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In the current study, we investigated a combination of docetaxel and thalidomide (DT therapy) in castration-resistant prostate cancer (CRPC) patients. We identified marker genes that predict the effect of DT therapy. Using an androgen-insensitive PC3 cell line, we established a docetaxel-resistant PC-3 cell line (DR-PC3). In DR-PC3 cells, DT therapy stronger inhibited proliferation/viability than docetaxel alone. Based on gene ontology analysis, we found versican as a selective gene. This result with the findings of cDNA microarray and validated by quantitative RT-PCR. In addition, the effect of DT therapy on cell viability was the same as the effect of docetaxel plus versican siRNA. In other words, silencing of versican can substitute for thalidomide. In the clinical setting, versican expression in prostate biopsy samples (before DT therapy) correlated with PSA reduction after DT therapy (p

// Hiroki Tamaki 1, 2 , Nanae Harashima 1 , Miho Hiraki 3 , Naoko Arichi 3 , Nobuhiro Nishimura 2 , Hiroaki Shiina 3 , Kohji Naora 2 , Mamoru Harada 1 1 Department of Immunology, Shimane University Faculty of Medicine, Shimane, Japan. 2 Department of Pharmacy, Shimane University Hospital, Shimane, Japan. 3 Department of Urology, Shimane University Faculty of Medicine, Shimane, Japan. Correspondence to: Mamoru Harada, e-mail: haramamo@med.shimane-u.ac.jp Keywords: prostate cancer, docetaxel, apoptosis, Bcl-2, Bcl-xL Received: July 26, 2014 Accepted: September 30, 2014 Published: October 15, 2014 ABSTRACT Docetaxel (DTX) is a useful chemotherapeutic drug for the treatment of hormone-refractory prostate cancer. However, emergence of DTX resistance has been a therapeutic hurdle. In this study, we investigated the effect of combining DTX with Bcl-2 family inhibitors using human prostate cancer cell lines (PC3, LNCaP, and DU145 cells). PC3 cells were less sensitive to DTX than were the other two cell lines. In contrast to ABT-199, which inhibits Bcl-2 and Bcl-w, both ABT-263 and ABT-737, which inhibit Bcl-2, Bcl-xL, and Bcl-w, significantly augmented the antitumor effect of DTX on PC3 cells. ABT-263 also enhanced the antitumor effect of DTX on a DTX-resistant PC3 variant cell line. The antitumor effect of ABT-263 was due mainly to its inhibitory effect on Bcl-xL. In a xenograft mouse model, DTX and ABT-737 combination therapy significantly inhibited PC3 tumor growth. Interestingly, although ABT-263 activated caspase-9 in PC3 cells, inhibition of caspase-9 unexpectedly promoted ABT-263-induced apoptosis in a caspase-8-dependent manner. This augmented apoptosis was also observed in LNCaP cells. These findings indicate that Bcl-xL inhibition can sensitize DTX-resistant prostate cancer cells to DTX, and they reveal a unique apoptotic pathway in which antagonism of Bcl-2 family members in caspase-9-inhibited prostate cancer cells triggers caspase-8-dependent apoptosis.

// Yozo Mitsui 1 , Hiroaki Yasumoto 1 , Taichi Nagami 1 , Miho Hiraki 1 , Naoko Arichi 1 , Noriyoshi Ishikawa 2 , Asuka Araki 2 , Riruke Maruyama 2 , Yuichiro Tanaka 3 , Rajvir Dahiya 3 , Hiroaki Shiina 1 1 Departments of Urology, Shimane University Faculty of Medicine, 89-1 Enya-cho, 693-8501 Izumo, Japan 2 Pathology (Organ Pathology Unit), Shimane University Faculty of Medicine, 89-1 Enya-cho, 693-8501 Izumo, Japan 3 Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California, USA Correspondence: Yozo Mitsui, email: // Keywords : adrenocortical tumor, Wif-1, epigenetics, Wnt signaling, cyclin D1 Received : March 24, 2014 Accepted : April 07, 2014 Published : April 08, 2014 Abstract Wnt/β-catenin signaling is considered to be an essential regulator of adrenocortical oncogenesis. Wnt inhibitory factor-1 (Wif-1), an extracellular regulator of Wnt signaling, is frequently down-regulated by hypermethylation of the promoter CpG. We investigated epigenetic regulation of Wif-1 and its association with adrenocortical (AC) tumor pathogenesis in light of Wnt activation. The AC tumors showed a high prevalence of Wif-1 promoter methylation and low prevalence of Wif-1 mRNA transcription as compared to the normal adrenal (NA) samples. Furthermore, a significant correlation was found between Wif-1 promoter methylation and mRNA transcription in the tumors. Either intracellular β-catenin accumulation or β-catenin mRNA transcription was significantly elevated in the AC tumors, which also showed an inverse correlation with Wif-1 mRNA transcription. Cyclin D1, a target gene of Wnt signaling, was also up-regulated in the AC tumors as compared with the NA samples. In addition, down-regulation of Wif-1was correlated with increased cyclin D1 at both mRNA and protein levels. However, despite the proposed activation of Wnt signaling in AC tumors, only 2 of 20 with intracellular β-catenin accumulation showed β-catenin mutations. Thus, genetic alterations of β-catenin and epigenetics-related Wif-1 promoter hypermethylation may be important mechanisms underlying AC tumor formation through aberrant canonical Wnt/β-catenin signaling activation.

Bladder cancer is the second most common genitourinary malignancy and has variable metastatic potential; however, choroidal and cutaneous metastases are extremely rare. Generally, a patient with these uncommon metastases has a very poor prognosis. We present a bladder cancer patient with a visual disorder in the right eye and multiple nodules on head and lower abdomen that developed 17 months after a radical cystectomy. These symptoms were determined to be caused by choroidal and cutaneous metastasis of bladder cancer. Although two cycles of combination chemotherapy were performed, the patient died 5 months after diagnosis of multiple metastases.

The proteoglycan versican (VCAN) promotes tumor progression and enhances metastasis in several cancers; however, its role in clear cell renal cell carcinoma (ccRCC) remains unknown. Recent evidence suggests that VCAN is an important target of chromosomal 5q gain, one of the most prevalent genetic abnormalities in ccRCC. Thus, we investigated whether VCAN expression is associated with the pathogenesis of ccRCC. VCAN expression was analyzed using three RCC and normal kidney cell lines as well as a clinical cohort of 84 matched ccRCC and normal renal tissues. Functional analyses on growth and progression properties were performed using VCAN-depleted ccRCC cells. Microarray expression profiling was employed to investigate the target genes and biologic pathways involved in VCAN-mediated ccRCC carcinogenesis. ccRCC had elevated VCAN expression in comparison with normal kidney in both cell lines and clinical specimens. The elevated expression of VCAN was significantly correlated with metastasis (P < 0.001) and worse 5-year overall survival after radical nephrectomy (P = 0.014). In vitro, VCAN knockdown significantly decreased cell proliferation and increased apoptosis in Caki-2 and 786-O cells, and this was associated with alteration of several TNF signaling–related genes such as TNFα, BID, and BAK. Furthermore, VCAN depletion markedly decreased cell migration and invasion which correlated with reduction of MMP7 and CXCR4. These results demonstrate that VCAN promotes ccRCC tumorigenesis and metastasis and thus is an attractive target for novel diagnostic, prognostic, and therapeutic strategies. Implications: This study highlights the oncogenic role of VCAN in renal cell carcinogenesis and suggests that this gene has therapeutic and/or biomarker potential for renal cell cancer. Mol Cancer Res; 15(7); 884–95. ©2017 AACR.

INTRODUCTION AND OBJECTIVES: Several epidemiologic reports using large cohorts suggest that tobacco smoking may be associated with prostate cancer (PC). Cytochrome P450 1A1 (CYP1A1) may play an important role in the initiation of various cancers including PC. However, the mechanisms of overexpression of CYP1A1 and smoking in PC have never been investigated. We assessed whether impaired regulation of CYP1A1 through DNA hypomethylation could be involved in smoking and contribute to the pathogenesis of PC. METHODS: We studied 3 PC cell lines, 69 benign hyperplasia (BPH) and 176 PC samples, using methylation-specific PCR analysis to focus on 3 regions of the CYP1A1 enhancer carrying a xenobiotic responsive element (XRE). In addition, we depleted the gene in LNCaP and DU145 by siRNA to validate its biological role in tumorigenesis. RESULTS: In all PC cell lines, CYP1A1 expression was enhanced after 5-aza-2-deoxycitidine treatment and bisulfite DNA sequencing confirmed hypermethylation at the CYP1A1 enhancer, indicating DNA promoter CpG methylation as a regulator of CYP1A1 expression. The level of methylation of CYP1A1 enhancer was significantly lower in PC as compared to BPH samples at all three enhancer sites (P

What's known on the subject? and What does the study add? The process of bladder regeneration with a bladder acellular matrix graft (BAMG) is thought to be accelerated by administration of vascular endothelial growth factor into the host bladder. In the present study, we showed that simultaneous implantation of bilateral ureters into a BAMG after a partial cystectomy is reasonable and provides an increased opportunity to the bio-scaffold for communication with host tissues from which a blood supply and stem cells will be generated. OBJECTIVE • To evaluate if the implantation of bilateral ureters into a bladder acellular matrix graft (BAMG) at the time of its implantation would enhance bladder regeneration in a partial substitution BAMG. MATERIALS AND METHODS • Partial cystectomies were performed under general anaesthesia in 12 pigs, followed by augmentation with a BAMG. • Six (ureteric implantation group) also received simultaneous implantation of bilateral ureters into the BAMG, while the remaining six (control group) did not have ureteric implantation. • In both groups, bladder regeneration was evaluated using endoscopic and histopathological methods at 1, 2, 4, and 8 weeks after implantation. RESULTS • At 1 week after BAMG implantation, there were significant inflammatory changes on the host bladder in both groups, while no significant endoscopic changes were seen on the BAMG luminal surfaces. • At 2 weeks, inflammatory changes were diminished and epithelialisation on the BMAG was identified, especially near the host bladder in both groups. • Similarly, epithelialisation on the BAMG near the implanted ureters was seen in the ureteric implantation group. • At 4 and 8 weeks, epithelialisation remained in progress in both groups, although it was more active and expansive in the ureteric implantation group. CONCLUSIONS • In our porcine model, endoscopic and histopathological examinations showed that simultaneous implantation of bilateral ureters into a BAMG enhanced epithelialisation of the AMG. • This new approach using host ureters and bladder as a potential source of bladder regeneration may provide for rapid and complete regeneration of a bladder substitute.

UNLABELLED What's known on the subject? and What does the study add? A bone scan index (BSI) can quantify the extent of bone involvement and response to treatment, but it has not been widely accepted, because of its time-consuming nature. The study is the first to demonstrate that automated BSI calculated with a computer-assisted diagnosis system is effective in judging the chemotherapeutic response of bone metastatic lesions in patients with castration-resistant prostate cancer. OBJECTIVE • To evaluate the value of an automated bone scan index (aBSI), calculated using a computer-assisted diagnosis system, to indicate chemotherapy response and to predict prognosis in patients with castration-resistant prostate cancer (CRPC) with bone metastasis. PATIENTS AND METHODS • Forty-two consecutive CRPC patients underwent taxane-based chemotherapy between November 2004 and March 2011 at our institution. • The aBSIs were retrospectively calculated at the diagnosis of CRPC and 16 weeks after starting chemotherapy. • Cox proportional hazards regression models were applied to multivariate analyses with and without aBSI response in addition to the basic model. • Based on the difference in the concordance index (c-index) between each model, the prognostic relevance of adding the aBSI response was determined. RESULTS • A decrease in aBSI was found in 28 patients (66.7%), whereas a response was shown by bone scan in only 23.8% of patients. • Patients with a reduction in aBSI had longer overall survival (OS) in comparison with the other patients (P= 0.0157). • Multivariate analysis without aBSI response showed that performance status (P= 0.0182) and PSA response (P= 0.0375) were significant prognosticators. • By adding the aBSI response to this basic model, the prognostic relevance of the model was improved with an increase in the c-index from 0.621 to 0.660. CONCLUSIONS • The aBSI reflected the chemotherapy response in bone metastasis. • The index detected small changes of bone metastasis response as quantified values and was a strong prognostic indicator for patients with CRPC.

To determine the definite border between normal and tumor kidney tissues during partial nephrectomy (PN) procedures using intraoperative indocyanine green (ICG)-based fluorescence imaging.Sixteen potential candidates for PN with organ-confined, small renal masses treated between July 2008 and June 2011 at Shimane University Hospital were enrolled. An ICG-based fluorescence navigation (FN) system was used to evaluate the border between the tumor and normal kidney parenchyma (step 1), the cavity following tumor excision (step 2), and the negative surgical margin of resected tissues (step 3). The R.E.N.A.L nephrometry score (RNS) was applied to evaluate the correlation between tumor anatomy and ICG-based fluorescence imaging.In step 1, in vivo probing revealed 14 tumors with a mean RNS of 7 points that showed quite low ICG fluorescence signals in the tumor mass as compared with normal kidney parenchyma. In step 2, in vivo probing around the bed revealed highly fluorescent signals with no remnant tumor residing in 10 cases with a mean RNS of 6 points. In step 3, ex vivo probing revealed cancer tissues involving normal parenchyma that were completely excised with minimum amounts of normal parenchyma in all 16 resected specimens.ICG-based FN system was very helpful for confirming negative margin status in even the most complex cases. Further evaluations may open the door for widespread use of this ICG-based FN system as a feasible and attractive alternative during a PN procedure.

Objective: The objective of this study was to identify lymphatic vessels draining from the prostate by using a fluorescence navigation (FN) system. Methods: Fourteen subjects were candidates for radical retropubic prostatectomy (RRP) and pelvic lymph node dissection (PLND). After an indocyanine green solution was injected into the prostate during RRP, lymphatic vessels draining from the prostate were analyzed using a FN system. After PLND based on lymphatic mapping by the FN system (in vivo probing) was performed in the external iliac, obturator and internal iliac regions; the fluorescence of the removed lymph nodes (LNs) was analyzed on the bench (ex vivo probing). Results: Under in vivo and ex vivo probing, the fluorescence intensity of internal iliac nodes was greater than that of external iliac or obturator nodes. Conclusion: The current study suggests that using a FN system after injecting indocyanine green is a safe and rational approach for detecting the lymphatic channel draining from the prostate. The major lymphatic pathway involved in the spreading of prostate cancer appears to relate to internal iliac LNs, which would mean that the standard PLND covering external iliac and obturator regions would not keep the cancer from spreading. Objectif : L’objectif de l’etude etait de reperer les vaisseaux lymphatiques quittant la prostate a l’aide d’un systeme d’imagerie par fluorescence (IF). Methodologie : Quatorze sujets devaient subir une prostatectomie radicale retropubienne (PRR) et une lymphadenectomie pelvienne. Apres injection d’une solution de vert d’indocyanine dans la prostate pendant la PRR, les vaisseaux lymphatiques drainant la prostate ont ete analyses par IF. Une lymphadenectomie pelvienne fondee sur la cartographie lymphatique par IF (exploration in vivo) a ensuite ete realisee dans les regions de la fosse iliaque externe, de l’obturateur et de la fosse iliaque interne; la fluorescence des ganglions lymphatiques retires a ete analysee sans delai (exploration ex vivo). Resultats : Lors de l’exploration in vivo et ex vivo, l’intensite de la fluorescence des ganglions iliaques internes etait plus forte que celle des ganglions iliaques externes ou des ganglions obturateurs. Conclusion : Cette etude porte a croire que l’IF apres injection de vert d’indocyanine est une methode sure et rationnelle pour reperer les vaisseaux lymphatiques drainant la prostate. La principale voie lymphatique de propagation du cancer de la prostate semble etre reliee aux ganglions lymphatiques iliaques internes, ce qui signifie que la lymphadenectomie pelvienne standard retirant les ganglions iliaques externes et obturateurs n’empecherait pas le cancer de se propager.

Urothelial cancer is a chemotherapy-sensitive malignancy, with the regimen of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) until recently considered to be the first choice for chemotherapy. Poor survival and substantial toxicity associated with M-VAC have led to investigations into alternative chemotherapy strategies, and the combination of gemcitabine and cisplatin (GC) may be promising. In addition, combination chemotherapy of taxanes along with gemcitabine and/or platinum-based agents is also considered to provide clinical benefits as second-line chemotherapy following M-VAC or GC therapy. In the near future, results of trials using molecular target therapies may bring improved outcomes for patients with bladder cancer.

The aim was to assess whether hepatocyte growth factor (HGF) and interleukin (IL)-6 in combination with prostate volume are able to accurately detect prostate cancer in patients with gray-zone prostate-specific antigen (PSA) levels. A total of 159 patients with PSA levels of

We analyzed clinical effects of flutamide as a second-line agent for maximum androgen blockade (MAB) in patients with relapsing prostate cancer who received bicalutamide as the first-line MAB agent. This study included 13 patients with progressive prostate cancer who had relapsed after first-line MAB, with bicalutamide at 80 mg/day. After checking for antiandrogen withdrawal syndrome, they were given flutamide at 375 mg/day as second-line MAB. The effectiveness of that therapy was evaluated by changes in prostatic specific antigen (PSA) levels, with response defined as a decrease of greater than 50% from the start of therapy. We also compared several factors between responders and non-responders. Nine (69.2%) of the 13 patients showed a decrease in PSA levels, of whom five (38.5%) had a greater than 50% decrease and were defined as responders. The median duration of PSA response was 11.0 months (range 5-20 months). Patients who had a longer duration of response to first-line MAB had a significantly greater response to second-line MAB. For advanced prostate cancer patients who progressed on first-line MAB with bicalutamide, flutamide administration as a second-line antiandrogen was found to be relatively effective, especially for those who showed a longer duration of response to the first-line MAB. Our results confirm previous findings that MAB using flutamide is an effective second-line hormonal therapy.

expression profiles for miR-10a and 10b in the nephrectomy and RMB specimens, binary logistic regression models were created for differentiation between local and aggressive disease. From the biopsy samples, the area under the curve, sensitivity, and specificity of this model were 0.818, 63.6, and 76.9, respectively. Decreased cancer specific survival was shown for patients with lower levels of miR-10b at 5 years follow up. CONCLUSIONS: We have identified a panel of 7 miRNA whose expression profiles are statistically different between local and aggressive ccRCC. This is the first study to stratify patients with ccRCC using biopsy tissue alone. The future utility of RMB may be in stratification and prognosis in addition to its current primary use of histologic diagnosis.

INTRODUCTION AND OBJECTIVES: Efficacy in the prostate cancer detection of real-time tissue elastogarpahy (RTE) has been reported. But RTE has a major problem that RTE is highly operator dependent procedure. We hypothesized that the pressure device might decrease the operator dependency and increase the prostate cancer detection rate of RTE. The pressure device run with water pressure was developed for this study, called this procedure real-time balloon inflation elastography (RBIE). The results of targeted prostate biopsy with RBIE was studied for detection of prostate cancer. METHODS: 233 patients and 1978 were enrolled in this study with abnormal findings of digital rectal examination (DRE), PSA and/ or TRUS. Median age was 73 year-old (range 54e89), median PSA was 7.6 ng/mL (range 0.8-2606.0), and median number of biopsy cores taken on each patient was 8 (range 8e10). All of 233 patients were examined with MRI prior to prostate needle biopsy. A total of 1978 specimens obtained by systemic biopsy were studied. The findings of RBIE, RTE, TRUS, PDUS and MRI (T2WI, dynamic contrast enhanced images (DCEI) and diffusion weighted image (DWI)) were compared to the histopathological findings of biopsy specimens. RESULTS: The prostate cancer was detected in 113 of 233 patients (48.5%), and 412 of 1978 specimens (20.8%). Gleason score of 5 to 6, 7 and 8 to 10 tumors was 110, 166 and 138 specimens respectively. Clinical stages of T1c, T2a-c, T3a-b, and T4 were 20, 60, 22 and 11 cases. The sensitivity of RBIE, RTE, TRUS, PDUS, T2WI, DCEI and DWI were 72.1%, 72.1%, 74.5%, 72.8%, 78.2%, 77.2% and 77.2%, the specificity were 94.3%, 93.6%, 85.4% 90.5%, 92.0%, 93.7% and 92.6%, respectively. Both of the sensitivity and the specificity of RBIE were not significantly inferior to those of MRI. The results of targeted biopsy (PPV) of RBIE, RTE, TRUS, PDUS, T2WI, DCEI and DWI were 76.7%, 74.8%, 57.4%, 67.0%, 72.0%, 76.4% and 73.3%. PPV of RBIE was also comparable to those of MRI. CONCLUSIONS: RBIE was low cost and low invasive procedure. The prostate cancer detection capability of RBIE might be not inferior to that of MRI, expensive and time consuming procedure. Furthermore, RBIE reveals prostate in real-time, so RBIE could enhance the prostate cancer detection as a biopsy guidance image.

// Yozo Mitsui 1,2 , Hiroshi Hirata 2 , Naoko Arichi 1 , Miho Hiraki 1 , Hiroaki Yasumoto 1 , Inik Chang 3 , Shinichiro Fukuhara 4 , Soichiro Yamamura 2 , Varahram Shahryari 2 , Guoren Deng 2 , Sharanjot Saini 2 , Shahana Majid 2 , Rajvir Dahiya 2 , Yuichiro Tanaka 2 and Hiroaki Shiina 1 1 Department of Urology, Shimane University Faculty of Medicine, Enya-cho, Izumo, Japan 2 Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, USA 3 Department of Oral Biology, Yonsei University College of Densitry, Seoul, South Korea 4 Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan Correspondence to: Yozo Mitsui, email: // Keywords : bone morphogenetic protein 2, renal cell carcinoma, DNA methylation, molecular marker Received : January 15, 2015 Accepted : February 10, 2015 Published : March 07, 2015 Abstract We investigated whether impaired regulation of bone morphogenetic protein-2 (BMP-2) via epigenetic pathways is associated with renal cell carcinoma (RCC) pathogenesis. Expression and CpG methylation of the BMP-2 gene were analyzed using RCC cell lines, and 96 matched RCC and normal renal tissues. We also performed functional analysis using BMP-2 restored RCC cells. A significant association of BMP-2 mRNA expression was also found with advanced tumor stage and lymph node involvement, while lower BMP-2 mRNA expression was significantly associated with poor overall survival after radical nephrectomy. In RCC cells, BMP-2 restoration significantly inhibited cell proliferation, migration, invasion, and colony formation. In addition, BMP-2 overexpression induced p21 WAF1/CIP1 and p27 KIP1 expression, and cellular apoptosis in RCC cells. BMP-2 mRNA expression was significantly enhanced in RCC cells by 5-aza-2’-deoxycitidine treatment. The prevalence of BMP-2 promoter methylation was significantly greater and BMP-2 mRNA expression was significantly lower in RCC samples as compared to normal kidney samples. Furthermore, a significant correlation was found between BMP-2 promoter methylation and mRNA transcription in tumors. Aberrant BMP-2 methylation and the resultant loss of BMP-2 expression may be a useful molecular marker for designing improved diagnostic and therapeutic strategies for RCC.

We investigated the clinical significance of chromogranin A (CgA) expression as a neuroendocrine (NE) marker during prostate cancer (PCa) progression, especially as a potential predictor of chemotherapeutic response in castration-resistant PCa (CRPC) patients based on immunohistochemical findings.Sixteen CRPC patients who underwent combination (docetaxel/estramustine/ carboplatin; DEC) chemotherapy were retrospectively studied. Immunostaining of CgA was performed using prostate biopsy samples obtained at the initial PCa diagnosis, during androgen deprivation therapy, at the time of CRPC diagnosis, and after 2 cycles of DEC therapy. The positive rate was expressed as the mean percentage of positively stained tumor cells against the total number of tumor cells. Differences in positive rates among the treatment courses were compared using a Mann-Whitney test.The mean percentage of CgA-positive PCa cells increased in a stepwise manner until CRPC development and then significantly decreased after DEC therapy. Subanalysis of CgA at CRPC diagnosis showed a more evident reduction of CgA expression after DEC therapy in patients who also had a high level of CgA as compared to those with a low CgA level (P = .003). Likewise, longer prostate-specific antigen progression-free survival was related to CRPC and high CgA (P = .028).NE differentiation of PCa cells is accelerated despite androgen deprivation and reaches a peak at the time of CRPC diagnosis. Although further studies using larger samples are needed, CgA expression in CRPC may be a candidate tissue biomarker to reflect the chemotherapy sensitivity of individual PCa cells.

In kidney transplant recipients, acute renal failure resulting from a ureteral obstruction by fungus balls is uncommon. We report a 60-year-old man diagnosed with ureteral obstruction caused by Candida albicans fungus balls early after transplant. Diagnosis was made by a T2-weighted magnetic resonance image, which demonstrated fungus balls as a low-intensity mass in the pelvis and microscopic examination findings in the urine. The patient was treated successfully with an antifungal agent and direct irrigation. It should be noted that fungus balls may cause ureteral obstruction of transplanted kidneys, possibly resulting in graft failure. Imaging of the kidneys and collecting system and aggressive debridement that adds to systemic therapy are necessary for early diagnosis and are central to a successful outcome.

protein (BMP)-2, a member of the transforming growth factor b superfamily, has been shown to act as a tumor suppressor in several cancers by activating signaling cascades that cause cell cycle arrest. In addition, the expression level of BMP-2 is downregulated because of promoter CpG hypermethylation. We hypothesized that impaired regulation of BMP-2 through epigenetic pathways is associated with the pathogenesis of renal cell carcinoma. METHODS: To test this hypothesis, CpG methylation of the BMP-2 gene was analyzed in 3 renal tumor cell lines and 96 renal tumor and matched normal renal tissue. Promoter CpG methylation was analyzed by methylation specific PCR using bisulfite-modified DNA as template. BMP-2 expression was measured by quantitative RT-PCR. RESULTS: BMP-2 mRNA expression was significantly enhanced after 5-aza-2€ treatment in renal tumor cell lines. The prevalence of BMP-2 promoter methylation was significantly higher and BMP-2 mRNA expression was significantly lower in renal tumor samples than in normal kidney samples (p

Objectives. We investigated the prevalence of the metabolic syndrome (MS) in kidney transplantation patients and assessed its development based on plasma adiponectin levels and the results of an oral glucose tolerance test (OGTT). Methods. We performed a cross-sectional study of 94 recipients with stable graft function who underwent kidney transplantation between January 1999 and October 2008. The presence of MS was determined using National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) criteria with body mass index (BMI) used in place of waist circumference. In addition, we measured plasma adiponectin level and performed a 75-g oral GTT. Results. Fourteen (14.9 %) recipients suffered from MS for a mean period of 46.7 months (range, 1-106) after transplantation. BMI at the time of transplantation was significantly greater in the MS group (23.4 ± 3.24 vs 20.1 ± 2.50; P

In the present single center study, we analyzed 277 kidney transplant patients (procedures performed between February 1984 and February 2006) to determine the impact of long-term dialysis on kidney transplant outcomes. Forty-four had been treated prior to renal transplantation with dialysis for more than 10 years (range, 10.0-32.5 years, average, 16.6 years; Group I), while the remaining 233 recipients showed an average end-stage renal disease period of 2.8 years (range, 0-9.8 years; Group II). There were no significant differences in patient survivals between the 2 groups: 97.3% vs 97.4% at 1 year; 85.7% vs 92.4% at 5 years; 85.7% vs 90.7% at 10 years (P = .2347). Five Group I patients died: 2 from infections, 2 from liver dysfunction, and 1 from cerebral bleeding. These causes of death were similar to those among Group II patients. Graft survival was not significantly different between the 2 groups: 95% vs 88.8% at 1 year; 75.5% vs 76.5% at 5 years; 75.5% vs 65.5% at 10 years (P = .6264). Our results suggested that dialysis treatment for more than 10 years did not have negative effects on posttransplantation patient and graft survival.

Introduction and Objective. Indocyanine green (ICG) emits infrared light with exposure to laser light. When intravenously injected, it binds to plasma proteins and predominantly persists in the vasculature, which is very useful for definition of the vascular network. The HyperEye Medical System (HEMS; Mizuho Ikakogyo Co., LTD, Tokyo, Japan) is a new device able to identify both near-infrared and visible rays “in situ” without needing to dim the operation room lighting. We speculated that intraoperative ICG imaging would be applicable for kidney transplantation, by providing “in situ” determination of successful vascular anastomosis. Materials and Methods. Four patients underwent intraoperative ICG imaging following intravenous administration of 1 mL of a solution containing 0.25% ICG. After performing vascular anastomosis, the allograft was examined using the HEMS light source device. Fluorescent signals were transmitted to a digital video processor connected to a television monitor and evaluated in real time. Results. In all 4 patients, intraoperative ICG imaging provided excellent resolution of blood flow at each step in real time, namely, coming from the recipient’s artery to the allograft renal artery, circulating throughout the whole grafted kidney, and draining through the allograft renal vein to the recipient’s vein. HEMS provides ICG fluorescence image in color, allowing surgeons to clearly discriminate the positional relationship between the target tissue and the surrounding tissue. No complications associated with ICG injection were noted. Conclusion. Our preliminary results indicate that HEMS is a feasible and safe ICG imaging system that helps prevent technical failure during vascular anastomosis, and also demonstrates blood supply to the grafted kidney.

What's known on the subject? and What does the study add? A bone scan index (BSI) can quantify the extent of bone involvement and response to treatment, but it has not been widely accepted, because of its time-consuming nature. The study is the first to demonstrate that automated BSI calculated with a computer-assisted diagnosis system is effective in judging the chemotherapeutic response of bone metastatic lesions in patients with castration-resistant prostate cancer.• To evaluate the value of an automated bone scan index (aBSI), calculated using a computer-assisted diagnosis system, to indicate chemotherapy response and to predict prognosis in patients with castration-resistant prostate cancer (CRPC) with bone metastasis.• Forty-two consecutive CRPC patients underwent taxane-based chemotherapy between November 2004 and March 2011 at our institution. • The aBSIs were retrospectively calculated at the diagnosis of CRPC and 16 weeks after starting chemotherapy. • Cox proportional hazards regression models were applied to multivariate analyses with and without aBSI response in addition to the basic model. • Based on the difference in the concordance index (c-index) between each model, the prognostic relevance of adding the aBSI response was determined.• A decrease in aBSI was found in 28 patients (66.7%), whereas a response was shown by bone scan in only 23.8% of patients. • Patients with a reduction in aBSI had longer overall survival (OS) in comparison with the other patients (P= 0.0157). • Multivariate analysis without aBSI response showed that performance status (P= 0.0182) and PSA response (P= 0.0375) were significant prognosticators. • By adding the aBSI response to this basic model, the prognostic relevance of the model was improved with an increase in the c-index from 0.621 to 0.660.• The aBSI reflected the chemotherapy response in bone metastasis. • The index detected small changes of bone metastasis response as quantified values and was a strong prognostic indicator for patients with CRPC.

Background: The expression level of protein G product 9.5 (PGP9.5) is downregulated because of promoter CpG hypermethylation in several tumors. We speculated that impaired regulation of PGP9.5 through epigenetic pathways is associated with the pathogenesis of prostate cancer. Methods: CpG methylation of the PGP9.5 gene was analyzed in cultured prostate cancer cell lines, 226 localized prostate cancer samples from radical prostatectomy cases, and 80 benign prostate hyperplasia (BPH) tissues. Results: Following 5-aza-2′-deoxycytidune treatment, increased PGP9.5 mRNA transcript expression was found in the LNCaP and PC3 cell lines. With bisulfite DNA sequencing, partial methylation of the PGP9.5 promoter was shown in LNCaP whereas complete methylation was found in PC3 cells. After transfection of PGP9.5 siRNA, cell viability was significantly accelerated in LNCaP but not in PC3 cells as compared with control siRNA transfection. Promoter methylation of PGP9.5 was extremely low in only one of 80 BPH tissues, whereas it was found in 37 of 226 prostate cancer tissues. Expression of the mRNA transcript of PGP9.5 was significantly lower in methylation (+) than methylation (−) prostate cancer tissues. Multivariate analysis of biochemical recurrence (BCR) after an radical prostatectomy revealed pT category and PGP9.5 methylation as prognostically relevant. Further stratification with the pT category in addition to methylation status identified a stepwise reduction of BCR-free probability. Conclusion: This is the first clinical and comprehensive study of inactivation of the PGP9.5 gene via epigenetic pathways in primary prostate cancer. Impact: CpG methylation of PGP9.5 in primary prostate cancer might become useful as a molecular marker for early clinical prediction of BCR after radical prostatectomy. Cancer Epidemiol Biomarkers Prev; 21(3); 487–96. ©2012 AACR.

A 65-year-old man (blood type O) came to our hospital for transplant of an unrelated kidney (6/6 mismatch of HLA genotype) donated by his living 60-year-old wife (blood type B). The planned right donor nephrectomy was uneventful, with a warm ischemic time of 5 minutes, but her right renal vein was too fragile and weak to be repaired for vascular anastomosis. Therefore, we used an artificial vascular graft (polytetrafluoroethylene) interposed between the donor renal vein and the recipient's left external iliac vein. On the 11th day after surgery, infraphrenic free air (identified by a chest radiograph) made us do an emergent laparoscopic examination that showed a perforation of his sigmoid colon. A transient transverse colostomy was therefore prepared. The transient transverse colostomy was closed 8 months after the kidney transplant. Twelve months after the transplant, the patient is doing well with a serum creatinine level of 150.44 micromol/L (1.7 mg/dL).

statistically equivalent improvements in IPSS and PVR postoperatively. CONCLUSIONS: Men with an elevated BMI had significantly less improvement in Qmax following laser prostatectomy than men with normal BMI. However, BMI had no influence on improvement in IPSS or PVR. This data may assist urologists when counseling overweight men regarding their expectations of symptom relief following laser prostatectomy.

Introduction and Objective Bone morphogenetic protein-2 (BMP-2) has been shown to function as a tumor suppressor with several different cancers, while its expression level is down-regulated by CpG hypermethylation. We hypothesized that impaired regulation of BMP-2 through epigenetic pathways is associated with the pathogenesis of renal cell carcinoma (RCC). Methods To test our hypothesis, CpG methylation of the BMP-2 gene was analyzed using 2 RCC cell lines, and 96 matched RCC and normal renal tissues. We also performed functional analysis using BMP-2 restored RCC cells. Results BMP-2 mRNA expression was significantly enhanced in the RCC cells by 5-aza-2′-deoxycitidie treatment. The prevalence of BMP-2 promoter methylation was significantly higher, while BMP-2 mRNA expression was significantly lower in RCC samples as compared to normal kidney samples. Furthermore, a significant correlation was found between BMP-2 promoter methylation and mRNA transcription in the tumors. There was also a significant association of BMP-2 mRNA expression with tumor stage and lymph node involvement, while lower BMP-2 mRNA expression was significantly associated with poor overall survival after a radical nephrectomy. In RCC cells, BMP-2 restoration significantly inhibited cell proliferation, migration, invasion, and colony formation. In addition, BMP-2 overexpression effectively induced p21WAF1/CIP1 and p27KIP1 expression, and cellular apoptosis in RCC cells. Conclusion This is the first study to show inactivation of the BMP-2 gene via epigenetic pathways in RCC. Aberrant BMP-2 methylation and the resultant loss of BMP-2 expression may be useful as a molecular marker for designing improved diagnostic and therapeutic strategies for RCC. Citation Format: Yozo Mitsui, Hiroshi Hirata, Naoko Arichi, Miho Hiraki, Hiroaki Yasumono, Inik Chang, Shinichiro Fukuhara, Soichiro Yamamura, Varahram Shahryari, Guoren Deng, Sharanjot Saini, Shahana Majid, Yuichiro Tanaka, Rajvir Dahiya, Hiroaki Shiina. Dysregulation of bone morphogenetic protein 2 serves as a candidate molecular marker in human renal cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3823. doi:10.1158/1538-7445.AM2015-3823

Objectives To determine the safety and efficacy of combination chemotherapy with docetaxel (DTX), estramustine phosphate (EMP), and carboplatin (CBDCA) in patients with hormone-refractory prostate cancer (HRPC). Methods This study included a total of 40 HRPC patients. We evaluated the activity of the following schedule: weekly DTX 30mg/m 2 iv, daily EMP 10mg/kg po, and CBDCA AUC=6 iv on day 1 of a every 4-wk cycle. Treatment was continued until disease progression or excessive toxicity. Results All patients were assessable for response. A median of six consecutive cycles was administered per patient. Levels of prostate-specific antigen decreased by more than 50% in 95.0% of the patients. Consumption of medication for cancer-induced pain was reduced in 84.6%. Partial response was attained in 66.7% of measurable lesions. Of patients with bone metastasis, 8.3% demonstrated partial response. With a median follow-up of 11.4 mo, the median time to progression was 12.0 mo, and the median overall survival time was 26.6 mo. The predominant toxicities were grade-3 or -4 anemia in 32.5% of the patients, leukopenia in 20.0%, and thrombocytopenia in 17.5%. However, all toxicity was temporary and reversible with dose reduction or temporary cessation of chemotherapeutic agents. There were no therapy-related deaths. Conclusions Combination chemotherapy with DTX/EMP/CBDCA was found to have significant clinical activity with an acceptable toxicity profile in HRPC patients. More suitable selection of patients may be beneficial in terms of improved overall survival in the future.

A recent report noted that cyclosporine (CsA) inhibits replication of the hepatitis C virus (HCV) in vitro. Thus, CsA may be a superior immunosuppressant for renal transplant recipients infected with HCV. In the present retrospective study, we assessed whether CsA reduced the clinical impact of HCV infection among those patients. A total of 405 renal transplants were performed between 1973 and 2005, of whom we studied 189 who received CsA-based immunosuppression (CsA group) vs 108 who received an azathioprine-based regimen (AZA group). There were 44 HCVAb carriers and 145 noncarriers in the CsA group, and 41 carriers and 67 noncarriers in the AZA group. Our results showed that patient survival rate was significantly worse among HCVAb carriers than among noncarriers, as the overall survival rates were 82.9% and 90.9%, respectively, after 10 years and 71.5% and 85.7%, respectively, after 20 years (P = .0003). Patient survival rates were also significantly worse in HCVAb carriers than in noncarriers in both groups, which were 83.2% and 95.0%, respectively, after 10 years, and 74.7% and 88.8%, respectively, after 20 years (P = .0147) in the CsA group, and 82.9% and 83.6%, respectively, after 10 years and 70.7% and 80.6%, respectively, after 20 years (P = .0171) in the AZA group. Conversely, no significant difference was seen in patient survival rate for HCVAb carriers between the two groups (83.2% vs 82.9% at 10 years, and 74.7% vs 70.7% at 20 years, P = .8195). Our results confirmed that HCV infection has a negative impact on the long-term survival of renal transplant patients who receive either a CsA-based or an AZA-based regimen, suggesting that CsA does not have a positive impact on HCV carriers.

The recent rapid increase of mass screening for prostate cancer by measuring PSA in Japan will increase the economic burden to the healthcare system. PSA Rapid Test (PRT) is a simple inexpensive test. The usefulness of PRT as a primary screening test for prostate cancer was evaluated.When we conducted educational lectures for prostate cancer in our city, screening for prostate cancer using PRT was offered to the male participants. The results of the tests were handed to participants in writing at the end of the lectures. When the results were judged as positive, letters of referral to our institute were enclosed.One hundred and fourteen (18.6%) of 614 men were judged as positive by PRT. Of the 114 men with positive PRT, 73 (64%) visited our institution. Finally, 37 men underwent a transrectal prostate biopsy and a diagnosis of prostate cancer was made in 21 men (3.4% of all participants). The total costs for the PSA tests in this study were summed to be approximately $2,300, while they would be approximately $9,200 if all participants had undergone screening using the conventional quantitative method from the outset.PRT is a low-cost method to detect patients with prostate cancer. We believe the PRT is useful as an initial screening test for detecting prostate cancer and that the combination of the PRT and more precise quantitative testing would be a reasonable way to reduce the cost and achieve high detection rate.

The precise mechanism of heterotopic ossification caused by several types of tumours is largely unknown. However, recent studies have indicated that bone morphogenetic protein 2 (BMP2) is closely linked to the Wnt/β-catenin signaling pathway in this rare phenomenon of bone formation. We report a rare case of adrenal myelolipoma (ML) in a 27-year-old woman with heterotopic bone formation. Immunohistochemical findings showed BMP2 expression in the cytoplasm of tumour cells, as well as the matrix adjacent to newly developed bone tissue. In addition, β-catenin was prominent in the cytoplasm and nuclei of BMP2-positive tumour cells. To the best of our knowledge, this is the first report of adrenal ML showing heterotopic ossification with accelerated expression of both BMP2 and β-catenin. Our case findings indicate that BMP2 overexpression via aberrant canonical Wnt/β-catenin signaling may contribute to heterotopic bone formation occurring in adrenal ML.