Comparison of sexual function after robot-assisted radical prostatectomy and carbon-ion radiotherapy for Japanese prostate cancer patients using propensity score matching.

BACKGROUND: The quality of life of patients is an important consideration when selecting treatments for localized prostate cancer (PCa). We retrospectively compared sexual function after robot-assisted radical prostatectomy (RARP) and carbon-ion radiotherapy (CIRT) using propensity score matching. METHODS: In total, 127 Japanese PCa patients treated with RARP and 190 treated with CIRT monotherapy were evaluated. We evaluated the Expanded Prostate Cancer Index Composite (EPIC) score before treatment and 12 and 24 months after treatment. After propensity score matching, data from 101 patients from each group were analyzed. The study protocol was approved by the Institutional Review Board of Gunma University Hospital (no. IRB2020-050, 1839). RESULTS: After propensity score matching, the mean EPIC sexual function summary scores in the RARP and CIRT groups were 46.4 and 48.2, respectively. At 12 and 24 months after treatment, these scores were 27.9 (39.9% decrease) and 28.2 (39.2% decrease) in the RARP group and 41.4 (14.1% decrease) and 41.6 (13.7% decrease) in the CIRT group, respectively. Both groups demonstrated significantly decreased scores after 12 and 24 months of treatment compared to before treatment (all p < 0.05). At 12 and 24 months, the sexual function summary score was significantly higher in the CIRT group than in the RARP group (p < 0.001). CONCLUSIONS: There was a smaller decrease in the EPIC sexual function score in the CIRT group than in the RARP group. These results provide useful information for treatment decision-making of Japanese PCa patients.

A prospective study of the relationship between CRPC patient's quality of life after enzalutamide and serum testosterone levels measured via LC-MS/MS.

BACKGROUND: Enzalutamide (ENZ) is used in the treatment of patients with castration-resistant prostate cancer (CRPC). The quality of life (QoL) of CRPC patients during ENZ treatment is very important, but predictive markers of QoL have not been identified. We investigated the relationship between the serum testosterone (T) level before ENZ treatment and QoL changes in CRPC patients. PATIENTS AND METHODS: This prospective study was conducted between 2014 and 2018 at Gunma University Hospital and related facilities. We analyzed 95 patients in whom QoL could be evaluated using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire at baseline, and after 4 and 12 weeks of ENZ treatment. Serum T levels were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: The study population of 95 patients had a median age of 72 years and median prostate-specific antigen level of 21.6 ng/mL. The median overall survival from the commencement of ENZ treatment was 26.8 months. The median serum T level before ENZ treatment was 50.0 pg/mL. The mean total FACT-P scores at baseline, and after 4 and 12 weeks of ENZ treatment, were 95.8, 91.7, and 90.1, respectively. Differences in FACT-P scores between the high T level (High-T) group and low T level (Low-T) group (distinguished based on median split of the T level) were examined. The mean FACT-P scores were significantly higher in the High-T than Low-T group after both 4 and 12 weeks of ENZ treatment (98.5 vs. 84.6 and 96.4 vs. 82.2, respectively, both p < 0.05). The mean FACT-P score was significantly lower in the Low-T group after 12 weeks than before ENZ treatment (p < 0.05). CONCLUSION: The serum T level before treatment may be useful for predicting QoL changes after ENZ treatment in CRPC patients.

Retroperitoneal urothelial carcinoma arising after bladder diverticulectomy: a case report.

BACKGROUND: Urothelial carcinoma arises from the inner urothelial membrane of the renal pelvis, ureter, and bladder and often causes macrohematuria. Here, we report a rare case in which the patient developed non-symptomatic urothelial carcinoma anatomically outside the bladder wall 17 years after bladder diverticulectomy. CASE PRESENTATION: An 82-year-old male patient previously underwent gastrectomy for stomach cancer and partial hepatectomy for intrahepatic cholangiocarcinoma. Follow-up computed tomography revealed a tumor in the retroperitoneal space, where a bladder diverticulum was removed 17 years earlier. Multiparametric magnetic resonance imaging suggested that the tumor was malignant with rectal invasion. Subsequent computed tomography-guided percutaneous biopsy revealed that the tumor was urothelial carcinoma. The patient underwent two courses of neoadjuvant chemotherapy followed by pelvic exenteration with pelvic lymph node dissection. He is currently receiving adjuvant therapy with an immune checkpoint inhibitor and has had no recurrence for 3 months. CONCLUSIONS: Multiparametric magnetic resonance imaging is a helpful tool for predicting both tumor malignancy and invasion before a pathologically confirmed diagnosis. Although this case is rare, urologists should be aware of the occurrence of urothelial carcinoma after bladder diverticulectomy in cases of incomplete resection of the diverticulum.

Arteriovenous fistula in a renal allograft with gross hematuria and subsequent acute kidney injury due to urinary tract obstruction: a case report.

BACKGROUND: Arteriovenous fistula (AVF) due to renal allograft biopsy is mechanical trauma resulting from the penetration of small arteries and veins by a core needle. Most AVFs are reported to resolve asymptomatically and spontaneously. This report presents a patient with acute kidney injury (AKI) due to urinary tract obstruction caused by a bleeding AVF in a renal allograft. CASE PRESENTATION: A 22-year-old Japanese woman who underwent living-donor kidney transplantation (KT) at 3 years due to end-stage renal disease caused by focal segmental glomerulosclerosis (FSGS) presented with a renal transplant AVF (gourd-shaped; 42 × 19 × 20 mm). The AVF was unexpectedly discovered by ultrasound before a surveillance biopsy at 10 years after KT. The patient had a history of recurrent FSGS, had undergone several renal allograft biopsies after KT, and did not experience symptoms or growth of the AVF for years. Nineteen years after KT, the patient developed AKI with sudden, asymptomatic, gross hematuria and anuria. Plain computed tomography revealed a hematoma in the pelvis of the renal allograft and bladder tamponade. The AVF was successfully treated by coil embolization. Hemodialysis was performed for AKI, and graft function was gradually recovered. CONCLUSIONS: Unexpected bleeding from a renal transplant AVF may lead to transplant dysfunction. Angiographic embolization against the ruptured renal transplant AVF may prevent rebleeding and rescue the renal allograft.

The utility of the [-2]pro-prostate-specific antigen level as a prognostic marker in patients with castration-resistant prostate cancer treated with enzalutamide.

BACKGROUND: The prostate health index (phi) derived using [-2]pro-prostate-specific antigen (p2PSA), a precursor of PSA, has been shown to predict cancer in the gray zone. However, the utility of p2PSA in predicting outcomes for castration-resistant prostate cancer (CRPC) patients remains unknown. Therefore, in this study, we aimed to evaluate the usefulness of p2PSA in predicting the efficacy and prognosis of enzalutamide treatment in CRPC patients. METHODS: We conducted a prospective study of CRPC patients treated with enzalutamide at our institution, measuring p2PSA levels in 98 pre-treatment serum samples. All patients were divided into two groups based on the median values of each parameter. The PSA progression-free survival (PSA-PFS) and overall survival (OS) were compared using the Kaplan-Meier method. This study was approved by the Institutional Review Board of Gunma University Hospital (IRB No. 2021-092, 1983). RESULTS: The median PSA level before enzalutamide treatment was 25.59 ng/mL, the median p2PSA level was 208.75 pg/mL, and the median phi was 187.95. PSA, p2PSA, and phi were not all predictors of PSA-PFS. However, the OS was significantly better in the low-value groups (log-rank p-values of PSA, p2PSA, and phi were 0.024, 0.034, and 0.018, respectively). In the docetaxel (DOC)-naive group (n = 58), PSA was not a predictor of OS, but p2PSA and phi were significantly associated with better OS in the low group. This relationship was not observed in the DOC-treated group. CONCLUSIONS: Our study elucidates the usefulness of p2PSA in predicting outcomes for CRPC patients treated with enzalutamide. It suggests that p2PSA and phi may be prognostic markers after enzalutamide administration in CRPC patients.

Combination therapy with novel androgen receptor antagonists and statin for castration-resistant prostate cancer.

BACKGROUND: One of the growth mechanisms of castration-resistant prostate cancer (CRPC) is de novo androgen synthesis from intracellular cholesterol, and statins may be able to inhibit this mechanism. In addition, statins have been reported to suppress the expression of androgen receptors (ARs) in prostate cancer cell lines. In this study, we investigated a combination therapy of novel AR antagonists and statin, simvastatin, for CRPC. METHODS: LNCaP, 22Rv1, and PC-3 human prostate cancer cell lines were used. We developed androgen-independent LNCaP cells (LNCaP-LA). Microarray analysis was performed, followed by pathway analysis, and mRNA and protein expression was evaluated by quantitative real-time polymerase chain reaction and Western blot analysis, respectively. Cell viability was determined by MTS assay and cell counts. All evaluations were performed on cells treated with simvastatin and with or without AR antagonists (enzalutamide, apalutamide, and darolutamide). RESULTS: The combination of darolutamide and simvastatin most significantly suppressed proliferation in LNCaP-LA and 22Rv1 cells. In a 22Rv1-derived mouse xenograft model, the combination of darolutamide and simvastatin enhanced the inhibition of cell proliferation. In LNCaP-LA cells, the combination of darolutamide and simvastatin led to reduction in the mRNA expression of the androgen-stimulated genes, KLK2 and PSA; however, this reduction in expression did not occur in 22Rv1 cells. The microarray data and pathway analyses showed that the number of differentially expressed genes in the darolutamide and simvastatin-treated 22Rv1 cells was the highest in the pathway termed "role of cell cycle." Consequently, we focused our efforts on the cell cycle regulator polo-like kinase 1 (PLK1), cyclin-dependent kinase 2 (CDK2), and cell cycle division 25C (CDC25C). In 22Rv1 cells, the combination of darolutamide and simvastatin suppressed the mRNA and protein expression of these three genes. In addition, in PC-3 cells (which lack AR expression), the combination of simvastatin and darolutamide enhanced the suppression of cell proliferation and expression of these genes. CONCLUSIONS: Simvastatin alters the expression of many genes involved in the cell cycle in CRPC cells. Thus, the combination of novel AR antagonists (darolutamide) and simvastatin can potentially affect CRPC growth through both androgen-dependent and androgen-independent mechanisms.

Fibroblast growth factor receptor inhibitor erdafitinib promotes Mcl-1 degradation and synergistically induces apoptosis with Bcl-xL/Bcl-2 inhibitor in urothelial cancer cells.

Metastatic urothelial cancer is a lethal disease. Although recent advances in immunotherapies and targeted therapy against fibroblast growth factor receptor (FGFR)2/3 mutation (erdafitinib) have improved patient survival, there is still a critical need for novel therapeutic strategies for patients who do not benefit from these treatments. Evasion of apoptosis through amplifying anti-apoptotic Bcl-2 family proteins (Mcl-1, Bcl-xL, Bcl-2) is one mechanism responsible for treatment resistance in urothelial cancers, suggesting that targeting anti-apoptotic proteins may be a possible therapeutic strategy for urothelial cancers. Here, we showed that erdafitinib increased Mcl-1 degradation mainly through previously unknown mechanisms and synergized with a BH3 mimetic drug targeting Bcl-xL/Bcl-2 to induce apoptosis in FGFR wild-type urothelial cancer cells. Strikingly, clinical sequencing data showed amplification of MCL1 or BCL2L1 (encoding Bcl-xL) in subsets of FGFR mutation-negative bladder cancer tissues. In conclusion, these findings suggest that exploiting apoptosis pathways may be a promising treatment strategy for patients with FGFR wild-type metastatic urothelial cancer with Mcl-1 or Bcl-xL overexpression.

Presepsin as a predictor of septic shock in patients with urinary tract infection.

BACKGROUND: Recently, presepsin has been reported to be a useful biomarker for early diagnosis of sepsis and evaluation of prognosis in septic patients. However, few reports have evaluated its usefulness in patients with urinary tract infections (UTI). This study aimed to evaluate whether presepsin could be a valuable marker for detecting severe sepsis, and whether it could predict the therapeutic course in patients with UTI compared with markers already used: procalcitonin (PCT) and C-reactive protein (CRP). METHODS: From April 2014 to December 2016, a total of 50 patients with urinary tract infections admitted to Gunma university hospital were enrolled in this study. Vital signs, presepsin, PCT, CRP, white blood cell (WBC) count, causative agents of urinary-tract infections, and other data were evaluated on the enrollment, third, and fifth days. The patients were divided into two groups: with (n = 11) or without (n = 39) septic shock on the enrollment day, and with (n = 7) or without (n = 43) sepsis on the fifth day, respectively. Presepsin was evaluated as a biomarker for systemic inflammatory response syndrome (SIRS) or septic shock. RESULTS: Regarding the enrollment day, there was no significant difference of presepsin between the SIRS and non-SIRS groups (p = 0.276). The median value of presepsin (pg/mL) was significantly higher in the septic shock group (p < 0.001). Multivariate logistic regression analysis showed that presepsin (≥ 500 pg/ml) was an independent risk factor for septic shock (p = 0.007). ROC curve for diagnosing septic shock indicated an area under the curve (AUC) of 0.881 for presepsin (vs. 0.690, 0.583, and 0.527 for PCT, CRP and WBC, respectively). Regarding the 5th day after admission, the median presepsin value on the enrollment day was significantly higher in the SIRS groups than in the non-SIRS groups (p = 0.006). On the other hand, PCT (≥ 2 ng/ml) on the enrollment day was an independent risk factor for SIRS. ROC curve for diagnosing sepsis on the fifth day indicated an AUC of 0.837 for PCT (vs. 0.817, 0.811, and 0.802 for presepsin, CRP, and WBC, respectively). CONCLUSIONS: This study showed that presepsin may be a good marker for diagnosing septic shock based on admission data in patients with UTI.

Prevalence and clinical characteristics of overactive bladder in systemic sclerosis.

Objectives: Overactive bladder (OAB) is a clinical diagnosis defined with the presence of urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence. Objective was to evaluate the demographic and clinical characteristics of Japanese systemic sclerosis (SSc) patients with OAB.Methods: OAB was diagnosed by OAB symptom score (OABSS) in 104 Japanese SSc patients (93 women and 11 men). Differential diseases of OAB were conducted by urologists.Results: The prevalence of OAB in SSc patients was 27.9% (29/104). SSc patients with OAB were characterized by old age, a long history of morbidity (15.4 vs. 11.2 years, p < .01), high anti-centromere antibody positive rate (75.9 vs. 44%, p < .05), high incidence of gastroesophageal reflux disease (93.1 vs. 73.3%, p < .05), low anti-SS-A antibody positive rate (6.9 vs. 26.8%, p < .05), and low incidence of internal lung disease (17.9 vs. 45.7%, p < .05) compared to SSc patients without OAB.Conclusion: This is the first study that evaluated the prevalence and clinical features of OAB in Japanese SSc patients. Since SSc patients might be prone to develop OAB, it was thought that OAB should be noted as one of the complications of SSc patients.

An exploratory retrospective multicenter study of prognostic factors in mCRPC patients undergoing enzalutamide treatment: Focus on early PSA decline and kinetics at time of progression.

BACKGROUND: Recent studies have shown that an early prostate-specific antigen (PSA) response to androgen receptor-targeting agents in metastatic castration-resistant prostate cancer (mCRPC) is associated with a better prognosis. We analyzed the early PSA response to enzalutamide (ENZ) by measuring the PSA doubling time (PSADT) and PSA velocity (PSAV) while monitoring oncologic outcomes and survival in Japanese patients. METHODS: We analyzed a total of 241 patients with mCRPC who were treated with ENZ. The patients' median age was 75 ± 7.9 years (range, 53-93 years). There were 171 (71%) predocetaxel cases, and 70 (29%) post docetaxel cases. PSA-progression-free survival (PFS) and overall survival (OS) were assessed according to Prostate Cancer Working Group 2 criteria. This study was approved by the Institutional Review Board of Gunma University Hospital (No. 1595). RESULTS: We observed 77 good response (GR; case in which PSA remained low after treatment) cases (31.9%), 125 acquired resistance (AR; decline in PSA after treatment followed by progression) cases (51.9%), and 39 primary resistance (PR; lack of decline in PSA) cases (16.2%). Predocetaxel, PSA-PFS, and OS were significantly higher compared with post docetaxel (PSA-PFS: 47.0 vs 13.4 weeks, P < .001; OS: not yet reached vs 80.7 weeks, P < .001). Multivariate analysis of prognostic factors, including PSA response at 4 weeks, was performed using Cox regression analysis. ECOG PS (0 vs 1-2), hemoglobin (Hb; ≥ 12.2 vs < 12.2 g/dL), time to CRPC ( ≥ 12 vs < 12 m), docetaxel treatment history (no vs yes), and a PSA reduction of 50% at 4 weeks were significant predictors of OS (all, P < .05). In cases of AR (n = 125), multivariate analysis showed that PSA kinetic factors, such as PSADT and PSAV (ng/mL/m), Hb, time to CRPC, PSADT ( ≥ 2 vs < 2 m), and PSAV ( < 20 vs ≥ 20 ng/mL/m), were all predictive of OS following PSA-progression (P < .05). CONCLUSIONS: Our study has demonstrated that PSA dynamics after ENZ administration may be a useful prognostic factor for mCRPC patients.

Screening for prostate cancer: History, evidence, controversies and future perspectives toward individualized screening.

Differences in the incidence and mortality rate of prostate cancer between the USA and Japan have been decreasing over time, and were only twofold in 2017. Therefore, countermeasures against prostate cancer could be very important not only in Western countries, but also in developed Asian countries. Screening for prostate cancer in the general population using transrectal ultrasonography, digital rectal examination and/or prostate acid phosphatase began in Japan in the early 1980s, and screening with prostate-specific antigen and digital rectal examination has been widespread in the USA since the late 1980s. Large- and mid-scale randomized controlled trials on screening for prostate cancer began around 1990 in the USA, Canada and Europe. However, most of these studies failed as randomized controlled trials because of high contamination in the control arm, low compliance in the screening arm or insufficient screening setting about screening frequency and/or biopsy indication. The best available level 1 evidence is data from the European Randomized Study of Screening for Prostate Cancer and the Göteborg screening study. However, several non-urological organizations and lay media around the world have mischaracterized the efficacy of prostate-specific antigen screening. To avoid long-term confusion about screening for prostate cancer, leading professional urological organizations, including the Japanese Urological Association, are moving toward the establishment of an optimal screening system that minimizes the drawbacks of overdetection, overtreatment and loss of quality of life due to treatment, and maximizes reductions in the risk of death as a result of prostate cancer and the development of metastatic prostate cancer.

Long-term longitudinal changes in baseline PSA distribution and estimated prevalence of prostate cancer in male Japanese participants of population-based PSA screening.

Japan has experienced a drastic increase in the incidence of prostate cancer (PC). To assess changes in the risk for PC, we investigated baseline prostate specific antigen (PSA) levels in first-time screened men, across a 25-year period. In total, 72,654 men, aged 50-79, underwent first-time PSA screening in Gunma prefecture between 1992 and 2016. Changes in the distribution of PSA levels were investigated, including the percentage of men with a PSA above cut-off values and linear regression analyses comparing log10 PSA with age. The 'ultimate incidence' of PC and clinically significant PC (CSPC) were estimated using the PC risk calculator. Changes in the age-standardized incidence rate (AIR) during this period were analyzed. The calculated coefficients of linear regression for age versus log10 PSA fluctuated during the 25-year period, but no trend was observed. In addition, the percentage of men with a PSA above cut-off values varied in each 5-year period, with no specific trend. The 'risk calculator (RC)-based AIR' of PC and CSPC were stable between 1992 and 2016. Therefore, the baseline risk for developing PC has remained unchanged in the past 25 years, in Japan. The drastic increase in the incidence of PC, beginning around 2000, may be primarily due to increased PSA screening in the country.

Assessment of antimicrobiral prophylaxis in transperineal prostate biopsy: A single-center retrospective study of 485 cases.

To verify the validity of our antimicrobial prophylaxis regimen for transperineal prostate biopsies, we investigated the rate of infectious complications in this procedure. We retrospectively investigated the infectious complications in 485 patients who underwent a transperineal prostate biopsy between 2014 and 2016 at our hospital. In the clinic, we use cefazolin (CEZ) for antimicrobial prophylaxis. Infectious complications were assessed up to postoperative day (POD) 30. Patients with infectious complications were further investigated to determine the site of infection, outbreak day, and type of pathogenic bacteria. The rate of infectious complications was 0.82% (4 out of 485 patients). Three patients developed prostatitis, 1 progressed into septic shock, and 1 patient developed epididymitis. The pathogenic bacteria identified were Pseudomonas aeruginosa (1 of 4), Enterococcus faecalis (1 of 4) and Escherichia coli that harbour extended-spectrum beta lactamase (ESBL-productive E. coli) (2 of 4). The earliest outbreak was POD 2 and the latest was POD 14. Infectious complications tended to increase in patients in whom an indwelling urethral catheter was inserted (p = 0.0567). However, there were no statistically significant relationships between any risk factor and the occurrence of infectious complications. We concluded that CEZ is adequate for the prevention of perioperative infectious complications in transperineal prostate biopsies. Furthermore, we reaffirmed the importance of correct perioperative management, including preoperative assessment.

Simvastatin Up-Regulates Annexin A10 That Can Inhibit the Proliferation, Migration, and Invasion in Androgen-Independent Human Prostate Cancer Cells.

BACKGROUND: Statins have recently been studied for their proapoptotic and antimetastatic effects. However, the exact mechanisms of their anticancer actions remain unclear. Using microarrays, we discovered up-regulation of annexin A10 (ANXA10) in PC-3 cells after simvastatin treatment. ANXA10 reportedly has antitumor effects. In this study, we evaluated the effects of simvastatin on ANXA10 signaling in androgen-independent prostate cancer cells. METHODS: PC-3, LNCaP-LA (which were derived from LNCaP cells and cultured in 10% charcoal-stripped fetal bovine serum for 3 months), and DU145 human prostate cancer cell lines were used. Prostate tissues were collected from 60 patients (benign prostatic hyperplasia [BPH], n = 20; prostate cancer with a Gleason score of 7, n = 20; prostate cancer with a Gleason score of 8-10, n = 20) at the time of prostate biopsies performed. We used a nude mouse tumor xenograft model with administration of simvastatin or phosphate-buffered saline via intraperitoneal injection. RESULTS: Simvastatin inhibited the proliferation, migration, and invasion of PC-3, LNCaP-LA, and DU145 cells. The expression level of ANXA10 was up-regulated by simvastatin in PC-3, LNCaP-LA, and DU145 cells. Transfection with ANXA10 inhibited PC-3 and LNCaP-LA cells proliferation, migration, and invasion. Knockdown of ANXA10 by siRNA increased the proliferation of PC-3 and LNCaP-LA cells. In a nude mouse xenograft model of PC-3 cells, simvastatin induced both reduction in the tumor size and up-regulation of ANXA10 expression. In human prostate biopsy samples, ANXA10 mRNA expression was significantly lower in the prostate cancer group than in the BPH group. Next, we found that up-regulation of ANXA10 in PC-3 resulted in down-regulation of S100 calcium binding protein A4 (S100A4), which is reportedly correlated with aggressiveness and a worse prognosis for patients with different types of carcinomas. Expression of S100A4 was down-regulated by simvastatin. In PC-3 cells, knockdown of S100A4 by siRNA inhibited the proliferation, migration, and invasion of PC-3 cells. CONCLUSION: Our results suggest that statins inhibit the proliferation, migration, and invasion of androgen-independent prostate cancer cells by up-regulation of ANXA10. Additionally, it is possible that S100A4 plays a role in these effects. Statins may be beneficial in the prevention and/or treatment of prostate cancer. Prostate 77: 337-349, 2017. © 2016 Wiley Periodicals, Inc.

Effects of Steroidal Antiandrogen or 5-alpha-reductase Inhibitor on Prostate Tissue Hormone Content.

BACKGROUND: The effects of a steroidal antiandrogen (AA) and 5-alpha-reductase inhibitor (5ARI) on prostate tissue hormone content and metabolism are not fully elucidated. The objective of this study is to investigate the hormone content and metabolism of the prostate tissues of patients treated with AA or 5ARI using the ultra-sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. METHODS: Thirty-nine patients with benign prostatic hyperplasia (BPH) undergoing transurethral surgery were included. Serum and prostate tissue hormone and prostate tissue hormone metabolism analyses were performed using LC-MS/MS after 1 month of treatment with chlormadinone acetate (CMA; steroidal AA, 50 mg/day) or dutasteride (DUTA; dual 5ARI, 0.5 mg/day). RESULTS: Serum testosterone (T), dihydrotestosterone (DHT), and adrenal androgen levels were lower in the CMA group than the control group. Prostate tissue T and DHT levels were also lower in the CMA group than the control group. In the DUTA group, only serum and prostate DHT concentrations were reduced compared to the control group; in contrast, those of other hormones, especially T and 4-androstene-3,17-dione in the prostate tissue, showed marked elevations up to 70.4- and 11.4-fold normal levels, respectively. Moreover, the hormone metabolism assay confirmed that the conversion of T to DHT was significantly suppressed while that of T to 4-androstene-3,17-dione was significantly accelerated in the prostate tissue of DUTA-treated patients. CONCLUSIONS: Although treatment with AA and 5ARI show similar clinical outcomes, their effect on tissue hormone content and metabolism varied greatly. Prostate 77: 672-680, 2017. © 2017 Wiley Periodicals, Inc.

A gonadotropin-releasing hormone antagonist reduces serum adrenal androgen levels in prostate cancer patients.

BACKGROUND: Adrenal androgens play an important role in the development of castration-resistant prostate cancer therapeutics. The effect of gonadotropin-releasing hormone (GnRH) antagonists on adrenal androgens has not been studied sufficiently. We measured testicular and adrenal androgen levels in patients treated with a GnRH antagonist. METHODS: This study included 47 patients with histologically proven prostate cancer. All of the patients were treated with the GnRH antagonist degarelix. The mean patient age was 73.6 years. Pre-treatment blood samples were collected from all of the patients, and post-treatment samples were taken at 1, 3, 6, and 12 months after starting treatment. Testosterone (T), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), 17ß-estradiol (E2), and androstenedione (A-dione) were measured by liquid chromatography-mass spectrometry. Dehydroepiandrosterone-sulfate (DHEA-S), luteinizing hormone, and follicle-stimulating hormone levels were measured by electro-chemiluminescence immunoassays. RESULTS: A significant reduction in T level (97.3% reduction) was observed in the patients 1 month after initiating treatment. In addition, levels of DHT, E2, DHEA-S, and A-dione decreased 1 month after initiating treatment (93.3, 84.9, 16.8, and 35.9% reduction, respectively). T, DHT, E2, DHEA-S, and A-dione levels remained significantly suppressed (97.1, 94.6, 85.3, 23.9, and 40.5% reduction, respectively) 12 months after initiating treatment. A significant decrease in DHEA level (15.4% reduction) was observed 12 months after initiating treatment. CONCLUSIONS: Serum adrenal androgen levels decreased significantly in patients treated with a GnRH antagonist. Thus, long-term GnRH antagonist treatment may reduce serum adrenal androgen levels.

Predictive value of different prostate-specific antigen-based markers in men with baseline total prostate-specific antigen <2.0 ng/mL.

OBJECTIVES: To investigate the predictive value of various molecular forms of prostate-specific antigen in men with baseline prostate-specific antigen <2.0 ng/mL. METHODS: The case cohort comprised 150 men with a baseline prostate-specific antigen level <2.0 ng/mL, and who developed prostate cancer within 10 years. The control cohort was 300 baseline prostate-specific antigen- and age-adjusted men who did not develop prostate cancer. Serum prostate-specific antigen, free prostate-specific antigen, and [-2] proenzyme prostate-specific antigen were measured at baseline and last screening visit. The predictive impact of baseline prostate-specific antigen- and [-2] proenzyme prostate-specific antigen-related indices on developing prostate cancer was investigated. The predictive impact of those indices at last screening visit and velocities from baseline to final screening on tumor aggressiveness were also investigated. RESULTS: The baseline free to total prostate-specific antigen ratio was a significant predictor of prostate cancer development. The odds ratio was 6.08 in the lowest quintile baseline free to total prostate-specific antigen ratio subgroup. No serum indices at diagnosis were associated with tumor aggressiveness. The Prostate Health Index velocity and [-2] proenzyme prostate-specific antigen/free prostate-specific antigen velocity significantly increased in patients with higher risk D'Amico risk groups and higher Gleason scores. CONCLUSIONS: Free to total prostate-specific antigen ratio in men with low baseline prostate-specific antigen levels seems to predict the risk of developing prostate cancer, and it could be useful for a more effective individualized screening system. Longitudinal changes in [-2] proenzyme prostate-specific antigen-related indices seem to correlate with tumor aggressiveness, and they could be used as prognostic tool before treatment and during active surveillance.

A CASE OF GROWING TERATOMA SYNDROME.

A 25-year-old man with a left testicular tumor underwent a high inguinal orchiectomy. Histopathological examination of the resected specimen revealed tumors of more than one histological type, mixed forms (seminoma, immature teratoma). Further evaluation revealed no metastasis (pT1N0M0S1 Stage IS).Four months after orchiectomy, alpha-fetoprotein (AFP) was elevated.CT scan revealed retroperitoneal masses of recurrent tumor. Although the AFP returned to normal level after four courses of BEP (bleomycin, etoposide and cisplatin), the retroperitoneal lymph nodes continued to grow. He underwent excision of the retroperitoneal lymph node dissection. Histopathological examination of the resected specimen revealed mature teratoma.Few reports examined about the development mechanism of growing teratoma syndrome (GTS). We considered that the development mechanism of GTS in this case is induction of differentiation. In this case report, we discuss the development mechanism of GTS based on bibliographical consideration.

Metformin inhibits the proliferation of human prostate cancer PC-3 cells via the downregulation of insulin-like growth factor 1 receptor.

Metformin is a biguanide drug that is widely used for the treatment of type 2 diabetes. Recent studies have shown that metformin inhibits cancer cell proliferation and tumor growth both in vitro and in vivo. The anti-tumor mechanisms of metformin include activation of the AMP-activated protein kinase/mTOR pathway and direct inhibition of insulin/insulin-like growth factor (IGF)-mediated cellular proliferation. However, the anti-tumor mechanism in prostate cancer remains unclear. Because activation of the IGF-1 receptor (IGF-1R) is required for prostate cell proliferation, IGF-1R inhibitors may be of therapeutic value. Accordingly, we examined the effects of metformin on IGF-1R signaling in prostate cancer cells. Metformin significantly inhibited PC-3 cell proliferation, migration, and invasion. IGF-1R mRNA expression decreased significantly after 48 h of treatment, and IGF-1R protein expression decreased in a similar manner. IGF-1R knockdown by siRNA transfection led to inhibited proliferation, migration and invasion of PC-3 cells. IGF-1 activated both ERK1/2 and Akt, but these effects were attenuated by metformin treatment. In addition, intraperitoneal treatment with metformin significantly reduced tumor growth and IGF-1R mRNA expression in PC-3 xenografts. Our results suggest that metformin is a potent inhibitor of the IGF-1/IGF-1R system and may be beneficial in prostate cancer treatment.

[SQUAMOUS CELL CARCINOMA WITH CLOACAL EXSTROPHY: A CASE REPORT].

A 41-year-old man with a history of cloacal exstrophy presented to a local clinic with abdominal pain and bowel sounds. He was noted to have pain at the site of scarring due to cloacal exstrophy and a laceration at its center, which was stained with feces. He was referred to our department because of an enterocutaneous fistula. Skin biopsy of the neoplastic lesion at this site led to a diagnosis of squamous cell carcinoma. Computed tomography showed tumor invasion of the ileum and right inguinal lymph node enlargement. We performed tumor resection, partial enterectomy, intestinal anastomosis, abdominal wall reconstruction with a left pedicled anterolateral thigh flap, split-thickness skin grafting, and right inguinal lymph node biopsy. Histopathological examination revealed cancer growth, invasion, and pearl formation in the lymph nodes, leading to a diagnosis of abdominal squamous cell carcinoma with metastasis to the inguinal lymph nodes. The skin graft took well, and the patient was discharged. He is scheduled for right inguinal lymph node dissection at a later date.