Ichiya Honma

Phase I clinical study of anti-apoptosis protein survivin-derived peptide vaccination for patients with advanced or recurrent urothelial cancer

Survivin, a member of the inhibitor of apoptosis protein family, is expressed in many malignant tumors including urothelial cancer but is hardly detectable in normal, differentiated adult tissues. Previously we reported CD8-positive cytotoxic T-lymphocytes (CTLs) were successfully induced by stimulation with survivin-2B80-88 peptide in vitro. We started a phase I clinical study of survivin-2B80-88 peptide vaccination for advanced urothelial cancer patients to assess the safety and efficacy of this vaccination. Nine patients were received vaccination and were evaluated for immunological evaluation, adverse events, and clinical responses. A total of 46 vaccinations were carried out. There was no severe adverse event. HLA-A24/survivin-2B80-88 peptide tetramer analysis revealed a significant increase in the peptide-specific CTL frequency after the vaccination in five patients. Slight reduction of the tumor volume was observed in one patient. Survivin-2B80-88 peptide-based vaccination is safe and should be further considered for potential immune and clinical efficacy in urothelial cancer patients.

Effect of human leukocyte antigen class I expression of tumor cells on outcome of intravesical instillation of bacillus calmette-guerin immunotherapy for bladder cancer.

Purpose: Various immune systems play important roles in the clinical efficacy of intravesical Bacillus Calmette-Guerin (BCG) instillation for bladder cancer. However, human leukocyte antigen (HLA) class I molecules on tumor cells and various immune system cells infiltrating to/around the tumor have not been evaluated, although many prognostic factors, including clinical, pathologic, and molecular ones, have been investigated. The aim of this study was to determine immunologic prognostic factors of BCG immunotherapy for bladder cancer. Experimental Design: Immunohistochemical staining for HLA class I, CD4, CD8, CD20, CD68, TIA-1, S-100, and FOXP3 was carried out on specimens from 30 patients who underwent BCG immunotherapy from whom both pretreatment and posttreatment specimens were obtained. We did univariate and multivariate analyses of factors affecting recurrence-free survival. The positive, weakly positive, and negative groups of cells that infiltrated to/around the tumor were compared with recurrence-free survival using the Kaplan-Meier method and log-rank test. Results: HLA class I was a significant prognostic factor both in univariate and multivariate analyses. The 5-year recurrence-free survivals of the patients with HLA class I–positive tumors and those with HLA class I–negative tumors were 55.7% and 19.1%, respectively (P = 0.019). There was a significant association between infiltration of CD8, CD20, and CD68-positive cells after BCG therapy and therapeutic effects. Conclusions: Our data show that expression of HLA class I molecules on tumor cells contributes significantly to the therapeutic effect of BCG immunotherapy for bladder cancer. It is suggested that CTLs may be one of main effectors in this therapy.

Silodosin and its potential for treating premature ejaculation: A preliminary report

Premature ejaculation is a common sexual problem, as is erectile dysfunction. We evaluated silodosin, a highly selective α1A‐adrenoceptor antagonist, as a new treatment option for premature ejaculation. α1‐Adrenoceptor antagonists are widely used for lower urinary tract symptoms, and clinical studies on silodosin have shown excellent clinical efficacy for lower urinary tract symptoms. However, compared with other α1‐adrenoceptor antagonists, silodosin appeared to suppress ejaculation in a relatively higher percent of trial participants. This suppression of ejaculation by silodosin suggested its potential for treating premature ejaculation. Consequently, we evaluated the feasibility of off‐label silodosin as a new treatment option for premature ejaculation. Eight patients suffering premature ejaculation were treated with silodosin. Silodosin (4 mg) was given 2 h before sexual intercourse. Intravaginal ejaculatory latency time, premature ejaculation profile item, clinical global impression change in premature ejaculation and systemic adverse events were recorded. Intravaginal ejaculatory latency time was significantly prolonged (from 3.4 min to 10.1 min, P = 0.003). All patients answered better (much better) or slightly better for their own premature ejaculation problem compared with pretreatment condition in the clinical global impression change. Premature ejaculation profile also significantly improved. Two (25%), three (37.5%) and seven patients (87.5%) experienced anejaculation, reduced semen volume and discomfort during orgasm, respectively. However, these problems were not of major concern for the participants. No systemic adverse effects were reported. The current results support the possible use of silodosin as a new treatment option for premature ejaculation, and suggest that a placebo controlled study assessing its clinical usefulness would be worthwhile.

Lymphangioma of the kidney.

Lymphangiomas are rare benign tumors that are congenital malformations of the lymphatic system. Most cases present in children as a soft, cystic mass in the neck and the axilla. Primary renal lymphangioma is exceedingly rare, with only 35 cases reported so far. We report a case of primary lymphangioma arising from the kidney. A 59‐year‐old man was referred for evaluation of a right renal mass found in an abdominal ultrasonography during a health checkup. Abdominal ultrasonography and computed tomography (CT) revealed a 3.2 × 2.9 cm multiloculated cystic mass in the upper pole of the right kidney. We could not deny malignant disease such as cystic renal cell carcinoma with any diagnostic modalities. The patient was brought to surgery. During the surgical procedure, the tumor was suspected to be lymphangioma of the kidney as a result of a frozen‐ section histopathological evaluation. Therefore enucleation of the tumor was performed. Pathological evaluation of the specimen revealed lymphangioma arising from the kidney. The patient is free of disease after a 3‐month follow‐up period.

Identification of an Immunogenic CTL Epitope of HIFPH3 for Immunotherapy of Renal Cell Carcinoma

Purpose: CD8+ CTLs have an essential role in immune response against tumor. Although tumor-associated antigens have been identified in renal cell carcinoma (RCC), few of these are commonly shared and investigated as therapeutic targets in the clinical medicine. In this report, we show that HIFPH3, a member of prolyl hydroxylases that function as oxygen sensor, is a novel tumor antigen and HIFPH3-specific CTLs are induced from peripheral blood lymphocytes of RCC patients. Experimental Design: Expression of HIFPH3 was examined by reverse transcription-PCR and immunostaining with anti-HIFPH3 antibody. To identify HLA-A24-restricted T-cell epitopes of HIFPH3, eight peptides were selected from the amino acid sequence of this protein and screened for their binding affinity to HLA-A24. Peptide-specific CTLs were induced by stimulating peripheral blood lymphocytes of HLA-A24-positive RCC patients with these peptides in vitro. HLA-A24-restricted cytotoxicity of the CTLs against HIFPH3+ RCC lines was assessed by chromium release assay. Results: HIFPH3 was overexpressed in many RCC cell lines and primary RCC tissues, whereas it was not detectable in normal adult tissues by reverse transcription-PCR. Of the eight peptides that contained HLA-A24-binding motif, HIFPH3-8 peptide (amino acid sequence, RYAMTVWYF) could induce the peptide-specific CTLs from 3 of 6 patients with HIFPH3-positive RCC. Furthermore, HIFPH3-8 peptide-specific CTLs showed cytotoxicity against HIFPH3+ RCC cell lines in a HLA-A24-restricted manner. Conclusions: HIFPH3 may be a target antigen in immunotherapy for RCC and HIFPH3-8 peptide could be used as a peptide vaccine for HLA-A*2402+/HIFPH3+ RCC patients.

Massive hematuria after cystoscopy in a patient with an internal iliac artery aneurysm

An unusual case is reported here of a patient with internal iliac artery aneurysm who developed massive hematuria after cystoscopic examination. A 75‐year‐old man presented with asymptomatic gross hematuria. Cystoscopic examination revealed that the bladder neck was congested and that the right‐side wall was being pressed on by an extrinsic mass. Computed tomography showed a right internal iliac artery aneurysm and tortuous perivesical vessels. Three days after the cystoscopic examination the patient suffered massive hematuria. Hemorrhage due to an arteriovesical or arterio‐ureteral fistula secondary to rupture of the internal iliac artery aneurysm was suspected, and an emergency operation was performed. At operation the aneurysm had not ruptured but overswelling perivesical vessels were found to have developed, and these fed a high blood flow to the bladder neck. In the present case cystoscopic examination injured the mucosa and led to massive hemorrhage from the bladder neck.

Hypoxia-inducible factor (HIF)-independent expression mechanism and novel function of HIF prolyl hydroxylase-3 in renal cell carcinoma.

PurposeWe previously found that hypoxia-inducible factor (HIF) prolyl hydroxylase-3 (PHD3) was frequently overexpressed in renal cell carcinomas (RCCs), unlike in normal tissues, and therefore, we studied the mechanism and role of PHD3 expression in RCC.MethodsThe von Hippel–Lindau (VHL)-gene-mutant RCC cell lines SMKT-R2 and SMKT-R3 and wild-type VHL cell lines Caki-1 and ACHN were used. Associations of the expression of PHD3 with HIF-α proteins and signal transduction pathways were evaluated under normoxic conditions. The effect of PHD3 on cell proliferation was also examined by small interference RNA and cDNA transfection. Moreover, the prognostic impact of PHD3 expression in clear cell RCC (CCRCC) was evaluated using primary cancer tissues.ResultsIn SMKT-R2 and SMKT-R3, HIF-α proteins were expressed and PHD3 was highly expressed. On the other hand, ACHN had low expression of HIF-α proteins and PHD3. However, Caki-1 had high expression of PHD3 even though there was no distinct expression of HIF-α proteins. PHD3 expression was inhibited by blockade of Akt and mammalian target of rapamycin (mTOR), but not by HIF-1α and HIF-2α double knockdown. In addition, PHD3 knockdown resulted in the promotion of cell proliferation in SMKT-R2, SMKT-R3 and Caki-1. On the other hand, forced expression of PHD3 reduced cell proliferation in ACHN. In immunohistochemistry, PHD3 expression was a significant factor for better recurrence-free survival in patients with CCRCC.ConclusionsPHD3 expression can be induced by the phosphatidylinositol-3 kinase/Akt/mTOR pathway in RCC independently of HIF proteins. Furthermore, PHD3 has an antiproliferative function independent of HIF protein status in RCC, indicating a novel expression mechanism and function of PHD3.

Dissociation between patients and their partners in expectations for sexual life after radical prostatectomy

To analyze expectations for sexual life after radical prostatectomy in patients and their partners, and its influence on sexual motivation and bothers in the postoperative period.

Clinical Outcomes of Patients with pT0 Bladder Cancer after Radical Cystectomy: A Single-institute Experience

OBJECTIVE To investigate the clinical outcomes of patients who underwent radical cystectomy for bladder cancer at a single institution and compare those who had pT0 specimens with those who had residual cancer. METHODS From January 1990 to December 2006, 186 patients underwent radical cystectomy with or without neoadjuvant chemotherapy for cT2 or higher stage urothelial carcinoma in the bladder in our hospital. We estimated the 5-year disease-free survival, cancer-specific survival and overall survival by the pathological stage. RESULTS The median follow-up of the 186 patients was 38.5 months (0-194). Of these, 51 received neoadjuvant chemotherapy. For all subjects, the 5-year disease-free survival was 54.9%, cancer-specific survival 61.0% and overall survival 57.1%. Of the 186 patients, 24 (12.9%) had no residual cancer in the bladder specimen at radical cystectomy. Of the 24 patients with pT0, only 1 (4.2%) died of bladder cancer. The 5-year disease-free survival, cancer-specific survival and overall survival rates in patients with pT0 were ∼96.0%. We found pT0 histology in 11 of the 51 patients (21.6%) with neoadjuvant chemotherapy and in 13 of the 135 patients (9.6%) with radical cystectomy alone (P = 0.047). CONCLUSIONS We demonstrated that the outcomes of patients who underwent radical cystectomy were similar to those in previous reports. Patients with pT0 showed favorable outcomes for disease-free survival, cancer-specific survival and overall survival in our study. However, they should be periodically followed up because pT0 does not always mean cure.

Simple and reliable predictor of urinary continence after radical prostatectomy: serial measurement of urine loss ratio after catheter removal.

To evaluate urine loss ratio after catheter removal as a predictive factor of urinary continence after radical prostatectomy.