Increased circulating polymorphonuclear myeloid-derived suppressor cells are associated with prognosis of metastatic castration-resistant prostate cancer.

Introduction: Myeloid-derived suppressor cell (MDSC) exhibits immunosuppressive functions and affects cancer progression, but its relationship with prostate cancer remains unclear. We elucidated the association of polymorphonuclear MDSC (PMN-MDSC) and monocytic MDSC (M-MDSC) levels of the total peripheral blood mononuclear cells (PBMCs) with prostate cancer progression and evaluated their roles as prognostic indicators. Methods: We enrolled 115 patients with non-metastatic hormone-sensitive prostate cancer (nmHSPC, n = 62), metastatic hormone-sensitive prostate cancer (mHSPC, n = 23), and metastatic castration-resistant prostate cancer (mCRPC, n = 30). Subsequently, the proportions of MDSCs in each disease progression were compared. Log-rank tests and multivariate Cox regression analyses were performed to ascertain the associations of overall survival. Results: The patients with mCRPC had significantly higher PMN-MDSC percentage than those with nmHSPC and mHSPC (P = 7.73 × 10-5 and 0.0014). Significantly elevated M-MDSC levels were observed in mCRPC patients aged <70 years (P = 0.016) and with a body mass index (BMI) <25 kg/m2 (P = 0.043). The high PMN-MDSC group had notably shorter median survival duration (159 days) than the low PMN-MDSC group (768 days, log-rank P = 0.018). In the multivariate analysis including age, BMI, and MDSC subset, PMN-MDSC was significantly associated with prognosis (hazard ratios, 3.48; 95% confidence interval: 1.05-11.56, P = 0.042). Discussion: PMN-MDSC levels are significantly associated with mCRPC prognosis. Additionally, we highlight the remarkable associations of age and BMI with M-MDSC levels in mCRPC, offering novel insights into MDSC dynamics in prostate cancer progression.

Androgen Receptor Splice Variant 7 in Asian Patients With Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: Androgen receptor splice variant 7 (ARV-7) is a resistance mechanism to hormonal therapy in metastatic castrate-resistant prostate cancer (mCRPC). It has been associated with poor outcomes. On progression to castrate resistance, ARV-7 positivity has been identified in global populations at an incidence of 17.8%-28.8%. Here, we characterize the incidence of ARV-7 positivity in Asian patients with mCRPC in a prospective fashion and evaluate its implications on treatment outcomes. METHODS: Patients with mCRPC from multiple centers in Southeast and East Asia were enrolled in a prospective manner before initiation of androgen receptor signaling inhibitors or docetaxel. ARV-7 status was evaluated at baseline with three commercially available assays: AdnaTest Prostate Cancer platform, Clearbridge method, and IBN method. Clinical outcomes at progression were assessed. The primary end point of this study was prevalence of ARV-7 positivity; secondary end points were incidence of ARV-7 positivity, prostate specific antigen (PSA) response rate, PSA progression-free survival (PFS), and overall survival (OS). RESULTS: A total of 102 patients with a median age of 72 years at enrollment participated. Overall, an incidence of ARV-7 positivity of between 14.3% and 33.7% in Asian patients with mCRPC was demonstrated depending on the assay used. Patients found to have ARV-7 positivity at enrollment had a numerically worse PSA PFS compared with ARV-7 negative patients. CONCLUSION: In this study, the incidence of ARV-7 positivity in Asian patients with mCRPC was shown to be similar to the global population. Patients with ARV-7 positivity appear to have more aggressive disease with numerically worse PSA PFS and OS. Further prospective studies are needed to fully characterize the relationship that ARV-7 positivity has on prognosis of Asian patients with mCRPC.

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.

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.

Robot-Assisted Radical Cystectomy with Modified Vesica Ileale Padovana (VIP) Neobladder Configuration Using a Hybrid Approach: Initial Experience.

PURPOSE: We developed a new technique to fold a neobladder (NB) simply by using a modified Vesica Ileale Padovana (VIP) with a hybrid approach. We provide a step-by-step description of our technique as it was used in this initial experience. METHODS: A total of 10 male patients with a median age of 66 years underwent robot-assisted radical cystectomy (RARC) with an orthotopic NB via a hybrid approach from March 2022 to February 2023. After the isolation of the bladder and bilateral pelvic lymphadenectomy, Wallace plate creation was performed, and the robot was undocked. We extracorporeally performed the removal of the specimen and a side-to-side ileoileal anastomosis, and then the VIP NB posterior plate was rotated 90 degrees counterclockwise using a 45 cm detubularized ileum. The robot was redocked; then, circumferential urethra-ileal anastomosis, side-to-middle anterior wall closure, and ureteric afferent limb anastomosis were performed. RESULTS: The median estimated blood loss was 524 mL, and the mean operative time was 496 min. Patients had a high continence rate, and no high-grade complications were observed. CONCLUSION: The NB configuration using the modified VIP method for a hybrid approach is a feasible surgical technique to minimize the movement of robotic forceps. In particular, it may be more useful in Asian individuals with narrow pelvises.

Bone scan index (BSI) scoring by using bone scintigraphy and circulating tumor cells (CTCs): predictive factors for enzalutamide effectiveness in patients with castration-resistant prostate cancer and bone metastases.

Reports of Bone Scan Index (BSI) calculations as imaging biomarkers to predict survival in patients with metastatic castration-resistant prostate cancer (mCRPC) have been mainly from retrospective studies. To evaluate the effectiveness of enzalutamide (ENZ) in Japanese patients with mCRPC and bone metastases using BSI (bone scintigraphy) and circulating tumor cell (CTC) analysis. Prospective, single-arm study at Juntendo University affiliated hospitals, Japan. Patients were administered 160 mg ENZ daily, with 3 monthly assessments: BSI, prostate specific antigen (PSA), CTC and androgen receptor splicing variant-7 (AR-V7) status. Primary endpoint: BSI-decreasing rate after ENZ treatment. Secondary endpoints: PSA-decreasing rate and progression free survival (PFS). Statistical analyses included the Wilcoxon t-test, Cox proportional hazard regression analysis, and log-rank test. Median observation period: 17.9 months, and median PFS: 13.8 (2.0-43.9) months (n = 90 patients). A decrease in BSI compared to baseline as best BSI change on ENZ treatment was evident in 69% patients at the end of the observation period (29% patients showed a complete response, BSI 0.00). At 3 months 67% patients showed a ≥ 50% PSA reduction, and 70% after ENZ treatment. PSA decline (3 months) significantly associated with a prolonged median PFS: 18.0 (estimated) versus 6.4 months (HR 2.977 [95% CI 1.53-5.78], p = 0.001). Best BSI decline response significantly associated with a prolonged PFS: 18.1(estimated) versus 7.8 months (HR 2.045 [95% CI: 1.07-3.90], p = 0.029). CTC negative status (n = 20) significantly associated with a prolonged PFS: 13.4 [estimated] vs 8.6 months (HR 2.366, 95% CI 0.97-5.71, p = 0.041). CTC positive/AR-V7 positive status significantly associated with a shorter PFS: 5.9 months (HR 8.56, 95% CI 2.40-30.43, p = 0.0087). -reduction (3 months) and BSI-reduction (on ENZ treatment) were significant response biomarkers, and a negative CTC status was a predictive factor for ENZ efficacy in patients with mCRPC.

Impact of cisplatin-induced acute kidney injury on long-term renal function in patients with solid tumors.

BACKGROUND: The reality of cisplatin-induced acute kidney injury (CIA) and its effects on long-term renal function remain unclear. The aim of this study was to investigate the incidence and risk factors for CIA development, and if CIA is a useful predictor of long-term renal dysfunction after cisplatin treatment. METHODS: This was a retrospective, single-center, observational, longitudinal follow-up, large cohort study in adult patients with solid tumors treated with cisplatin-based systematic chemotherapy. Electronic medical records were used for all demographic and medical data. AKI was defined by Kidney Disease Improving Global Outcomes (KDIGO) criteria. We assessed long-term renal dysfunction using %ΔeGFR/Y; (the last eGFR value during follow-up)-(the baseline eGFR)/(the baseline eGFR)/year of follow-up × 100. RESULTS: A total of 2191 patients received 8,482 cycles of cisplatin. CIA was observed 359 times (4.2%). Significant risk factors for developing CIA, using multiple linear regression analysis, included: cisplatin administration immediately before the onset of CIA (p < 0.01), liver cancer (p = 0.02), colon cancer (p = 0.04), hypertension (p = 0.03), high estimated glomerular filtration rate (eGFR) (p < 0.01), and high C-reactive protein (CRP) (p = 0.04). Significant risk factors for %ΔeGFR/Y, using multivariate linear regression analysis, included: esophageal cancer (p < 0.01), lung cancer (p < 0.01), pharyngeal cancer (p = 0.02), Head and neck cancer (p < 0.01), liver cancer (p = 0.02), potassium (p < 0.01), and CIA (p < 0.01). CONCLUSIONS: To our knowledge, this is the first study to show that CIA is a significant predictive risk factor for long-term renal dysfunction after cisplatin administration. Effective strategies are needed to prevent CIA in cancer patients.

Gut environment changes due to androgen deprivation therapy in patients with prostate cancer.

BACKGROUND: It is estimated that by 2040 there will be 1,017,712 new cases of prostate cancer worldwide. Androgen deprivation therapy (ADT) is widely used as a treatment option for all disease stages. ADT, and the resulting decline in androgen levels, may indirectly affect gut microbiota. Factors affecting gut microbiota are wide-ranging; however, literature is scarce on the effects of ADT on gut microbiota and metabolome profiles in patients with prostate cancer. METHODS: To study the changes of gut microbiome by ADT, this 24-week observational study investigated the relationship between testosterone levels and changes in gut microbiota in Japanese patients with prostate cancer undergoing ADT. Sequential faecal samples were collected 1 and 2 weeks before ADT, and 1, 4, 12, and 24 weeks after ADT. Blood samples were collected at almost the same times. Bacterial 16 S rRNA gene-based microbiome analyses and capillary electrophoresis-time-of-flight mass spectrometry-based metabolome analyses were performed. RESULTS: In total, 23 patients completed the study. The α- and ß-diversity of gut microbiota decreased significantly at 24 weeks after ADT (p = 0.017, p < 0.001, respectively). Relative abundances of Proteobacteria, Gammaproteobacteria, Pseudomonadales, Pseudomonas, and concentrations of urea, lactate, butyrate, 2-hydroxyisobutyrate and S-adenosylmethionine changed significantly after ADT (p < 0.05). There was a significant positive correlation between the abundance of Proteobacteria, a known indicator of dysbiosis, and the concentration of lactate (R = 0.49, p < 0.01). CONCLUSIONS: The decline in testosterone levels resulted in detrimental changes in gut microbiota. This dysbiosis may contribute to an increase in frailty and an increased risk of adverse outcomes in patients with prostate cancer.

Prediction of recovery time of urinary incontinence following robot-assisted laparoscopic prostatectomy.

OBJECTIVES: Postoperative urinary incontinence recovery following robot-assisted laparoscopic prostatectomy is an important outcome. We investigated whether factors that affect urinary incontinence can predict the duration of postoperative incontinence recovery. METHODS: A total of 310 patients underwent robot-assisted laparoscopic prostatectomy. Continence recovery was defined as either pad-free or a safety pad only status. Univariate and multivariate analyses were performed on clinical variables to identify those that were associated with continence recovery. A scoring system to predict recovered continence was constructed using statistically significant variables. The validity of this tool was tested in a new cohort of 273 patients. RESULTS: Factors associated with recovery of urinary incontinence were membranous urethral length, preservation of bilateral neurovascular bundles, and a preoperative Prostate Imaging Reporting and Data System score of ≥3 in the apex. Age was related only to incontinence recovery at 1 month. To prepare the score, weighting was performed using the estimated values. Using the developed scoring system, participants in the verification set were divided into three groups. The early recovery group had a median incontinence recovery of 4 (4-12) weeks, the medium recovery group, 12 (4-24) weeks, and the late recovery group, 24 (24-48) weeks, which was a significant difference (p < 0.001). CONCLUSIONS: The applied scoring system based on preoperative factors related to incontinence and derived from patient groups was significantly associated with continence recovery time. In patients undergoing robot-assisted laparoscopic prostatectomy, our unit-weighted regression model of clinical variables can predict the duration of continence recovery.

Kidney Transplantation for a Patient With Protein C Deficiency Using Activated Protein C Concentrate: A Case Report.

BACKGROUND: Thrombophilia causes thrombosis after kidney transplantation (KT). Protein C deficiency is a rare form of hereditary thrombophilia. To our knowledge, there are few reports on KT for patients with protein C deficiency, and there are no reports of KT in patients with protein C deficiency administered with activated protein C concentrate. METHOD: Here we reported the case of a patient with protein C deficiency who underwent KT without the occurrence of any fresh thrombosis after administration of an activated protein C concentrate. The patients was a 49-year-old woman diagnosed with immunoglobulin A nephropathy at 20 years of age. During pregnancy, she experienced deep vein thrombosis of the lower extremities and pulmonary embolism for which she was started on warfarin. After a thorough examination, the patient was diagnosed with protein C deficiency. The patient had end-stage kidney disease and received a preemptive living donor kidney transplant from her mother. RESULTS: To prevent thrombosis, we switched from oral warfarin to continuous heparin 7 days before surgery. Heparin was discontinued 6 hours before surgery, and continuous activated protein C concentrate was administered 12 hours before surgery. Heparin administration was resumed 6 hours after the surgery. Warfarin administration was restarted 3 days after the surgery, and heparin was discontinued 11 days post-surgery. The surgery was performed without complications. After the KT, the patient's renal function steadily improved, and no fresh thrombosis were observed. CONCLUSIONS: Thrombosis can cause graft loss and pulmonary embolism, thus appropriate administration of activated protein C concentrate may help prevent thrombosis.

Efficacy of cabazitaxel and androgen splicing variant-7 status in circulating tumor cells in Asian patients with metastatic castration-resistant prostate cancer.

Androgen receptor splice variant-7 (AR-V7) expression in circulating tumor cells (CTCs) in metastatic castration-resistant prostate cancer (mCRPC) is associated with abiraterone and enzalutamide resistance. We determine whether cabazitaxel (CBZ) is equally effective in AR-V7-positive and -negative CRPC and whether AR-V7-positive patients retain CBZ sensitivity. This is the first prospective, open-label, Asian validation study of CBZ in Japanese patients with mCRPC after docetaxel (n = 48; four CBZ cycles; 2017-2020, Juntendo University Hospitals). Primary endpoint was prostate-specific antigen response rate (PSA-RR); secondary endpoints included overall survival (OS), bone scan index (BSI) PSA-RR (≥ 50% decline from baseline) for CTC-/ARV7-, CTC+ /ARV7-, and CTC +/ARV7+ groups. PSA-RR ≥ - 30% was 38% (18/48) and ≥ - 50% was 26% (12/48). BSI-change rate ≥ - 30% was 19% (9/41) and ≥ - 50% was 17% (8/41). Median OS was 13.7(12.2-18.9) months. PSA decline in early CBZ treatment associated with OS (p = 0.00173). BSI decline associated with OS (p = 0.0194). PSA-RR(≥ 50%) was 43%(6/14) in CTC-/ARV7-, 19%(5/26) in CTC+ ARV7-, and 12%(1/8) in CTC+/ARV7+ ( p > 0.05). AR-V7 in CTCs at baseline not associated with OS. AR-V7 was not associated with CBZ resistance in CTCs. Reductions in BSI and PSA in early stages of CBZ treatment may predict OS.

Delayed Vasovagal Reaction with Reflex Syncope Following COVID-19 Vaccination.

Coronavirus disease 2019 (COVID-19) has become a pandemic, and vaccines remain the only effective tools available for ending it. However, their side effects, such as syncope, which mimics sudden cardiac death, are serious concerns. We herein report 6 cases of delayed vasovagal syncope and presyncope (VVR) caused by COVID-19 vaccination among 25,530 COVID-19 patients. The prevalence of delayed VVR due to COVID-19 vaccination was 0.026%. In addition, no delayed VVR was found among 17,386 patients who received the influenza vaccine. Delayed VVR is likely to be overlooked if medical staff are not aware of this symptom. This report provides significant information regarding effects of COVID-19 vaccination.

Clinical use of expanded prostate cancer index composite-based health-related quality of life outcomes after robot-assisted radical prostatectomy for localized prostate cancer.

Background: This study aimed to assess the longitudinal health-related quality of life (HRQOL) using the Expanded Prostate Cancer Index Composite (EPIC) and HRQOL change between the nerve-sparing technique in Japanese men treated with robot-assisted radical prostatectomy (RARP). Methods: A total of 573 patients who received RARP were included in this study. EPIC questionnaire was administered before treatment and up to 36 months after RARP. Clinical recovery was defined as half of the standard deviation of the baseline score for each domain. We divided all patients into recovery group or nonrecovery group. The time from survey to each domain recovery was calculated using the Kaplan-Meier method. We compared the sexual and urinary score change between groups using analysis of variance to confirm the effect of nerve-sparing technique. Results: The median age was 67 years (interquartile range, 62-71 years). The mean score of all urinary domains worsened noticeably after 1 month. All postoperative urinary summary, function, and incontinence scores were significantly lower than preoperative scores up to 3 years post-RARP. Postoperative sexual summary and functional scores were significantly lower than preoperative score at all follow-up times throughout the 36 months. The recovery rate for the urinary incontinence domain was the lowest (44.5%), whereas the recovery rate for the urinary irritative-obstructive domain was the highest (73.7%). In the sexual domain, the bother domain had a higher recovery rate (73.0%) than the functional domain (29.7%). Although the recovery of sexual domains was slower compared with other domains, by 36 months after RARP, almost all values had recovered. Compared with other technique groups, bilateral intrafascial nerve-sparing group showed significantly decreased change in subscale scores before and after RARP in several sexual and urinary domain. Conclusion: The time course and extent of functional and bother domain recovery documented in this study may prove useful for RARP patient selection in Japan.

Vasospasm-induced ST-segment elevation myocardial infarction in a premenopausal woman with endothelial dysfunction.

ST-segment elevation myocardial infarction (STEMI) can be caused by coronary artery vasospasm (VSA) due to endothelial dysfunction. However, the clinical role of endothelial function tests in VSA-induced STEMI is not fully understood. We present the case of a 43-year-old woman with atypical chest pain and no coronary risk factors. STEMI caused by VSA was diagnosed. Flow-mediated vasodilatation (FMD) and EndPAT tests were performed; the FMD and reactive hyperaemia index were 3.8% and 1.23, respectively. Endothelial dysfunction is the putative cause of STEMI. FMD and EndPAT tests might be useful for predicting adverse outcomes in young premenopausal women with VSA.