A phase I/II study of cancer peptide vaccine S-288310 in patients with advanced urothelial carcinoma of the bladder.

Background: S-288310, a cancer peptide vaccine composed of two HLA-A*24:02-restricted peptides derived from two oncoantigens, DEP domain-containing 1 (DEPDC1) and M-phase phosphoprotein 1 (MPHOSPH1), was investigated in urothelial carcinoma (UC) of the bladder. Patients and methods: Thirty eight HLA-A*24:02-positive patients with progressive UC were enrolled in this study. In the phase I part of the study, three patients each were treated with S-288310 at 1 mg or 2 mg/peptide subcutaneously once a week to evaluate safety and tolerability. In the phase II, 32 patients were randomized to receive either 1 mg or 2 mg to evaluate the difference in cytotoxic T lymphocytes (CTL) induction and safety. Results: S-288310 was safe and well tolerated in the phase I. Of 27 patients evaluable for immune responses in the phase II, there was no difference in CTL induction rate between the 1 mg (100%) and 2 mg (80.0%) groups. Of 32 patients receiving S-288310 in the phase II, the most frequent drug-related AE was the injection site reaction that was observed in 29 patients (90.6%), but none of the patients discontinued administration due to these reactions and no dose relationship in the frequency and severity was observed. The objective response rate of the 32 patients was 6.3% and the disease control rate was 56.3%. The median overall survival (OS) rates for patients vaccinated with S-288310 after one regimen of chemotherapy, 2 regimens, or 3 or more were 14.4, 9.1 and 3.7 months, respectively, and 32.2% of patients post first-line treatment were alive at 2 years. OS of patients who showed CTL induction to both peptides was longer than that of those with CTL induction to no or one peptide. Conclusion: S-288310 was well-tolerated and effectively induced peptide-specific CTLs, which were correlated with longer survival for patients with UC of the bladder. Trial registration ID: JapicCTI-090980.

Genome-wide microRNA expression profiling in renal cell carcinoma: significant down-regulation of miR-141 and miR-200c.

We investigated expression profiles of microRNA (miRNA) in renal cell carcinoma [clear cell carcinomas (CCC) and chromophobe renal cell carcinomas (ChCC)] and in normal kidneys by using a miRNA microarray platform which covers a total of 470 human miRNAs (Sanger miRBase release 9.1). Unsupervised hierarchical cluster analysis revealed that CCC and ChCC were separable and that no subgroups were identified in CCCs. We found that 43 miRNAs were differentially expressed between CCC and normal kidney, of which 37 were significantly down-regulated in CCC and the other 6 were up-regulated. We also found that 57 miRNAs were differentially expressed between ChCC and normal kidney, of which 51 were significantly down-regulated in ChCC and the other 6 were up-regulated. Together, these observations indicate that expression of miRNAs tends to be down-regulated in both CCC and ChCC compared with normal kidney. We observed that miR-141 and miR-200c were the most significantly down-regulated miRNAs in CCCs. Indeed, in all cases of CCC analysed, both miR-141 and miR-200c were down-regulated in comparison with normal kidney. Microarray data and quantitative RT-PCR showed that these two miRNAs were expressed concordantly. TargetScan algorithm revealed that ZFHX1B mRNA is a hypothetical target of both miR-141 and -200c. We established by quantitative RT-PCR that, in CCCs in which miR-141 and miR-200c were down-regulated, ZFHX1B, a transcriptional repressor for CDH1/E-cadherin, tended to be up-regulated. Furthermore, we found that overexpression of miR-141 and miR-200c caused down-regulation of ZFHX1B and up-regulation of E-cadherin in two renal carcinoma cell lines, ACHN and 786-O. On the basis of these findings, we suggest that down-regulation of miR-141 and miR-200c in CCCs might be involved in suppression of CDH1/E-cadherin transcription via up-regulation of ZFHX1B.

High-resolution analysis of DNA copy number alterations and gene expression in renal clear cell carcinoma.

We analysed chromosomal copy number aberrations (CNAs) in renal cell carcinomas by array-based comparative genomic hybridization, using a genome-wide scanning array with 2304 BAC and PAC clones covering the whole human genome at a resolution of roughly 1.3 Mb. A total of 30 samples of renal cell carcinoma were analysed, including 26 cases of clear cell carcinoma (CCC) and four cases of chromophobe renal cell carcinoma (ChCC). In CCCs, gains of chromosomes 5q33.1-qter (58%), 7q11.22-q35 (35%) and 16p12.3-p13.12 (19%), and losses of chromosomes 3p25.1-p25.3 (77%), 3p21.31-p22.3 (81%), 3p14.1-p14.2 (77%), 8p23.3 (31%), 9q21.13-qter (19%) and 14q32.32-qter (38%) were detected. On the other hand, the patterns of CNAs differed markedly between CCCs and ChCCs. Next, we examined the correlation of CNAs with expression profiles in the same tumour samples in 22/26 cases of CCC, using oligonucleotide microarray. We extracted genes that were differentially expressed between cases with and without CNAs, and found that significantly more up-regulated genes were localized on chromosomes 5 and 7, where recurrent genomic gains have been detected. Conversely, significantly more down-regulated genes were localized on chromosomes 14 and 3, where recurrent genomic losses have been detected. These results revealed that CNAs were correlated with deregulation of gene expression in CCCs. Furthermore, we compared the patterns of genomic imbalance with histopathological features, and found that loss of 14q appeared to be a specific and additional genetic abnormality in high-grade CCC. When we compared the expression profiles of low-grade CCCs with those of high-grade CCCs, differentially down-regulated genes tended to be localized on chromosomes 14 and 9. Thus, it is suggested that copy number loss at 14q in high-grade CCC may be involved in the down-regulation of genes located in this region.

A mutant form of JAB/SOCS1 augments the cytokine-induced JAK/STAT pathway by accelerating degradation of wild-type JAB/CIS family proteins through the SOCS-box.

Cytokines exert biological functions by activating Janus tyrosine kinases (JAKs), and JAK inhibitors JAB (also referred to as SOCS1 and SSI1) and CIS3 (SOCS3) play an essential role in the negative regulation of cytokine signaling. We have found that transgenic (Tg) mice expressing a mutant JAB (F59D-JAB) exhibited a more potent STAT3 activation and a more severe colitis than did wild-type littermates after treatment with dextran sulfate sodium. We now find that there is a prolonged activation of JAKs and STATs in response to a number of cytokines in T cells from Tg mice with lck promoter-driven F59D-JAB. Overexpression of F59D-JAB also sustained activation of JAK2 in Ba/F3 cells. These data suggested that F59D-JAB up-regulated STAT activity by sustaining JAK activation. To elucidate molecular mechanisms related to F59D-JAB, we analyzed the effects of F59D-JAB on the JAK/STAT pathway using the 293 cell transient expression system. We found that the C-terminal SOCS-box played an essential role in augmenting cytokine signaling by F59D-JAB. The SOCS-box interacted with the Elongin BC complex, and this interaction stabilized JAB. F59D-JAB induced destabilization of wild-type JAB, whereas overexpression of Elongin BC canceled this effect. Levels of endogenous JAB and CIS3 in T cells from F59D-JAB Tg-mouse were lower than in wild-type mice. We propose that F59D-JAB destabilizes wild-type, endogenous JAB and CIS3 by chelating the Elongin BC complex, thereby sustaining JAK activation.

Autocrine expression of neurotrophins and their receptors in prostate cancer.

Previously, it has been demonstrated that the neurotrophins and their receptors are present in human prostate tissue, but neither their functional role nor localization is clearly understood. We studied the expression of neurotrophins and their receptors in prostate cancer. Between 1990 and 1999, 48 prostate cancer specimens were obtained from patients undergoing radical prostatectomy, of whom 25 received neoadjuvant hormonal therapy (NHT) and 23 were untreated. The specimens were analyzed immunohistochemically for neurotrophins (nerve growth factor, brain derived neurotrophic factor, neurotrophin 3, neurotrophin 4/5) and their receptors (TrkA, TrkB, TrkC, p75NTR). Immunohistochemical studies revealed that both benign and malignant prostate gland epithelial cells expressed the neurotrophins and their receptors to various degrees, but no obvious immunopositive reaction was observed in stromal cells. In benign epithelial cells, the neurotrophins were localized to secretory cells and the receptors were localized to basal cells. The neurotrophins, TrkA and TrkC were expressed to a similar extent in prostate cancer specimens obtained from patients both with and without NHT. In contrast, the expression of TrkB was down-regulated and the expression of p75NTR was up-regulated in prostate cancer after hormonal therapy. These findings suggest that neurotrophins are secreted by prostate cancer cells in an autocrine fashion. Neurotrophins may be involved, through their receptors, in the escape mechanism from cell death after androgen depletion found in prostate cancer.

[A male case of primary bilateral breast cancers during estrogen therapy for prostate cancer].

An 82-year old man received total androgen blockade therapy (bilateral orchiectomy and 375 mg/day flutamide) for the treatment of stage C prostate cancer. Serum PSA levels were undetectable for 13 months and thereafter increased gradually. We administered estramustine phosphate sodium (EPS) instead of flutamide under the diagnosis of hormone refractory prostate cancer. EPS therapy was discontinued after 9 months because serum PSA levels increased again. Then, the patient complained of bilateral breast nodules and pain. Bilateral mammectomies were performed due to bilateral breast cancers which had been diagnosed by aspiration biopsies and radiographic examinations, but he died four months after the operations. Final pathological diagnosis was ductal adenocarcinoma of the breasts. Immunohistochemical study revealed expressions of PSA in the breast cancers. We diagnosed double cancers of the prostate and the breast because of the different expression patterns of progesterone receptor between them. We review the literatures and discuss the differential diagnosis of prostate cancer and PSA-producing breast cancer.

Malignant neurofibroma of the urinary bladder.

Malignant neurofibroma of the urinary bladder is a very rare entity and usually associated with von Recklinghausen's disease. We present the first case of sporadic malignant neurofibroma of the urinary bladder and a review of the literature.

Emphysematous cystitis following brain contusion.

Emphysematous cystitis is a rare disorder most commonly seen in patients with urinary tract infection and diabetes mellitus. We present a nondiabetic case of a 46-year-old woman with this entity following brain contusion.

[Xanthogranulomatous epididymitis. A case report].

A 45-year-old man with spinal injury and diabetes mellitus who complained high fever and progressive enlargement of left intrascrotal mass visited to our hospital. Preoperative ultrasonography demonstrated epididymitis and abscess formation. Left high orchiectomy was performed because testicular tumor could not be denied. Epididymis was replaces by bright yellow mass associated with abscess and adhered to testis strongly. Histopathologically, the mass diagnosed xanthogranulomatous epididymitis consisted of foamy macrophages and chronic inflammatory cells. This is the first case in Japanese medical literature.

Prediction of alpha-blocker response in men with benign prostatic hyperplasia by magnetic resonance imaging.

OBJECTIVES: To assess the value of magnetic resonance imaging (MRI) for predicting the alpha-blocker response in men with symptomatic benign prostatic hyperplasia (BPH) and to examine the relationship between MRI and the area density of smooth muscle cells in BPH. METHODS: Twenty-eight men were consecutively enrolled in this study and received tamsulosin 0.2 mg once daily for 4 to 6 weeks. The efficacy of tamsulosin was determined by measuring improvements in the maximum urinary flow rate (Qmax) and International Prostate Symptom Score (IPSS). The patients underwent T2-weighted MRI and were separated into a high (H) or iso-low (IL) group according to the signal intensity of the inner gland of the prostate compared with that of bone marrow of the proximal femur head. The area density of smooth muscle cells was determined using immunostaining with antiactin antibody in 16 prostate specimens. RESULTS: IPSS significantly decreased after the administration of tamsulosin from 16 +/- 1 to 8 +/- 1 (n = 28, P <0.0001 ), and 76.7% of the patients had an improved IPSS of 25% or greater. Qmax was significantly increased in group IL (P = 0.03) but not in group H. Of the patients in group IL, 53.3% had a Qmax response (an increase of Qmax of 30% or more); 15.4% did so in group H (P = 0.04). The area density of smooth muscle cells was 48.1 +/- 3.7% in group IL (n = 9) and 36.7 +/- 3.2% in group H (n = 7, P = 0.04). CONCLUSIONS: MRI is useful in estimating the area density of smooth muscle cells in the prostate and in predicting Qmax response for alpha-blocker therapy in patients with symptomatic BPH.

Simple technique of ligation and division of dorsal vein complex during radical retropubic prostatectomy.

A simple technique for ligation and division of the dorsal vein complex during radical retropubic prostatectomy is described. The dorsal vein complex and anterior wall of the membranous urethra were collectively ligated with a "theta theta" suture using 1-0 catgut and then divided during radical retropubic prostatectomy. This technique prevents dislodgment of the catgut during the procedure, enables maximal preservation of the striated urethral sphincter, and guarantees a lower risk of postoperative urinary incontinence.

Erythropoietin-producing renal cell carcinoma arising from acquired cystic disease of the kidney.

A 49-year-old woman had been on hemodialysis for 18 years. She presented with left back pain and macrohematuria. Radiologic studies demonstrated a left renal tumor with acquired cystic disease of the kidney. Her serum erythropoietin (EPO) level was 78.4 U/L despite no history of EPO supplementation. Left radical nephrectomy was performed. Pathologic examination revealed EPO-producing renal cell carcinoma. After surgery, the patient's serum EPO level decreased markedly to 15.1 U/L. The measurement of serum EPO levels may be useful for detecting and monitoring a recurrence of renal cell carcinoma with acquired cystic disease of the kidney in patients on long-term hemodialysis.

Testis sparing surgery for infantile synchronous bilateral teratoma of the testis.

We report a rare case of infantile synchronous bilateral testicular teratoma treated by testis sparing surgery. Preoperative ultrasonography, tumor marker status and intraoperative findings were suggestive of benign neoplasia. Under these circumstances we performed high orchiectomy for the left testis and testis sparing surgery for the right. Surgical treatment of teratoma in childhood is controversial, especially when it occurs bilaterally. In this report we discuss testis sparing surgery as the treatment for this disease.

Renal needle biopsy along the retrograde puncture line of the renal calyx: a new promising technique.

The Biopty-gun is a useful tool in conducting percutaneous renal biopsies, but bleeding is still a significant complication. To reduce the rate of severe bleeding complications, we attempted a new method of renal needle biopsy using a retrograde access technique. Retrograde puncture of the renal calyx was performed using the Lawson nephrostomy kit. The 18-gauge needle of the Bioptygun was inserted along the puncture wire and fired. A 7-french pigtail catheter was retained in the renal pelvis for a few days following the procedure. This biopsy is a promising and safe technique.

A simple technique for vesicourethral anastomosis in retropubic radical prostatectomy.

Vesicourethral anastomosis during radical retropubic prostatectomy is often difficult. We present a new simple technique using a Nélaton catheter to aid in accurate suture placement for vesicourethral anastomosis.

Role of platelet-activating factor in two-kidney, one-clip hypertension.

BACKGROUND: Platelet-activating factor (PAF) is a bioactive phospholipid which is a potent hypotensive agent. To investigate the role of PAF in renovascular hypertension, we determined the PAF concentration and its production level assessed by the activity of cholinephosphotransferase (CPT) in renal tissue and examined the effect of a PAF antagonist on the mean arterial pressure (MAP) in control and two-kidney with one clipped (2K1C) hypertensive rats. MATERIALS AND METHODS: The concentration of PAF and CPT in the renal medulla and cortex were determined by radioassay. Also, the effect of a PAF antagonist, CV-6209, on MAP was also examined in both 2K1C hypertensive and normal control rats. RESULTS: The PAF concentration and CPT activity were significantly higher in the medulla than in the cortex in both 2K1C hypertensive and normal control rats, and both values in the medulla were also significantly higher in the clipped kidney than in the contralateral unclipped kidney or in control rat kidneys. We also observed a significant negative correlation between the PAF concentration in the medulla, and the medulla weight in the clipped kidney of 2K1C hypertensive rats. Infusion of the PAF antagonist, CV-6209, did not affect MAP in 2K1C hypertensive rats, but was significantly increased (P < 0.05) in control rats. CONCLUSIONS: These findings suggest that PAF, whose production is induced by renal ischemia due to renal artery stenosis, plays an important role in the renomedullary vasodepressor system, but the effect of PAF as a vasodilator in the peripheral vessels is limited in 2K1C hypertension.

Three approaches for laparoscopic unroofing of simple and complicated renal cysts.

We report 2 cases of simple renal cysts which were marsupialized with 2 laparoscopic approaches involving either transperitoneal, with reflection of the colon medially or dissection through the mesocolon, and a case of a multilocular renal cyst which was treated by the retroperitoneal approach. Although laparoscopic unroofing of a renal cyst is a safe and effective alternative to open surgical techniques, the transperitoneal approach should only be used for simple renal cysts. The retroperitoneal approach for complicated renal cysts may be indicated if preoperative examinations exclude the possibility of malignancy.

Muscarinic receptor subtypes and receptor-coupled phosphatidylinositol hydrolysis in rat bladder smooth muscle.

BACKGROUND: The purpose of this study was to evaluate the muscarinic receptor subtypes expressed in rat bladder smooth muscle and characterize the muscarinic receptor-coupled phosphatidylinositol (PI) hydrolysis in order to clarify the first step of bladder smooth muscle contraction. METHODS: Expressions of mRNAs of muscarinic receptor subtypes were examined by Northern blot analysis. Changes in the mass of inositol 1,4,5-trisphosphate (IP3) and the inhibitory effects of muscarinic subtype specific antagonists on PI hydrolysis were determined after carbachol stimulation. RESULTS: mRNAs of m2 and m3 genes, encoding M2 and M3 receptors, were expressed in rat bladder smooth muscle. Carbachol produced a rapid increase of IP3, which returned to the basal level within 30 seconds. 4-Diphenylacetoxyl-N-methylpiperidine methiodide (4-DAMP; M1 and M3 antagonist) strongly inhibited the PI hydrolysis, but methoctramine (M2 antagonist) partially inhibited it at 10(-4) mol/L. The IC50 value for atropine was 9.5 x 10(-9) mol/L, for pirenzepine 6.4 x 10(-6) mol/L, and for 4-DAMP 1.5 x 10(-7) mol/L. CONCLUSION: M2 and M3 receptors are expressed in rat urinary bladder. Only M3 receptor was involved in the production of IP3, which might induce the initial phase of contractile response in rat bladder smooth muscle after carbachol stimulation.

[Cystic lymphangioma of the tunica vaginalis testis. A case report].

A 42-year-old man who complained progressive enlargement of an intrascrotal mass visited to our hospital. Preoperative sonography revealed multiple cystic masses adjacent to the left testis. Total surgical excision was performed. The cystic masses were arising from tunica vaginalis testis. Histopathologically, a cystic lymphangioma was diagnosed because of the morphological features and the immunohistochemical stainings of CD34 and Factor VIII related antigen which were observed positive reactions in endothelial cells of the cysts.

Modulation of platelet-activating factor synthesis by recombinant interferon-alpha in human renal cell carcinoma.

Platelet-activating factor (PAF), a potent phospholipid chemical mediator of inflammation, is involved in multiple cellular functions. Since PAF has a strong effect on platelet aggregation and on the enhancement of capillary permeability, it is possible that this factor plays an important role in tumor progression. In human renal cell carcinoma (RCC), it has recently been reported that immunotherapy with interferon (IFN) is effective for the prevention of tumor recurrence and progression. To evaluate the role of PAF and the effect of interferon-alpha (IFN-alpha) on PAF production in RCC, we measured PAF content and the activity of choline phosphotransferase (CPT), an enzyme involved in the de novo biosynthesis of PAF, in RCC specimens obtained from 30 patients who had undergone radical nephrectomy for RCC, and in specimens of normal renal cortex and normal renal medulla. PAF was present in both RCC and the normal renal tissues. Although CPT activity in RCC was similar to that in normal renal cortex, CPT activity in the normal medulla was significantly higher than that in RCC and the normal cortex. No correlation was found between CPT activity and the pathological findings in RCC. Although there was no difference in CPT activity in normal renal tissues between patients treated preoperatively with IFN-alpha and those untreated, CPT activity in RCC was significantly reduced in patients who had received IFN-alpha compared with those who had not. These findings suggest that IFN-alpha may modulate the production of PAF in RCC patients.