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Hormonal therapies including androgen deprivation therapy and androgen receptor (AR) pathway inhibitors such as abiraterone and enzalutamide have been widely used to treat advanced prostate cancer. However, treatment resistance emerges after hormonal manipulation in most prostate cancers, and it is attributable to a number of mechanisms, including AR amplification and overexpression, AR mutations, the expression of constitutively active AR variants, intra-tumor androgen synthesis, and promiscuous AR activation by other factors. Although various AR mutations have been reported in prostate cancer, specific AR mutations (L702H, W742L/C, H875Y, F877L, and T878A/S) were frequently identified after treatment resistance emerged. Intriguingly, these hot spot mutations were also revealed to change the binding affinity of ligands including steroids and antiandrogens and potentially result in altered responses to AR pathway inhibitors. Currently, precision medicine utilizing genetic and genomic data to choose suitable treatment for the patient is becoming to play an increasingly important role in clinical practice for prostate cancer management. Since clinical data between AR mutations and the efficacy of AR pathway inhibitors are accumulating, monitoring the AR mutation status is a promising approach for providing precision medicine in prostate cancer, which would be implemented through the development of clinically available testing modalities for AR mutations using liquid biopsy. However, there are few reviews on clinical significance of AR hot spot mutations in prostate cancer. Then, this review summarized the clinical landscape of AR mutations and discussed their potential implication for clinical utilization.

BACKGROUND/AIM To explore the prognostic value of lower urinary tract symptoms (LUTS) in patients with newly diagnosed regional lymph node-positive prostate cancer. PATIENTS AND METHODS The prognostic value of LUTS for progression-free (PFS) and overall (OS) survival, as well as the differential prognostic impact of radiotherapy by LUTS was investigated. RESULTS Univariate Cox-model analysis showed a statistically significantly increased hazard risk for PFS and OS for men with International Prostate Symptom Score (IPSS)≥19 and Overactive Bladder Symptom Score (OABSS) ≥8 at diagnosis. Patients with lower IPSS had a better PFS at 5 years (70.0% vs. 51.9%, p=0.027) and OS at 5 year (89.3% vs. 73.6%, p=0.016). Similarly, a lower OABSS was associated with greater PFS at 5 years (67.4% vs. 23.4%, p

Early detection and long-term monitoring are important for urothelial carcinoma of the bladder (UCB). Urine cytology and existing markers have insufficient diagnostic performance. Here, we examined medium-sized extracellular vesicles (EVs) in urine to identify specific markers for UCB and evaluated their usefulness as diagnostic material. To identify specific markers in urinary EVs derived from UCB, we undertook shotgun proteomics using urine from four UCB patients and four healthy subjects. Next, 29 healthy specimens, 18 noncancer specimens, and 33 UCB specimens, all from men, were analyzed for urinary EVs by flow cytometry to evaluate the diagnostic performance of UCB-specific EVs. Nanoparticle-tracking analysis indicated that the size of EVs extracted from urine was mostly400 nm. By shotgun proteomics, we detected several proteins characteristic of UCB and found that carcinoembryonic antigen-related adhesion molecule (CEACAM) proteins were increased in patients. Flow cytometric analysis revealed that the degree of expression of CEACAM1, CEACAM5, and CEACAM6 proteins on the surface of EVs varied among patients. Extracellular vesicles expressing CEACAM proteins also expressed mucin 1, suggesting that they were derived from tumorigenic uroepithelial cells. The number of EVs expressing CEACAM1, 5, and 6 proteins was significantly increased in UCB (mean ± SD, 8.6 ± 13%) compared to non-UCB (0.69 ± 0.46) and healthy (0.46 ± 0.34) by flow cytometry. The results of receiver operating characteristic (ROC) analysis showed a good score of area under the ROC curve of 0.907. We identified EVs that specifically express CEACAM proteins in urine and have potential for diagnostic applications. These EVs are potential targets in a new liquid biopsy test for UCB patients.

Although Y‐box binding protein‐1 (YB‐1) is known to be overexpressed in prostate cancer, especially castration‐resistant prostate cancer (CRPC), the mechanism of its overexpression remains unclear. We aimed to elucidate the mechanism of YB‐1 overexpression in CRPC. Gene amplification in CRPC cells and tissues was examined by public database analysis, and digital PCR. The significance of YB‐1 amplification for the YB‐1/androgen receptor (AR) axis and prognosis was examined by public database analysis and immunohistochemistry. YB‐1 amplification was mainly observed in CRPC tissues by public database analysis and confirmed in CRPC cells and tissues by digital PCR. Expression of YB‐1 was increased in CRPC tissues compared with treatment‐naïve tissues. Furthermore, YB‐1 and phosphorylated YB‐1 levels were associated with AR and AR V7 expression levels. Finally, YB‐1 amplification was associated with poor outcomes in CRPC. Taken together, the present findings suggest that YB‐1 amplification contributes to progression to CRPC through regulation of AR and AR V7 expressions, and that YB‐1 is a promising therapeutic target in CRPC., Y‐box binding protein‐1 (YB‐1) amplification was observed in castration‐resistant prostate cancer (CRPC) and associated with an augmented androgen receptor signaling and poor prognosis. Taken together, the present findings suggest that YB‐1 amplification contributes to progression to CRPC, and that YB‐1 is a promising therapeutic target in CRPC.

Objective To investigate the somatic mutation profiles of testicular germ cell tumors in Japanese men. Methods We analyzed the somatic missense mutation profile of testicular germ cell tumors among 21 Japanese men with seminoma (n = 14), pure embryonic carcinoma (n = 3) and mixed testicular germ cell tumor (n = 4) by targeted next-generation sequencing of 409 cancer-related genes covering 1.23 Mb of the genome. Results We identified a total of 22 missense mutations in 21 primary testicular germ cell tumor samples (0.89 mutations/Mb), of which seven mutations were confirmed to be absent from the germline. KIT:p.Asn822Tyr, KIT:p.Leu576Pro, PIK3CA:p.Glu542Lys and FBXW7:p.Arg505His were statistically and functionally potential. A total of 18 missense mutations were previously unknown in testicular germ cell tumors. PDGFRA amplification from one patient with seminoma was detected. KIT, BCR, PIK3CG, PIK3CA and PDGFRA mutations involved in aberrant signaling of the KIT-PI3K-AKT pathway was detected in 27.3% of detected mutations. Conclusions The present investigation identified a low mutation rate in testicular germ cell tumors among Asian patients, 18 novel mutations and PDGFRA amplification. Limitations of the present study are the small sample and missing normal DNA for some testicular germ cell tumors.

Chemotherapy is a standard therapy for muscle-invasive bladder cancer (MIBC). However, genomic alterations associated with chemotherapy sensitivity in MIBC have not been fully explored. This study aimed to investigate the genomic landscape of MIBC in association with the response to chemotherapy and to explore the biological role of genomic alterations. Genomic alterations in MIBC were sequenced by targeted exome sequencing of 409 genes. Gene expression in MIBC tissues was analyzed by western blotting, immunohistochemistry, and RNA microarray. Cellular sensitivity to gemcitabine and gemcitabine metabolite was examined in bladder cancer cells after modulation of candidate gene. Targeted exome sequencing in 20 cases with MIBC revealed various genomic alterations, and we focus on DPYD. Conversely, high DPYD and dihydropyrimidine dehydrogenase (DPD) expression was associated with poor response to gemcitabine-containing chemotherapy among patients with MIBC, as well as gemcitabine resistance in bladder cancer cells. DPD suppression rendered cells vulnerable to gemcitabine, while DPD overexpression made cells gemcitabine-resistant through reduced activity of the cytotoxic gemcitabine metabolite difluorodeoxycytidine diphosphate. This study revealed the novel role of DPD in gemcitabine metabolism. It has been suggested that DPYD genomic alterations and DPD expression are potential predictive biomarkers in gemcitabine treatment.

This study aimed to investigate the significance of HSD3B1 gene status including germline polymorphism and somatic alterations in prostate cancer. Patients with prostate cancer treated with androgen-deprivation therapy, as well as tissues from metastatic prostate cancer, were included. Genomic DNA was extracted from cancer tissues and whole blood samples, and HSD3B1 (rs1047303, 1245C) was genotyped by Sanger sequencing. The association of HSD3B1 genotype with progression-free survival according to metastatic volume was examined. Copy number alteration and gene expression of HSD3B1 were examined in prostate cancer cells and public datasets. Among 194 patients, 121 and 73 patients were categorized into low- and high-volume diseases respectively. In multivariate analysis, the adrenal-permissive genotype (AC/CC) was significantly associated with increased risk of progression compared with the adrenal-restrictive genotype (AA) in low volume, but not high-volume diseases. Somatic mutation in HSD3B1 was detected at least in two cases of castration-resistant prostate cancer tissues. HSD3B1 amplification and overexpression were detected in castration-resistant prostate cancer cells and tissues. The current findings suggest that both germline and somatic alterations of HSD3B1 may cooperatively promote castration resistance in prostate cancer and HSD3B1 as a promising biomarker for precision medicine, warranting further investigations.

There are many models to predict lymph node involvement in patients with prostate cancer. We aimed to externally validate several models in a Japanese cohort.We considered patients who were treated with robotic-assisted radical prostatectomy with extended pelvic lymph node dissection for prostate cancer. The risk of lymph node involvement was calculated for each patient in several models. Model performance was assessed by calculating the receiver operating characteristic curve and the area under the curve, calibration plots, and decision curve analyses.We identified lymph node involvement in 61 (18.4%) of the 331 considered patients. Patients with lymph node involvement had a higher prostate-specific antigen level, percentage of positive biopsy cores, primary Gleason grade, Gleason group grade, and clinical T-stage category. The Memorial Sloan Kettering Cancer Center web calculator presented the highest area under the curve (0.78) followed by the Yale formula area under the curve (0.77), the updated version of Briganti nomogram of 2017 area under the curve (0.76), and the updated version of the Partin table by Tosoian et al. had an area under the curve of 0.75. However, the 95% confidence interval for these models overlapped. The calibration plot showed that the Memorial Sloan Kettering Cancer Center web calculator and the updated version of the Briganti nomogram calibrated better. In the decision curve analyses, all models showed net benefit; however, it overlapped among them. However, the Memorial Sloan Kettering Cancer Center web calculator and the updated Briganti nomogram presented the highest net benefit for lymph node involvement risks35%.Models predicting lymph node involvement were externally validated in Japanese men. The Memorial Sloan Kettering Cancer Center web calculator and the updated Briganti nomogram of 2017 were the most accurate performing models.

Introduction Testosterone suppression in serum during androgen deprivation therapy (ADT) can affect the oncologic outcome of ADT. Although genetic variants in sex hormone-binding globulin (SHBG) were reported to be correlated with serum testosterone level, the association with serum testosterone during ADT remains unclear. Therefore, this study investigated the impact of a missense polymorphism in the SHBG gene among men treated with primary ADT for metastatic prostate cancer. Patients and Methods This study included 104 Japanese men with metastatic prostate cancer. The association of SHBG gene polymorphism (rs6259, D356N) with clinicopathologic parameters including serum testosterone levels during ADT, as well as prognosis, including progression-free survival and overall survival, was examined. Results The serum testosterone levels during ADT were comparable between men carrying the homozygous wild-type (GG) and heterozygous/homozygous variant (GA/AA) in the SHBG gene. When adjusted for age, Gleason score, initial prostate-specific antigen, and clinical T-stage, the heterozygous/homozygous variant (GA/AA) in the SHBG gene was associated with a higher risk of progression (hazard ratio, 2.20; 95% confidence interval, 1.10-4.18; P = .027) and any-cause death (hazard ratio, 3.21; 95% confidence interval, 1.31-7.35; P = .012). Conclusions This study suggested genetic variation in SHBG (rs6259) might be an independent prognostic biomarker among men treated with primary ADT for metastatic prostate cancer.

Inadequate suppression of testosterone during androgen-deprivation therapy impairs its efficacy. This study investigated the significance of genetic polymorphism in CYP19A1, which encodes aromatase that catalyzes androgens into estrogens, among men treated with primary ADT for metastatic prostate cancer. This study included 80 Japanese patients with metastatic prostate cancer whose serum testosterone levels during ADT were available. The association of CYP19A1 gene polymorphism (rs1870050) with clinicopathological parameters including serum testosterone levels during ADT as well as progression-free survival and overall survival was examined. Serum testosterone levels during ADT of men carrying homozygous wild-type (AA) in the CYP19A1 gene [median (interquartile range); 11.6 (8.3–20.3) ng/dl] were higher than those in men carrying the heterozygous/homozygous variant (AC/CC) [median (interquartile range); 10.0 (6.4–12.8) ng/dl]. When adjusted by Gleason score, initial PSA, M-stage and serum testosterone level during ADT, heterozygous/homozygous variant (AC/CC) in the CYP19A1 gene was associated with a lower risk of progression to castration resistance [hazard ratio (95% confidence interval), 0.53 [0.29–0.92], p = 0.025], but not to any-cause death [hazard ratio (95% confidence interval), 0.74 [0.36–1.49], p = 0.40]. These findings suggest that genetic variation in CYP19A1 (rs1870050) might affect the prognosis of patients with metastatic prostate cancer when treated with ADT by regulating serum testosterone levels.

A 70-year-old woman, with an 8 cm tumor in the left kidney and multiple lung tumor and was diagnosed with Renal Cell Carcinoma (cT3aN0M1). The kidney tumor were unresectable and we started treatment with Tyrosine Kinase Inhibitors (sunitinib, pazopanib, axitinib, temsirolimus), but they failed because of disease progression or adverse events. We used nivolumab for 5th line treatment; then, interstitial pneumonia was observed. The renal tumor shrunk and pulmonary metastatic foci revealed prominent disappearance. The renal tumor became resectable and we tried nephrectomy. Pathological findings were clear cell carcinoma with marked necrosis, hyperplasia and internal bleeding.

Objective Androgen metabolism is a key component in therapeutic resistance to androgen deprivation therapy (ADT). This study aimed to reveal the significance of genetic polymorphisms in genes involved in androgen metabolism, including CYP17A1, AKR1C3, and HSD17B, on serum testosterone levels during ADT, as well as the prognosis of men undergoing ADT for metastatic prostate cancer (CaP). Materials and methods This study included 104 Japanese patients with metastatic CaP, for whom serum testosterone data during ADT were available for 80 patients. The association of CYP17A1 (rs743572), AKR1C3 (rs12529), HSD17B1 (rs605059), HSD17B3 (rs2066479), and HSD17B4 (rs7737181) with serum testosterone levels during ADT and prognosis (progression-free survival and overall survival) was examined. Enzymatic activity in AKR1C3 H5Q was examined using recombinant protein. Results Homozygous wild-type (GG allele; median [interquartile range], 12.0 ng/ml [8.0–19.0 ng/ml]) AKR1C3 rs12529 was associated with higher serum testosterone levels during ADT compared with variant-type (GC/CC alleles; median [interquartile range], 9.0 ng/ml [6.4–10.8 ng/ml]). Consistently, variant-type (GC/CC alleles) AKR1C3 rs12529 showed significantly lower risk of progression (hazard ratio [95% confidence interval], 0.47 [0.24–0.96], P = 0.039) compared with homozygous wild-type (GG allele) on multivariate analysis. Meanwhile, other genetic variations were associated with neither serum testosterone during ADT nor prognosis. Enzyme activity of wild-type AKR1C3 was comparable to the H5Q mutant. Conclusions Taken together, this study demonstrated that AKR1C3 polymorphism, which was associated with serum testosterone levels during ADT, may be a prognostic factor of the progression to castration-resistant prostate cancer in Japanese men with metastatic CaP.

Objective Bacillus Calmette–Guerin (BCG) instillation therapy is widely used to reduce intravesical recurrence in non-muscle invasive bladder cancer (NMIBC). In this study, we aimed to reveal the genetic variations associated with intravesical recurrence after BCG therapy for NMIBC in a genome-wide association study (GWAS). Materials and methods This study included Japanese patients with NMIBC, in whom genomic DNA was obtained from whole blood samples. The association between genetic variation and treatment failure was analyzed by GWAS in 44 patients treated with BCG instillation as a discovery cohort. Candidate single-nucleotide polymorphisms (SNPs) were examined separately in 47 patients treated with BCG instillation and in 62 patients treated with chemotherapeutic agent instillation as validation studies. Results Among the 44 patients in the discovery cohort, 14 cases experienced intravesical recurrent diseases. GWAS identified 12 candidate SNPs (rs9374832, rs35176001, rs363765, rs2127120, rs4277759, rs73664140, rs1607282, rs12141654, rs4541358, rs6986852, rs12373386, and rs17637903). In the validation study, a genetic risk stratification model using the number of risk alleles in rs363765 and rs6986852 discriminated the risk of intravesical recurrence after BCG therapy, but not after non-BCG therapy. Conclusion This study suggested that several SNPs were associated with intravesical recurrence after BCG therapy for NMIBC. A genetic risk model may be useful to predict intravesical recurrence after BCG therapy, warranting further research and development for clinical application.

Background Several immune checkpoint blockades (ICBs) such as anti-CTLA-4 monoclonal antibody (mAb) and anti-PD-1 mAb are in clinical use. In renal cell carcinoma (RCC), it is indicated that anti-PD-1 mAb nivolumab is effective for patients who received antiangiogenic therapy regimens. However, efficacy of nivolumab as a neoadjuvant therapy has not been indicated. We report the case in which nivolumab was effective for the lung metastatic lesions of renal cell carcinoma and we could resect the primary tumor. Case presentation A 69-year-old woman was referred to our hospital and diagnosed as metastatic left RCC, cT3aN0M1 (multiple lung metastasis), cStageIV. After sequential treatment with TKIs and mTOR inhibitor, nivolumab was administered as the fifth treatment. Drug induced interstitial pneumonia occurred 6 days after the initial administration, so nivolumab was not administered thereafter. In course of 4 months, the lung metastatic lesions sharply reduced and we could resect the primary tumor. In addition, we analyzed tumor infiltrated lymphocytes (TILs) in this case with flow cytometry and compared with the other 20 tumors resected from September 2017 to May 2018 in Kyushu university hospital. The phenotype of TILs in stagIV RCC after nivolumab administration was close to those of low stage RCC. Conclusion Currently, nivolumab treatment as a neoadjuvant therapy for metastatic RCC is not common. We report a metastatic RCC case in which we resected primary tumor after administration of nivolumab and analyzed TILs with flow cytometry.