Determination of enzalutamide long-term safety and efficacy for castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy: a multicenter prospective DELC study.

BACKGROUND: Alternative anti-androgen therapy has been widely used as a first-line treatment for castration-resistant prostate cancer, and it may affect treatment outcome of subsequent agents targeting the androgen receptor axis. We conducted the prospective observational DELC (Determination of Enzalutamide Long-term safety and efficacy for Castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy) study to evaluate the efficacy of enzalutamide in patients with castration-resistant prostate cancer who underwent prior combined androgen blockade with bicalutamide and then alternative anti-androgen therapy with flutamide. METHODS: The DELC study enrolled 163 Japanese patients with castration-resistant prostate cancer who underwent alternative anti-androgen therapy with flutamide following failure of initial combined androgen blockade with bicalutamide in multiple institutions between January 2016 and March 2019. Primary endpoint was overall survival. Administration of enzalutamide was started at 160 mg orally once daily in all patients. RESULTS: The rate of decline of prostate-specific antigen by 50% or more was 72.2%, and median overall survival was 42.05 months. Multivariate analysis revealed that higher pretreatment serum levels of prostate-specific antigen (≥11.3 ng/mL; P = 0.004), neuron-specific enolase (P = 0.014) and interleukin-6 (≥2.15 pg/mL; P = 0.004) were independent risk factors for overall survival. Fatigue (30.0%), constipation (19.6%) and appetite loss (17.8%) were the most common clinically relevant adverse events. The enzalutamide dose was not reduced in any patient under the age of 70, but adherence was decreased in those over 70. CONCLUSIONS: In the DELC study, the safety of enzalutamide was comparable to that in previous reports. Serum levels of neuron-specific enolase and interleukin-6 were suggested as prognostic factors for castration-resistant prostate cancer with potential clinical utility.

Localization and potential role of prostate microbiota.

Introduction: We aimed to clarify the presence and localization of the prostate microbiota and examine its association with benign prostate enlargement (BPE). Methods: The microbiota of prostate tissues and catheterized urine from 15 patients were analyzed by 16S metagenomic analysis and compared to show that the prostate microbiota was not a contaminant of the urinary microbiota. Fluorescence in situ hybridization (FISH) and in situ hybridization (ISH) using the specific probe for eubacteria was performed on prostate tissue to show the localization of bacteria in the prostate. The BPE group was defined as prostate volume ≥30 mL, and the non-BPE group as prostate volume <30 mL. The microbiota of the two groups were compared to clarify the association between prostate microbiota and BPE. Results: Faith's phylogenetic diversity index of prostate tissue was significantly higher than that of urine (42.3±3.8 vs 25.5±5.6, P=0.01). Principal coordinate analysis showed a significant difference between the microbiota of prostate tissue and catheterized urine (P<0.01). FISH and ISH showed the presence of bacteria in the prostatic duct. Comparison of prostate microbiota between the BPE and non-BPE groups showed that the Chao1 index of the BPE group was significantly lower than that of the latter [142 (50-316) vs 169 (97-665), P=0.047] and the abundance of Burkholderia was significantly higher in the BPE group than in the latter. Conclusions: We demonstrated that the prostate microbiota was located in the prostatic duct and reduced diversity of prostate microbiota was associated with BPE, suggesting that prostate microbiota plays a role in BPE.

Circulating extracellular vesicles carrying Firmicutes reflective of the local immune status may predict clinical response to pembrolizumab in urothelial carcinoma patients.

Bacterial flora has clinical significance for the host. The metabolic environment created by this flora influences immunotherapy in urothelial carcinoma. However, there are no reports on the clinical significance of bacterial flora in the host bloodstream. We aimed to clarify the correlation between extracellular vesicle (EV)-derived blood microflora information and tumor immunological status in urothelial carcinoma (UC) patients. Serum samples were collected from 20 healthy donors, 50 patients with localized UC, and 31 patients with metastatic UC (mUC) who had undergone pembrolizumab treatment. Bacterial DNA in EVs was extracted from each sample. Metagenomic sequencing was performed after amplification of the V1-V2 region of the bacterial 16S rRNA gene. Using the matched tumor tissue and serum samples, we revealed that the smaller amount of peripheral EVs carrying Firmicutes DNA was significantly correlated with the higher number of infiltrating T cells within tumor tissues (CD3; p = 0.015, CD4; p = 0.039, CD8; p = 0.0084) and the higher expression of activation markers on their surface (ICOS on both CD4; p = 0.0013 and CD8 T cells; p = 0.016 and 4-1BB on CD4 T cells; p = 0.016). In terms of circulating metabolic information, L-Ser and L-Pro levels, which play important roles in T cell expansion and proliferation, were significantly higher in the Firmicutes-low group (p = 0.010). All of the patients with higher Firmicutes abundance had disease progression without any clinical response (p = 0.026) and significantly inferior prognosis for pembrolizumab therapy (p = 0.035). This is the first study on the importance of peripheral bacterial EVs in cancer patients treated with cancer immunotherapy.

The Firmicutes/Bacteroidetes ratio of the human gut microbiota is associated with prostate enlargement.

BACKGROUND: The pathophysiology of the prostate enlargement underlying lower urinary tract symptoms is unknown. Meanwhile, the gut microbiota can contribute to various host conditions. We hypothesized that the gut microbiota plays a role in prostate enlargement. METHODS: We included 128 patients who underwent prostate biopsies at our hospitals between December 2018 and March 2020, excluding those who had used antibiotics within the past 6 months and those who were diagnosed with prostate cancer of cT3 or higher. Patients with prostate volumes ≥30 ml were defined as the prostate-enlargement (PE) group; those with prostate volumes <30 ml were defined as the non-PE group. Their gut microbiotas were analyzed via 16S rRNA metagenomic analyses of rectal swab samples and were compared between the groups. RESULTS: The PE group included 66 patients; the non-PE group included 62 patients. Age, body mass index, and prostate-specific antigen levels did not significantly differ between the groups. Linear discriminant analysis effect size analysis indicated a higher proportion of Firmicutes and Actinobacteria in the PE group and a higher proportion of Bacteroidetes in the non-PE group. The Firmicutes/Bacteroidetes (F/B) ratio was significantly higher in the PE group than in the non-PE group (2.21 ± 0.39 vs. 1.61 ± 0.40, p = 0.015). CONCLUSION: The F/B ratio of the gut microbiota was associated with prostate enlargement. Although the detailed mechanisms are unclear, the gut microbiota might affect prostate enlargement.

Decreased renal function increases the nighttime urine volume rate by carryover of salt excretion to the nighttime.

To determine the pathophysiology of nocturnal polyuria associated with renal dysfunction, patients who underwent laparoscopic nephrectomy were prospectively studied. The diurnal variation in urine volume, osmolality, and salt excretion were measured on preoperative day 2 and postoperative day 7. The factors associated with an increase in the nighttime urine volume rate with decreased renal function were evaluated using multiple linear regression analysis. Forty-nine patients were included. The estimated glomerular filtration rate decreased from 73.3 ± 2.0 to 47.2 ± 1.6 mL/min/1.73 m2 (P < 0.01) and the nighttime urine volume rate increased from 40.6% ± 2.0% to 45.3% ± 1.5% (P = 0.04) with nephrectomy. The nighttime urine osmolality decreased from 273 ± 15 to 212 ± 10 mOsm/kg and the nighttime salt excretion rate increased from 38.7% ± 2.1% to 48.8% ± 1.7% (both P < 0.01) with nephrectomy. Multiple linear regression analysis showed that the increase in the nighttime urine volume rate was strongly affected by the increase in the nighttime salt excretion rate. A decrease in renal function causes an increase in the nighttime urine volume rate, mainly because of an increase in nighttime salt excretion.Trial registration number: UMIN000036760 (University Hospital Medical Information Network Clinical Trials Registry).Date of registration: From 1 June 2019 to 31 October 2020.

Erectile Dysfunction in Germ Cell Tumor Survivors.

PURPOSE: Germ cell tumors (GCTs) are the most common malignant neoplasms in adolescents and young adults, and most patients with these tumors can be completely cured. Therefore, maintaining quality of life (QOL) is important. Erectile dysfunction (ED) is one factor that reduces the QOL of GCT survivors. We aimed to clarify the relationship between ED and age, follow-up period, serum levels of hormones, and treatment methods for GCT survivors. MATERIALS AND METHODS: We evaluated ED using the Sexual Health Inventory for Men questionnaire (SHIM) and measured serum levels of hormones in survivors after GCT treatment. The relationships between the SHIM score responses and age, serum levels of hormones, follow-up period, and treatment methods were assessed using a logistic analysis. RESULTS: Fifty-two GCT survivors were enrolled and 46 survivors completed the SHIM. The median age, follow-up period, and SHIM score were 38 years, 35 months, and 18, respectively. Regarding the SHIM scores, 85% had scores <22 and 46% had scores <17. The percentage of SHIM scores <17 was 69% in patients with under 2 years of follow-up. It significantly improved to 33% in patients with over 2 years of follow-up. The multivariate analysis identified the follow-up period as an independent factor for SHIM scores <17. Age, serum levels of hormone, and treatment method were not significant factors for SHIM scores <17. CONCLUSIONS: Improvement of SHIM score can be expected after GCT treatment regardless of age, serum levels of hormone, and treatment method.

Novel hydrogen-producing Si-based agent reduces oxidative stress, and improves sperm motility and in vitro fertilization rate in varicocoele.

BACKGROUND: Varicocoele-induced male infertility potentially involves oxidative stress. Although varicocoelectomy is recommended for varicocoele patients presenting abnormal semen findings, no pharmacotherapeutic methods currently exist. We have recently developed a silicon-based agent that produces hydrogen by the reaction with water. OBJECTIVES: This study aimed to investigate the therapeutic effects of oral administration of a Si-based agent on varicocoele rat. MATERIALS AND METHODS: Twenty-one rats were divided into four groups: varicocoele + normal diet (n = 5), varicocoele + Si-based agent-supplemented diet (n = 6), sham + normal diet (n = 5), and sham + Si-based agent-supplemented diet (n = 5). All rats were euthanized four weeks after surgery. RESULTS: The mean left epididymal sperm motility was 74.4% in the sham group, 72.3% in the sham + Si group, 57.6% in the varicocoele group, and 66.9% in the varicocoele + Si group. Epididymal sperm motility was significantly lower in the varicocoele group, but was significantly higher upon Si-based agent ingestion (P < .01). The mean left testicular weight, Johnsen's score, and left epididymal sperm concentration did not differ significantly between groups. The 8-OHdG concentration and DNA fragmentation rate were significantly increased in the varicocoele group, but were significantly decreased in the Si-based agent intake group (P < .01). Additionally, the IVF rate was significantly lower in the varicocoele group (26.3%) compared with the sham group (73.4%; P < .01), and was significantly higher in the varicocoele + Si group (51.8%) compared with the varicocoele group (P < .05), indicating that the Si-based agent improves IVF rates. DISCUSSION AND CONCLUSION: Oral intake of the silicon-based agent improves epididymal sperm motility and in vitro fertilization rates through hydrogen production and subsequent reduction of oxidative stress. Considering the lack of effective noninvasive methods, this Si-based agent is potentially applicable for treating varicocoele-induced abnormal semen parameters.

[A Case of Retroperitoneal Primary Castleman's Disease which was Difficult to Differentiate from Liposarcoma].

A 38-year-old man had a right lower retroperitoneal mass found by abdominal echography in a medical examination, and he consulted the internal medicine of Sumitomo Hospital. On the suspicion of malignant lymphoma, he received a laparotomy with biopsy. Pathological examination revealed that the tumor was either benign lymphadenopathy or low-grade malignant lymphoma, and he was follow-up. Two years later, he was introduced to our department because the follow-up computed tomography revealed signs of a tumor and a mass of adjunctive adipose tissue that increased markedly. Thus, we suspected that the tumor was liposarcoma before the operation, and performed retroperitoneal tumor resection. However, we found that the tumor was pathologically a hyaline vascular type of Castleman's disease and the pathological examination showed no malignant cells in the peritumoral adipose tissue. Since Castleman's disease lacks the characteristic symptoms or image findings, the preoperative diagnosis is generally difficult. Cases with growth of the peritumoral adipose tissue are rare, and the differentiation from the liposarcoma is usually difficult. We discussed how to perform the differential diagnosis of Castleman's disease, and especially about the differential diagnosis of liposarcoma.

[A Case of Androgen Insensivity Syndrome with a Seminoma in the Abdominal Undescended Testis].

A 48-year-old female was referred to our hospital for further urological examination of primary amenorrhea. She had been suffering from amenorrhea since 12 years old. Although she had normal female external genitalia, she had a blind-ended vagina with complete absence of the uterus.Laboratory tests showed high testosterone level and the 46 XY karyotype. Thus, our diagnosis was androgen insensivity syndrome. Magnetic resonance imaging showed bilateral intra-abdominal testes. We performed laparoscopic bilateral gonadalectomy. Pathological diagnosis was seminoma in the right gonad. She is free of recurrence 6 months after operation.

[Unfixed Mesh Plug Migration from Inguinal Ring to Urinary Bladder].

A 65-year-old man presented to a clinic with a chief complaint of macrohematuria and frequent urination. The computed tomographic scan and cystoscopy revealed a dome of bladder tumor. He was referred to our hospital with the diagnosis of bladder tumor. He had undergone bilateral inguinal hernia repair and magnetic resonance imaging suggested mesh plug migration on the urinary bladder inserted into the right inguinal lesion 11 years previously. Under the diagnosis of mesh plug migration, partial cystectomy with extraction of the foreign body was performed. After the surgery he was well and symptoms had disappeared.

[OUTCOME OF BLADDER PRESERVATION USING LOW DOSE CHEMORADIATION THERAPY IN PATIENTS WITH LOCALLY INVASIVE BLADDER CANCER].

(Purpose) We investigated the outcome of selective organ preservation in invasive bladder cancer using chemoradiation therapy. (Patients and method) We examined locally invasive bladder cancer in 60 patients (51 men, 9 women; mean age at treatment 66.1 years) who underwent chemoradiation therapy for bladder preservation in the Department of Urology at Sumitomo Hospital between 2000 and 2015. The clinical stage was T1, T2, T3 and T4 in 4, 24, 17, 4 patients. Our protocol includes transurethral resection of the bladder tumor (TURBT) and 46 Gy radiation (2 Gy/fraction) to the bladder with concurrent cisplatin chemotherapy (20 mg/body/day, 10 days, intravenously). The initial evaluation included urine cytology and transurethral bladder biopsy. If patients developed superficial residual or recurrent cancer, they were treated with TURBT and/or intravesical Bacillus Calmette-Guerin (BCG), while patients with invasive residual or recurrent cancer were advised to undergo a salvage cystectomy. The mean follow-up was 55 months. (Results) The first assessment after the chemoradiation therapy showed that the complete remission rate for evaluable cases was 72% (38/53) and bladder preservation was achieved in 56 patients (93%). The 1-, 3-, and 5-year overall survival rate was 95, 86, and 78%, respectively. The 1-, 3-, and 5-year cancer-specific survival rate was 97, 90, and 85%, respectively. The 5-year patient survival rate with an intact bladder was 68%. Hydronephrosis and cisplatin dose (<200 mg) were independent adverse factors of overall survival in a Cox model (HR 4.5 and 4.1, respectively). (Conclusions) Chemoradiation therapy for invasive bladder cancer can achieve similar survival rate to those in patients treated with radical cystectomy, and enable the majority of patients to preserve the bladder.

[A Case of Bilateral Adrenal Incidentaloma in which MTX-Related Lymphoproliferative Disease Could Be Diagnosed by Computed Tomography-Guided Biopsy and MTX Administration History].

The patient was a 76-year-old man. Because bilateral adrenal tumor (right adrenal gland 7 cm, left adrenal gland 1.5 cm) was detected in by computed tomography (CT) in methotrexate (MTX) administration for articular rheumatism from 2011, he was referred to this hospital in February, 2016. An endocrine examination, and imaging study did not lead to a definitive diagnosis and CT-guided lower needle biopsy was performed. The pathological diagnosis was diffuse large B cell lymphoma. Also, in situ hybridization revealed EBER-positive and the diagnosis of MTX-related lymphoproliferative disease (MTXLPD) was made in conjunction with the medical history. After MTX cancellation, the tumor became markedly smaller. The annual incidence of this disorder in the RA patients during MTX internal use is reported as 0.06%. According to the site of origin, lymphatic extranodal disease accounts for approximately half of the cases, but this is the third case of primary adrenal origin reported.

[A CASE THAT TS-1+CDDP THERAPY WAS EFFECTIVE FOR BLADDER PRIMARY SIGNET RING CELL ADENOCARCINOMA].

Since we experienced a case that S-1+Cisplatin (CDDP) therapy was effective for bladder primary signet ring cell adenocarcinoma of pT4N0M0, we report here the time course of its pathophysiology and the treatment of that patient, and discuss the justification of the chemotherapy for the T4 case with the comparison of the previous cases. The present case is a 66 years old man. Because he was aware of the urinary frequency and the sense of incongruity at abdominal region for approximately three months, he visited our hospital for the consultation of his symptoms in July, 2015. The anterior wall showed a torose lesion by cystoscopy from the left sidewall, and we found the histopathology signet ring cell adenocarcinoma after transurethral resection of the bladder tumor. As a result of thorough investigation of thoracic abdominal CT, whole body PET-CT and endoscopy of the upper gastrointestinal tract, we diagnosed it as bladder primary signet ring cell adenocarcinoma with cT3N0M0. Consequently, we tried total cystectomy in August, 2015, however both bladder and pelvic wall were adhered strongly each other; we gave up the total cystectomy and changed the strategy to the urinary diversion by bilateral ureterocutaneous fistula. A biopsy of the adhesion site of the right pelvic wall showed the invasion of the signet ring cell adenocarcinoma, which enabled us to diagnose as pT4bN0M0. Therefore, we performed the chemotherapy with the S-1+CDDP for 12 courses, 16 months from August, 2015 after the surgery. After the initiation of the chemotherapy, the tumor marker was tended to decrease for eight months, but turned to increase thereafter. Because there was no evidence for neither distant nor lymph node metastases of tumor revealed by CT and the MRI, we diagnosed it as Stable Disease at least by CT and MRI examinations for 16 months. The major side-effects were not found during the strengthened chemotherapy without the recurrence until January, 2017. Since this case is very rare, we report the time courses and treatment strategy of a patient with bladder primary signet ring cell adenocarcinoma.

[RETROSPECTIVE ANALYSIS OF POSITIVE SURGICAL MARGIN AT RADICAL PROSTATECTOMY].

We retrospectively reviewed 182 patients who underwent radical prostatectomy in our hospital between April, 2009 to December, 2012, and who had not received any prior hormonal therapy. We also excluded the patients who couldn't followed up more than 6 months after surgery and pN1 patients. Positive surgical margins were observed in 65 cases. We determined what were the significant factors associated with the margin status. The another aim of present study is to evaluate the risk factor which might have significance for biochemical recurrence. BMI ≥ 25.0, prostate volume < 40 cm3, and biopsy positive core ≥ 25% were significant predictors of positive surgical margin. PSA nadir ≥ 0.02 ng/ml and pT3 were the significant factors which associated with biochemical recurrence of those patients with positive margin status.

Phytohormones in Japanese mugwort gall induction by a gall-inducing gall midge.

A variety of insect species induce galls on host plants. Liquid chromatographic/tandem mass spectrometric analyses showed that a gall midge (Rhopalomyia yomogicola) that induces galls on Artemisia princeps contained high levels of indole-3-acetic acid and cytokinins. The gall midge larvae also synthesized indole-3-acetic acid from tryptophan. Close observation of gall tissue sections indicated that the larval chamber was surrounded by layers of cells having secondary cell walls with extensive lignin deposition, except for the part of the gall that constituted the feeding nutritive tissue which was composed of small cells negatively stained for lignin. The differences between these two types of tissue were confirmed by an expression analysis of the genes involved in the synthesis of the secondary cell wall. Phytohormones may have functioned in maintaining the feeding part of the gall as fresh nutritive tissue. Together with the results in our previous study, those presented here suggest the importance of phytohormones in gall induction.

Community-based prostate cancer screening in Japan: predicting factors for positive repeat biopsy.

OBJECTIVES: To assess possible predictors in determining criteria for repeat biopsy in a prostate cancer screening population. METHODS: A total of 50 207 men over 55 years-of-age have participated in a prostate cancer screening program in Otokuni, Kyoto, Japan for 12 years. Transperineal systematic biopsy was carried out in case of positive digital rectal examination (DRE) or positive transrectal ultrasonography (TRUS) or a prostate-specific antigen (PSA) value greater than 10.0 ng/mL. For those with a PSA level from 4.1 to 10.0 ng/mL, and negative DRE and TRUS findings, biopsy was indicated only when PSA density (PSAD) was greater than 0.15. The same indication was applied for the repeat biopsy. RESULTS: A repeat biopsy after an interval of more than 2 years was carried out in 140 patients and was positive in 50 (36%) patients. The PSA value at the diagnosis of cancer declined from the initial value in six (12%) patients. On multivariate logistic regression analysis, PSA velocity (PSAV) as well as PSAD and DRE findings at latest screening were independent predictors for positive repeat-biopsy outcome. The odds ratio (95% confidence intervals) of PSAV >0.48, latest PSAD >0.33 and positive latest DRE were 4.17 (1.05-18.5), 4.15 (1.31-14.0), and 3.62 (1.06-13.2), respectively. A combination of three variables defined as positive if any of these were positive, reduced 31% of unnecessary biopsies while missing 8% of low volume, low grade cancers. CONCLUSIONS: A combination of latest PSAD, PSAV and positive DRE at latest screening might help to reduce unnecessary repeat biopsies in high-risk patients with an initial negative biopsy.

Effects of hydrogen in working gas on valence States of oxygen in sputter-deposited indium tin oxide thin films.

X-ray photoelectron spectroscopy (XPS) and Rutherford backscattering spectroscopy-elastic recoil detection analysis (RBS-ERDA) revealed that hydrogen in working gas for dc-plasma sputter deposition resided in indium tin oxide (ITO) films and generated the O(-) state seen as the suboxide-like O 1s peak in XPS. Growth of the suboxide-like O 1s peak was parallel with an increase of the resided hydrogen quantified by RBS-ERDA. The first-principles band structure calculation revealed that the electronic structure of In(2)O(3) crystal was realized typically for the most conductive as-deposited film grown in the gas containing hydrogen of 1%. The as-deposited film grown in the gas containing hydrogen of more than 1% exhibited rather high density but low mobility of carriers and showed the electronic structure above 4 eV originated from the O(-) state due to the resided hydrogen in addition to that of the most conducting one. Both well preserved In(2)O(3) band structure and proper concentration of the O(2-) vacancy are indispensable for achieving the highest conductivity; however, the O(-) state lowers efficiency of the carrier doping using the O(2-) vacancy in the lattice and increases density of the ionized scattering center for the carriers.

Significant antitumor activity of cationic multilamellar liposomes containing human interferon-beta gene in combination with 5-fluorouracil against human renal cell carcinoma.

Immunotherapy is one of the most effective treatments against metastatic renal cell carcinoma (RCC). However, the response rate is not high. Therefore, more effective therapies are necessary for patients with metastatic RCC. We previously reported on the significant antitumor activity of cationic multilamellar liposome containing human interferon-beta (huIFN-beta) gene (IAB-1) against RCC. We then examined the antitumor effect of IAB-1 in combination with anticancer drugs against RCC. The cytotoxicity of IAB-1 alone, and in combination with anticancer drugs, cisplatin, adriamycin, 5-fluorouracil, gemcitabine, paclitaxel and irinotecan hydrochloride against the human RCC cell line NC65 was examined by the colorimetric method using tetrazolium salt. For the in vivo study, we used NC65 cells inoculated into the severe combined immunodeficiency mouse. The results showed that the in vitro combination therapy with IAB-1 and 5-FU was more cytotoxic than IAB-1 alone. However, synergistic cytotoxicity was not observed when combined with IAB-1 and other anticancer drugs. NC65 tumors transfected with IAB-1 in mice were smaller than those receiving an injection of empty liposome or the recombinant huIFN-beta protein. Treatment with IAB-1 in combination with 5-FU resulted in significant anticancer activity. IAB-1 enhanced the activity of thymidine phosphorylase (TP), which converts 5-FU to the active metabolite, FdUMP. In contrast, IAB-1 decreased the activity of thymidylate synthase (TS), which is a target enzyme of 5-FU. In conclusion, these findings indicate that a combination of IAB-1 and 5-FU may have enhanced antitumor activity against human RCC, suggesting its potential clinical application. The mechanism of enhanced cytotoxicity by combination therapy with IAB-1 and 5-FU may up-regulate TP activity and down-regulate TS activity.

Ten year trend in prostate cancer screening with high prostate-specific antigen exposure rate in Japan.

BACKGROUND: The tendency of the results and quality control of prostate cancer screening serially performed for 10 years in an area of Japan were evaluated. METHODS: A total of 39 213 men over 55 years of age have participated in the mass screening of prostate cancer in the Otokuni District, since 1995. Men whose prostate-specific antigen (PSA) levels were more than 4.1 ng/mL were indicated for the second screening. In the second screening, prostate-specific antigen density (PSAD) was calculated in men whose PSA levels ranged from 4.1 to 10.0 ng/mL. RESULTS: Secondary screening was indicated in a total of 2428 subjects, of whom 1633 underwent it. Prostate cancer was diagnosed in 267 men. As a result of the evaluation of the indication of prostate biopsy according to the PSAD in 894 who underwent secondary screening for the first time, the procedure was judged to be unnecessary in 269 (35%) of 765 cases. Of these 269 subjects, 23 (8.5%) were found to have cancer. Clinically localized prostate cancer increased by 17%, and locally advanced and metastatic cancers decreased by 12% in the second compared with the first five years of the ten-year period. The exposure rate of PSA screening in the Otokuni District was 65% with the application for the rate of screenees whose PSA level was 4.1 ng/mL or above. CONCLUSIONS: The Japanese basic health screening system allows the determination of high-PSA exposure areas. Serial prostate cancer screening showed a tendency of stage migration in the screened cancer patients. The use of PSAD in secondary screening substantially reduces the necessity of prostate biopsy; however, the encouragement of PSA-positive individuals to periodically receive prostate cancer screening is essential to maintain the quality of the screening system.

Oncogenic role of NALP7 in testicular seminomas.

To isolate novel molecular targets for treatment of testicular germ cell tumor (TGCT), we performed genome-wide expression profile analysis of testicular seminomas using a cDNA microarray. We here report identification of NACHT, leucine-rich repeat and PYD containing 7 (NALP7 ), that was significantly transactivated in testicular seminomas. Subsequent semi-quantitative RT-PCR and northern blot analyses confirmed an approximately 3.3-kb transcript that was expressed exclusively in testis, although the expression level of this gene in normal testis was much lower than in tumor cells, suggesting an important role of this gene in germ-cell proliferation. Immunohistochemical analysis using anti-NALP7 polyclonal antibody detected the endogenous NALP7 protein in the cytoplasm of embryonal carcinoma cells and testicular seminoma tissues. Transfection of small interfering RNA (siRNA) for NALP7 significantly reduced the NALP7 expression and resulted in growth suppression of testicular germ-cell tumors. These findings imply that NALP7 may play a crucial role in cell proliferation, as well as testicular tumorigenesis, and it appears to be a promising candidate for development of targeted therapy for TGCTs.