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Background Because of the advanced age of patients with cardiovascular disease (CVD), prevention of sleep disorder and dementia is a priority for cardiac rehabilitation (CR) during their long-term care. This study aimed to investigate the association of physical activity with sleep quality and cognitive function in elderly patients with CVD in the CR maintenance phase. Methods We conducted a multicenter study through the Clinical Exercise Physiology Association Japan network, which included 102 elderly patients (mean age, 74 ± 7.4 years) with CVD undergoing phase III CR at 6 institutions. Physical activity was assessed using a triaxial accelerometer for 7 consecutive days and was classified as locomotive and household activities. Physical fitness was assessed via 6-min walking distance (6MD), hand grip power, 10-m walking speed, one leg standing time with eyes open, and 10 times sit-to-stand tests. Sleep quality and cognitive function were evaluated using the Pittsburgh sleep quality index (PSQI) and mini-mental state examination (MMSE) scores, respectively. Results The patients performed 5506.8 ± 3743.6 steps/day and scored 5.8 ± 3.5 points in the PSQI and 28.4 ± 1.7 points in the MMSE. Sleep latency and MMSE scores correlated with locomotive activity, but not with household activity. Locomotive activity and 6MD were independent predictors of sleep latency and MMSE score, respectively. When patients with heart failure were excluded, the relationship between sleep latency and locomotive activity was preserved, but the relationship between exercise tolerance and cognitive function disappeared. Conclusion Locomotive activity and exercise tolerance are associated with sleep latency and cognitive function in elderly patients with CVD continuing phase III CR. However, in this study, the relationship between exercise tolerance and cognitive function was offset by the presence of heart failure.

INTRODUCTION AND OBJECTIVE:No reliable biomarker is available for predicting worse clinical outcome in chemo-resistant urothelial carcinoma (UC) patients treated with pembrolizumab. We focused on a...

A 25-year-old man, with a retroperitoneal bulky mass invading the posterior pancreas head, was referred to investigate and treat his rapidly advancing disease. An endoscopic ultrasonography guided-fine needle aspiration biopsy (EUS-FNAB), performed the next day, and followed by immunostaining for human chorionic gonadotropin (hCG), led to a histological diagnosis of choriocarcinoma. An elevated level of serum hCG also supported the diagnosis. Systemic chemotherapy by etoposide and cisplatin was initiated within a week, with precautions taken to avoid tumour lysis syndrome and choriocarcinoma syndrome. EUS-FNAB enabled a prompt diagnosis and suitable treatment for choriocarcinoma and was considered as an effective diagnostic tool for rare tumours with rapid progression.

Reports frequently describe the worsening of oncologic outcome in patients who developed high-grade complications after curative surgery for esophageal, gastric, and breast cancers. We investigated the extent of this correlation in patients with bladder cancer after radical cystectomy (RC). During 2002–2017, we performed 326 RC and urinary diversion procedures and collected data regarding complications in these patients within 90 days postoperatively. We evaluated the severity of complications based on the modified Clavien–Dindo classification (grades 0–5). Grade ≥ 3 complications were considered high grade. After adjusting for confounding factors using a Cox regression model, we calculated the hazard ratios (HRs) for high-grade complications associated with recurrence-free survival (RFS) and cancer-specific survival (CSS). During a median follow-up period of 61 months, 38 patients (12%) developed high-grade complications (grade ≥ 3). The main causes (76%) of high-grade complications were gastrointestinal and infection problems. The RFS and CSS differed significantly between patients with high-grade complications and those without complications. After adjusting for confounding factors in the multivariate analysis, high-grade complications remained a significant risk factor for both RFS [HR 2.11; 95% confidence interval (CI) 1.07–4.15, p = 0.030] and CSS (HR 2.74; 95% CI 1.05–7.14, p = 0.039). High-grade complications after RC led to worse RFS and CSS outcomes, similar to those observed in patients with other cancers. A large-scale study is needed to further verify these findings, and discussions of knowledge and experiences are required to reduce the incidence of postoperative high-grade complications.

INTRODUCTION AND OBJECTIVES:No reliable biomarker is available for predicting worse clinical outcome in chemo-resistant urothelial carcinoma (UC) patients treated with pembrolizumab. We focused on ...

A 61-year-old man who had undergone total nephrouretectomy eight months earlier for right ureteral carcinoma was referred for the investigation of elevated serum hepatobiliary enzymes. Computed tomography revealed a small mass invading the lower bile duct. Duodenoscopy revealed a central ulcerative tumor near the major papilla, and a biopsy histologically confirmed metastatic ureteral carcinoma. Endoscopic biliary stenting ameliorated the cholangitis, and gemcitabine-based chemotherapy was initiated. The patient was stable for a year until a duodenal stenosis developed and required duodenal stenting. Endoscopic procedures play important roles in the management of rare metastases to the duodenum.

We investigated the relationship between pretreatment neutrophil-to-lymphocyte ratio (pre-NLR) levels just before the initiation of treatment with pembrolizumab and clinical outcomes in platinum-resistant metastatic urothelial carcinoma (UC) patients treated with pembrolizumab.Our study population comprised 78 patients diagnosed with metastatic UC and treated with pembrolizumab after platinum-based chemotherapy at our institutions between December 2017 and April 2019. We examined the relationships between pre-NLR levels just before pembrolizumab treatment and clinical outcomes. A pre-NLR level of ≥3.35 was defined as elevated according to a calculation by a receiver-operating curve analysis.The high pre-NLR group consisted of 33 patients (42.3%). Overall, 29.5% of patients had a clinical response and the sum of the target lesion longest diameter was decreased in 18.8% of the high pre-NLR group, which was significantly lower than that in the low pre-NLR group (58.1%, P = 0.005). Six-month progression-free survival and cancer-specific survival rates for the high pre-NLR group were 9.1 and 58.0%, which were significantly lower than those for their counterpart (45.9 and 89.1%, P0.001 and P = 0.002, respectively). The pre-NLR level was an independent indicator of disease progression and cancer-specific death (P0.001 and P = 0.003). Furthermore, patients with a postpembrolizumab NLR level that had decreased ≥25% from the pre-NLR level had significantly lower disease progression and cancer-specific death rates than their counterparts (P = 0.01 and P = 0.022, respectively).Elevated pre-NLR may be a novel biomarker for identifying poor responders to pembrolizumab among platinum-resistant metastatic UC patients.

Key Clinical Message Foreign body aspiration is a potentially life‐threatening event. The nature of the inhaled objects is highly variable, ranging from organic to inorganic material. Although most pills are radiolucent, lanthanum carbonate is radiopaque and may be identified on chest X‐rays.

Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm arising from the mesothelial cells lining the parietal pleura and it exhibits poor prognosis. Although there has been significant progress in MPM treatment, development of more efficient therapeutic approaches is needed. BMAL1 is a core component of the circadian clock machinery and its constitutive overexpression in MPM has been reported. Here, we demonstrate that BMAL1 may serve as a molecular target for MPM. The majority of MPM cell lines and a subset of MPM clinical specimens expressed higher levels of BMAL1 compared to a nontumorigenic mesothelial cell line (MeT-5A) and normal parietal pleural specimens, respectively. A serum shock induced a rhythmical BMAL1 expression change in MeT-5A but not in ACC-MESO-1, suggesting that the circadian rhythm pathway is deregulated in MPM cells. BMAL1 knockdown suppressed proliferation and anchorage-dependent and independent clonal growth in two MPM cell lines (ACC-MESO-1 and H290) but not in MeT-5A. Notably, BMAL1 depletion resulted in cell cycle disruption with a substantial increase in apoptotic and polyploidy cell population in association with downregulation of Wee1, cyclin B and p21(WAF1/CIP1) and upregulation of cyclin E expression. BMAL1 knockdown induced mitotic catastrophe as denoted by disruption of cell cycle regulators and induction of drastic morphological changes including micronucleation and multiple nuclei in ACC-MESO-1 cells that expressed the highest level of BMAL1. Taken together, these findings indicate that BMAL1 has a critical role in MPM and could serve as an attractive therapeutic target for MPM.

OBJECTIVES The purpose of this study was to retrospectively analyze the characteristics of patients with retroperitoneal sarcoma and to examine pathological findings, first site of recurrence and recurrence free-survival after surgery. METHODS From June 2003 to May 2010, we performed 10 surgeries for retroperitoneal sarcomas. We chose 9 tumors after excluding 1 tumor that had already disseminated in the abdominal cavity. We examined patient characteristics, pathological findings and the first site of recurrence (local or distant metastasis). We also analyzed recurrence-free survival after surgery with the Kaplan-Meier method. RESULTS The patients' median age was 60 years (31-71 years), and the median tumor diameter was 10.0 cm (2.7-45 cm). Pathological diagnosis revealed 7 cases of dedifferentiated liposarcoma and 2 cases of leiomyosarcoma. En-block resection with adjacent organs was achieved in 8 of 9 patients. During follow-up, 5 of 9 patients experienced tumor local recurrence. There were no cases in which distant metastases appeared before local recurrence. The median duration between surgery and local recurrence was 13 months (3-27 months). The median duration from surgery to death was 30 months (5-78 months). CONCLUSIONS Although we resected adjacent organs together when we could not achieve a sufficient margin, the rate of local recurrence after surgery for retroperitoneal sarcoma was high. Given this result using treatment with surgery alone, it is necessary to prospectively establish multimodal treatments with chemotherapy and radiotherapy to reduce local tumor recurrence.

Previously, we investigated endocrine disrupting effects of 17 β-estradiol (E(2)) on Japanese quail (Coturnix japonica) in the avian reproduction test according to the testing guidelines, in which new endpoints such as blood vitellogenin (VTG) concentration in parent quails and pathology of F(1) chicks were added, and consequently these additional endpoints suggested to be sensitive markers for detecting any impacts of endocrine disrupting effects (Shibuya et al., 2005b). In the present study, to investigate low dose effects of estrogenic endocrine disrupting chemicals in birds, the avian reproduction study of E(2) at low dose levels was conducted using Japanese quail with additional endpoints such as observations of F(1) chicks until 10 weeks of age, histopathology of F(1) chicks at 14 days and 10 weeks of age and blood VTG concentration in parent quails. Sixteen pairs of 10-week-old quails were fed a low phytoestrogen diet containing E(2) at 0 (control), 0.3, 3, and 30 ppm for 6 weeks, and parent quails, eggs and offspring were examined. F(1) chicks were maintained up to 14 days or 10 weeks of age. Serum E(2) and VTG concentrations in males of the E(2) 3- and 30-ppm groups and in females of the E(2) 30-ppm groups were significantly elevated. In the E(2) 30-ppm group, two parent females died, and toxic changes such as suppression of body weight gain, decrease in food consumption and atrophic and degenerative changes of the reproductive organs were observed in parent quails. In the same group, the number of eggs laid and the fertility rate of eggs were significantly decreased. In addition, the viability of F(1) chicks in the E(2) 30-ppm group were significantly decreased at 10 weeks of age. On the other hand, no abnormalities described above were observed in any parent quails, eggs and F(1) chicks in the E(2) 3- and 0.3-ppm groups, although the fertility rates of eggs in both groups were decreased and the body weight gain of F(1) females in the E(2) 3-ppm group was significantly suppressed. In the histopathological examination of F(1) chicks maintained up to 10 weeks of age, persistent right oviduct and atrophy of the oviduct gland were observed in females of E(2)-treatment groups with significantly high incidences. Moreover, cystic dilatation and tubular degeneration of the seminiferous tubules and atrophy of the cloacal gland were also observed in males of the E(2)-treatment groups. Thus, the dietary treatment of low dose E(2) (even 0.3 ppm) to parent quails resulted in decreased viability and induction of abnormalities in the oviduct, testis and cloacal gland in F(1) chicks maintained up to 10 weeks of age. These results suggest that additional endpoints such as observations of F(1) chicks until 10 weeks of age, histopathology of F(1) chicks at 14 days and 10 weeks of age and blood VTG concentration in parent quails would be useful and sensitive endpoints for evaluating estrogenic endocrine disrupting effects in the avian reproduction study.

A 55-year-old man who presented himself with gross hematuria and right back pain was found to have a right renal mass with evidence of metastasis to the lymph nodes, bone and lung (cT1bN1M1). He underwent a transperitoneal right nephrectomy. Tumor expressed markers of CD10, P504S and CK19 immunohistochemically, so histopathological examination revealed tubulocystic carcinoma of the right kidney (pT3a). After the patient received sunitinib therapy, computed tomography revealed reduction in the size of the metastatic lung nodule and lymph nodes, indicating a partial response. He is alive without disease progression at 12 months after nephrectomy. Tubulocystic carcinoma has been referred to by Amin et al as low-grade collecting duct carcinoma and is not yet included in the World Health Organization (WHO) 2004 classification of renal tumors. The cells lining the tumor range from cuboidal to columnar and have large nuclei with low-grade changes and abundant eosinophilic or amphophilic cytoplasm. Hobnail cells are commonly seen. Immunohistochemically, tubulocystic carcinomas are strongly positive for markers of the proximal nephron (CD10, P504S) and the distal nephron (parvalbumin, CK19). Despite a low nuclear grade, tubulocystic carcinomas occasionally show progressive behavior clinically. Although there is no established salvage therapy, sunitinib was found to be effective for this patient.

Leucine-rich repeat (LRR) -containing G protein coupled receptor (LGR) family members are characterized by the presence of a seven-transmembrane domain and LRR motifs. We describe a new function for Lgr4 in the development of the gall bladder and cystic duct and in the epithelium-mesenchyme interaction. Lgr4 expression was observed in the gall bladder epithelium when the gall bladder primordium elongated ventrally. Although Lgr4 hypomorphic mutant (Lgr4(Gt/Gt)) embryos developed a normal gall bladder bud at embryonic day (E) 10.25, no further elongation was observed at later stages. At E12.5, the mesenchyme surrounding the gall bladder had completely disappeared in Lgr4(Gt/Gt) embryos, while the gall bladder remained unelongated. Neighboring tissues such as liver and pancreas were unaffected, as revealed by expression of marker genes. This is the first report of a mutant mouse that lacks a gall bladder and cystic duct without affecting the other tissues that derive from the same hepatic diverticulum.

OBJECTIVES In this study, we sought to define the incidence of benign renal tumors in our institute and to clarify the clinical factors associated with benign renal tumors, in order to assist in forming preoperative differential diagnoses. METHODS From October 2002 to July 2007, we performed 157 nephrectomies in patients preoperatively diagnosed with renal cell carcinoma. We chose 81 tumors, all of which were less than 5 cm, for further study. We reviewed double-phase helical CT imaging retrospectively, specifically focusing on attenuation patterns and homogeneity. We also compared clinical factors, including age, sex and tumor size, between the benign and malignant renal tumors. RESULTS The patient's median age was 67 years (mean age, 63 years), and the median tumor diameter was 3.0 cm (mean, 3.2 cm). Benign renal tumors were found in 10 (12%) of the 81 tumors; these included seven cases of oncocytoma and three cases of angiomyolipoma with minimal fat. Several factors were significant clinical determinants of differentiation between benign and malignant renal tumors: homogeneity in CT, female gender, and small tumor size all predominated in cases of benign tumors. Attenuation pattern in CT, however, was not a significant factor (p = 0.344). CONCLUSIONS When a patient, especially a female, presents with a small and homogeneous renal tumor, careful consideration should be given to the possibility of a benign process, which needs further consideration before performing excessive surgery.

We encountered one pituitary carcinoma derived from the pars intermedia in an untreated female B6C3F1 mouse in a carcinogenicity study. A white nodule (6 × 5 × 3 mm) was observed in the base of the brain at necropsy. Tumor cells were histologically arranged in a solid sheet or nest-like structures, and had round or oval nuclei and pale eosinophilic granular cytoplasm. Sporadic mitotic figures were seen in the tumor while necrosis was a prominent feature. In addition, distinct infiltration into the brain parenchyma was observed. Immunohistochemically, tumor cells were positive for α-melanocyte stimulating hormone (α-MSH), γ-melanocyte stimulating hormone (γ-MSH), β-endorphin and adenocorticotropic hormone (ACTH), but were negative for prolactin. However, there were no histological abnormalities such as adrenocortical hyperplasia related to the pars intermedia tumor. These results suggest that the tumor cells might not have actively secreted proopiomelanocortin (POMC)-derived peptides. The present report provides additional histopathological evidence of pituitary carcinoma of the pars intermedia in aging mice.

Spontaneous occurrence of renal tubule carcinoma in mice is known to be rare. The following features of this tumor are recognized as areas of hemorrhage and massive necrosis and many show atypical cells and numerous mitotic figures. The present renal tubule carcinoma developed in an untreated B6C3F1 male mouse at the age of 109 weeks. The tumor mass occupied nearly the entire renal cortex and invasion of normal renal tissue was observed. The tumor had solid cell nests, a gland-like structure, definite neovascularization and capsular invasion. The tumor cells had clear eosinophilic cytoplasm, a brush border structure and high proliferative activity. Although tumors derived from the proximal tubule reportedly show basophilic cytoplasm, the tumor cells in this mouse had clear eosinophilic cytoplasm. Consequently, the animal was diagnosed as having an unusual renal tubule carcinoma (classification: solid type). (J Toxicol Pathol 2007; 20: 253-256)

Aim: The aim of this study was to compare the efficacy and safety of α1-adrenoceptor (α1-AR) antagonist monotherapy with combination therapy using α1-AR antagonist and anticholinergic agent for benign prostatic hyperplasia (BPH) with storage symptoms as the chief complaint. Methods: In this prospective comparative study, either 25–75 mg/day of naftopidil monotherapy (monotherapy group) or combination therapy using 25–75 mg/day of naftopidil and an anticholinergic agent (10–20 mg/day of propiverine hydrochloride or 2–6 mg/day of oxybutynin hydrochloride; cotherapy group) were administered for 12 weeks to 101 BPH patients with storage symptoms. Results: International prostate symptom score (IPSS) and quality of life (QOL) index improved significantly in both groups, with no marked differences between groups. Maximum flow rate (Qmax) and residual urine volume (RUV) tended to improve in both groups, again with no marked differences between groups. However, median post-therapeutic RUV was significantly worse for the cotherapy group (45.0 mL) than for the monotherapy group (13.5 mL; P = 0.0210). Ratio of patients with increased RUV was also significantly worse for cotherapy (22.9%) than for monotherapy (5.0%; P = 0.038). Conclusions: Although the anticholinergic dosage was low, the present results suggest that naftopidil monotherapy was as useful as combination therapy of naftopidil and an anticholinergic agent. Therefore, naftopidil is a useful agent as the first choice in BPH patients with storage symptoms.

On September 25th, 2003, a 39-year-old man complained of asymptomatic gross hematuria. He was admitted to a nearby hospital and evaluated. Cystoscopy revealed a non-papillary broad base tumor in the anterior wall of the bladder. On October 2nd, a TUR-Bt was performed. The pathological diagnosis was difficult to determine because mitosis and nuclear pleomorphism were apparent. He next came to our hospital for further evaluation. We diagnosed his condition as an inflammatory pseudotumor of the bladder because fibroblasts and inflammatory cells had increased; however, we did not see abnormal nuclear mitosis or severe pleomorphism. Although we did not perform a complete TUR-Bt, the mass regressed spontaneously and did not reoccur. The presence of mitosis and mild nuclear pleomorphisms make certain cases difficult to diagnose as inflammatory pseudotumors. Inflammatory pseudotumors are generally considered benign, and some cases regress spontaneously. It is important that we are able to identify and characterize these pseudotumors in order to avoid more invasive surgeries whenever possible.

To analyze the roles of insulin receptor substrate (IRS) proteins in insulin-stimulated cell cycle progression, we examined the functions of rat IRS-1 and IRS-3 in Chinese hamster ovary cells overexpressing the human insulin receptor. In this type of cell overexpressing IRS-1 or IRS-3, we showed that: 1) overexpression of IRS-3, but not IRS-1, suppressed the G1/S transition induced by insulin; 2) IRS-3 was more preferentially localized to the nucleus than IRS-1; 3) phosphorylation of glycogen synthase kinase 3 and MAPK/ERK was unaffected by IRS-3 overexpression, whereas that of protein kinase B was enhanced by either IRS; 4) overexpressed IRS-3 suppressed cyclin D1 expression in response to insulin; 5) among the signaling molecules regulating cyclin D1 expression, activation of the small G protein Ral was unchanged, whereas insulin-induced gene expression of c-myc, a critical component for growth control and cell cycle progression, was suppressed by overexpressed IRS-3; and 6) insulin-induced expression of p21, a cyclin-dependent kinase inhibitor, was decreased by overexpressed IRS-3. These findings imply that: 1) IRS-3 may play a unique role in mitogenesis by inhibiting insulin-stimulated cell cycle progression via a decrease in cyclin D1 and p21 expressions as well as suppression of c-myc mRNA induction in a manner independent of the activation of MAPK, protein kinase B, glycogen synthase kinase 3 and Ral; and 2) the interaction of IRS-3 with nuclear proteins may be involved in this process.

The case is reported of urothelial carcinoma (clear cell variant) that was diagnosed with useful immunohistochemistry stain. A 70-year-old man, who had undergone left radical nephrectomy for renal cell carcinoma in August 2003 and partial lobectomy for pulmonary metastasis in May 2005, complained of hematuria in June 2005. On evaluation, a papillary pedunculated tumor was detected in the left wall of the urinary bladder. A transurethral resection of the bladder tumor (TUR-Bt) was performed in July 2005. The pathological diagnosis was difficult due to diffuse clear cell appearance. Immunohistochemistry stain showed urothelial carcinoma, not metastasis of the renal cell carcinoma. Finally it was diagnosed as urothelial carcinoma clear cell variant. Urothelial carcinoma has many variants that show a variety of appearances and characteristics. These should be well known before medical therapy is initiated.

TIMELESS (TIM) is a mammalian homolog of a Drosophila circadian rhythm gene, but its circadian properties in mammals have yet to be determined. TIM appears to be essential for replication protection and genomic stability. Recently, the involvement of TIM in human malignancies has been reported; therefore, we investigated the role of TIM in lung cancer. Microarray expression analysis of lung cancer cell lines showed that TIM expression was elevated 3.7-fold (P < 0.001) in non-small cell lung cancer cell lines (n = 116) compared to normal lung controls (n = 59). In addition, small cell lung cancer cell lines (n = 29) expressed TIM at levels 2.2-fold (P < 0.001) higher than non-small cell lung cancer. Western blot analysis of 22 lung cancer cell lines revealed that all of them expressed TIM protein and that 20 cell lines (91%) expressed TIM protein at higher levels than a normal control line. Remarkably, immunohistochemistry of 30 surgically resected lung cancer specimens showed that all lung cancer specimens but no matched normal lung tissues were positive for TIM expression. Moreover, immunohistochemistry of surgically resected specimens from 88 consecutive patients showed that high TIM protein levels correlated with poor overall survival (P = 0.013). Mutation analysis for TIM in 23 lung cancer cell lines revealed no mutation. TIM knockdown suppressed proliferation and clonogenic growth, and induced apoptosis in H157 and H460 cells. Taken together, our findings suggest that TIM could be useful as a diagnostic and prognostic marker for lung cancer and targeting it would be of high therapeutic value for this disease.

Sex reversal effects of nonylphenol and bisphenol A on the gonads in F1(AWE × WE) Japanese quail (Coturnix japonica) embryos were investigated using an in vivo screening model developed previously. The F1 (AWE × WE) Japanese quail are a useful avian model because sex differentiation is confirmed by the plumage color before hatching, ruled by a criss-cross inheritance. The nonylphenol at 200, 2,000, 20,000, and 200,000 ng/egg and bisphenol A at 20, 200, 2,000, and 20,000 ng/egg were injected into the egg white just before incubation. At 16 d of incubation, embryos were subjected to a complete necropsy, and their gonads were both grossly observed and examined histopathologically and morphometrically. Grossly, genetic sex was confirmed because plumage color coincided completely with the external sex phenotype of the gonads in all embryos. Histopathologically, feminization of the male gonad, called ovotestis, developed in the left testis in all nonylphenol- and bisphenol A-treated groups. The incidence of the lesion in all treated groups was significantly higher than that in the control group, whereas there were no dose-dependent changes in the incidence and area of the ovotestis in both nonylphenol- and bisphenol A-treated groups. The present study revealed that nonylphenol and bisphenol A have a dose-independent potential of ovotestis induction in the Japanese quail embryo. Environ. Toxicol. Chem. 2012; 31: 1091–1097. © 2012 SETAC

Purpose To determine the incidence and prognosis of prostatic ductal adenocarcinoma. Materials and methods From November 2002 to December 2005, we performed 122 radical prostatectomies and pelvic lymph node dissections. We further analyzed 64 cases after excluding 56 cases that had received neoadjuvant hormone therapy and two cases for which we were only able to perform limited follow-up examinations. We reviewed all of the surgical specimens and reclassified them according to the 2004 WHO classification system. We differentiated prostatic cases of ductal adenocarcinoma that were larger than 5 mm in diameter from cases of acinar adenocarcinomas. We then examined these two groups for the pathological stages of the neoplasms and the incidence of postoperative prostate-specific antigen (PSA) failure. Postoperative PSA failure was defined as a PSA value more than 0.2 ng/ml. Results We found eight cases (12%) of prostatic ductal adenocarcinoma among the 64 cases treated with radical prostatectomies. The mean age (+/- SD) of these patients was 65.3 (+/- 4.3) years old, and the mean PSA level (+/- SD) was 12.4 (+/- 5.4) ng/ml. Seven of the cases (11%) were mixed-type ductal adenocarcinomas, which contained acinar and ductal components. In addition, one case was identified as pure ductal adenocarcinoma. Seminal vesicle invasion was detected in four cases and lymph nodes metastases were identified in one case. During the follow-up period, four of the eight cases of ductal adenocarcinoma (50%) and twelve of the 56 cases of acinar adenocarcinoma (21%) showed postoperative PSA failure. The median follow-up period was 24 months (range: 12 to 48 months). Conclusions We identified eight cases of ducal adenocarcinoma (12% of the examined cases), which suggests this disease is not as rare as previously reported. Compared to the cases of acinar adenocarcinoma, the cases of ductal adenocarcinoma were at a more advanced pathological stage and resulted in a higher rate of postoperative PSA failure. Therefore, we believe that patients that show even a limited degree of ductal adenocarcinoma should receive aggressive therapy.

In September 2003, a 58-year-old woman complained of bladder irritation and urinary frequency. She was admitted to a nearby hospital, and an evaluation was performed. Urine cytology revealed a class V, and a tumor was detected in the lower left ureter with mild hydroneprhosis of the left kidney. We performed a left ureteronephrectomy with partial cystectomy in April 2004. The pathological diagnosis was clear cell carcinoma with small foci of conventional urothelial carcinoma of the left ureter (pT3pN0, G3 > G2, INFgamma). And now she lives well without recurrence in August 2005. This is the first case report of clear cell carcinoma of the ureter in Japan.

Dehydroepiandrosterone (DHEA), the most abundant human adrenal steroid, improves insulin sensitivity and obesity in human and model animals. In a previous study, we reported that orally administered DHEA suppresses the elevated activities of hepatic gluconeogenic enzymes like glucose-6-phosphatase (G6Pase) in C57BL/KsJ-db/db mice (Aoki K, Saito T, Satoh S, Mukasa K, Kaneshiro M, Kawasaki S, Okamura A, Sekihara H (1999) Diabetes 48: 1579-1585). However, the molecular mechanisms by which DHEA ameliorates insulin resistance are not clearly understood. In the present study, we cultured the human hepatoma cell line HepG2 with DHEA and measured the enzyme activity and protein expression of G6Pase to investigate the direct effect of DHEA on glucose metabolism in hepatocytes. DHEA significantly suppressed both the activity and protein expression of G6Pase. Moreover, DHEA decreased the gene expression of G6Pase and phosphoenolpyruvate carboxykinase, both of which were maximal at 1 μM DHEA, whereas the mRNA level of glucose-6-phosphate translocase was unchanged. Furthermore, DHEA enhanced 2-deoxyglucose uptake, although its effect was much smaller than that of insulin. These results suggest that DHEA may act at multiple steps in the regulation of glucose metabolism in the liver.

In January 2005, a 66-year-old man underwent radical cystectomy and ileal neobladder reconstruction for invasive bladder cancer. A total of 3 years after the cystectomy, left-side ureteral cancer was diagnosed, and a nephroureterectomy was carried out in May 2008. In October 2011, he complained of asymptomatic macroscopic hematuria. We detected multiple papillary pedunculated and broad-based tumors in the left side and the dome of the neobladder. The patient underwent transurethral resection of the bladder tumor, and a pathological diagnosis of high-grade pTa urothelial carcinoma was made. A total of 4 months later, tumors recurred in the right side and anterior wall of the neobladder. We carried out transurethral resection of the bladder tumor again; the pathological diagnosis was high-grade pTa urothelial carcinoma with carcinoma in situ. Bacillus Calmette-Guerin instillation was carried out seven times into the neobladder, without any severe side-effects. Tumor recurrence was not observed up to 8 months after bacillus Calmette-Guerin treatment.

Primary aldosteronism is associated with glucose intolerance and diabetes, which is due in part to impaired insulin release caused by reduction of potassium, although other possibilities remain to be elucidated. To evaluate the in vivo effects of aldosterone on glucose metabolism, a single dose of aldosterone was administered to mice, which resulted in elevation of the blood glucose level. In primary cultured mouse hepatocytes, the gene expression of gluconeogenic enzymes such as glucose-6-phosphatase (G6Pase), fructose-1,6-bisphosphatase and phosphoenolpyruvate carboxykinase increased in response to aldosterone in a dose-dependent manner even at a concentration similar to a physiological condition (10(-9) M). The inhibitory effect of insulin on G6Pase gene expression was partially suppressed by aldosterone. Furthermore, aldosterone enhanced G6Pase promoter activity in human hepatoma cell line HepG2, which was prevented by co-treatment with a glucocorticoid antagonist RU-486, but not a mineralocorticoid antagonist spironolactone. In contrast, aldosterone had no effects on major insulin signaling pathways including insulin receptor substrate-1, protein kinase B, and forkhead transcription factor. These results suggest that aldosterone may affect the inhibitory effect of insulin on hepatic gluconeogenesis through the glucocorticoid receptor, which may be one of the causes of impaired glucose metabolism in primary aldosteronism.

Dehydroepiandrosterone (DHEA) is known to improve hyperglycemia in diabetic db/db mice that are obese and insulin resistant. In a previous study, we reported that DHEA suppresses the elevated hepatic gluconeogenic glucose-6-phosphatase (G6Pase) activity and gene expression in C57BL/KsJ-db/db mice. In the present study, we evaluated the total amount of gluconeogenesis using NaH[ 14 C]CO 3 and hepatic glucose production using fructose as a substrate in primary cultured hepatocytes. Despite hyperinsulinemia, the glucose production of db/db mice in the total body and hepatocytes was elevated as compared to their heterozygote littermate C57BL/KsJ-db/+m mice. Administration of DHEA significantly decreased the blood glucose level and increased the plasma insulin level in db/db mice. Administration of DHEA decreased the elevated total body and hepatic glucose production in db/db mice. In addition, the glucose production in the primary cultured hepatocytes of db/db mice was decreased significantly by the direct addition of DHEA or DHEA-S to the medium. These results suggest that administration of DHEA suppresses the elevated total body and hepatic glucose production in db/db mice, and this effect on the liver is considered to result from increased plasma insulin and DHEA or DHEA-S itself.