Review of renal oncocytosis (multiple oncocytic lesions) with focus on clinical and pathobiological aspects.

Renal oncocytosis is a recently established disease entity characterized by numerous oncocytic tumors and diffuse involvement of oncocytic changes in renal parenchymal epithelia. In this article, we review this disease with a focus on its clinical and pathobiological aspects. Clinically, renal oncocytosis may occur in a sporadic form without any underlying disease or may be associated with chronic renal failure/long-term hemodialysis. However, Birt-Hogg-Dubé syndrome, characterized by skin tumors such as fibrofolliculoma or trichodiscoma, pulmonary lesions including bullae and spontaneous pneumothorax, and renal tumors should be evaluated in the differential diagnosis. The disease can develop either unilaterally or bilaterally. The involved renal parenchyma contains several to multiple brownish-colored nodules of varying size and is entirely replaced by lesions at the overt stage. Histologically, oncocytic tumors in both the dominant mass and smaller lesions encompass so-called hybrid tumor, chromophobe renal cell carcinoma (RCC), and renal oncocytoma (RO). Regarding renal parenchymal abnormalities, infiltrative growth of oncocytic cells, cortical cysts with oncocytic features, or extensive oncocytic change in non-neoplastic tubules can also be observed. Histochemical, immunohistochemical, and molecular genetic features of chromophobe RCC and RO arising in the setting of renal oncocytosis are generally identical to those in the sporadic type. However, hybrid tumors seem to be histologically distinct from chromophobe RCC and RO. In FISH analyses of some hybrid tumors, a gain of chromosomes 1, 2, 6, 10, and 17 was identified. In one tumor, no germ line mutation of folliculin gene was identified. Published data show that tumors follow a benign course. Further studies will be necessary to clarify the pathogenesis of renal oncocytosis.

Potential of histone deacetylase inhibitors for bladder cancer treatment.

Bladder cancer incidence increases with age, presumably reflecting a cumulative exposure to carcinogens and ever-increasing life expectancy. While aberrant protein expression due to DNA mutations is an essential step during oncogenesis, one recent interest has been the role of epigenetic changes in regulating bladder tumor development. Because aberrant histone acetylation has been linked to malignant diseases in several cases, histone deacetylase inhibitors have great potential as new anticancer drugs owing to their ability to modulate transcription and induce differentiation and apoptosis. We herein review the current knowledge on epigenetic issues in bladder cancer, particularly regarding histone acetylation, and discuss its implications for understanding the molecular basis and treatment of this disease.

[Low-dose docetaxel in combination with dexamethasone for hormone-refractory prostate cancer].

PURPOSE: Efficacy and tolerability of docetaxel-based chemotherapy against hormone-refractory prostate cancer (HRPC) has been shown lately. The objective of this study was to evaluate retrospectively the efficacy and toxicity of low-dose docetaxel in combination with dexamethasone. PATIENTS AND METHODS: Sixteen patients, with a median age of 69.5 years (range 54-85 years), diagnosed with HRPC were administered a treatment regimen consisting of docetaxel (60-80 mg/body or 50 mg/m2) once every 3 or 4 weeks and dexamethasone 1 mg daily at our institution between November, 2004 and March, 2010. RESULTS: The patients received a median of 11.5 cycles of treatment (range, 2-35 cycles). Eleven of 16 patients (68.8%) had a > or = 50% decrease in serum prostate-specific antigen. The median progression-free survival and overall survival times were 7.1 and 20.3 months, respectively. Grade 3 neutropenia occurred only in 2 patients. Infective endocarditis, gastrointestinal or cerebral hemorrhage, and compressive fracture were occurred in each patient. CONCLUSIONS: The combination of low-dose docetaxel every 3-4 weeks and dexamethasone daily was effective and well tolerated in patients with HRPC. However, it is necessary to pay continuous attention to side effects due to the frequent presence of comorbid diseases particularly in the elderly.

Combined chemotherapy with gemcitabine and cisplatin for metastatic urothelial carcinomas in patients 80 years of age and over.

BACKGROUND: This retrospective study aimed to determine the efficacy and toxicity of a combined chemotherapeutic regimen of gemcitabine and cisplatin (GC) for the treatment of metastatic urothelial carcinomas (UCs) in patients 80 years of age and over. PATIENTS AND METHODS: Twelve patients who were at least 80 years old and had been diagnosed with metastatic UC were treated with GC. The patient cohort consisted of 9 men and 3 women, with a median age of 83 (range 80-84) years. The median follow-up was 54 (range 14-80) months. RESULTS: Five out of the 12 patients (42%) showed an objective response, with two achieving a clinically complete response and three a partial response with GC. The median time to progression was 6 months, and the median overall survival was 14 months. The grade 3 and 4 toxicities of the regimen were primarily hematological, including anemia (33%), neutropenia (58%), and thrombocytopenia (50%). No grade 3 or 4 non-hematological toxicities were found. CONCLUSION: GC appears to be an effective and well-tolerated regimen for the treatment of metastatic UCs in very old patients.

Knockdown of Akt isoforms by RNA silencing suppresses the growth of human prostate cancer cells in vitro and in vivo.

The serine/threonine kinase Akt has three highly homologous isoforms in mammals: Akt1, Akt2, and Akt3. Recent studies indicate that Akt is often constitutively active in many types of human malignancy. Here we investigated the expression and function of Akt isoforms in human prostatic carcinoma cells. Initially, we used Western blotting to examine Akt expression in four human prostate cancer cell lines. Next, small-interfering RNAs (siRNAs) specific for Akt isoforms were used to elucidate their role on the in vitro and in vivo growth of prostate cancer cells. Expression of Akt1 and Akt2 was detected in all cells tested, but Akt3 was expressed only in cancer cells that did not express androgen receptors. All synthetic siRNAs against Akt isoforms suppressed their expression and inhibited the growth of cancer cells in vitro. Furthermore, atelocollagen-mediated systemic administration of siRNAs significantly reduced the growth of tumors that had been subcutaneously xenografted. These results suggest that targeting Akt isoforms could be an effective treatment for prostate cancers.

Long-term results of combined chemotherapy with gemcitabine and cisplatin for metastatic urothelial carcinomas.

BACKGROUND: This retrospective study aimed to determine the long-term effects and toxicity of a combined chemotherapeutic regimen of gemcitabine and cisplatin (GC) in the treatment of metastatic urothelial carcinomas (UCs). METHODS: Seventy-one patients with metastatic UC were treated with GC (gemcitabine 1000 mg/m(2) on days 1, 8, and 15 and cisplatin 70 mg/m(2) on day 2 every 28 days). The patients were divided into 3 groups: patients who had not undergone prior chemotherapy (group 1), patients who relapsed more than 6 months after being treated with the prior cisplatin-based regimen (group 2), and patients in whom the prior cisplatin-based regimen demonstrated no effect (group 3). The median follow-up was 42 months. RESULTS: In group 1, 20 of the 32 patients (63%) showed an objective response, with 6 achieving a clinically complete response (CR) and 14 a partial response (PR) with GC. Ten of 32 patients (31%) and 1 of 7 patients (14%) showed objective responses in groups 2 and 3, respectively. Patients in group 2 who had previously been treated with regimens other than GC showed a better objective response (58%) than those with GC (15%). The median time to progression in group 1 was 6 months, and the median overall survival was 14 months. In all, the nonhematological toxicities associated with GC were quite mild. Grade 3-4 toxicity was primarily hematological, including anemia (19%), neutropenia (36%), and thrombocytopenia (42%). CONCLUSIONS: GC is therefore considered to be a highly effective and well-tolerated regimen with moderate toxicity for the treatment of metastatic UCs.

Anti-tumor effect of small interfering RNA targeting the androgen receptor in human androgen-independent prostate cancer cells.

Early phase prostate cancer is usually androgen-dependent, with the androgen/androgen receptor (AR) signaling pathway playing a central role. At this stage, the cancer responds well to androgen ablation therapy, but prostate cancers eventually acquire androgen independence and more aggressive phenotypes. Several studies, however, have shown that the majority of tumors still express functional AR, which is often amplified and mutated. To determine if the AR is a plausible therapeutic target, we investigated the anti-tumor effect of small interfering RNAs targeting the AR (siAR) in the human prostate cancer cells, LNCaP and 22Rv1, which express mutated AR. In both types of cells, transfection of siAR suppressed mutated AR expression and significantly reduced cell growth. Furthermore, atelocollagen-mediated systemic siAR administration markedly inhibited the growth of 22Rv1 cells subcutaneously xenografted in castrated nude mice. These results suggest that the AR is still a key therapeutic target even in androgen-independent prostate cancer (AIPC). Silencing of AR expression in AIPC opens promising therapeutic perspectives.

Inhibition of bladder tumour growth by histone deacetylase inhibitor.

OBJECTIVE: To examine the expression profile of histone deacetylase (HDAC)-1 and explore its potential role in the development of bladder cancer, using valproic acid (VPA), a HDAC inhibitor, which reduces tumour growth and metastasis formation in animal models. MATERIALS AND METHODS: The study comprised clinical samples from patients with urinary bladder cancer, mouse urinary bladder tissue specimens, and two human urinary bladder cancer cell lines (HT-1376 and 5637). HDAC1 mRNA and protein expression were examined using real-time reverse transcription-polymerase chain reaction and immunohistochemical methods. Female C3H/He mice were given VPA (0, 250, 500 and 750 mg/kg body weight, intraperitoneal, every day) from the start or 4 weeks after 0.05%N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) treatment, and were humanely killed and sampled at 8 and 12 weeks. RESULTS: A significantly higher level of HDAC1 mRNA was expressed in human urinary bladder cancer specimens. The immunohistochemical study showed that HDAC1 was expressed in the cytoplasm and nucleus in the specimens. BBN treatment increased HDAC1 mRNA expression in the urinary bladder. VPA administration seemed to delay the incidences of BBN-induced mouse urinary bladder tumour, possibly through p21(WAF1) protein expression. CONCLUSION: These results indicate that HDAC might be an effective molecular target for cancer therapy.

[Intrascrotal rhabdomyosarcoma in adult: a case report].

The patient was a 34-year-old man presenting with the right intra-scrotal painless mass. With a diagnosis of right intrascrotal tumor, the patient underwent right high orchiectomy. The pathological diagnosis of pleomorphic rhabdomyosarcoma arisen from the right spermatic cord was made. Computed tomography revealed a single metastasis in the para-vena cava lymph node. Systemic chemotherapy with vincristine, actinomycin D, plus cyclophosphamide (VAC therapy), and etoposide plus cisplatin (EP therapy) were made according to Intergroup Rhabdomyosarcoma Study (IRS)-IV Regimen 45. But the chemotherapy was ineffective and a retoroperitoneal lymphadenectomy (RPLND) was therefore performed. After 3 months following RPLND, the tumor relapsed in a pelvic lymph node involved in right ureter and ileocaecal valve. Resection of the tumor with ileocaecum was performed and then intraoperative radiotherapy (15 Gy) against the tumor bed was performed to ensure the curative effects. After his recovery, he received a total of 6 courses of systemic chemotherapy consisting of vincristin, ifosphamide, etoposide (IRS-IV Regimen 47). The patient was rigorously followed up for 42 months after the final chemotherapy, with no tumor recurrence.

Androgens upregulate aquaporin 9 expression in the prostate.

OBJECTIVES: Aquaporins (AQP) function as selective pores allowing water, glycerol and other small solutes to pass through the cell membrane. We previously reported that AQP are expressed in the prostates of both humans and rats. The present study investigated the androgen-dependent expression of AQP9 in the prostate in vivo and in vitro. METHODS: Rat ventral prostate tissue specimens and a normal human prostatic epithelial cell line (PNT2) were used. AQP9 messenger ribonucleic acid (mRNA) and protein expression were examined using real-time polymerase chain reaction, Western blotting and immunohistochemical methods. Androgen modulation was achieved by surgical castration, treatment with testosterone propionate (5 microg/g bodyweight) or bicalutamide (20 microg/g bodyweight), and the ribonucleic acid interference (RNAi) method of the androgen receptor (AR). The synthetic small interfering RNA was transfected into PNT2 at a concentration of 10 nM, and the RNAi effect was evaluated using a Western blotting analysis. RESULTS: AQP9 mRNA and protein were expressed in the rat prostate. Surgical castration or bicalutamide treatment significantly decreased their expression. In addition, the treatment with testosterone propionate after castration restored the expression to the level of the controls. An RNAi experiment in PNT2 also decreased the expression. CONCLUSIONS: AQP9 expression in the prostate is controlled by androgens.

Inactivation of AR activates HGF/c-Met system in human prostatic carcinoma cells.

Clinical studies with prostate cancer tissue indicate that alterations in androgen receptor (AR) or c-Met overexpression are associated with androgen-independent progression. We investigated the interaction between AR and c-Met signaling in human prostate cancer cells. Androgen withdrawal or AR-specific small interfering RNA significantly reduced the growth rate while each maneuver induced the expression of c-Met. Knockdown of both AR and c-Met expression markedly inhibited the cell growth. Furthermore, microarray analysis indicated that the activation of c-Met down-regulated the expression of DNA repair-related genes including 8-oxoguanine DNA glycosylase. Exogenous hepatocyte growth factor also induced the production of intracellular reactive oxygen species and resulted in the accumulation of DNA damages. These results suggested that the activation of c-Met signaling may lead to induction of spontaneous mutations or genomic instability, which may lead to the progression of androgen-independent state. Thus, c-Met signaling is utilized for survival and growth under the androgen-depleted condition.

Fibroblast growth factor receptor 3 protein expression in urothelial carcinoma of the urinary bladder, exhibiting no association with low-grade and/or non-invasive lesions.

Activating mutations of fibroblast growth factor receptor 3 (FGFR3), found in autosomal dominant human skeletal dysplasia, were reported to be involved in tumorigenesis and correlate with low-grade and superficial lesions of urothelial carcinoma. FGFR3 protein expression was immunohistochemically investigated in 126 cases of urothelial carcinoma of the urinary bladder to evaluate the role of this receptor in tumor behavior. p53 expression and the proliferating activity of tumor cells, assessed by Ki-67 expression, were also analyzed in parallel. Cytoplasmic and/or membrane immunostaining for FGFR3 was observed in 62 (49.2%) cases, including 20 (15.9%) cases of intense staining and 42 (33.3%) of moderate staining. p53 expression and Ki-67 labeling index (LI) were significantly correlated with high tumor grade (p=0.0093 and <0.0001, respectively) and invasion (p=0.0041 and <0.0001, respectively). Although there were two groups of interesting cases: low-grade and non-invasive tumors negative for p53 but positive for FGFR3, and high-grade and invasive tumors positive for p53 but negative for FGFR3, no statistically significant relationship was found between FGFR3 expression and tumor grade, invasion, p53 expression or Ki-67 LI. These results suggest that FGFR3 protein expression in bladder cancer is unlikely to affect tumor behavior as a unique single factor.