Cardiovascular disease risk assessment and multidisciplinary care in prostate cancer treatment with ADT: recommendations from the APMA PCCV expert network.

PURPOSE: Androgen deprivation therapy (ADT) is the mainstay approach for prostate cancer (PCa) management. However, the most commonly used ADT modality, gonadotropin-releasing hormone (GnRH) agonists, has been associated with an increased risk of cardiovascular disease (CVD). METHODS: The PCa Cardiovascular (PCCV) Expert Network, consisting of multinational urologists, cardiologists and oncologists with expertise in managing PCa, convened to discuss challenges to routine cardiovascular risk assessment in PCa management, as well as how to mitigate such risks in the current treatment landscape. RESULTS: The experts identified several barriers, including lack of awareness, time constraints, challenges in implementing risk assessment tools and difficulties in establishing multidisciplinary teams that include cardiologists. The experts subsequently provided practical recommendations to improve cardio-oncology care for patients with PCa receiving ADT, such as simplifying cardiovascular risk assessment, individualising treatment based on CVD risk categories, establishing multidisciplinary teams and referral networks and fostering active patient engagement. A streamlined cardiovascular risk-stratification tool and a referral/management guide were developed for seamless integration into urologists' practices and presented herein. The PCCV Expert Network agreed that currently available evidence indicates that GnRH antagonists are associated with a lower risk of CVD than that of GnRH agonists and that GnRH antagonists are preferred for patients with PCa and a high CVD risk. CONCLUSION: In summary, this article provides insights and guidance to improve management for patients with PCa undergoing ADT.

Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial.

BACKGROUND: PROpel met its primary endpoint showing statistically significant improvement in radiographic progression-free survival with olaparib plus abiraterone versus placebo plus abiraterone in patients with first-line metastatic castration-resistant prostate cancer (mCRPC) unselected by homologous recombination repair mutation (HRRm) status, with benefit observed in all prespecified subgroups. Here we report the final prespecified overall survival analysis. METHODS: This was a randomised, double-blind, phase 3 trial done at 126 centres in 17 countries worldwide. Patients with mCRPC aged at least 18 years, Eastern Cooperative Oncology Group performance status 0-1, a life expectancy of at least 6 months, with no previous systemic treatment for mCRPC and unselected by HRRm status were randomly assigned (1:1) centrally by means of an interactive voice response system-interactive web response system to abiraterone acetate (orally, 1000 mg once daily) plus prednisone or prednisolone with either olaparib (orally, 300 mg twice daily) or placebo. The patients, the investigator, and study centre staff were masked to drug allocation. Stratification factors were site of metastases and previous docetaxel at metastatic hormone-sensitive cancer stage. Radiographic progression-free survival was the primary endpoint and overall survival was a key secondary endpoint with alpha-control (alpha-threshold at prespecified final analysis: 0·0377 [two-sided]), evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03732820, and is completed and no longer recruiting. FINDINGS: Between Oct 31, 2018 and March 11, 2020, 1103 patients were screened, of whom 399 were randomly assigned to olaparib plus abiraterone and 397 to placebo plus abiraterone. Median follow-up for overall survival in patients with censored data was 36·6 months (IQR 34·1-40·3) for olaparib plus abiraterone and 36·5 months (33·8-40·3) for placebo plus abiraterone. Median overall survival was 42·1 months (95% CI 38·4-not reached) with olaparib plus abiraterone and 34·7 months (31·0-39·3) with placebo plus abiraterone (hazard ratio 0·81, 95% CI 0·67-1·00; p=0·054). The most common grade 3-4 adverse event was anaemia reported in 64 (16%) of 398 patients in the olaparib plus abiraterone and 13 (3%) of 396 patients in the placebo plus abiraterone group. Serious adverse events were reported in 161 (40%) in the olaparib plus abiraterone group and 126 (32%) in the placebo plus abiraterone group. One death in the placebo plus abiraterone group, from interstitial lung disease, was considered treatment related. INTERPRETATION: Overall survival was not significantly different between treatment groups at this final prespecified analysis. FUNDING: Supported by AstraZeneca and Merck Sharp & Dohme.

Fully Automated Continuous Centrifugal Microfluidics Isolates Natural Killer Cells with High Performance and Minimal Stress.

Natural killer (NK) cells are a part of the innate immune system, providing the first line of defense against cancer cells and pathogens at an early stage. Hence, they are attracting attention as a valuable resource for allogeneic cell immunotherapy. However, NK cells exist with limited proportion in blood, and obtaining sufficient clinical-grade NK cells with highly viable and minimal stress is critical for successful immune cell therapy. Conventional purification methods via immunoaffinity or density gradient centrifugation had several limitations in yield, purity, and cellular stress, which might cause an increased risk for graft versus host disease and reduced efficacy due to NK cell malfunction, exhaustion, and apoptosis. Moreover, reducing the variations of isolation performance caused by the manual process is another unmet need for uniform quality of the living drug. Here, an automated system using an NK disc (NKD) based on continuous centrifugal microfluidics (CCM) technology was developed to isolate NK cells from whole blood with high yield, purity, reproducibility, and low stress. The CCM technology, which operates fluidic manipulation under disc rotation, enabled precise extraction of the ultra-thin target fluid layer generated by blood centrifugation. Compared to the conventional manual method, the CCM-NKD isolated NK cells with higher yield (recovery rate) and purity, while maintaining better reproducibility. Furthermore, since the CCM-NKD maintained substantially milder centrifugation conditions (120 ×g for 10 min) compared to the conventional approach (1200 ×g for 20 min), it showed reduced cellular stress and increased antioxidant capacity in the isolated NK cells. Based on the results, the CCM-NKD is expected to be a useful tool to provide highly intact and viable cell weapons for successful immune cell therapy.

Clinical Efficacy of Neoadjuvant Intravesical Mitomycin-C Therapy Immediately Before Transurethral Resection of Bladder Tumor in Patients With Nonmuscle-invasive Bladder Cancer: Preliminary Results of a Prospective, Randomized Phase II Study.

PURPOSE: Intravesical mitomycin-C is recommended immediately after transurethral resection of bladder tumor for nonmuscle-invasive bladder cancer. However, a lack of compliance occurs due to the associated complications. Here, we aimed to assess the efficacy and safety of intravesical mitomycin-C before transurethral resection of bladder tumor in patients with nonmuscle-invasive bladder cancer. MATERIALS AND METHODS: This was a single-center, open-label, parallel-arm, randomized phase II clinical trial in patients with suspected nonmuscle-invasive bladder cancer before transurethral resection of bladder tumor. Participants were randomly assigned (1:1) to receive 2 doses of intravesical mitomycin-C (40 mg/20 mL) 1 day and 4 hours before transurethral resection of bladder tumor (n = 49) or no treatment (n = 50) with block randomization (size 2 and 4), stratified by bacillus Calmette-Guérin/intravesical mitomycin-C. The primary endpoint was recurrence-free survival and secondary endpoints were progression-free survival and adverse events in the per-protocol analysis. RESULTS: Seventy-one patients (33, intervention; 38, control) were well matched for baseline characteristics. Sixty-one had been followed without recurrence for at least 10.4 months; 3 and 8 patients showed recurrence in the intervention and control groups, respectively. The 1-year recurrence-free survival rate was 97% and 89% for the intervention and control groups, respectively. Neoadjuvant intravesical mitomycin-C resulted in a reduction (63%) in the relative recurrence risk (hazard ratio, 0.37; 80% 1-sided confidence interval, -∞-0.65, P = .11). Disease progression occurred in 3 patients in the control group (P = .051) but not in the intervention group. Neoadjuvant intravesical mitomycin-C was well tolerated, and adverse events were local and of grade 1/2. CONCLUSIONS: Two doses of neoadjuvant intravesical mitomycin-C are safe and effective in reducing nonmuscle-invasive bladder cancer recurrence and progression after transurethral resection of bladder tumor.

Pain and health-related quality of life with olaparib versus physician's choice of next-generation hormonal drug in patients with metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations (PROfound): an open-label, randomised, phase 3 trial.

BACKGROUND: The PROfound study showed significantly improved radiographical progression-free survival and overall survival in men with metastatic castration-resistant prostate cancer with alterations in homologous recombination repair genes and disease progression on a previous next-generation hormonal drug who received olaparib then those who received control. We aimed to assess pain and patient-centric health-related quality of life (HRQOL) measures in patients in the trial. METHODS: In this open-label, randomised, phase 3 study, patients (aged ≥18 years) with metastatic castration-resistant prostate cancer and gene alterations to one of 15 genes (BRCA1, BRCA2, or ATM [cohort A] and BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L [cohort B]) and disease progression after a previous next-generation hormonal drug were randomly assigned (2:1) to receive olaparib tablets (300 mg orally twice daily) or a control drug (enzalutamide tablets [160 mg orally once daily] or abiraterone tablets [1000 mg orally once daily] plus prednisone tablets [5 mg orally twice daily]), stratified by previous taxane use and measurable disease. The primary endpoint (radiographical progression-free survival in cohort A) has been previously reported. The prespecified secondary endpoints reported here are on pain, HRQOL, symptomatic skeletal-related events, and time to first opiate use for cancer-related pain in cohort A. Pain was assessed with the Brief Pain Inventory-Short Form, and HRQOL was assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P). All endpoints were analysed in patients in cohort A by modified intention-to-treat. The study is registered with ClinicalTrials.gov, NCT02987543. FINDINGS: Between Feb 6, 2017, and June 4, 2019, 245 patients were enrolled in cohort A and received study treatment (162 [66%] in the olaparib group and 83 [34%] in the control group). Median duration of follow-up at data cutoff in all patients was 6·2 months (IQR 2·2-10·4) for the olaparib group and 3·5 months (1·7-4·9) for the control group. In cohort A, median time to pain progression was significantly longer with olaparib than with control (median not reached [95% CI not reached-not reached] with olaparib vs 9·92 months [5·39-not reached] with control; HR 0·44 [95% CI 0·22-0·91]; p=0·019). Pain interference scores were also better in the olaparib group (difference in overall adjusted mean change from baseline score -0·85 [95% CI -1·31 to -0·39]; pnominal=0·0004). Median time to progression of pain severity was not reached in either group (95% CI not reached-not reached for both groups; HR 0·56 [95% CI 0·25-1·34]; pnominal=0·17). In patients who had not used opiates at baseline (113 in the olaparib group, 58 in the control group), median time to first opiate use for cancer-related pain was 18·0 months (95% CI 12·8-not reached) in the olaparib group versus 7·5 months (3·2-not reached) in the control group (HR 0·61; 95% CI 0·38-0·99; pnominal=0·044). The proportion of patients with clinically meaningful improvement in FACT-P total score during treatment was higher for the olaparib group than the control group: 15 (10%) of 152 evaluable patients had a response in the olaparib group compared with one (1%) of evaluable 77 patients in the control group (odds ratio 8·32 [95% CI 1·64-151·84]; pnominal=0·0065). Median time to first symptomatic skeletal-related event was not reached for either treatment group (olaparib group 95% CI not reached-not reached; control group 7·8-not reached; HR 0·37 [95% CI 0·20-0·70]; pnominal=0·0013). INTERPRETATION: Olaparib was associated with reduced pain burden and better-preserved HRQOL compared with the two control drugs in men with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations who had disease progression after a previous next-generation hormonal drug. Our findings support the clinical benefit of improved radiographical progression-free survival and overall survival identified in PROfound. FUNDING: AstraZeneca and Merck Sharp & Dohme.

Olaparib in patients with mCRPC with homologous recombination repair gene alterations: PROfound Asian subset analysis.

BACKGROUND: The Phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control; randomized 2:1 to olaparib or control) in men with homologous recombination repair gene alterations and metastatic castration-resistant prostate cancer whose disease progressed on prior next-generation hormonal agent. METHODS: We present efficacy and safety data from an exploratory post hoc analysis of olaparib in the PROfound Asian subset. Analyses were not planned, alpha controlled or powered. Of 101 Asian patients enrolled in Japan (n=57), South Korea (n=29) and Taiwan (n=15), 66 and 35 patients received olaparib and control, respectively. RESULTS: Radiographic progression-free survival (rPFS) and overall survival (OS) favored olaparib versus control in Cohort A [rPFS 7.2 vs. 4.5 months, HR 0.58, 95% CI 0.29-1.21, P = 0.14 (nominal); OS 23.4 vs. 17.8 months, HR 0.81, 95% CI 0.40-1.74, P = 0.57 (nominal)] and Cohorts A+B [rPFS 5.8 vs. 3.5 months, HR 0.69, 95% CI 0.42-1.16, P = 0.13 (nominal); OS 18.6 vs. 16.2 months, HR 0.96, 95% CI 0.56-1.70, P = 0.9 (nominal)]. Olaparib showed greatest improvement in patients harboring BRCA alterations [rPFS 9.3 vs. 3.5 months, HR 0.17, 95% CI 0.06-0.49, P = 0.0003 (nominal); OS 26.8 vs. 14.3 months, HR 0.62, 95% CI 0.24-1.79, P = 0.34 (nominal)]. Safety data were consistent with the known profile of olaparib, with no new safety signals identified. CONCLUSION: In PROfound, there was a statistically significant improvement in outcomes reported in the global population of patients with metastatic castration-resistant prostate cancer and alterations in homologous recombination repair genes whose disease progressed on prior next-generation hormonal agent compared with control. For the subset of Asian patients reported here, exploratory analysis suggested that there was also an improvement in outcomes versus control. The safety and tolerability of olaparib in Asian patients were similar to that of the PROfound global population. CLINICAL TRIAL NUMBER: ClinicalTrials.gov NCT02987543.

The effect of subsequent immunosuppressant use in organ-transplanted patients on prostate cancer incidence: a retrospective analysis using the Korean National Health Insurance Database.

BACKGROUNDS: Prostate cancer (PC) is the most common solid organ cancer. However, there is still no definite consensus before and after organ transplantation (TPL). We aimed to analyze whether PC incidence increased in TPL patients with subsequent use of immunosuppressants using the Korean National Health Insurance Database. METHODS: TPL patients between 2003 and 2015(N = 12,970) were age- and year-matched to non-TPL patients (N = 38,910) in a 1:3 ratio. Multivariate Cox regression analysis adjusted for significant prognostic clinicopathological parameters, including the duration of immunosuppressant agent use (0-300 or > 300 days), and Kaplan-Meier analysis with log-rank test were used to evaluate the association of TPL with PC incidence between the groups. RESULTS: Median overall survival was 4.86 years; overall mortality rate was 3.4% (n = 1761). Regardless of differences in baseline characteristics between the groups, multivariate analysis for PC incidence showed that age, immunosuppressant use, and TPL organ subtypes were significant factors for the overall population, whereas only age was significant in the TPL group (p < 0.05). After adjusting for age, underlying disease, and prescribed medication (aspirin, statin), multiple subgroup analysis models for PC incidence were evaluated. PC incidence was increased in the TPL group (hazard ratio [HR] 1.965, p < 0.001); however, PC incidence in the TPL group became insignificant after adjusting for immunosuppressant use (p = 0.194). Kaplan-Meier curves also showed that PC incidence was significantly different according to age and TPL with the use of immunosuppressants between the TPL and non-TPL groups. CONCLUSIONS: PC incidence was higher in the TPL group using immunosuppressants than in the non-TPL group. TRIAL REGISTRATION:  The study was retrospectively registered.

Association between Postoperative Detection of Circulating Tumor Cells and Recurrence in Patients with Prostate Cancer.

PURPOSE: The clinical implications of postoperative detection of circulating tumor cells in prostate cancer are largely unknown. We investigated the association between postoperative circulating tumor cell detection after radical prostatectomy and disease recurrence in prospectively enrolled patients with prostate cancer. MATERIALS AND METHODS: A total of 203 patients with an undetectable prostate specific antigen who had undergone radical prostatectomy for prostate cancer were prospectively enrolled. Circulating tumor cell sampling was performed at a median of 4.5 months after surgery. The primary end point was biochemical recurrence-free survival. Detection of circulating tumor cells in the blood of patients was performed using a novel approach with a replication-competent adenovirus controlled by prostate specific antigen/prostate specific membrane antigen transcription regulatory elements (Ad5/35E1aPSESE4). RESULTS: Circulating tumor cells were detected in 73 (36.0%) patients with undetectable prostate specific antigen concentrations after surgery. The 3-year biochemical recurrence-free survival rate from the time of surgery was significantly higher in circulating tumor cell-negative than in circulating tumor cell-positive cases (81.6% vs 48.9%, log rank p <0.001). Multivariable analysis showed that postoperative circulating tumor cell detection was independently associated with an increased risk of biochemical recurrence (HR 5.42, 95% CI 3.24-9.06, p <0.001). C-index was increased in combinations of multivariable model and postoperative circulating tumor cell detection compared with the multivariable model alone. CONCLUSIONS: Circulating tumor cells in the blood were frequently detected in patients with undetectable prostate specific antigen levels after radical prostatectomy for localized prostate cancer. Furthermore, circulating tumor cell detection was associated with an increased risk of biochemical recurrence, suggesting that circulating tumor cell detection precedes prostate specific antigen rise after surgery in cases of prostate cancer recurrence. Large-scale validation is needed in the future.

Survival of patients receiving systematic therapy for metachronous or synchronous metastatic renal cell carcinoma: a retrospective analysis.

BACKGROUND: The differences in progression-free survival (PFS) and cancer-specific survival (CSS) of metastatic renal cell carcinoma (mRCC) patients according to treatment, type of metastasis, and Heng criteria risk are unclear. In this study, we compared survival according to various such parameters. METHODS: Between 2000 to 2014, 214 mRCC patients, of whom 171 (79.9%) were intermediate-risk and 43 (20.1%) were poor-risk, were retrospectively selected; 126 (58.9%) patients were treated with immunotherapy (IT) and 88 (41.1%) with targeted therapy (TT). Moreover, 144 patients had synchronous mRCCs (67.3%, SM) and 70 had metachronous mRCCs (32.7%, MM). The Kaplan-Meier method and log-rank test were used to compare progression-free survival (PFS) and CSS. RESULTS: During a median 4.2 (1.0-70.4) months of systemic treatment and 98.3 (4.8-147.6) months of follow-up, the median PFS and CSS were 4.7 (95% confidence interval [CI]: 3.8-5.5) and 13.8 (95% CI, 9.8-18.3) months, respectively. The PFS and CSS were significantly better in the MM (5.9 and 21.3 months) and intermediate-risk groups (5.2 and 18.3 months) than those in the SM (4.4 and 9.6 months) and poor-risk groups (2.7 and 5.8 months), respectively (p < 0.05). Further stratification showed that TT produced significantly better PFS than IT in intermediate-risk patients with SM and a treatment-free interval (TFI) < 1 year, and in those with MM with a TFI ≥1 year (p < 0.05). There were no differences in survival outcomes according to various other subgroup stratifications (p > 0.05). CONCLUSION: Dividing patients into specific subcategories helps to better predict therapeutic outcomes.

Risk of second primary Cancer among bladder Cancer patients: a population-based cohort study in Korea.

BACKGROUND: For the expanding population of bladder cancer survivors in Korea, the development of subsequent cancers is a significant concern. Here, we provide the second primary cancer incidence rates and types in Korean patients with bladder cancer. METHODS: Using population-based data from the Korea Central Cancer Registry from 1993 to 2013, we studied the standardized incidence ratios among 48,875 individuals with an initial diagnosis of bladder cancer. Standardized incidence ratios for second primary cancers were evaluated according to age at diagnosis, latency, diagnostic year, and treatment. RESULTS: Over the same period, the overall risk of a second primary cancer was reduced by 6% in patients with bladder cancer compared with the development of a new malignancy in the general population (standardized incidence ratio = 0.94; 95% CI, 0.91-0.97, p < 0.05). For specific cancers, the standardized incidence ratios for stomach, colon, liver, and non-Hodgkin lymphoma were significantly lower in patients with bladder cancer. However, the risk of prostate and kidney cancer in patients with bladder cancer were significantly increased. The risk of lung squamous cell carcinoma and lung adenocarcinoma as second primary cancers was significantly elevated in patients with bladder cancer. CONCLUSION: Korean patients with bladder cancer have a 6% lower risk of developing a second primary cancer. However, they have a higher risk of developing subsequent prostate and kidney cancers, lung squamous cell carcinoma, and lung adenocarcinoma, suggesting the need for continual intensive cancer surveillance among bladder cancer survivors.

The neutrophil-to-lymphocyte ratio makes the Heng risk model improve better the prediction of overall survival in metastatic renal cell cancer patients.

OBJECTIVE: The aim of this study was to predict the discriminating prognostic power of the neutrophil-to-lymphocyte ratio for overall survival in patients with metastatic renal cell carcinoma and to make a new model using the neutrophil-to-lymphocyte ratio. METHODS: From 2007 to 2014, 190 patients with metastatic renal cell carcinoma treated with either systemic immunotherapy or/and vascular endothelial growth factor-targeted therapy were enroled. A multivariable proportional hazard model was developed to investigate the effects of the neutrophil-to-lymphocyte ratio as predictive prognostic factors for overall survival. This new model was incorporated into the current Heng risk model to validate a modified prognostic classification for overall survival. RESULTS: In multivariable analysis, a high neutrophil-to-lymphocyte ratio [hazard ratio (HR) = 1.65] was a significant independent predictor of shorter overall survival (P = 0.005). Additional neutrophil-to-lymphocyte ratio markers improved the discriminating power of the Heng risk classification, as compared to the existing classification model (C-statistic: 0.7198 vs. 0.6943, P = 0.008). The reclassification of patient prognostic categories using the new model showed a total overall net improvement of 61.4% (P < 0.001). CONCLUSION: The neutrophil-to-lymphocyte ratio was a significant prognostic factor of overall survival in metastatic renal cell carcinoma patients treated with systemic therapy. Adding the neutrophil-to-lymphocyte ratio to the Heng model significantly improved the discriminatory power of risk prediction in metastatic renal cell carcinoma.

The effect of predisposing atheroembolic risk factors on renal functional recovery between laparoscopy and open technique in patients with T1-stage renal cell carcinoma who underwent partial nephrectomy: a retrospective comparison study.

Objective: The present study aimed to determine the effect of an increasing number of predisposing atheroembolic risk factors on the development of chronic kidney disease (CKD) after partial nephrectomy (PN) in patients with T1-stage renal cell carcinoma (RCC). Methods: The study included 147 patients with T1-stage RCC with a normal contralateral kidney and without preoperative CKD, who underwent open (OPN, N = 83, 56.5%) or laparoscopic PN (LPN, N = 64, 43.5%) between 2003 and 2014. Postoperative CKD was defined as an estimated glomerular filtration rate <60 ml/min/1.73 m2. The predictive factors for CKD between OPN and LPN were statistically assessed among various known clinicopathological factors associated with renal function in PN with a significance of two-sided P value <0.05. Results: During a median follow-up of 42 months, the recurrence rate was 0.7% (n = 1), and the rate of postoperative CKD was 11.6% (n = 17). Significant differences in CKD-free survival were observed among patients with atheroembolic risks 5-7, 3-4 and 1-2 (P = 0.027). Regarding the predictive factors for the postoperative development of CKD between OPN and LPN, a predisposing atheroembolic risk ≥3 was significant among other clinicopathological factors in multivariate analysis (hazard ratio, 3.007, P = 0.031). Conclusion: Patients with T1-staged RCC with ≥3 predisposing atheroembolic risk factors have a significantly higher risk of developing CKD after PN. Patients who underwent LPN had a lesser incidence of CKD development than patients who underwent OPN with ≥3 predisposing atheroembolic risk factors.

Prostate Cancer in a Patient with a Family History of BRCA Mutation: a Case Report and Literature Review.

One of the most significant risk factors for prostate cancer (PC) is a family history of the disease, with germ-line mutations in the breast cancer predisposition gene (BRCA) 2 conferring the highest risk. We here report a 56-year-old man presented with painful gait disturbance and diagnosed PC with multiple disseminated bone metastases. The patient had a strong family history of breast cancer with his 2 nieces affected. Furthermore, his aunts and uncles from both sides were diagnosed with stomach, ovarian, and colorectal cancers. His genomic sequencing analysis of the BRCA genes revealed the same BRCA2 deleterious mutation that his breast cancer-affected nieces carried. Previous studies have suggested that BRCA2-mutated PC is associated with a more aggressive phenotype and poor prognosis. Our experience in the present case also indicated the urgent needs for novel treatment modality and PC screening in this high-risk group of patients.

Overexpression of BRCA1 or BRCA2 in prostatectomy specimens is predictive of biochemical recurrence after radical prostatectomy.

AIMS: To investigate the protein expressions of breast cancer 1 (BRCA1) and 2 (BRCA2) in prostatectomy specimens of localized prostate cancer (PC) patients, along with their associations with cancer characteristics and prognosis. METHODS AND RESULTS: Immunohistochemistry for BRCA1 and BRCA2 was performed on tissue microarrays of 510 PC cases treated from 2002 to 2012. The cytoplasmic immunoreactivity was scored for intensity, and clinicopathological parameters, including biochemical recurrence (BCR), were evaluated. During a median follow-up of 44 months, 128 patients developed BCR, with positive staining rates of 93.3% (n = 476) and 41.6% (n = 212) for BRCA1 and BRCA2, respectively, in the malignant tissues. The BRCA2 expression differed significantly between BCR-positive and BCR-free cases [hazard ratio (HR): 1.75, P = 0.002]. BRCA1 and BRCA2 correlated significantly with age [odds ratio (OR): 0.131] and pN stage (OR: 6.00), pN stage (OR: 1.717) and BCR (OR: 1.972), respectively (P < 0.05). Multivariate analysis showed that BRCA1 (HR: 0.435), BRCA2 (HR: 2.45), pT3 stage (HR: 2.253), resection margin positivity (HR: 1.58), prostate size (HR: 0.975) and Gleason score (HR: 2.214-2.253) were independent predictors of BCR (P < 0.05). Moreover, BRCA2 correlated significantly with BCR-free survival (P = 0.0017). CONCLUSIONS: BRCA1 or BRCA2 overexpression is a significant predictive factor for BCR in PC patients.

A retrospective study of predictive factors for unexpectedly prolonged or shortened progression-free survival and overall survival among patients with metastatic renal cell carcinoma who received first-line targeted therapy.

BACKGROUND: To identify predictors of prolonged or shortened progression-free survival (PFS) and overall survival (OS) among patients with metastatic renal cell carcinoma (mRCC) who received first-line targeted therapies. METHODS: This retrospective study included 146 patients with mRCC who were treated during 2007-2015. These patients were divided into a group with the worst response (WG), an expected group (EG), and a group with the best response (BG), based on their PFS (≤3 monthsnths, 3-18 monthsnths, and >18 monthsnths, respectively) and OS (<1 year, 1-3 years, and >3 years, respectively). To identify significant predictive factors, the BG and WG were compared to the EG using the Memorial Sloan Kettering Cancer Center and Heng risk models. RESULTS: The overall PFS and OS were 9.3 months and 16.4 months, respectively. The median PFS for the WG (41.8 %), EG (45.9 %), and BG (12.3 %) were 2.7 months, 9.3 months, and 56.6 months, respectively, and the median OS for the WG (45.9 %), EG (35.6 %), and BG (18.5 %) were 5.5 months, 21.6 months, and 63.1 months, respectively; these outcomes were significantly different (p < 0.001). Nephrectomy (odds ratio [OR]: 7.15) was a significant predictor of PFS in the BG, and the significant predictors of OS in the BG were MSKCC intermediate risk (OR: 0.12), poor risk (OR: 0.04), and a disease-free interval of <1 year (OR: 0.23) (all, p < 0.05). Anemia (OR: 3.25) was a significant predictor of PFS in the WG, and the significant predictors of OS were age (OR: 1.05), anemia (OR: 4.13), lymphocytopenia (OR: 4.76), disease-free interval of <1 year (OR: 4.8), and synchronous metastasis (OR: 3.52) (all, p < 0.05). CONCLUSION: We identified several significant predictors of unexpectedly good and poor response to first-line targeted therapy among patients with mRCC.

Bladder chondrosarcoma plus urothelial carcinoma in recurred transitional cell carcinoma of the upper urinary tract: a case report and literature review.

BACKGROUND: Sarcomatoid urothelial carcinoma (SUC) is a rare malignant neoplasm of the urinary bladder comprising 0.2-0.6 % of all histological bladder tumor subtypes. It presents as a high-stage malignancy and exhibits aggressive biological behavior, regardless of the treatment employed. It is defined as histologically indistinguishable from sarcoma and as a high-grade biphasic neoplasm with malignant epithelial and mesenchymal components. The mean age of patients presenting with SUC is 66 years, and the male-to-female ratio is 3:1. In addition, gross hematuria is usually present. The prognosis of SUC is poorer than that of typical urothelial carcinoma because of uncertainty concerning the optimal treatment regimen. CASE PRESENTATION: We report the case of a 77-year-old woman with SUC containing a chondrosarcoma component who, 12 years previously, had undergone a nephroureterectomy for pT3N0M0 ureter cancer of the contralateral upper urinary tract. From the 4th year of follow-up after nephroureterectomy, multiple recurrent bladder tumors staged as Ta transitional cell carcinoma developed, and six transurethral resections of the bladder (TURB) with multiple intravesical instillations were performed without any evidence of metastases and upper tract recurrences. In 2015, a right partial distal ureterectomy and an additional TURB were performed due to a papillary mass at the right contralateral ureterovesical junction of the bladder, which was confirmed as a high-grade pT1 transitional cell carcinoma. After a further 2 years of follow-up, total pelvic exenteration with an ileal conduit diversion was performed to remove the mass, which was a pT4N0M0 tumor composed of carcinomatous and sarcomatous elements compatible with a sarcomatoid carcinoma including grade 3 transitional cell carcinoma and chondrosarcoma. Immunohistochemical examination showed that tumor cells were positive for vimentin and p63 and negative for NSE and Cd56 markers. In the first postoperative month, a metastatic lung nodule was detected on chest CT. The patient was scheduled for adjuvant gemcitabine-cisplatin chemotherapy. CONCLUSIONS: The present case was interesting because we cannot be sure if the SUC chondrosarcoma originated from the 12-year-ago proximal ureter tumor, the 2-year-ago contralateral distal ureter tumor, or a new primary bladder tumor. Genetic profiling might have been useful to determine the origin of the SUC chondrosarcoma.

The prevalence and outcomes of pT0 disease after neoadjuvant hormonal therapy and radical prostatectomy in high-risk prostate cancer.

BACKGROUND: To identify the prevalence and clinical outcomes of pT0 disease following neoadjuvant hormonal therapy (NHT) and radical prostatectomy (RP) in high-risk prostate cancer. METHODS: We retrospectively included 111 patients who had received NHT and RP for the treatment of high-risk prostate cancer. We classified the patients into two groups, the pT0 group and the non-pT0 group, depending on whether a residual tumor was observed. RESULTS: We identified 6 cases (5.4%) with pT0 disease after reviewing the slides of all patients. There was no recurrence of disease in the pT0 group during a median follow-up of 59 months. Among the 105 patients in the non-pT0 group, biochemical recurrence (BCR) developed in 60 patients (57.1%), with the median time to BCR being 14 months. CONCLUSIONS: Among the 111 patients with high-risk prostate cancer, we found 6 cases that showed a complete pathological response after NHT and no recurrence of disease during the follow-up, meaning that the androgen deprivation therapy could potentially eradicate high-risk prostate cancer. This is one of the largest studies demonstrating the prevalence of pT0 disease and its outcomes after NHT among patients with high-risk prostate cancer.

DHCR24 is an independent predictor of progression in patients with non-muscle-invasive urothelial carcinoma, and its functional role is involved in the aggressive properties of urothelial carcinoma cells.

PURPOSE: The DHCR24 gene that encodes 3b-hydroxysterol Δ24-reductase, an oxidoreductase involved in cholesterol biosynthesis, has been identified as a progression-related gene based on the quantitative real-time PCR (qPCR) gene signature. Here, the functional role of DHCR24 and its clinical relevance in non-muscle-invasive urothelial carcinoma (NMIUC) were investigated. METHODS: Primary NMIUC tissue specimens (n = 162) were analyzed by qPCR. Immunohistochemical staining was also performed on 63 subsets of NMIUC tissues. The present study was also undertaken in order to verify the effect of DHCR24 on human urothelial carcinoma cells. RESULTS: The mRNA expression levels of DHCR24 were significantly higher for patients in with higher grades of tumors than for those with lower grades of tumors (P = 0.003). Kaplan-Meier estimates revealed significant differences in the time to progression between low- and high-mRNA expression groups (log-rank test, P < 0.001). Multivariate Cox regression analysis revealed that the level of DHCR24 expression is an independent predictor of progression (hazard ratio, 5.464; 95 % confidence interval, 1.746-17.099; P = 0.004). The results of immunohistochemical staining were generally concordant with mRNA expression levels. Enforced expression of DHCR24 caused proliferation, adhesion, and migration, while DHCR24 loss resulted in slower proliferation and a reduction in cell viabilities compared with control cells. CONCLUSIONS: DHCR24 was found to be closely associated with progression among patients with NMIUC and showed aggressive properties in human UC cells.

Pelvic floor musculature and bladder neck changes before and after continence recovery after radical prostatectomy in pelvic MRI.

PURPOSE: To evaluate the changes in pelvic floor anatomy using MRI before and after continence recovery after radical prostatectomy (RP). MATERIALS AND METHODS: Thirteen men with prostate cancer who underwent RP (mean age, 67.4 ± 8.8 years) volunteered for this study. Prostate MRIs were performed during the preoperative (i), incontinent (ii), and continent (iii) periods. The membranous urethra length (MUL), puborectalis muscle (PRM) thickness, and the position of the bladder neck in relation to the pubic bone (Dx) and the pubococcygeous line (Dy) were measured. We compared all parameters in the preoperative, incontinent, and continent periods. RESULTS: MUL2 and MUL3 was significantly longer compared with MUL1, although no difference was found between MUL2 and MUL3. PRM3 thickness was significantly increased compared with PRM2 thickness. The Dx of the continence period was shorter than that of the incontinence period. The Dy of the continence period was longer than that of the incontinence period. CONCLUSION: The PRM thickened and the bladder neck moved upward and forward during the continence period. The changes in PRM thickness and the position of bladder neck may play an important role in the recovery of continence after RP.

Favorable risk factors in patients with positive surgical margin after robot-assisted radical prostatectomy.

INTRODUCTION: Positive surgical margin (PSM) has classically been associated with biochemical recurrence (BCR) following radical prostatectomy (RP) and immediate adjuvant radiotherapy has been advocated based on two large randomized prospective clinical studies. However, a significant percentage of patients with PSM never experience BCR. This study evaluated factors potentially affecting risk of BCR among the patients with PSM after robot-assisted radical prostatectomy (RARP). MATERIALS AND METHODS: From a prospectively maintained database, 699 patients with localized prostate cancer who underwent a RARP without any adjuvant therapy were identified. Median follow up was 46.0 months. To determine the pathologic and clinical factors that influenced BCR, univariate and multivariate analyses using the Cox proportional hazards model were performed. BCR-free survival curves were estimated with Kaplan-Meier method. RESULTS: Surgical margins were positive in 115 patients (16.5%), of whom 23 (20%) had BCR. In the univariate analyses, serum PSA level, surgical Gleason score (GS), and non-organ confined disease were significantly associated with BCR in men with PSM. Multivariate Cox analysis showed that BCR was significantly associated with PSA (p = 0.011), and the surgical GS (p = 0.008). In patients with lower PSA cutoff (5.3 ng/mL), GS ≤ 7, and organ-confined disease, there were no BCR. CONCLUSIONS: In this study, we identified favorable risk factors in patients with PSM following RARP. The results suggest that immediate adjuvant therapy for PSM may not be necessary in men with Gleason score 7 or less, organ-confined disease, and low preoperative PSA.