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.

[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.

[Congenital pelvic arteriovenous fistula in a male. A case report].

A congenital arteriovenous fistula (AV fistula) in the true pelvis is extremely rare, especially in males. We present a case of this disease with pollakiuria and intrarectal discomfort. Diagnosis was made by computed tomography and magnetic resonance imaging and confirmed by cine angiography. Because the AV fistula involved the bladder, prostate and rectum, ligation of the main feeding arteries was performed. He also had benign prostatic hypertrophy and was treated by conservative therapy because of a high risk of massive bleeding in surgical treatment.

[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.

[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.

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.

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.

Regulation of prostaglandin synthesis by reduced glutathione in urinary bladder epithelium.

A possible mechanism is presented by which reduced glutathione (GSH) regulates prostaglandin (PG) synthesis in microsomes of the porcine bladder epithelium. At a concentration of GSH less than 10(-5) M, microsomes produced more PGI2 and PGF2 alpha than PGE2. At a greater GSH concentration, PGE2 synthesis was remarkably enhanced. On the other hand, PGI2 and PGF2 alpha synthesis was inhibited. In the presence of 10(-3) M GSH, ten times more PGE2 was produced than the other PGs. The concentration of GSH in porcine bladder epithelium was about 0.6 mM. This reciprocal effect of GSH was also observed in rabbit and bovine bladder epithelium. These findings suggest that GSH is involved in the regulation of PG synthesis in urinary bladder epithelium. GSH may influence the physiological and pathophysiological changes elicited by PGs in the lower urinary tract.

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.

Membrane fluidity and lipid composition of rat testicles in experimental cryptorchidism.

Membrane fluidity and lipid composition of rat testis in experimental bilateral cryptorchidism were studied. Membrane fluidity measured by fluorescence anisotropy of diphenylhexatriene decreased on the 3rd day of intraabdominal fixation, at an early stage of cryptorchidism. Lipid composition of testicular membrane was changed drastically by the treatment, and time-dependent changes were observed during the course of the experiment. Cholesterol content increased significantly, but phospholipid content was not affected by the treatment. The ratio of cholesterol to phospholipids increased significantly. Fatty acid moieties of phospholipids varied during the course of the experiment. The ratio of unsaturated to saturated fatty acids decreased on the 3rd day. These changes indicated a different physical state of cryptorchid membranes from normals, and the changes may be involved in the pathophysiology of cryptorchidism.

Effects of thiols on prostaglandin synthesis in bovine bladder epithelium.

The regulation of prostaglandin (PG) synthesis was characterized in microsomes of bovine bladder epithelium. Coenzyme A (CoA) and its metabolite cysteamine drastically decreased total PG synthesis. Furthermore, CoA inhibited solubilized cyclooxygenase which was precipitated by anti-cyclooxygenase antibody. Reduced glutathione (GSH) slightly increased total PG production and changed the pattern of PG synthesis. Other thiols, cysteine and ergothioneine, did not change total PG production. None of the thiols stimulated the incorporation of arachidonic acid into the phospholipid fraction. These findings suggest that CoA may directly regulate cyclooxygenase activity and GSH may subsequently change the pattern of PG production in bovine bladder epithelium.

Interferon as adjunctive treatment for non-metastatic renal cell carcinoma.

OBJECTIVE: To investigate the effect of recombinant alpha 2b-interferon therapy on natural killer (NK) activity and antibody-dependent cell-mediated cytotoxicity (ADCC) in the peripheral blood in patients with renal cell carcinoma who had undergone radical nephrectomy. PATIENTS AND METHODS: Between January 1988 and June 1989, 20 patients (14 men and six women, mean age 59 years, range 43-80) received interferon (IFN) therapy following radical nephrectomy for renal cell carcinoma. Thirteen patients had stage I disease, one had stage II and six had stage III; none had metastases. RESULTS: There was a significant increase in NK activity at 5 and 7 months after starting IFN therapy but there was no increase in ADCC. CONCLUSIONS: Low doses of IFN administered long-term increased NK activity in patients with renal cell carcinoma. This finding should be helpful in designating protocols for randomized studies of post-operative IFN administration as adjuvant therapy.

Changes of rat urinary bladder during acute phase of spinal cord injury.

Spinal cord injury (SCI) at Th13 was induced in female Wistar rats, and changes in the urinary bladder were examined during the acute phase of SCI. Wet weights of the spinal bladders increased twofold over controls by 7 days after SCI. Intravesical volumes increased sixfold over control values by day 3, and then decreased 7 days after the injury. Maximal pressure within the bladder decreased in all spinal rats compared with controls. Smooth muscle cells were isolated from the urinary bladder, and their total protein and DNA content were measured by multiparametric cytofluorometry. DNA content of isolated smooth muscle cells decreased by day 3 and remained 7 days after the spinal injury. Total protein content of isolated smooth muscle cells was decreased 1 day after and increased 7 days after the spinal injury, just when spinal reflex of the bladder recovered. These findings suggest that hypertrophy of smooth muscle cells in urinary bladder is related to the activity of peripheral autonomic nerve and that smooth muscle cells already begin to hypertrophy during the spinal shock period to adjust themselves to the new state, that is, the spinal bladder.

Lipid composition of the plasma membrane isolated from normal and precancerous rat bladder epithelium.

Four-week-old Wistar strain rats were given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) solution for 12 weeks and used as a precancerous model. Sixteen-week-old rats of the same strain were used as controls. Plasma membranes (PMs) were prepared from normal and precancerous bladder epithelium. The lipid content and the fatty acid compositions of total lipids, phospholipids, and their subclasses were analysed. The following observations were made: 1) Precancerous PMs had longer chains composed of more unsaturated fatty acids than the normal ones. 2) There were high amounts of arachidonic acid in rat bladder epithelium, and it accounted for more than fifty percent of phosphatidylethanolamine. PMs of precancerous epithelium had more arachidonic acid than those of the normal epithelium. These findings may be useful for the early detection of precancerous epithelium.

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.

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.

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.

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.