Akira Joraku

Bacillus Calmette–Guerin (BCG) immunotherapy for bladder cancer: Current understanding and perspectives on engineered BCG vaccine

Since the first report in 1976, accumulated clinical evidence has supported intravesical Bacillus Calmette–Guerin (BCG) therapy as one of the standard methods of management of intermediate‐ and high‐risk non‐muscle invasive bladder cancer. Despite its efficacy, intravesical BCG therapy is associated with a variety of adverse events (AEs), most of which are tolerable or controllable with supportive care. However, some patients receiving intravesical BCG therapy may experience uncommon but severe AEs, leading to cessation of BCG therapy. Not all, but most severe AEs result from either local or systemic infection with live BCG. Intravesical instillation of BCG elicits multiple immune reactions, although the precise immunological mechanism of BCG therapy is not clear. It is convenient to separate the complex reactions into the following three categories: infection of urothelial cells or bladder cancer cells, induction of immune reactions, and induction of antitumor effects. Recently, our knowledge about each category has increased. Based on this understanding, predictors of the efficacy of intravesical BCG therapy, such as urinary cytokine measurement and cytokine gene polymorphism, have been investigated. Recently, preclinical studies using a novel engineered mycobacterium vaccine have been conducted to overcome the limitations of BCG therapy. One approach is Th1 cytokine‐expressing recombinant forms of BCG; another approach is development of non‐live bacterial agents to avoid AEs due to live BCG infection. We also briefly describe our approach using an octaarginine‐modified liposome‐incorporating BCG cell wall component to develop future substitutes for live BCG. (Cancer Sci 2013; 104: 22–27)

Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling

The Wnt signaling pathway is involved in normal embryonic development and controls the homeostatic self-renewal of stem cells in adult tissues. Constitutive activation of Wnt signaling contributes to cancer development and progression. We identified a CXXC4 homozygous deletion at 4q24 in an aggressive renal cell carcinoma (RCC) using single-nucleotide polymorphism (SNP) arrays. CXXC4 encodes Idax, which negatively regulates Wnt signaling by binding to the PDZ domain of Dishevelled. CXXC4 mRNA levels in tumor samples were significantly lower in patients with metastases compared with those without (P=0.0016). Patients whose tumors had lower CXXC4 expression than normal kidney showed a poorer cause-specific survival outcome than those with higher expression (P=0.0095). Decreased expression of CXXC4 also correlated with cytoplasmic staining of β-catenin. Knockdown of CXXC4 induced the nuclear translocation of β-catenin and altered expression of a set of genes involved in cell proliferation, invasion and survival. Furthermore, reduced expression of CXXC4 by small interfering RNAs promoted cell proliferation and inhibited apoptosis after 5-FU and doxorubicin treatment in RCC cells. These data suggest that CXXC4 plays a critical role in tumor progression of RCC through Wnt signaling. Wnt signaling could thus be a potential molecular target in RCC indicating decreased CXXC4 expression.

Negative Impact of Metabolic Syndrome on the Responsiveness to Sildenafil in Japanese Men

INTRODUCTION Several recent studies suggested that the prevalence of erectile dysfunction (ED) was higher in men with metabolic syndrome (MS). AIM We analyzed the impact of MS on the responsiveness to sildenafil. METHODS A total of 133 ED patients were evaluated for the prevalence of MS and graded on severity of ED. MS was diagnosed according to the International Diabetes Federation (IDF) definition. The severity of ED was evaluated by the International Index of Erectile Function (IIEF) questionnaire. Hormonal parameters were measured for all patients, and the IIEF questionnaire was conducted after administration of eight tablets of 50-mg doses of sildenafil. If the scores to questions 3 and 4 of the IIEF were 4 or higher after administration, the patients were defined as responders to sildenafil. MAIN OUTCOME MEASURES To clarify the negative impact of MS on the responsiveness to sildenafil. RESULTS The mean age of the patients was 56.9 years, and 25 patients were diagnosed with MS. The IIEF-erectile function score and the response rate for sildenafil decreased as the number of MS components increased. Logistic regression analysis showed that the presence of MS along with severity of ED and history of pelvic surgery were significant independent risk factors of nonresponse for sildenafil. The hazard ratio for the presence of MS was 3.30 (95% confidence interval [CI]: 1.17-9.73). No meaningful association was observed between total testosterone or free testosterone levels and MS in this population. CONCLUSION We demonstrated the negative impact of MS on the responsiveness to sildenafil. Erectile function and response rate for sildenafil decreased as the number of MS components increased.

Immunoprotection against murine bladder carcinoma by octaarginine-modified liposomes incorporating cell wall of Mycobacterium bovis bacillus Calmette-Guérin

To develop a prototype of a non‐live bacterial agent that consists of a cell wall (CW) preparation from heat‐killed bacillus Calmette‐Guérin (BCG‐CW) incorporated into octaarginine‐modified cationized liposomes as a vector (R8‐liposome‐BCG‐CW), and to evaluate its immunoprotective potentiation in mice, as although BCG is an established effective immunotherapy for nonmuscle‐invasive bladder cancer, more active and less toxic treatments are needed.

Pattern of intravesical recurrence after surgical treatment for urothelial cancer of the upper urinary tract: a single institutional retrospective long-term follow-up study.

Objectives:  To estimate the risk of intravesical recurrence in patients with primary urothelial cancer of the upper urinary tract.

Bladder reconstruction using a collagen patch prefabricated within the omentum

Objective:  We present our experience with a novel bladder reconstruction model using a collagen sponge pre‐embedded within the omentum. The aim of the study is to evaluate tissue regeneration of the reconstructed bladder and the effect of prefabricating the collagen patch within the omentum.

Prognostic impact of young age on stage IV prostate cancer treated with primary androgen deprivation therapy.

To elucidate whether the disease characteristics and prognosis of stage IV prostate cancer treated with primary androgen deprivation therapy differ between young and elderly patients.

The liposome-incorporating cell wall skeleton of Mycobacterium bovis bacillus Calmette-Guéin can directly enhance the susceptibility of cancer cells to lymphokine-activated killer cells through up-regulation of natural-killer group 2, member D ligands.

• To conduct a preclinical evaluation of the ability of natural killer cells to cytolyze bladder cancer cells that were modified to show enhanced expression of natural‐killer group 2, member D (NKG2D) ligands by R8‐liposome‐bacillus Calmette‐Guéin (BCG)‐cell wall skeleton (CWS) treatment.

Expression of the oncoprotein gankyrin and phosphorylated retinoblastoma protein in human testis and testicular germ cell tumor.

The oncoprotein, gankyrin, is known to facilitate cell proliferation through phosphorylation and degradation of retinoblastoma protein. In the present study, we evaluated the expression of gankyrin and phosphorylated retinoblastoma protein in human testis and testicular germ cell tumors.

High prevalence of hypogonadism determined by serum free testosterone level in Japanese testicular cancer survivors

Hypogonadism is a major complication in testicular cancer survivors, but its prevalence varies among studies. In Japan, free testosterone has been used for diagnosis of late‐onset hypogonadism syndrome. In the present study, we evaluated the hormone level of testicular cancer survivors and its impact on their quality of life.