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This study aimed to develop a prostatic pharmacokinetic model of ceftazidime and suggest more effective dosing strategy for the bacterial prostatitis, based on a site-specific pharmacokinetic and pharmacodynamic perspective. Subjects were prostatic hyperplasia patients prophylactically receiving a 0.5-h infusion of 1.0 g or 2.0 g ceftazidime before transurethral resection of the prostate. Plasma and prostate samples were premeditatedly collected after the administration and the concentrations were measured by high-performance liquid chromatography. The prostate tissue/plasma ratio in area under the drug concentration-time curve was approximately 0.476. The prostatic population pharmacokinetic model incorporated creatinine clearance (CL cr ) into ceftazidime clearance was developed, and adequately predicted prostate tissue concentrations by diagnostic scatter plots and visual predictive checks. Aiming for a bactericidal target of 70% of time above minimum inhibitory concentration (T > MIC) in prostate tissue, 2.0 g twice daily achieved ≥90% expected probability against main pathogens like Escherichia coli and Proteus species in patients regardless of renal function (CL cr = 60 and 90 mL/min). However, since the expected probability of attaining the bactericidal target of 0.5-h infusion dosing regimen did not achieve 90% against Pseudomonas aeruginosa in patients with CL cr = 60 and 90 mL/min, 4-h infusion dosing regimen of 2.0 g three times daily (6 g/day) might be required for empirical treatment. Based on site-specific simulations, the present study provides more effective dosing strategy for bacterial prostatitis., (© 2024, The American College of Clinical Pharmacology.)

The pharmacokinetic (PK)/pharmacodynamic (PD) approach has been widely used in clinical practice to optimize antimicrobial treatment. To promote the appropriate use of antimicrobial agents, it is important to consider certain factors, such as patient (e.g., age, physique, medical history, comorbidities, and organ dysfunction), site of infection (the target site where many causative bacteria are present), and microorganism (causative bacteria and susceptibility), and the dosing regimen should be selected based on the PK/PD approach. However, for renally excreted antibiotics, dosing regimens based on only renal function, such as creatinine clearance, are mainly used. Therefore, other factors such as patient pathological factors, antibiotic penetration of target sites, susceptibility of the causative bacteria to antibiotic, and clinical evaluation (efficacy and toxicity) should be considered simultaneously. These studies aimed to tailor the dosing of antimicrobial agents to individual patients by considering these factors. Multifaceted PK/PD evaluation may improve antimicrobial efficacy and safety, thereby contributing to the successful treatment of infectious diseases. Furthermore, improved treatment success rates may help manage the prevalence of antimicrobial-resistant bacteria, which is expected to become a significant problem in the future.

This study aimed to assess the dosing regimens of ampicillin/sulbactam for pneumonia based on pulmonary pharmacokinetic (PK)/pharmacodynamic (PD) target attainment. Using the literature data, we developed pulmonary PK models and estimated the probabilities of attaining PK/PD targets in lung tissue. Against bacteria other than A. baumannii (the general treatment), the PK/PD target was set as both 50% time above the minimum inhibitory concentration (T > MIC) for ampicillin and 50% T > 0.5 MIC for sulbactam. For the A. baumannii treatment, the PK/PD target was set as 60% T > MIC for sulbactam. The pulmonary PK/PD breakpoint was defined as the highest minimum inhibitory concentration (MIC) at which the target attainment probability in the lung tissue was ≥90%. The lung tissue/serum area under the drug concentration-time curve from 0 to 3 h (AUC 0-3h ) ratios for ampicillin and sulbactam were 0.881 and 0.368, respectively. The ampicillin/sulbactam AUC 0-3h ratio in the lung tissue was 3.89. For the general treatment, the pulmonary PK/PD breakpoint for ampicillin/sulbactam at 3 g four times daily in typical patients with creatinine clearance (CL cr ) of 60 mL/min was 2 μg/mL, which covered the MIC 90s (the MICs that inhibited the growth of 90% of the strains) of most gram-positive and gram-negative bacteria. For the A. baumannii treatment, the pulmonary PK/PD breakpoint for ampicillin/sulbactam at 9 g 4-h infusion three times daily (27 g/day) in patients with a CL cr of 60 mL/min was 4 μg/mL, which covered the MIC 90 of A. baumannii . A PK/PD evaluation for pneumonia should be performed in the lung tissue (the target site) rather than in the blood because sulbactam concentrations are lower in lung tissue. These findings should facilitate the selection of ampicillin/sulbactam regimens for pneumonia caused by various bacteria, including A. baumannii .

Detection of post-transplant malignant tumors and the analysis of the associated risk factors is important for monitoring the progress after renal transplantation. In this study, we retrospectively examined the medical records of 298 patients who underwent renal transplantation at two facilities in Nagasaki Prefecture (Nagasaki University Hospital and National Hospital Organization Nagasaki Medical Center). Of the 298 patients, 45 (15.1%) patients had developed malignant tumors with 50 lesions. The most common type of malignant tumor was skin cancer (eight patients; 17.8%), followed by renal cancer (six patients; 13.3%), and pancreatic cancer and colorectal cancer, (four patients; 9.0% each). Five patients (11.1%) had multiple cancers, four of whom had skin cancer. The cumulative incidence within 10 and 20 years after renal transplantation was 6.0 and 17.9%, respectively. Univariate analysis identified age at transplantation and administration of cyclosporine and rituximab as risk factors, while multivariate analysis identified age at transplantation and administration of rituximab as independent factors. The administration of rituximab was associated with the development of malignant tumors. However, further investigation is required to establish the association with post-transplant malignant neoplasms.

What Is Known and Objective: Linezolid (LZD) may cause thrombocytopenia, which can result in discontinuation of treatment. In this study, the blood LZD trough concentration was estimated based on population pharmacokinetic (PK) parameters derived from two previously published models in the Japanese population to determine the rate of achieving the target trough value when the risk of thrombocytopenia is low and to clarify its relationship with the onset of thrombocytopenia., Methods: This study included adult patients hospitalized at Shimane University Hospital, who received LZD treatment for at least 4 days from January 2010 to December 2017. Patients whose platelet count fell below 70% before LZD administration were categorized as the thrombocytopenic group. Patient PK parameters were calculated based on the population PK models described by Matsumoto et al. and Sasaki et al., and these parameters were designated A and B, respectively. Based on these parameters, the rate of achieving an LZD trough concentration of less than 8 μg/ml, which is the safety target achievement rate, was calculated using a random simulation for each patient. We further analysed the association between the incidence of thrombocytopenia and patient factors, including safety target achievement rate, through univariate, multivariate, and receiver operating characteristic (ROC) analyses., Results and Discussion: Patients (n = 77) aged 72 ± 11 years and weighing 56.7 ± 10.9 kg, with a creatinine clearance (CL cr ) of 60.5 ± 47.2 ml/min and a cirrhosis prevalence of 9.1%, were analysed. All patients received LZD at a dose of 600 mg twice daily for a total of 10.9 ± 8.9 days. Univariate analyses revealed significant differences (p < 0.05) in the duration of LZD therapy, serum creatinine, creatinine clearance, LZD clearance, and the safety target achievement rate for parameters A and B between the thrombocytopenic and non-thrombocytopenic groups. A multivariate analysis of these factors stratified with the cutoff values obtained by ROC analysis revealed that the duration of LZD therapy and the safety target achievement rates for parameters A and B were significant factors (odds ratios for duration of LZD therapy: 7.436 [95% confidence interval (CI): 1.918-28.831] and 4.712 [95% CI: 1.567-14.163]; odds ratio for safety target achievement rate: 0.060 [95% CI: 0.016-0.232] and 0.167 [95% CI: 0.056-0.498] for parameters A and B, respectively). When the safety target achievement rates for patients treated with LZD were compared between the thrombocytopenic and non-thrombocytopenic groups, the safety target achievement rate was higher in the non-thrombocytopenic group in both the patients treated with LZD for less than 10 days and those for 10 days or more. Therefore, the safety target achievement rate estimated by the PK/PD simulation may represent to be an important index for risk assessment of LZD-induced thrombocytopenia., What Is New and Conclusion: The risk of LZD-induced thrombocytopenia, which increased with the duration of LZD therapy, may be predicted using the safety target achievement rate obtained by the blood concentration simulation., (© 2022 John Wiley & Sons Ltd.)

Background: We aimed to develop population pharmacokinetic (PK) models of ampicillin and sulbactam using pooled data analysis and to optimize dosing regimens of ampicillin-sulbactam (combination ratio of 2:1) in pediatric patients., Methods: Population PK models of ampicillin and sulbactam were separately developed by simultaneously fitting plasma and urine data from pediatric patients in 14 published studies. Based on these models, we estimated the probability of attaining a pharmacodynamic (PD) target [50% of time that free drug concentrations above the minimum inhibitory concentration, 50% fT > minimum inhibitory concentration (MIC)] against MIC90 [MIC that blocked the growth of 90% of the strains] of common bacteria in community-acquired pneumonia., Results: The analysis included 54 pediatric patients (0.083-16.42 years of age, 4.0-77.0 kg of body weight). A total of 284 plasma concentrations and 90 urinary excretions from 0 to 6 hours after administration were used for population PK modeling. The data were adequately described by 2-compartment models for ampicillin and sulbactam. Age was not a statistically significant covariate in the PK of either drug. The PK/PD breakpoint MICs for 45 mg/kg 3 times daily and 75 mg/kg 4 times daily (q.i.d.) were 0.25 and 1 μg/mL, respectively. For empiric therapy of community-acquired pneumonia, because MIC90 values for the main target pathogens is high (MIC90 = 2 μg/mL for Streptococcus pneumoniae and MIC90 = 4 μg/mL for Haemophilus influenzae), 75 mg/kg q.i.d. (Food and Drug Administration-approved maximum dosage in United States) might be better than 45 mg/kg 3 times daily (within approved dosage in Japan) to cover many pathogens., Conclusions: From the results of this PK/PD approach, 75 mg/kg q.i.d. (Food and Drug Administration-approved maximum dosage) should be recommended in the empiric therapy of community-acquired pneumonia., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Wiskott-Aldrich syndrome (WAS) is an X-chromosome recessive immunodeficiency disease characterized by the triad of thrombocytopenia, eczema, and susceptibility to infection owing to WAS protein gene abnormalities. Kidney transplantation is rarely offered to WAS patients with end-stage renal disease because of concerns that thrombocytopenia and immune disorders may affect the clinical outcome. Here, we report the case of a 20-year-old kidney transplant patient who developed end-stage renal disease owing to immunoglobulin (Ig)A nephropathy caused by WAS. Despite recurrent IgA nephropathy and T-cell-mediated rejection 7 months after transplantation, two rounds of steroid pulse therapy attenuated his renal function and urinary abnormality. His serum creatinine level was maintained at approximately 1.5 mg/dL 1 year after transplantation. No other WAS-related complications were observed throughout the clinical course. Although WAS can cause poor prognosis in kidney transplant patients, careful follow-up may allow kidney transplantation to be performed., (© 2021. Japanese Society of Nephrology.)

This study aims to define the penetration of ampicillin and sulbactam into prostate tissue, develop a prostatic pharmacokinetic model of each drug, and assess the appropriateness of ampicillin-sulbactam regimens for the treatment of prostatitis and the prophylaxis of postoperative infection, based on a pharmacokinetic and pharmacodynamic simulation. Subjects were prostatic hyperplasia patients prophylactically receiving a 0.5-hour infusion of 1.5 g (1:0.5 g) or 3 g (2:1 g) ampicillin-sulbactam before transurethral resection of the prostate. Ampicillin and sulbactam concentrations in plasma and prostate tissue were measured. The prostate tissue/plasma ratios of both ampicillin and sulbactam were approximately 0.37 (area under the drug concentration-time curve), and penetration was similar. The prostatic population pharmacokinetic model, which included a covariate analysis, adequately predicted prostate tissue concentrations in our patient population. For therapeutic use, aiming for a bactericidal target of 50% of time above minimum inhibitory concentration (T > MIC) in prostate tissue, 3 g ampicillin-sulbactam 4 times daily achieved ≥90% expected probability against only Enterococcus faecalis in typical patients with a creatinine clearance (CL cr ) of 30 mL/min. For prophylactic use, aiming for a bacteriostatic target of 30% T > MIC, 3 g ampicillin-sulbactam 4 times daily achieved ≥90% expected probability of attaining the bacteriostatic target against E. faecalis and Proteus species when CL cr was 30 mL/min. Based on prostatic simulations, the present study provides helpful recommendations for the treatment of bacterial prostatitis and preoperative prophylaxis in prostatectomy., (© 2020, The American College of Clinical Pharmacology.)

Herein, we describe a case of an elderly patient with muscular dystrophy for whom control of the plasma vancomycin (VCM) concentration proved difficult when he developed a catheter-related bloodstream infection. The pharmacist initially carried out therapeutic drug monitoring using an estimate of the creatinine clearance (CL cr ) level, which was based on the serum creatinine (SCr) and serum cystatin-C (CysC) levels, but was ultimately unable to control the plasma VCM concentration. Therefore, the plasma VCM concentration was predicted ex post facto using population pharmacokinetic parameters as a covariate; that is, directly including the glomerular filtration rate (GFR CysC ) estimated from the CysC level, which is not affected by the muscle mass. As a result, the estimated VCM concentration was closer to the actual concentration than that predicted using CL cr . Furthermore, the results of examining the predictive accuracy according to the assessment of renal function at the time of initial VCM administration suggested that estimation of the trough concentration using GFR CysC might be useful in elderly patients with muscular dystrophy.

Purpose: Compartment syndrome that occurs after lengthy surgery in the lithotomy position is known as well-leg compartment syndrome. It has serious consequences for patients, including amyotrophic renal failure, limb loss, and sometimes even death. This study aimed to identify effective preventive measures against well-leg compartment syndrome using a retrospective cohort study of 1,951 patients (985 and 966 in the prevention and control groups, respectively)., Material and Methods: The following preventive interventions were analyzed: (1) changing from the lithotomy position to the open-leg position, (2) removing lower leg pressure caused by the lithotomy position, (3) limiting leg elevation based on the height of the right atrium, (4) horizontally repositioning the operating table every 3 hours, and (5) decompressing the contact area of the lower leg in the lithotomy position during operation., Results: Eight cases of well-leg compartment syndrome occurred in the control group, whereas no well-leg compartment syndrome occurred in the prevention group., Conclusion: These findings suggest that the five interventions assessed can prevent the development of well-leg compartment syndrome., (© 2020 The Authors.)

Flomoxef is used to treat bacterial prostatitis; however, its prostatic pharmacokinetics have not been fully clarified. Flomoxef (500 or 1000 mg) was administered to patients with benign prostatic hypertrophy (n = 54). After a 0.5-h infusion, venous blood samples were drawn at time points of 0.5-5 h, and prostate tissue samples were collected at time points of 0.5-1.5 h during transurethral resection of the prostate. The drug concentrations in plasma and prostate tissue were analyzed pharmacokinetically and used for a stochastic simulation to predict the probability of attaining pharmacodynamic target in prostate tissue. Showing dose linearity in the prostatic pharmacokinetics, flomoxef rapidly penetrated into prostate tissue, with a prostate/plasma ratio of 0.48-0.50 (maximum drug concentration) and 0.42-0.55 (area under the drug concentration-time curve). Against the tested populations of Escherichia coli, Klebsiella and Proteus species isolates, 0.5-h infusion of 1000 mg three times daily achieved a ≥90% expected probability of attaining the bactericidal target (70% of the time above the minimum inhibitory concentration [MIC]) in prostate tissue. The site-specific pharmacodynamic-based breakpoint (the highest MIC at which the target-attainment probability in prostate tissue was >90%) values were 0.25 mg/L (MIC for 90th percentile of E. coli and Klebsiella species) for 500 mg four times daily and 0.5 mg/L (MIC 90 of Proteus species) for 1000 mg four times daily. These results help to fully characterize the prostatic pharmacokinetics of flomoxef, while also helping to rationalize and optimize the dosing regimens for prostatitis based on site-specific pharmacodynamic target attainment., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Aim: To evaluate whether a combination method involving the transrectal (TR) and transperineal (TP) approach can increase the cancer detection rate relative to the TR approach regarding repeat prostate biopsy., Patients and Methods: One thousand and nineteen patients underwent initial prostate biopsies and 298 repeat prostate biopsies. All initial biopsies were conducted transrectally. Of the repeat biopsies, 179 (60.1%) were performed using the combined transrectal and transperineal (TR+TP) approach; 113 (37.9%) were carried out transrectally. All biopsies were performed under ultrasound guidance using a 16-gauge core biopsy needle; 651 were diagnosed as prostate cancer; 224 patients underwent radical prostatectomies (RPs). We evaluated the cancer detection rates between the biopsy methods in the repeat biopsy cohort and compared the clinical and pathological features of the RP specimens between the initial and repeat biopsy groups., Results: A median of 12 and 20 cores were obtained in the initial and repeat biopsy patients, respectively. Cancer detection rates regarding biopsies 1, 2, 3, 4 and 5 were 49.2% (551/1,119), 34.7% (75/216), 33.3% (20/60), 26.7% (4/15) and 14.3% (1/7), respectively. There were no significant differences between the TR and the TR+TP approach (32.7% vs. 33.5%). RP specimens diagnosed using repeat biopsies showed more anterior dominant tumors relative to those diagnosed using the initial biopsies (59.5% vs. 35.9%; p<0.001)., Conclusion: The TR+TP combination approach could not increase cancer detection rates relative to the TR approach in the repeat biopsy cohort. However, 16-gauge needle biopsy demonstrated acceptable cancer detection rates in the comparatively small number of biopsy cores., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Composite pheochromocytoma is a rare pathological condition characterized by elements of both pheochromocytoma and neurogenic tumors. However, detailed clinical outcomes of this tumor have not been fully shown. From 2007 to 2013, we experienced three cases of adrenal composite pheochromocytoma. In this report, we investigate the clinicopathological features of these three cases of composite pheochromocytoma and compare them with previously reported cases., Case Presentations: Cases 1 and 2 were a 29-year-old Japanese woman and a 59-year-old Japanese man, respectively. They underwent laparoscopic left adrenalectomy, and pathological examination revealed composite pheochromocytoma-ganglioneuroma. Case 3 was a 53-year-old Japanese man who had been receiving hemodialysis for 17 years. He underwent laparoscopic right adrenalectomy, and pathological examination revealed composite pheochromocytoma-ganglioneuroblastoma. Although the Ki67-positive rates varied from 1.0 to 6.2% among the three cases, no clinical recurrences occurred. Despite the relatively high rate of Ki67 positivity, complete tumor resection resulted in favorable clinical outcomes., Conclusion: We experienced three cases of adrenal composite pheochromocytoma. Although the clinical findings and treatment outcomes of composite pheochromocytoma were similar to those of ordinary pheochromocytoma, further studies of the biological behavior and genetic profiles of composite pheochromocytoma are necessary to achieve a better understanding of this tumor.

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., (© 2014 Wiley Periodicals, Inc.)

Introduction: Cavernous hemangiomas are common benign tumors of the skin or liver but can also rarely originate from the retroperitoneal space, especially adjacent to the renal hilum. Qualitative characterization of these retroperitoneal tumors using available imaging modalities is relatively difficult., Case Presentation: A 40-year-old Japanese woman was incidentally noted to have a round homogenous tumor adjacent to the left renal hilum on computed tomography. The preoperative diagnosis was paraganglioma according to hormonal and clinical findings. The tumor was successfully resected via a laparoscopic approach, and histopathological examination of the tumor revealed cavernous hemangioma., Conclusions: Cavernous hemangioma is a rare but relatively benign disease when considering the different types of retroperitoneal tumors. We were able to effectively treat the retroperitoneal cavernous hemangioma via laparoscopy.

We retrospectively reviewed patients who were treated with an indwelling ureteral stent to manage extrinsic ureteral obstruction due to advanced gynecological and gastrointestinal cancers. A total of 34 patients, including 17 with gynecological cancer and 17 with gastrointestinal cancer, underwent a successful initial ureteral stent placement from January 2007 to December 2011. Functional ureteral stent failures, which required percutaneous nephrostomy within 3 months after initial ureteral stenting, occurred in 14 of the 34 patients (41%) during follow-up. The risk factors of functional ureteral stent failure were bilateral ureteral obstruction, elevated serum creatinine level, poor performance status, subsequent therapy for primary cancer after ureteral stent placement, presence of peritonitis carcinomatosa, and gastrointestinal cancer. Patients with gastrointestinal cancer had a higher rate of stent failure than did those with gynecological cancer (p = 0.01). Median survival from the diagnosis of hydronephrosis for patients with gastrointestinal and gynecological cancers was 9 and 23 months, respectively (p = 0. 02). Retrograde ureteral stenting is a useful treatment for malignant ureteral obstruction. However, patients with gastrointestinal cancer had a high stent failure rate and a short survival time from the diagnosis of hydronephrosis. Indications for retrograde ureteral stenting for malignant ureteral obstruction should be carefully considered while taking into account stent failure risk, patient prognosis and quality of life.

Spermatocytic seminoma is a rare germ cell tumor which was first described by Masson in 1946. We experienced a case of bilateral spermatocytic seminoma. A 56-year-old man presented with painless swelling of left scrotal contents. This patient was diagnosed with bilateral testicular tumor after various image examinations (ultrasonography/computerized tomography/magnetic resonance imaging) and bilateral high orchidectomy was performed. Histological diagnosis was bilateral spermatocytic seminoma, pT1. After the operation, this patient was followed closely without adjuvant therapy. There has been no sign of recurrence at five months after the operation.

A total of 100 patients with benign prostatic hyperplasia (BPH) and overactive bladder (OAB) symptoms (BPH/OAB), enrolled between June 2006 to March 2008, were randomly divided into 2 groups of morning medication (M) and evening medication (E) groups, then 50 mg of naftopidil was given once a day after breakfast or supper for 8 weeks. Data were available for efficacy analysis on 80 patients (M group ; 43, E group ; 37). Naftopidil significantly improved the overall international prostatic symptom score ; from 19.2±7.9 to 11.7±5.8 in the M group and from 19.4±6.4 to 12.3±6.8 in the E group (p<0.0001), QOL score from 4.9±0.8 to 3.2±1.4 in the M group and from 5.0±0.8 to 3.6±1.3 in the E group (p<0.0001), and OAB symptom score from 7.8±2.6 to 5.0±2.5 in the M group (p<0.0001) and from 8.6±2.9 to 5.8± 3.3 in the E group (p<0.0001). There was no significant difference in the incidence of adverse effects between the M group (6.1%) and E group (2.2%). These results suggest that naftopidil improves storage symptoms as well as voiding symptoms regardless of timing of administration.

We report clinical outcomes of secondary endocrine therapy with oral estrogen for relapsed prostate cancer. A total of 18 patients were treated with oral estrogen as a secondary endocrine therapy for relapsed prostate cancer between February 2002 and December 2007. One mg/day of ethinylestradiol was administered orally and the dose was increased to 3 mg/day if necessary. A decrease of serum prostate specific antigen (PSA) level was seen in all of the 15 patients who were able to take ethinylestradiol without severe side effects. The PSA level was decreased more than 50% in 11 out of 15 (73.3%) patients. Median re-relapse-free survival was 15 (3-32) months. This effectiveness was as good as intravenous high-dose diethylstilbestrol diphosphate (DES-DP) treatment which was used as a secondary endocrine therapy for relapsed prostate cancer at our institute previously. Oral administration of ethinylestradiol is effective and outpatients can be treated at a low cost, so it should be considered as one of the treatment options for relapsed prostate cancer after initial endocrine therapy.

We report a case in which we extracted retroperitoneal schwannoma by a nerve sparing procedure under microscopic surgery. A 63-year-old male was diagnosed with left ureter stone and left hydronephrosis. A left retroperitoneal tumor was found by the abdominal ultrasound sonography. Abdominal computed tomography and magnetic resonance imaging revealed the mass 20 mm in diameter in the retroperitoneal cavity. We considered that the tumor arose from the left femoral nerve, and removed it under microscopic surgery. There was no malignancy. There was neither recurrence nor neuropathy after operation. Since it is rare to find the origin nerve of schwannoma before operation, we report our experience.

Objectives: Endothelial Per-ARNT-Sim (PAS) domain protein-1 (EPAS-1)/hypoxia-inducible factor (HIF)-2alpha is a recently identified, endothelial-specific, hypoxia-induced transcription factor and is reputed to have an important role in tumor angiogenesis and tumor progression. Only a few studies have reported on the clinical correlation with grade, stage, necrosis, and microvessel density in transitional cell carcinoma of the bladder. In vitro studies have reported no concordance of EPAS-1/HIF-2alpha mRNA and protein expression. We sought to elucidate these two issues., Methods: Surgical specimens from 110 patients with transitional cell carcinoma comprised the study, including 51 from radical cystectomy and 59 from transurethral resection of bladder tumor. Immunohistochemistry and in situ hybridization were performed with antibodies against EPAS-1/HIF-2alpha, CD31, and a human EPAS-1/HIF-2alpha cDNA subclone probe., Results: EPAS-1/HIF-2alpha protein expression was found almost exclusively in high-grade and high-stage tumors (P <0.0001). EPAS-1/HIF-2alpha mRNA expression was detectable only in high-grade (grade 3) and high-stage (pT3a or greater) cases with positive EPAS-1/HIF-2alpha protein expression (P = 0.0017). The presence of necrosis correlated with EPAS-1/HIF-2alpha expression, tumor grade, and tumor stage (P <0.0001). Microvessel density was much lower in invasive, larger tumor nodules in EPAS-1/HIF-2alpha-positive cases than in the negative cases (P <0.0001)., Conclusions: EPAS-1/HIF-2alpha protein and mRNA levels correlate with higher grade and advanced bladder transitional cell carcinoma. In lower stage cases, no concordance was found between transcription and translation of EPAS-1/HIF-2alpha gene expression. Because EPAS-1/HIF-2alpha mRNA is only detectable in highly invasive cancer cases, it may serve as a therapeutic target (eg, by an antisense mRNA approach) for bladder cancer.

Endothelial Per-ARNT-Sim (PAS) domain protein-1 (EPAS-1)/hypoxia-inducible factor-2alpha (HIF-2alpha) is a member of the basic helix-loop-helix/PAS domain protein family and is considered to be an endothelial-specific, hypoxia-inducible transcription factor. Because hypoxia is a fundamental element of tumor biology determining clinical outcome, we performed an immunohistochemical study of EPAS-1 expression in a cohort of bladder cancer cases and assessed the possible correlation of EPAS-1 expression with tumor hypoxia and growth. In the 67 cases (37 radical cystectomy and 30 transurethral resection) studied, overexpression of EPAS-1/HIF-2alpha protein was not found in cancer cells or in normal tissues but was mostly found in stroma around cancer cells, and strong positive staining was noted in perinecrotic regions. The perinecrotic/tumorous expression of EPAS-1/HIF-2alpha was correlated statistically with higher histological grade (P < 0.001), advanced pathological T stage (P < 0.001), and presence of necrosis (P < 0.001). A parallel immunohistochemical analysis of a marker gene of vascular endothelial growth factor demonstrated its positive correlation with tumor grade, stage, and EPAS-1/HIF-2alpha overexpression, supporting the correlation of EPAS-1/HIF-2alpha up-regulation with tumor angiogenesis. To further clarify the relationship between hypoxia and vascularity in the perinecrotic/tumorous area with EPAS-1/HIF-2alpha expression, tissue microvessel density (MVD) was assessed. No significant correlation (P = 0.442) was found between EPAS-1/HIF-2alpha expression and MVD if the 67 tumors of different stages were all included. However, EPAS-1/HIF-2alpha-positive cases had lower MVD than EPAS-1/HIF-2alpha-negative cases (P = 0.001) if only invasive cancer cases were analyzed. In addition, in all EPAS-1/HIF-2alpha-positive staining cases, EPAS-1/HIF-2alpha-positive foci had lower MVD than EPAS-1/HIF-2alpha-negative foci (P < 0.001). Finally, using serial sections, the location of EPAS-1/HIF 2alpha expression was identified mainly in tumor-associated macrophage (TAM) as well as in some fibroblast cells. Focal TAM infiltration was identified at a higher level in EPAS-1-positive cases than EPAS-1-negative cases (P < 0.001). This is the first clinical report suggesting that hypoxia-induced, perinecrotic EPAS-1/HIF-2alpha expression is correlated with tumor progression and angiogenesis at higher grade and stage through focal TAM infiltration in invasive bladder cancer.

To date, the rodent ventral prostate (VP) has been the focus of many studies on androgen action, less attention has been directed to the lateral prostate (LP) and the dorsal prostate (DP). The rodent VP has no clear homologous counterpart in the human prostate. The rodent LP and DP is the only prostate lobe comparable to the peripheral zone of the human prostate, where hormone-induced prostate cancer mainly occurs. To explore its utility for prostate targeting, we have studied the gene expression of PSP94 with rat probasin (rPB), a gene commonly used for prostate targeting in prostate cancer research and a gene typically responsive to androgen regulation. Firstly, we demonstrated PSP94 gene transcription being more specific to the LP and DP lobes than rPB, where rPB RNA was detected in the LP and DP and other lobes at different levels. Secondly, we found that PSP94 gene transcription decreased relatively slowly in response to androgen deprivation but recovered rapidly in response to testosterone replacement after complete ablation of PSP94 transcription. In the VP, gene transcripts of rPB were specifically responsive to androgen deprivation; however, they responded relatively slowly in the LP and DP. RNase protection experiments indicated that the slow response was not due to abnormal persistence of PSP94 messenger RNA specifically in the DP and LP lobes in comparison with rPB. Thirdly, Western blot analysis revealed that both PSP94 and rPB expression is specific to the LP and DP at the protein level, exhibiting slow responses to testosterone replacement after castration. We conclude that PSP94 gene expression at the transcriptional level is more specific to the LP and DP than rPB and thus less sensitive to androgen ablation. This may have clinical implications for strategies to target the prostate in cancer therapy.

Introduction: A variety of cancers suppress host immune defenses by secretion of soluble factors. Conditioned media (CM) from numerous cancer cell lines possess the ability to suppress proliferation of activated T cells. The effects of CM from the prostate cancer cell line DU-145 on T cell activation was investigated., Materials and Methods: Human PBMC, purified T cells and Jurkat T cells were treated with DU-145 CM. Proliferation, cell cycle, apoptosis, Fas expression/and cytokine secretion were assessed by thymidine incorporation, flow cytometry and ELISA., Results: DU-145 CM increased proliferation of concanavalin-A (ConA) activated peripheral blood mononuclear cells (PBMC) increasing the percentage of cells in the S/G2 phase of cell cycle. Treatment of the Jurkat T cell line with DU-145 CM induced a potent proliferative response. ConA-induced proliferation of purified T cells from human PBMC and murine splenocytes was augmented in a dose-dependent manner by addition of DU- 145 CM. DU- 145 CM treatment of ConA-activated T cells induced an increase in interleukin-2 (IL-2) production. The soluble factor(s) responsible for promoting T cell proliferation was dependent on protein synthesis by the DU- 145 cells and possessed a molecular weight greater than 10 kDa., Conclusion: DU- 145 cells secrete a soluble factor(s) > 10 kDa, whose production is dependent on protein synthesis and which acts as a promoter of T cell activation.