anastomosis leakage.

Urine spermine and multiparametric magnetic resonance imaging for prediction of prostate cancer in Japanese men.

Objectives: To investigate the role of urine spermine and spermine risk score in predicting prostate cancer (PCa) diagnoses in combination with multiparametric magnetic resonance imaging (mpMRI). Methods: Three hundred forty seven consecutive men with elevated prostate-specific antigen (PSA) with mpMRI examination were prospectively enrolled in this study. In 265 patients with PSA levels between 4 and20 ng/ml, pre-biopsy urine samples were analyzed for spermine levels with ultra-high performance liquid chromatography (UPLC-MS/MS). Transperineal image-guided prostate biopsies with 16-18 cores were performed. Logistic regressions were used to form different models for the prediction of the PCa, and the performances were compared using the area under the curve (AUC). Results: The median serum PSA level and prostate volume were 7.4 ng/mL and 33.9 mL, respectively. PCa and high-grade PCa (ISUP group ≥2, HGPCa) were diagnosed in 66.0% (175/265) and 132/265 (49.8%) cases, respectively. The urine spermine levels were significantly lower in men with PCa (0.87 vs. 2.20, P < 0.001). Multivariate analyses showed that age, PSA, PV, urine spermine level, and Prostate Imaging Reporting and Data System (PI-RADS) findings were independent predictors for PCa. The Spermine Risk Score is a multivariable model including PSA, age, prostate volume, and urine spermine. Adding the Spermine Risk Score to PI-RADS improved the AUC from 0.73 to 0.86 in PCa and from 0.72 to 0.83 in high grade PCa (HGPCa) prediction (both P < 0.001). At 90% sensitivity for HGPCa prediction using Spermine Risk Score, 31.1% of unnecessary biopsies could be avoided. In men with equivocal MRI PI-RADS score 3, the AUC for HGPCa prediction was 0.58, 0.79, and 0.87 for PSA, PSA density, and Spermine Risk Score, respectively. Conclusion: Urine Spermine Risk Score, including mpMRI could accurately identify men at high risk of HGPCa and reduce unnecessary prostate biopsies. Spermine Risk Score could more accurately predict HGPCa than PSA density in men with MRI showing equivocal PI-RADS 3 lesions.

Retrospective observational study of a novel smartphone app on the management of patients with mild cognitive impairment or mild dementia.

Introduction: In this study, we aimed to evaluate the feasibility, utility, and potential effects of LQ-M/D App, a smartphone application developed by Life Quest Inc., Tokyo, Japan, for patients with mild cognitive impairment (MCI) and mild dementia. The app incorporates cognitive and physical exercise training, lifestyle habit acquisition features, and a continuity improvement feature added in the post-update version to enhance user engagement. The continuity improvement feature includes the optimization of training content, and disease education, and enables family monitoring via a family app. Methods: A retrospective analysis was conducted on app usage, cognitive and exercise training implementation and interruptions, questionnaire response rates, and cognitive assessments in a single institution. A total of 20 patients used the app, with 10 patients using the pre-update version without the continuity improvement feature, and the other 10 patients using the post-update version with the continuity improvement feature. Results and Conclusion: The results demonstrated that the LQ-M/D App could be effectively used by the study population, and the continuity improvement feature positively influenced app usage in several aspects. Although a potential association between app usage and cognitive ability was suggested, the scatter in the data points warrants cautious interpretation. Limitations of the study included a small sample size, a single institution setting, and the retrospective nature of the study. In the future, a randomized controlled trial design using a larger sample size and multiple institutions to further evaluate the effectiveness of LQ-M/D App in managing MCI and mild dementia should be performed.

Plasma levels and urinary excretion of protein Z in patients with urolithiasis.

OBJECTIVES: Protein Z (PZ) is a γ-carboxyglutamic acid protein present in plasma that is involved in blood coagulation. Detailed analysis of urinary stones from patients with urolithiasis has revealed that PZ is often found in urinary stones composed of calcium oxalate monohydrate. In this study, we compared blood and urinary PZ concentrations between healthy individuals and patients with urolithiasis. METHODS: Plasma and urine were collected from healthy individuals and patients with urolithiasis who provided informed consent. PZ was detected as a urinary stone matrix protein in some of the patients. PZ was quantified by ELISA, creatinine was measured by the enzymatic method, and the total protein concentration was measured by the Bradford method. RESULTS: The plasma PZ level was 2.54 ± 1.02 µg/mL in healthy individuals and that in urolithiasis patients classified by stone history were from 1.16 ± 0.77 to 3.73 ± 1.09 µg/mL, which was not significantly different. The urinary excretion of PZ (PZ/creatinine) was also not different in patients with urolithiasis and in healthy individuals (from 54.1 ± 40.9 to 95.4 ± 69.4 ng/mg vs. 73.3 ± 36.0 ng/mg). A positive correlation was found between the plasma PZ level and creatinine-corrected urinary PZ concentration (r = 0.46). CONCLUSIONS: Both the plasma level and urinary excretion of PZ in urolithiasis patients were not significantly different with normal individuals. PZ detected in urinary stones as a matrix protein is thought to be incorporated into urinary stones regardless of blood and urine levels of PZ.

High prevalence of frailty in patients with lower urinary tract symptoms.

AIM: Older adults are more likely to be frail and have a high prevalence of urological diseases such as lower urinary tract symptoms (LUTS). The purpose of this study was to clarify the prevalence and characteristics of comorbid frailty in older patients with urological diseases. METHODS: We retrospectively reviewed the medical records of 970 patient who visited the Department of Urology, Juntendo University Hospital between October 2015 and October 2016. Patients were selected who were 65 years of age or older and were being evaluated by the Kihon Checklist (KCL) to assess frailty. We examined the prevalence of comorbid frailty in urological diseases, identified factors associated with comorbid frailty in urological diseases, and examined KCL scores in urological diseases with a high prevalence of frailty. RESULTS: A total of 405 participants were included. Of these, 21.7% were frail, 20.5% were pre-frail, and 57.8% were robust. LUTS, overactive bladder, and neurogenic bladder showed a statistically significant relationship with comorbid frailty, with high frailty prevalence rates of 44/140 (31.4%), 19/36 (52.8%), and 4/6 (66.7%), respectively. Factors related to the comorbid frailty according to multivariate analysis were female sex (P = 0.001), older age (P < 0.001), and LUTS (P < 0.033). Of the KCL subscale scores, instrumental activities of daily living (P = 0.008), physical function (P < 0.001), oral function (P = 0.008), housebound (P = 0.009), and depression (P = 0.034) were higher in LUTS patients than in non-LUTS patients. CONCLUSIONS: Among patients with urological diseases, those with LUTS were found to have a high prevalence of frailty. Geriatr Gerontol Int 2023; 23: 609-615.

PKD1 Mutation Is a Biomarker for Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) occurs in 1 in 500-4000 people worldwide. Genetic mutation is a biomarker for predicting renal dysfunction in patients with ADPKD. In this study, we performed a genetic analysis of Japanese patients with ADPKD to investigate the prognostic utility of genetic mutations in predicting renal function outcomes. METHODS: Patients clinically diagnosed with ADPKD underwent a panel genetic test for germline mutations in PKD1 and PKD2. This study was conducted with the approval of the Ethics Committee of Juntendo University (no. 2019107). RESULTS: Of 436 patients, 366 (83.9%) had genetic mutations. Notably, patients with PKD1 mutation had a significantly decreased ΔeGFR/year compared to patients with PKD2 mutation, indicating a progression of renal dysfunction (-3.50 vs. -2.04 mL/min/1.73 m2/year, p = 0.066). Furthermore, PKD1 truncated mutations had a significantly decreased ΔeGFR/year compared to PKD1 non-truncated mutations in the population aged over 65 years (-6.56 vs. -2.16 mL/min/1.73 m2/year, p = 0.049). Multivariate analysis showed that PKD1 mutation was a more significant risk factor than PKD2 mutation (odds ratio, 1.81; 95% confidence interval, 1.11-3.16; p = 0.020). CONCLUSIONS: The analysis of germline mutations can predict renal prognosis in Japanese patients with ADPKD, and PKD1 mutation is a biomarker of ADPKD.

Extended versus standard pelvic lymph node dissection yields no difference in 3-year biochemical recurrence rates.

Background: extended pelvic lymph node dissection (ePLND) increases the detection rate of lymph node positive prostate cancer compared to a standard pelvic lymph node dissection (sPLND). However, improvement of patient outcomes remains questionable. Here we report and compare 3-year postoperative PSA recurrence rates between patients that underwent sPLND versus ePLND at the time of prostatectomy. Methods: 162 patients received a sPLND (which involvedremoval of periprostatic, external iliac, and obturator lymph nodes bilaterally), and 142 patients received an ePLND (which involved removal of periprostatic, external iliac, obturator, hypogastric, and common iliac nodes bilaterally). Decision to undergo ePLND versus sPLND at our institution was changed in 2016 based on the National Comprehensive Cancer Network guideline. The median follow-up time was 7 and 3 years for sPLND and ePLND patients, respectively. All node-positive patients were offered adjuvant radiotherapy. Kaplan-Meier analysis was carried out to assess the impact of a PLND on early postoperative PSA progression-free survival. Subgroup analyses were done for node-negative and node-positive patients, as well as Gleason score. Results: Gleason score and T stage were not significantly different between patients who received an ePLND and sPLND. The pN1 rate for ePLND and sPLND were 20% (28/142) and 6% (10/162), respectively. There was no difference in the use of adjuvant treatments in the pN0 patients. Significantly, more ePLND pN1 patients received adjuvant androgen deprivation therapy (25/28 vs. 5/10 P = 0.012) and radiation (27/28 vs. 4/10 P = 0.002). Yet, no difference in biochemical recurrence between ePLND and sPLND was observed (P = 0.44). This remained true in subgroup analyses of node-positive (P = 0.26), node-negative (P = 0.78), Gleason Score 6-7 (P = 0.51), and Gleason Score 8-10 (P = 0.77). Conclusions: PLND provided no additional therapeutic benefit, even though ePLND patients were significantly more likely to have node-positive disease and undergo adjuvant treatment, compared to a sPLND.

Public support for patients with intractable diseases in Japan: impact on clinical indicators from nationwide registries in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: Clinical practice guidelines recommend antihypertensive and tolvaptan therapies for patients with autosomal dominant polycystic kidney disease (ADPKD) in Japan. However, tolvaptan therapy may pose an economic burden. The Japanese Ministry of Health, Labour and Welfare supports patients with intractable diseases. This study aimed to confirm the impact of the intractable disease system in Japan on the clinical treatment of ADPKD. METHODS: We analyzed the data of 3768 patients with ADPKD having a medical subsidy certificate from the Japanese Ministry of Health, Labour and Welfare in 2015-2016. The following quality indicators were use: the adherence rate to the 2014 clinical practice guideline for polycystic kidney disease (prescription rates of antihypertensive agents and tolvaptan in this cohort) and the number of Japanese patients with ADPKD nationwide started on renal replacement therapy in 2014 and 2020. RESULTS: Compared with new applications from 2015 to 2016, the prescription rates of antihypertensives and tolvaptan for the indicated patients at the 2017 renewal application increased by 2.0% (odds ratio = 1.41, p = 0.008) and 47.4% (odds ratio = 10.1, p > 0.001), respectively. These quality indicators improved with antihypertensive treatment, especially in patients with chronic kidney disease stages 1-2 (odds ratio = 1.79, p = 0.013) and in those aged < 50 years (odds ratio = 1.70, p = 0.003). The number of patients with ADPKD who were started on renal replacement therapy in Japan decreased from 999 in 2014 to 884 in 2020 in the nationwide database (odds ratio = 0.83, p < 0.001). CONCLUSIONS: The Japanese public intractable disease support system contributes to improvement of ADPKD treatment.

Genetic association of mosaic loss of chromosome Y with prostate cancer in men of European and East Asian ancestries: a Mendelian randomization study.

Background: Genomic instability is a significant hallmark of aging and has a major impact on aging biology. Mosaic loss of chromosome Y (mLOY) in blood cells is a common chromosomal abnormality in aging men and is considered an indicator of genomic instability. Previous studies have indicated a connection between mLOY and prostate cancer risk, but the causal relationship has not been fully established. Methods: To determine the causal effect of mLOY on prostate cancer, we conducted a Mendelian Randomization (MR) study in two ancestral groups. We utilized 125 and 42 mLOY-associated variants as instrumental variables (IVs) in European and East Asian GWAS of prostate cancer, respectively. Summary-level data on prostate cancer was obtained from the PRACTICAL consortium (79,148 cases and 61,106 controls of European ancestry) and the Biobank Japan consortium (5,408 cases and 103,939 controls of East Asian ancestry). A single population was used to assess the causal relationship in East Asian ancestry. Our main method for obtaining MR results was inverse-variance weighted (IVW), and we conducted sensitivity analyses to confirm the robustness of our results. Finally, we combined the estimates from both sources using a fixed-effects meta-analysis. Results: Our MR analysis using the IVW method showed that a one-unit increase in genetically predicted mLOY was associated with an increased risk of prostate cancer in the PRACTICAL consortium (OR = 1.09%, 95% CI: 1.05-1.13, p = 1.2 × 10-5), but not in the Biobank Japan consortium (OR = 1.13%, 95% CI: 0.88-1.45, p = 0.34). Sensitivity analyses robustly indicated increased odds ratios for prostate cancer with every one-unit increase in genetically predicted mLOY for the PRACTICAL consortium. Furthermore, mLOY was found to be associated with prostate cancer risk in a meta-analysis of both sources (OR = 1.09%, 95% CI: 1.05-1.13, p = 8.0 × 10-6). Conclusion: Our MR study provides strong evidence that higher mLOY increases the risk of prostate cancer. Preventing mLOY may be a means of reducing the risk of developing prostate cancer.