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To understand the evolution of GII.P6-GII.6 and GII.P7-GII.6 strains, the prevalent human norovirus genotypes, we analysed both the RdRp region and VP1 gene in globally collected strains using authentic bioinformatics technologies. A common ancestor of the P6- and P7-type RdRp region emerged approximately 50 years ago and a common ancestor of the P6- and P7-type VP1 gene emerged approximately 110 years ago. Subsequently, the RdRp region and VP1 gene evolved. Moreover, the evolutionary rates were significantly faster for the P6-type RdRp region and VP1 gene than for the P7-type RdRp region and VP1 genes. Large genetic divergence was observed in the P7-type RdRp region and VP1 gene compared with the P6-type RdRp region and VP1 gene. The phylodynamics of the RdRp region and VP1 gene fluctuated after the year 2000. Positive selection sites in VP1 proteins were located in the antigenicity-related protruding 2 domain, and these sites overlapped with conformational epitopes. These results suggest that the GII.6 VP1 gene and VP1 proteins evolved uniquely due to recombination between the P6- and P7-type RdRp regions in the HuNoV GII.P6-GII.6 and GII.P7-GII.6 virus strains.

The continence self-management programme fee (CSPF) for hospitalized patients was revised in 2020 to include those receiving consistent care on an out-patient basis. We extracted candidate patients for CSPF on an out-patient basis (out-patient candidates hereafter) from those for whom-CSPF had been calculated during hospitalization at our hospital, and defined those who had undergone a medical examination related to continence care as out-patient calculation candidates. Of the 956 patients for whom CSPF had been calculated during hospitalization, 482 patients (50%) were out-patient candidates ; 275 (54%) and 169 (33%) of whom were seen in the urology and neurosurgery departments, respectively. Of the 482 out-patient candidates, 238 (49%) were out-patient calculation candidates ; 197 (83%) and 14 (6%) of whom were seen in the urology and neurosurgery departments, respectively. Forty-two and 41 of the calculation candidates were cases of benign prostatic hyperplasia and bladder cancer, respectively. The CSPF was actually processed 93 times for 78 of the 482 out-patient candidates (16%). There were various obstacles in the current system of calculating the fees to realize consistent care from hospitalization to out-patient care.

Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection., 「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.

Objectives: The microsurgical approach is considered the most reliable procedure in varicocelectomy. However, as there are difficulties in identifying the spermatic artery at the peripheral level, we had introduced intraoperative indocyanine green angiography (ICGA) for identification of arteries. In this study, we further investigated the usefulness of intraoperative ICGA in combination with an ordinary Doppler detector in microsurgical subinguinal varicocelectomy. Methods: A total of 140 men who underwent microsurgical subinguinal varicocelectomy at Gunma University Hospital were included. An operating microscope equipped with a near-infrared charge-coupled device was used for intraoperative ICGA. After exposing the vessels, arteries were identified using endoscopic vision only or with assistance of Doppler detector or ICGA, or of both. The number of preserved arteries was compared among the groups. Results: ICGA clearly visualized the internal spermatic arteries in all cases, allowing the surgeon to perform real-time identification and isolation of the spermatic artery intraoperatively. The use of ICGA or Doppler detector significantly increased the number of preserved arteries compared to the microscope-only operation from 1.11 to 1.75 (p < 0.05) and 1.57 (p < 0.05), respectively. The additional use of ICGA with Doppler detector further increased the number of preserved arteries to 2.41 (p < 0.05). Conclusions: Intraoperative ICGA facilitated safe and quick microsurgical subinguinal varicocelectomy by enabling visualization of thin spermatic cord blood vessels. Improved preservation of thin arteries, which is essential for patients with infertility, can be achieved with the combined use of ICGA and ordinary Doppler detector.

To elucidate the host genetic loci affecting severity of SARS-CoV-2 infection, or Coronavirus disease 2019 (COVID-19), is an emerging issue in the face of the current devastating pandemic. Here, we report a genome-wide association study (GWAS) of COVID-19 in a Japanese population led by the Japan COVID-19 Task Force, as one of the initial discovery GWAS studies performed on a non-European population. Enrolling a total of 2,393 cases and 3,289 controls, we not only replicated previously reported COVID-19 risk variants (e.g., LZTFL1, FOXP4, ABO, and IFNAR2), but also found a variant on 5p35 (rs60200309-A at DOCK2) that was significantly associated with severe COVID-19 in younger (-8 (odds ratio = 2.01, 95% confidence interval = 1.58-2.55). This risk allele was prevalent in East Asians, including Japanese (minor allele frequency [MAF] = 0.097), but rarely found in Europeans. Cross-population Mendelian randomization analysis made a causal inference of a number of complex human traits on COVID-19. In particular, obesity had a significant impact on severe COVID-19. The presence of the population-specific risk allele underscores the need of non-European studies of COVID-19 host genetics.

Background The optimal management of clinical T4 (cT4) prostate cancer (PC) is still uncertain. At our institution, carbon ion radiotherapy (CIRT) for nonmetastatic PC, including tumors invading the bladder, has been performed since 2010. Since carbon ion beams provide a sharp dose distribution with minimal penumbra and have biological advantages over photon radiotherapy, CIRT may provide a therapeutic benefit for PC with bladder invasion. Hence, we evaluated CIRT for PC with bladder invasion in terms of the safety and efficacy. Methods Between March 2010 and December 2016, a total of 1337 patients with nonmetastatic PC received CIRT at a total dose of 57.6 Gy (RBE) in 16 fractions over 4 weeks. Among them, seven patients who had locally advanced PC with bladder invasion were identified. Long-term androgen-deprivation therapy (ADT) was also administered to these patients. Adverse events were graded according to the Common Terminology Criteria for Adverse Event version 5.0. Results At the completion of our study, all the patients with cT4 PC were alive with a median follow-up period of 78 months. Grade 2 acute urinary disorders were observed in only one patient. Regarding late toxicities, only one patient developed grade 2 hematuria and urinary urgency. There was no grade 3 or worse toxicity, and gastrointestinal toxicity was not observed. Six (85.7%) patients had no recurrence or metastasis. One patient had biochemical and local failures 42 and 45 months after CIRT, respectively. However, the recurrent disease has been well controlled by salvage ADT. Conclusions Seven patients with locally advanced PC invading the bladder treated with CIRT were evaluated. Our findings seem to suggest positive safety and efficacy profiles for CIRT.

This study aimed to first elucidate prostate-specific antigen (PSA) kinetics in prostate cancer patients treated with carbon ion radiotherapy (CIRT). From 2010 to 2015, 131 patients with prostate adenocarcinoma treated with CIRT (57.6 Gy relative biological effectiveness (RBE) in 16 fractions) alone were recruited. PSA was measured at 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, and 60 months post-CIRT. PSA bounce was defined as PSA increase over a cutoff followed by spontaneous decrease to or below the pre-bounce nadir. PSA failure was determined using the Phoenix criteria (nadir + 2.0 ng/mL). As a result, non-failure-associated temporary increase in PSA exhibited two distinct patterns, namely a classical bounce and a surge at one month. PSA bounce of &sup3, 0.2 ng/mL was observed in 55.7% of the patients. Bounce amplitude was &lt, 2.0 ng/mL in 97.6% of cases. Bounce occurred significantly earlier than PSA failure. Younger age was a significant predictor of bounce occurrence. Bounce positivity was a significant predictor of favorable 5-year PSA failure-free survival. Meanwhile, a PSA surge of &sup3, 0.2 ng/mL was observed in 67.9% of patients. Surge amplitude was significantly larger than bounce amplitude. Larger prostate volume was a significant predictor of PSA surge occurrence. PSA surge positivity did not significantly predict PSA failure. In summary, PSA bounce was distinguishable from PSA failure with regard to timing of occurrence and amplitude (earlier and lower for bounce, respectively). These data are useful for post-CIRT surveillance of prostate cancer patients.

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.

Investigating oncological outcomes in patients registered in the Japanese Prostate Cancer Outcome Study of Permanent Iodine-125 Seed Implantation (J-POPS) in terms of biochemical relapse-free survival (bRFS) by the Phoenix and the newly developed J-POPS definitions, exploration of predictive factors for bRFS, and preliminary verification of pitfalls of prostate-specific antigen (PSA) failure definitions. Between July 2005 and June 2007, 2316 clinically localized patients underwent permanent seed implantation. The primary endpoint was bRFS. One of the secondary endpoints was overall survival (OS). The median age was 69 and performance status was 0 in 99.1% of participants. The median biologically effective dose (BED) was about 180 Gy2. During a median follow-up of 60.0 months, 8.4 and 5.9% had PSA failure by the Phoenix and the J-POPS definitions, respectively. The 5-year bRFSs based on the Phoenix and the J-POPS definitions were 89.1 and 91.6%, respectively. The 5-year OS was 97.3%. According to multivariate analyses, only age affected bRFS based on the Phoenix definition, whereas the risk group and BED independently affected bRFS based on the J-POPS definition. A spontaneous PSA decrease was seen in 91.1% of participants after PSA failure based on the Phoenix definition alone, but in only 22.2% after PSA failure based on the J-POPS definition alone. The world’s largest registration study, J-POPS, consisted of patients with longevity, and a highly quality-controlled BED resulted in excellent bRFS and OS. The high likelihood of PSA bounce by the Phoenix definition should be taken into account, especially in younger patients. NCT00534196.

Objectives To investigate the predictive value of various molecular forms of prostate-specific antigen in men with baseline prostate-specific antigen

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 9999: XX–XX, 2017. © 2017 Wiley Periodicals, Inc.

Background To date, research has not determined the optimal procedure for adjuvant androgen deprivation therapy (ADT) in patients with locally advanced prostate cancer (PCa) treated for 6 months with neoadjuvant ADT and external-beam radiation therapy (EBRT). Methods A multicenter, randomized, phase 3 trial enrolled 303 patients with locally advanced PCa between 2001 and 2006. Participants were treated with neoadjuvant ADT for 6 months. Then, 280 patients whose prostate-specific antigen levels were less than pretreatment levels and less than 10 ng/mL were randomized. All 280 participants were treated with 72 Gy of EBRT in combination with adjuvant ADT for 8 months. Thereafter, participants were assigned to long-term ADT (5 years in all; arm 1) or intermittent ADT (arm 2). The primary endpoint was modified biochemical relapse-free survival (bRFS) with respect to nonmetastatic castration-resistant prostate cancer (nmCRPC) progression, clinical relapse, or any cause of death. Results The median follow-up time after randomization was 8.2 years. Among the 136 and 144 men assigned to trial arms 1 and 2, respectively, 24 and 30 progressed to nmCRPC or clinical relapse, and 5 and 6 died of PCa. The 5-year modified bRFS rates were 84.8% and 82.8% in trial arms 1 and 2, respectively (hazard ratio, 1.132; 95% confidence interval, 0.744-1.722). Conclusions Although modified bRFS data did not demonstrate noninferiority for arm 2, intermittent adjuvant ADT after EBRT with 14 months of neoadjuvant and short-term adjuvant ADT is a promising treatment strategy, especially in a population of responders after 6 months of ADT for locally advanced PCa.

The PROPHET (Prostate Cancer: Prostate Health Index Trial) is a prospective study to clarify the diagnostic impact of laboratory based and prostate volume adjusted p2PSA ([-2] proenzyme prostate specific antigen) related indexes on prostate cancer and clinically significant prostate cancer with prostate specific antigen less than 10 ng/ml.Between April 2015 and March 2017, 421 men 50 to 79 years old in the prostate specific antigen range above age specific cutoffs and below 10 ng/ml were registered in the PROPHET. We investigated the diagnostic impacts of various clinical laboratory based free prostate specific antigen related and p2PSA related indexes on any grade and high Gleason grade group prostate cancer.Of the 363 eligible participants 179, 141 and 80 were diagnosed with any grade, and Gleason Grade Group 2-5 and 3-5 prostate cancer, respectively. The AUC-ROCs distinguishing nonprostate cancer vs prostate cancer, nonprostate cancer plus low Gleason Grade Group and low volume vs remaining prostate cancer with a higher Gleason Grade group or a higher volume on the PHI (Prostate Health Index) were significantly superior to the AUC-ROCs of prostate specific antigen and free-to-total prostate specific antigen. At 90% sensitivity in all investigated p2PSA related indexes the false-positive rate was superior to that of prostate specific antigen and free-to-total prostate specific antigen in any group comparison in terms of the Gleason Grade Group and positive biopsy cores. In 35% to 42% of men without prostate cancer and/or those with less aggressive prostate cancer the PHI would avoid unnecessary biopsy.Laboratory based p2PSA related indexes were significantly superior for detecting clinically significant prostate cancer compared to free-to-total prostate specific antigen. The indexes those would avoid up to 42% of prostate biopsies in men without aggressive cancer while maintaining 90% sensitivity.

Proton and carbon ion radiotherapy for the treatment of prostate cancer is associated with a lower incidence of adverse events than conventional radiotherapy. There are few reports on the quality of life of patients treated with particle therapy, and limited patient-reported outcomes. Analysis of quality of life is important for patients treated with radiotherapy alone or in combination with hormonal therapy, and long-term results, dose fractionation and costs need to be included in the analysis. This information might help both clinical decision-making and selection of appropriate treatments according to the individual needs of patients. This study reviews the literature on the quality of life and outcomes of patients treated with particle therapy, and discusses future directions.

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 Goteborg 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.

Background/aim The aim of this study was to evaluate the efficacy and safety of hypofractionated intensity-modulated radiotherapy (IMRT) for intermediate- and high-risk prostate cancer. Patients and methods Seventy-five consecutive patients with intermediate- and high-risk prostate cancer treated with IMRT (63 Gy/21 fractions/7 weeks) between 2010 and 2013 were retrospectively analyzed. PSA relapse and adverse events were determined based on the Phoenix criteria and the Common Terminology Criteria for Adverse Events v4.0, respectively. Results The 5-year PSA relapse-free rate, clinical relapse-free rate, and overall survival rate for all patients was 92.1%, 95.1%, and 92.9%, respectively. The incidence of late grade 2 gastrointestinal- and genitourinary-toxicity at 5 years was 1.3% and 17.1%, respectively. No grade 3 or greater toxicities were observed. Conclusion These data indicate that hypofractionated IMRT (63 Gy in a total of 21 fractions with 3 fractions per week) is effective and safe for intermediate- and high-risk prostate cancer.

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.

BACKGROUND/AIM To evaluate bone mineral density (BMD) in Japanese patients with prostate cancer (PCa) after administering androgen deprivation therapy (ADT) for 2 years. PATIENTS AND METHODS A total of 84 Japanese patients with PCa were enrolled in this study during the period 2008-2011. BMD was measured by dual energy X-ray absorptiometry, every 6 months. The fracture risk assessment tool (FRAX) score was calculated before starting ADT. We evaluated the change in BMD over a 2-year period and the relationship between this change, the FRAX score, and the estimated glomerular filtration rate (eGFR). RESULTS Compared to baseline, BMD decreased by 2.50% at 6 months after ADT, by 4.28% after 12 months, by 5.34% after 18 months, and by 6.16% after 2 years (all p

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.

We reviewed the current evidence for three novel prostate tumor markers (PCA3, TMPRSS2:ERG and proPSA) that have been recently reported predominantly in Western countries. We focus our attention on Asian men in both clinical and basic research studies. There have been no reports on the clinical usefulness of these three markers for Asians living in Western countries. In Asian countries, evidence for the clinical usefulness of PCA3 and proPSA-related indices including Prostate Health Index is being accumulated, mainly in Japan. The process for how a novel marker is approved in the clinical setting is also discussed.

Statins have become of interest in research due to their anticancer effects. However, the exact mechanism of their anticancer properties remains unclear. The authors previously reported that statins decrease intracellular cholesterol levels in androgen-independent prostate cancer cells. In de novo androgen synthesis, cholesterol is the primary material and certain enzymes have important roles. The present study aimed to determine whether simvastatin alters the expression of androgen synthesis-associated enzymes in androgen-independent prostate cancer cells. A novel combination therapy of statins and other drugs that inhibit the overexpression of enzymes involved in androgen synthesis was explored. The cytotoxicity of simvastatin and meclofenamic acid was assessed in prostate cancer cells using MTS and migration assays. Testosterone and dihydrotestosterone concentrations in the culture medium were measured using liquid chromatography-tandem mass spectrometry. RAC-α-serine/threonine-protein kinase (Akt) phosphorylation was detected by western blot analysis. Following treatment with simvastatin, aldo-keto reductase family 1 member C3 (AKR1C3) expression increased in PC-3 (>60-fold) and LNCaP-LA cells, however not in 22Rv1 cells. Small interfering (si)RNA was used to clarify the effects of AKR1C3 expression. The reduction in AKR1C3 expression in PC-3 cells following siRNA transfection was not associated with basal cell proliferation and migration; however, treatment with simvastatin decreased cell proliferation and migration. The combination of simvastatin and meclofenamic acid, an AKR1C3 inhibitor, further enhanced the inhibition of cell proliferation and migration compared with treatment with either drug alone. Furthermore, treatment with simvastatin attenuated insulin-like growth factor 1-induced Akt activation; however, the combination of simvastatin and meclofenamic acid further inhibited Akt activation. These results suggest that the combination of simvastatin and meclofenamic acid may be an effective strategy for the treatment of castration-resistant prostate cancer.

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), 17β-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.

BACKGROUND/AIM Androgen deprivation therapy (ADT) is a mainstay therapy for prostate cancer (PCa). ADT induces bone loss and increases the risk of osteoporosis and fractures. Recently, loss of bone quality has received attention as a factor that causes loss of bone strength independent of bone mineral density (BMD). Pentosidine has been identified as a surrogate marker of bone quality. Therefore, bone quality markers were evaluated retrospectively in PCa patients receiving ADT with or without denosumab. PATIENTS AND METHODS This study included 46 PCa patients. Twenty patients received denosumab. We measured pentosidine as bone quality marker and TRACP-5b as bone turnover marker. Pre- and 12-month BMD was measured in the lumbar spine and femoral neck. RESULTS In the denosumab group (D+), BMD at the lumbar spine was increased by 6.7% compared with the group that did not receive denosumab (D-) at 12 months (p=0.0015). BMD at the femoral neck was increased by 3.1% at 12 months (p=0.0076). The mean value of TRAP-5b was lower in the D+ group than the D- group at 12 months (p

An urgent need exists to develop a more sophisticated screening system in order to improve diagnostic accuracy of clinically significant cancer and also to reduce the drawbacks of prostate-specific antigen (PSA) screening including overdetection and overtreatment. The most promising next-generation PSA test, which can improve the management of prostate cancer, may be proenzyme PSA (proPSA) or precursor PSA (pPSA). proPSA has pro-leader peptide sequences of seven or less amino acids and previous studies demonstrated that [-2]proPSA, which contains only a 2-amino-acid propeptide leader, could be more useful not only to distinguish between men with and without cancer, but also between tumors with aggressive features with performance exceeding other classical PSA-related indices including ratio of free PSA to total PSA (%f-PSA) and PSA density. Recently, it was demonstrated that baseline [-2]proPSA-related indices were independent factors to predict pathological reclassification at one year or several years after entering active surveillance. Furthermore, a retrospective study suggested that [-2]proPSA might be a useful predictive marker for future developing clinically manifested prostate cancer as well as aggressive tumors. ProPSA-related indices may have the potential for developing a more ideal risk classification for men at risk for prostate cancer, with a screening system maintaining the sensitivity of detecting clinically significant prostate cancer while saving cost, individualized treatment strategies, and follow-up procedures of active surveillance or active treatments. At a minimum, proPSA will be one of the most important new markers on the prostate cancer management in the near future.

Mammalian target of rapamycin inhibitor has exhibited promising anticancer activity for the treatment of renal cell carcinoma (RCC). However, many patients acquire resistance to therapeutic agents leading to treatment failure. The objective of this study was to determine whether treatment with YM155, a novel small molecule inhibitor of survivin, could reverse rapamycin resistance in a rapamycin-resistant RCC. We induced a rapamycin-resistant clear cell carcinoma cell line (Caki-1-RapR). We showed that survivin gene expression was significantly up-regulated in Caki-1-RapR compared with that in its parent cells (Caki-1). Therefore, we hypothesized that targeting of survivin in Caki-1-RapR could reverse the resistant phenotype in tumor cells, thereby enhancing the therapeutic efficacy of rapamycin. We used both in vitro and in vivo models to test the efficacy of YM155 either as a single agent or in combination with rapamycin. In Caki-1-RapR cells, YM155 significantly decreased survivin gene and protein expression levels and cell proliferation in a dose-dependent manner in vitro. In addition, YM155 treatment significantly reversed rapamycin resistance in cancer cells. In a nude mouse tumor xenograft model, YM155 significantly inhibited the growth of Caki-1-RapR tumor. In addition, YM155 significantly enhanced the antitumor effects of rapamycin in Caki-1-RapR tumor. Our results suggest a potentially novel strategy to use YM155 to overcome the resistance in tumor cells, thereby enhancing the effectiveness of molecular target therapy in RCC.

Prostate cancer incidence and mortality in most native Asian populations have gradually increased, but are around one-third lower than in corresponding Asian-American cohorts, which are themselves lower than the rates observed in other American cohorts. Although genetic and environmental factors, particularly a Western diet, could partially explain these differences, lower exposure to PSA screening in Asian individuals might be a major contributing factor. Genetic features and diet are, however, unlikely to differ substantially within the same region of Asia, and age-stratified PSA levels in men from various Asian countries are almost identical; therefore, variation in the epidemiology of prostate cancer among native Asian populations might be attributable to differences in access to PSA testing, urology clinics, and available therapies. Conversely, the proportion of patients with metastatic prostate cancer is substantially higher even in the more developed Asian countries than in migratory Asian populations residing in Western countries and in Westerners. Consequently, the most appropriate approaches to the management of prostate cancer in Asian countries probably also differ, and therefore individualized prostate cancer screening and treatment strategies based on the epidemiological features and socioeconomic status of each country are needed.

Background The clinical usefulness of [−2]pro-PSA (where PSA is prostate-specific antigen) in prostate cancer diagnosis has been emphasized in recent studies. To determine proper blood sample handling conditions for [−2]pro-PSA evaluation, we analyzed the preanalytical stability of [−2]pro-PSA. Methods Blood samples from 22 Japanese males were stored under various conditions before total PSA (tPSA), free PSA, and [−2]pro-PSA concentrations were measured, and the preanalytical stability of [−2]pro-PSA and the changes in the Prostate Health Index (phi) were assessed. Results [−2]Pro-PSA was stable in serum for at least 24 hr at both room temperature (RT) and at 4°C. However, [−2]pro-PSA levels in whole blood increased rapidly over time, particularly at RT. Mean recovery (%) of [−2]pro-PSA in whole blood at RT was >110% at 1 hr after drawing of blood. The phi tended to increase over time in a pattern similar to the change in[−2]pro-PSA. Conclusions Preanalytical stability was lower for [−2]pro-PSA than for free PSA or tPSA. Whole-blood [−2]pro-PSA increased in a time-dependent manner, particularly at RT. Thus, whole blood samples collected at RT should be centrifuged within 1 hr after drawing. The [−2]pro-PSA in serum is stable for at least 24 hr at both RT and at 4°C.

Objectives To investigate the natural history of men with low levels of baseline prostate-specific antigen in terms of risk of increased prostate-specific antigen, developing prostate cancer and also the likelihood of detecting clinically insignificant cancer in population-based screening. Methods A total of 10 653 men aged between 55 and 68 years with baseline prostate-specific antigen levels of 2.0 ng/mL or lower screened annually were enrolled. The cumulative risks of increased prostate-specific antigen and developing cancer were investigated. The relationships of baseline prostate-specific antigen with clinicopathological features of screening-detected cancer were also investigated. Results A total of 1405 men (13.2%) showed serum prostate-specific antigen above 2.0 ng/mL and 68 (0.6%) were diagnosed with prostate cancer during the observation period. Cumulative probabilities of increased prostate-specific antigen above 2.0 ng/mL over 10 years were 7.7%, 18.3%, 57.3%, and 88.7% in men with baseline prostate-specific antigen levels of 0.0–0.5, 0.6–1.0, 1.1–1.5, and 1.6–2.0 ng/mL, respectively. The cumulative probabilities of developing prostate cancer at 4 years in men with baseline prostate-specific antigen of 0.0–1.0 and 1.1–2.0 ng/mL were 0.05% and 1.10%, respectively. Patients with unfavorable clinicopathological features were diagnosed at 3 years, and at 1 year after the initial screening visit in men with baseline prostate-specific antigen levels of 0.0–1.0 and 1.1–2.0 ng/mL, respectively. Conclusions The cumulative probabilities of increased prostate-specific antigen and developing prostate cancer significantly increase with higher baseline prostate-specific antigen ranges. Our database could contribute to the establishment of a natural history-adjusted screening system in the future.

Purpose Active surveillance (AS) is one potential solution to avoiding the overtreatment of favorable prostate cancer. By handling the AS strategy more safely, tumor aggressiveness may be evaluated more accurately. The aim of the present study was to evaluate the predictive impact of baseline prostate-specific antigen (PSA) isoform [−2]proPSA (p2PSA)-related indices on the pathological reclassification at 1 year during an AS program. Methods Between 2002 and 2003, 134 males diagnosed with low-risk prostate cancer were registered in the Japanese multicenter study cohort as candidates for AS, and 118 (88 %) males actually proceeded to AS. Of the 118 patients, the 67 that underwent protocol biopsy at 1 year after beginning AS were enrolled in the present study. The predictive significance of various baseline clinicopathological features and p2PSA-related indices on pathological reclassification at 1 year after beginning AS were investigated. Results The pathological reclassification rate was 37.3 %. According to the univariate analysis, prostate volume (p = 0.049), number of biopsy cores (p = 0.047), percentage of positive biopsy cores (p = 0.023), p2PSA to free PSA ratio (%p2PSA) (p = 0.003) and prostate health index (phi) (p = 0.010) at baseline were significantly different between the reclassification and non-reclassification groups. By multivariate logistic regression analysis, baseline %p2PSA (p = 0.008) and phi (p = 0.008) were the only independent predictive factors for pathological upgrade at 1 year after AS commencement. Conclusions Baseline %p2PSA and phi may predict the pathological reclassification at 1 year after starting AS, which could be due to the under detection of clinically significant prostate cancer at AS enrollment.