Katsuhiro Fukuta

Simple Method of Preventing Postoperative Inguinal Hernia After Radical Retropubic Prostatectomy

OBJECTIVES To establish a novel and simple method of preventing post-retropubic prostatectomy (RRP) inguinal hernia. Inguinal hernias occur in 8%-22% of men within 1-2 years of RRP. Although manipulation during RRP might weaken the normal fascia structure at the internal inguinal ring with the vas deferens, the exact mechanism of post-RRP inguinal hernia remains unknown. METHODS Several surgeons performed RRP at our hospital on 271 patients between April 2004 and September 2009. Among these patients, post-RRP measures to prevent inguinal hernia were applied to 101 patients (group A) and not applied to 170 patients (group B). We released the bilateral spermatic cord from the peritoneum before suturing the wound, which should prevent the intestinal tract coated with the peritoneum from pushing through the internal inguinal tract. We compared the incidence of postoperative inguinal hernia between the 2 groups. RESULTS The patients were followed up for an average of 11.6 (range: 2-22 months) and 23.9 (range: 23-24 months) months in groups A and B, respectively. Inguinal hernia developed in no patients in group A and in 20 (11.8%) in group B. The hernia-free rate was significantly lower in group B than group A. All postoperative inguinal hernias were indirect. The median interval between surgery and hernia diagnosis was 10.6 months (range, 2-24), and 16 patients (80%) were diagnosed within 12 months. CONCLUSIONS We developed a simple method of preventing inguinal hernia after RRP. Our technique is simple enough to complete within a few minutes, and the outcome is excellent.

Clinical Impact of Palliative Treatment Using Octreotide for Inoperable Malignant Bowel Obstruction Caused by Advanced Urological Cancer

Malignant bowel obstruction (MBO), an occasional complication in patients with advanced urological cancer, causes gastrointestinal symptoms such as nausea and vomiting leading to suffering which severely impairs quality of life (QOL). Drug therapy, especially octreotide, a synthetic analog of somatostatin, is reportedly effective in controlling the symptoms of MBO. In the present study, we administered octreotide to urological cancer patients with MBO and evaluated the improvement of subjective symptoms, oral intake, and nasogastric intubation. Fourteen terminally ill urological cancer patients suffering with MBO were included (age range 55-92, 10 male, 4 female). Octreotide was administered at 300μg/day to those patients subcutaneously as a continuous injection. Significant improvements in subjective symptoms were observed in thirteen patients (92.8%), and ten patients (71.4%) were able to resume oral intake. Four patients required nasogastric drainage before the administration of octreotide, but nasogastric intubation was discontinued in all these cases after the use of octreotide. Early initiation of octreotide resulted in better improvement of MBO symptoms, and no adverse event was observed in any of the patients. These results revealed that 300μg/day dose of octreotide is safe and effective for managing gastrointestinal symptoms of terminally ill urological cancer patients with MBO. We also recommend starting the treatment with ocreotide as soon as MBO is diagnosed.

Induction of multinucleated cells and apoptosis in the PC-3 prostate cancer cell line by low concentrations of polyethylene glycol 1000

Polyethylene glycol (PEG) has been reported to inhibit the development of colonic lesions in carcinogen‐treated rats when administered orally. However, the precise mechanism for the chemopreventive activity of PEG remains largely elusive. Based on a characteristic feature of PEG as a ‘fusogen’, we investigated its potential as a chemotherapeutic agent through the induction of multinucleated cell formation and apoptosis induction in PC‐3 prostate cancer cells. When PC‐3 cells were treated with 0.5 and 1.0% PEG 1000, multinucleated cells were induced at a frequency of 8.4 and 13%, respectively, 36 h after PEG treatment under high cell density (1 × 106 cells in 100 µL PEG solution) in vitro. Although abnormality of cell cycle progression was not evident in PEG‐treated PC‐3 cells, multinucleated cells substantially disappeared at around 38 h due to apoptosis. In contrast, no apparent growth suppression was observed when PC‐3 cells were exposed to up to 1.0% PEG at a much lower cell density, namely under ordinary culture conditions. Furthermore, injection of 0.5% PEG solution in vivo into PC‐3 xenografts implanted in BALB/c‐nu/nu male mice significantly suppressed tumor growth compared to phosphate‐buffered saline injection. Multinucleated TdT‐mediated dUTP‐biotin nick end‐labeling (TUNEL)‐positive cells were observed inside the PEG‐injected tumors. PEG was here demonstrated to have anticell proliferation and antitumor effects via induction of apoptosis, possibly by cell fusion. PEG injection therapy could therefore be adopted as an alternative chemotherapeutic strategy for localized prostate cancers, including those that become refractory to androgen‐deprivation therapy. (Cancer Sci 2008; 99: 1055–1062)

Genomic Landscape of Experimental Bladder Cancer in Rodents and Its Application to Human Bladder Cancer: Gene Amplification and Potential Overexpression of Cyp2a5/CYP2A6 Are Associated with the Invasive Phenotype.

Non-muscle invasive (superficial) bladder cancer is a low-grade malignancy with good prognosis, while muscle invasive (invasive) bladder cancer is a high-grade malignancy with poor prognosis. N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) induces superficial bladder cancers with papillary morphology in rats and invasive bladder cancers with infiltrating phenotype in mice. In this study, we analyzed genomic landscapes of rodent BBN-induced bladder cancers using array-based comparative genomic hybridization (array CGH). While no significant copy number alterations were detected in superficial bladder tumors in rats, copy number gains in chromosomal regions 2D-E1, 7qA3, 9F2, and 11C-D were detected in invasive bladder tumors in mice. Amplification of representative genes located on 2D-E1 and 7qA3 chromosomal regions was confirmed by quantitative PCR. Cyp2a22 and Cyp2a5 genes but not Cyp2g1, Cyp2a12, and Rab4b genes on mouse chromosome 7qA3 were amplified in invasive bladder cancers. Although the human ortholog gene of Cyp2a22 has not been confirmed, the mouse Cyp2a5 gene is the ortholog of the human CYP2A6 gene located in chromosomal region 19q13.2, and CYP2A6 was identified by database search as one of the closest human homolog to mouse Cyp2a22. Considering a possibility that this region may be related to mouse 7qA3, we analyzed CYP2A6 copy number and expression in human bladder cancer using cell lines and resected tumor specimens. Although only one of eight cell lines showed more than one copy increase of the CYP2A6 gene, CYP2A6 amplification was detected in six out of 18 primary bladder tumors where it was associated with the invasive phenotype. Immunohistochemical analyses of 118 primary bladder tumors revealed that CYP2A6 protein expression was also higher in invasive tumors, especially in those of the scattered type. Together, these findings indicate that the amplification and overexpression of the CYP2A6 gene are characteristic of human bladder cancers with increased malignancy and that CYP2A6 can be a candidate prognostic biomarker in this type of cancer.

Feasibility of metronomic chemotherapy with tegafur-uracil, cisplatin, and dexamethasone for docetaxel-refractory prostate cancer

Objectives: To evaluate the efficacy of tegafur–uracil (UFT), a prodrug of 5-fluorouracil, plus cisplatin and dexamethasone in patients with docetaxel-refractory prostate cancers. Methods: Twenty-five patients with docetaxel-refractory prostate cancer were administered oral UFT plus intravenous cisplatin (UFT-P therapy) and dexamethasone. Treatment responses were assessed monthly via prostate-specific antigen (PSA) level measurements. Treatment-related adverse events and overall survival were also assessed. Results: UFT-P therapy resulted in decreased PSA levels in 14 (56%) patients and increased PSA levels in 11 (44%). In patients with increased PSA levels, 7 (64%) of the 11 patients displayed decreased PSA doubling times. The UFT-P therapy response rate was 84% (21/25 patients). Imaging studies revealed that tumor shrinkage during UFT-P therapy occurred in 1 patient in whom bilateral hydronephrosis caused by lymph node metastasis improved. The median survival time from docetaxel initiation was 36 months. In UFT-P-treated patients, the median PSA progression and overall survival times were 6 and 14 months, respectively. UFT-P treatment-related adverse events were mild diarrhea, general fatigue, and anorexia. Treatment was not discontinued for any of the patients. UFT-P therapy did not cause serious hepatic or renal dysfunction or pancytopenia. Conclusions: UFT-P therapy is a safe and effective treatment for patients with docetaxel-refractory prostate cancer, although large-scale, multicenter, prospective studies are needed to validate these findings.

MP36-04 GENE AMPLIFICATION AND OVEREXPRESSION OF CYP2A6 IN EARLY STAGE OF INVASIVE BLADDER CANCER

The interaction between vimentin and plectin was examined by immunoprecipitation. The spatial correlation between vimentin, plectin and F-actin in BCa cells was analyzed by confocal microscopy. To evaluate the functions of invadopodia, cells were assayed for extracellular matrix (ECM) degradation, Matrigel invasion, transendothelial invasion and lung metastasis. RESULTS: In invasive BCa cells, the expression levels of vimentin and plectin were elevated and the vimentin IF-plectin-invadopodia F-actin link was formed. Disruption of this link severely impaired invadopodia formation, reducing the capacities of ECM degradation, Matrigel invasion, transendothelial invasion and metastasis. CONCLUSIONS: Our results strongly suggest that plectin anchoring invadopodia to vimentin IF scaffolds and stabilizes invadopodia, which is a critical molecular step for BCa cell invasion and extravasation for metastasis.

511 IDENTIFICATION OF CYP2A6 GENE RELATED TO INVASIVE BLADDER CARCINOGENESIS

phospho-H2A.X foci than did C18-2 and CDDP10-3, suggesting continued accumulation or persistence of DSBs. In immunohistochemistry with ERCC1, six of eight positive cases did not have complete response to CRT, whereas 12 of 14 negative cases had complete response. Sensitivity and specificity were 75% and 85.7%, respectively (p 0.008). CONCLUSIONS: Our results suggest that in some bladder cancer cells, ERCC1 expression correlates with IR resistance but not with cisplatin resistance. Moreover, the lack of ERCC1 expression correlated well with the efficacy of CRT, and especially with that of IR, in our clinical study. Although further study is needed, ERCC1 expression level may predict the efficacy of CRT for MIBC.