Comorbid functional dyspepsia reflects IL-33-mediated airway neuronal dysfunction in asthma.

BACKGROUND: Neuronal dysfunction is implicated in the pathophysiology of asthma and functional dyspepsia (FD). However, the relationship between these diseases remains unclear. OBJECTIVE: This study aimed to clarify the clinical implications of comorbid FD in asthma and to explore the unified pathway between asthma and FD by focusing on airway neuronal dysfunction. METHODS: Clinical indices and biomarkers, including capsaicin cough sensitivity (C-CS), were compared between patients with asthma with and without FD. C-CS was determined based on the capsaicin concentration that induced at least two (C2) or five coughs (C5). Additionally, the associations of airway inflammation with airway innervation and gastrointestinal motility were evaluated in mouse models of type 2 airway inflammation. RESULTS: Patients with asthma with FD had worse asthma control and cough severity and lower C2 and C5 thresholds than those without FD. The severity of FD symptoms was negatively correlated with C2 and C5 thresholds. FD and poor asthma control were predictors of heightened C-CS (defined as C5 of ≤ 2.44 µM) in asthma. A mouse model of papain-induced airway inflammation developed airway hyperinnervation and gastrointestinal dysmotility, and both pathologies were ameliorated by an anti-interleukin (IL)-33 antibody. Moreover, papain-induced gastrointestinal dysmotility was mitigated by silencing the airway sensory neurons using QX-314, a sodium channel blocker. Furthermore, sputum IL-33 levels were significantly elevated in patients with asthma with FD or heightened C-CS compared with those in their counterparts. CONCLUSION: FD is significantly associated with airway neuronal dysfunction in asthma. IL-33-mediated airway neuronal dysfunction may contribute to the interaction between asthma and FD.

High-density lipoproteins mediate small RNA intercellular communication between dendritic cells and macrophages.

HDL are dynamic transporters of diverse molecular cargo and play critical roles in lipid metabolism and inflammation. We have previously reported that HDL transport both host and nonhost small RNAs (sRNA) based on quantitative PCR and sRNA sequencing approaches; however, these methods require RNA isolation steps which have potential biases and may not isolate certain forms of RNA molecules from samples. HDL have also been reported to accept functional sRNAs from donor macrophages and deliver them to recipient endothelial cells; however, using PCR to trace HDL-sRNA intercellular communication has major limitations. The present study aims to overcome these technical barriers and further understand the pathways involved in HDL-mediated bidirectional flux of sRNAs between immune cells. To overcome these technical limitations, SYTO RNASelect, a lipid-penetrating RNA dye, was used to quantify a) overall HDL-sRNA content, b) bidirectional flux of sRNAs between HDL and immune cells, c) HDL-mediated intercellular communication between immune cells, and d) HDL-mediated RNA export changes in disease. Live cell imaging and loss-of-function assays indicate that the endo-lysosomal system plays a critical role in macrophage storage and export of HDL-sRNAs. These results identify HDL as a substantive mediator of intercellular communication between immune cells and demonstrate the importance of endocytosis for recipient cells of HDL-sRNAs. Utilizing a lipid-penetrating RNA-specific fluorescence dye, we were able to both quantify the absolute concentration of sRNAs transported by HDL and characterize HDL-mediated intercellular RNA transport between immune cells.

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

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

A gain-of-function mutation in the acid-sensing ion channel 2a induces marked cerebellar maldevelopment in rats.

Specific amino acid substitutions in degenerin mechano-gated channels (DEGs) of C. elegans convert these channels into constitutively active mutants that induce the degeneration of neurons where DEGs are expressed. Acid-sensing ion channel-2a (ASIC2a), a proton-gated cation channel predominantly expressed in central neurons, is a mammalian ortholog of DEGs, and it can remain unclosed to be cytotoxic once the same mutations as the DEG mutants are introduced into its gene. Here we show that heterozygous transgenic (Tg) rats expressing ASIC2a-G430F (ASIC2aG430F), the most active form of the gain-of-function mutants, under the control of the intrinsic ASIC2a promoter exhibited marked cerebellar maldevelopment with mild whole-brain atrophy. The Tg rats were small and developed an early-onset ataxic gait, as evidenced by rotarod and footprint tests. The overall gross-anatomy of the Tg brain was normal just after birth, but a reduction in brain volume, especially cerebellar volume, gradually emerged with age. Histological examination of the adult Tg brain revealed that the cell-densities of cerebellar Purkinje and granule cells were markedly reduced, while the cytoarchitecture of other brain regions was not significantly altered. RT-PCR and immunoblot analyses demonstrated that ASIC2aG430F transcripts and proteins were already present in various regions of the neonatal Tg brain before the deforming cerebellum became apparent. These results suggest that, according to the spatiotemporal pattern of the wild-type (WT) ASIC2a gene expression, the ASIC2aG430F channel induced lethal degeneration in Tg brain neurons expressing both ASIC2aG430F and ASIC2a channels.

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

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

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

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

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

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

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

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

Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4/heparin antibody formation after orthopedic surgery.

Platelet-activating antibodies, which recognize platelet factor 4 (PF4)/heparin complexes, induce spontaneous heparin-induced thrombocytopenia (HIT) syndrome or fondaparinux-associated HIT without exposure to unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). This condition mostly occurs after major orthopedic surgery, implying that surgery itself could trigger this immune response, although the mechanism is unclear. To investigate how surgery may do so, we performed a multicenter, prospective study of 2069 patients who underwent total knee arthroplasty (TKA) or hip arthroplasty. Approximately half of the patients received postoperative thromboprophylaxis with UFH, LMWH, or fondaparinux. The other half received only mechanical thromboprophylaxis, including dynamic (intermittent plantar or pneumatic compression device), static (graduated compression stockings [GCSs]), or both. We measured anti-PF4/heparin immunoglobulins G, A, and M before and 10 days after surgery using an immunoassay. Multivariate analysis revealed that dynamic mechanical thromboprophylaxis (DMT) was an independent risk factor for seroconversion (odds ratio [OR], 2.01; 95% confidence interval [CI], 1.34-3.02; P = .001), which was confirmed with propensity-score matching (OR, 1.99; 95% CI, 1.17-3.37; P = .018). For TKA, the seroconversion rates in patients treated with DMT but no anticoagulation and in patients treated with UFH or LMWH without DMT were similar, but significantly higher than in patients treated with only GCSs. The proportion of patients with ≥1.4 optical density units appeared to be higher among those treated with any anticoagulant plus DMT than among those not treated with DMT. Our study suggests that DMT increases risk of an anti-PF4/heparin immune response, even without heparin exposure. This trial was registered to www.umin.ac.jp/ctr as #UMIN000001366.

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

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

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

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

High salt loading induces urinary storage dysfunction via upregulation of epithelial sodium channel alpha in the bladder epithelium in Dahl salt-sensitive rats.

We aimed to investigate whether high salt intake affects bladder function via epithelial sodium channel (ENaC) by using Dahl salt-resistant (DR) and salt-sensitive (DS) rats. Bladder weight of DR + high-salt diet (HS, 8% NaCl) and DS + HS groups were significantly higher than those of DR + normal-salt diet (NS, 0.3% NaCl) and DS + NS groups after one week treatment. We thereafter used only DR + HS and DS + HS group. Systolic and diastolic blood pressures were significantly higher in DS + HS group than in DR + HS group after the treatment period. Cystometrogram showed the intercontraction intervals (ICI) were significantly shorter in DS + HS group than in DR + HS group during infusion of saline. Subsequent infusion of amiloride significantly prolonged ICI in DS + HS group, while no intra-group difference in ICI was observed in DR + HS group. No intra- or inter-group differences in maximum intravesical pressure were observed. Protein expression levels of ENaCα in the bladder were significantly higher in DS + HS group than in DR + HS group. ENaCα protein was localized at bladder epithelium in both groups. In conclusion, high salt intake is considered to cause urinary storage dysfunction via upregulation of ENaC in the bladder epithelium with salt-sensitive hypertension, suggesting that ENaC might be a candidate for therapeutic target for urinary storage dysfunction.

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

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

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

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

Low serum dehydroepiandrosterone examined by liquid chromatography-tandem mass spectrometry correlates with poor prognosis in hormone-naïve prostate cancer.

BACKGROUND: There is no consensus on blood adrenal androgen concentrations in men with different stages and pathological grades of prostate cancer. In this study, dehydroepiandrosterone (DHEA) concentrations in blood were examined by ultrasensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS). We analyzed the correlation between DHEA concentrations in blood and clinicopathological findings of prostate cancer. METHODS: We analyzed 196 men (mean age 70 years) with prostate cancer. The patients underwent systematic needle biopsy, and peripheral blood sampling was conducted for measurement of DHEA. DHEA concentrations in blood were determined using LC-MS/MS method. Patient age, serum prostate-specific antigen, prostate volume measured by ultrasound, and DHEA levels in blood were compared with Gleason score and clinical stage by multivariate analyses. RESULTS: Median value of PSA and prostate volume were 11.5 ng/ml and 27.7 ml, respectively. Median concentration of DHEA in blood was 1,506.4 pg/ml. There was no correlation between serum DHEA and clinical variables such as age, serum PSA, and prostate volume. In multivariate analysis, low serum DHEA levels in prostate cancer patients were significantly related to high Gleason score and advanced clinical stage. Serum PSA levels in prostate cancer patients were also significantly associated with high Gleason score and advanced clinical stage. High serum PSA and low serum DHEA levels were significantly associated with poor prognosis factors in men with hormone-naïve prostate cancer. CONCLUSIONS: DHEA concentrations in blood were examined by newly developed ultrasensitive LC-MS/MS. We confirmed that low serum DHEA levels in prostate cancer patients were related to high Gleason score and advanced clinical stage. These results suggest that serum DHEA level may be a useful prognostic factor in prostate cancer patients.

A CASE OF GROWING TERATOMA SYNDROME.

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

[EFFICACY OF MICROSURGICAL SUBINGUINAL VARICOCELECTOMY USING INDOCYANINE GREEN FLUORESCENCE ANGIOGRAPHY: A PILOT STUDY].

Microsurgical subinguinal varicocelectomy is one of the best treatment modalities for varicoceles. However, the difficulty in identifying testicular arteries that should be spared is a limitation of this technique. We assessed the efficacy of intraoperative indocyanine green angiography (ICGA) during microsurgical subinguinal varicocelectomy in three pilot cases. We performed microsurgical subinguinal varicocelectomy using a surgical microscope for observing infrared fluorescence in patients with infertility or chronic pain associated with varicoceles. After the exposure of the spermatic cord blood vessels, ICG was injected intravenously to identify and isolate the testicular artery. Thereafter, the varicose veins were repeatedly ligated, while preserving a few lymphatic vessels and the spermatic duct. The testicular artery could be clearly identified by ICGA and were able to separate under ICGA. The preserved arteries were confirmed by ICGA at the end of microsurgical operation. Though, all the internal spermatic veins could be safely ligated, while sparing the testicular arteries and lymphatic vessels. Microsurgical subinguinal varicocelectomy using intraoperative ICGA facilitated safe and quick surgery by enabling the visualization of the spermatic cord blood vessels. This is the first report to indicate the usefulness of vessel visualization by ICGA during microsurgical subinguinal varicocelectomy.

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

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

Interleukin-18 may lead to benign prostatic hyperplasia via thrombospondin-1 production in prostatic smooth muscle cells.

BACKGROUND: Although inflammation plays an important role in the development of benign prostatic hyperplasia (BPH), little is known about the exact mechanism underlying this pathogenesis. Here, we investigated the relationship between the inflammatory reaction and BPH. METHODS: cDNA microarray analysis was used to identify changes in inflammation-related gene expression in a recently established rat model that mimics human BPH. To investigate the genes identified in the analysis, quantitative (q)RT-PCR, Western blotting, immunostaining, and a cell proliferation assay were conducted using BPH model tissues, human prostate tissues, and normal human prostate cultured cells. RESULTS: Of the 31,100 genes identified in the cDNA analysis, seven inflammatory-response-related genes were expressed at a >2-fold higher level in rat BPH tissues than in normal rat prostate tissues. The levels of the most commonly expressed pro-inflammatory cytokine, IL-18, significantly increased in rat BPH tissues. In humans, IL-18 was localized in the epithelial and stromal components, while its receptor was strongly localized in smooth muscle cells. Furthermore, in human prostate smooth muscle cell line (PrSMC), IL-18 effected dose-dependent increases in the phosphorylated Akt and thrombospondin-1 (TSP-1) levels. TSP-1 promoted proliferation of the human prostate stromal cells (PrSC). CONCLUSIONS: IL-18 may act directly in BPH pathogenesis by inducing TSP-1 production in prostatic smooth muscle cells via Akt phosphorylation.

High testosterone levels in prostate tissue obtained by needle biopsy correlate with poor-prognosis factors in prostate cancer patients.

BACKGROUND: There is currently no consensus on the correlations between androgen concentrations in prostate tissue and blood and stage and pathological grade of prostate cancer. In this study, we used a newly-developed ultra-sensitive liquid-chromatography tandem mass spectrometry method to measure testosterone (T) and dihydrotestosterone (DHT) concentrations in blood and needle biopsy prostate specimens from patients with prostate cancer. METHODS: We analyzed androgen levels in 196 men diagnosed with prostate cancer. All patients had undergone systematic needle biopsy, and an additional needle biopsy from the peripheral zone was conducted for the simultaneous determination of T and DHT. We analyzed the relationships between T and DHT levels in tissue and blood and Gleason score, clinical stage, and percentage of positive biopsy cores, using multivariate analysis. RESULTS: The median T and DHT levels in blood were 3551.0 pg/mL and 330.5 pg/mL, respectively. There was a strong correlation between serum T and DHT. The median T and DHT levels in prostate tissue were 0.5667 pg/mg and 7.0625 pg/mg, respectively. In multivariate analysis, serum prostate-specific antigen and tissue T levels were significantly associated with poor prognosis; high T levels in prostate tissue were significantly related to high Gleason score (p = 0.041), advanced clinical stage (p = 0.002), and a high percentage of positive biopsy cores (p = 0.001). CONCLUSIONS: The results of this study indicate that high T levels in prostate tissue are related to high Gleason score, advanced clinical stage, and a high percentage of positive biopsy cores in patients with prostate cancer. T level in needle biopsy specimens may therefore be a useful prognostic factor in prostate cancer patients.