Masaaki Tachibana

Pretreatment Neutrophil-to-Lymphocyte Ratio as an Independent Predictor of Recurrence in Patients With Nonmetastatic Renal Cell Carcinoma

PURPOSE We investigated the prognostic significance of the neutrophil-to-lymphocyte ratio to predict recurrence in patients with nonmetastatic renal cell carcinoma. MATERIALS AND METHODS We retrospectively reviewed the records of 192 patients with nonmetastatic renal cell carcinoma (T1-4N0M0) who underwent nephrectomy between 1986 and 2000. Mean followup was 93 months (range 6 to 232) months. We assessed the prognostic value of the pretreatment neutrophil-to-lymphocyte ratio, and other clinical and laboratory parameters on univariate and multivariate analysis. RESULTS Presentation mode, tumor stage, C-reactive protein, lymphocyte count and the neutrophil-to-lymphocyte ratio significantly correlated with recurrence-free survival on univariate analysis. The recurrence-free survival rate in patients with a neutrophil-to-lymphocyte ratio of less than 2.7 was 93.7% at 5 years and 79.8% at 10 years, significantly higher than the 77.9% and 58.4%, respectively, in patients with a ratio of 2.7 or greater (p = 0.0205). Multivariate analysis revealed that T stage and the neutrophil-to-lymphocyte ratio were independent predictors of recurrence. The 10-year survival rate in patients at low risk (T2 or less and neutrophil-to-lymphocyte ratio less than 2.7), intermediate risk (T2 or less and ratio 2.7 or greater, or T3 or greater and ratio less than 2.7) and high risk (T3 or greater and ratio 2.7 or greater) was 82.0%, 63.6% and 33.0%, respectively, which were significantly different. CONCLUSIONS An increased pretreatment neutrophil-to-lymphocyte ratio is an independent predictor of recurrence. The combination of T stage and the neutrophil-to-lymphocyte ratio can be used to stratify recurrence risk in patients with nonmetastatic renal cell carcinoma.

Prognostic value of neutrophil-to-lymphocyte ratio and establishment of novel preoperative risk stratification model in bladder cancer patients treated with radical cystectomy.

OBJECTIVE Preoperative prognostic factors in bladder cancer patients have not been fully established. This study was undertaken to investigate preoperative prognostic factors, including neutrophil-to-lymphocyte ratio (NLR), and to develop a novel prognostic factors-based risk stratification model for disease-specific survival (DSS) in bladder cancer patients treated with radical cystectomy (RC). METHODS We performed a retrospective analysis of 189 consecutive bladder cancer patients treated with RC at our institution. Prognostic value of the preoperative clinical and laboratory parameters were evaluated by univariate and multivariate Cox proportional hazard model analyses, and patients were stratified according to relative risks (RRs) for DSS. RESULTS One-, 3-, and 5-year DSS rates were 86.8%, 70.8%, and 61.7%, respectively. In univariate analysis, tumor size, clinical T stage, hydronephrosis, concomitance of carcinoma in situ, and some laboratory findings (hemoglobin [Hb] level, platelet count, C-reactive protein, neutrophil count, lymphocyte count, and NLR) were significantly associated with poor prognosis. In multivariate analysis, tumor size, hydronephrosis, Hb level, and NLR were independent factors for predicting poor prognosis. Patients were stratified into 3 risk groups: low (RR = 1.000-3.717), intermediate (RR = 4.149-9.315), and high (RR = 10.397-38.646). The differences among the groups were significant. CONCLUSIONS NLR was an independent prognostic factor, as were tumor size, hydronephrosis, and Hb levels, and the combination of these factors can stratify DSS risks in bladder cancer patients treated with RC. This information may be useful for identifying patients who might be candidates for clinical trials of multimodal treatment strategies, including innovative neoadjuvant treatments.

Followup of Neutrophil-to-Lymphocyte Ratio and Recurrence of Clear Cell Renal Cell Carcinoma

PURPOSE An increase in the pretreatment neutrophil-to-lymphocyte ratio is associated with poor prognosis for various cancers, including renal cell carcinoma. However, the clinical implication of a posttreatment change in the neutrophil-to-lymphocyte ratio in patients with cancer remains unclear. MATERIALS AND METHODS We reviewed the records of 250 patients with nonmetastatic clear cell renal cell carcinoma and analyzed associations among clinicopathological variables, the preoperative and postoperative neutrophil-to-lymphocyte ratio, and recurrence-free survival. RESULTS The 10-year recurrence-free survival rate for patients with a preoperative neutrophil-to-lymphocyte ratio of 2.7 or greater was significantly lower than that for those with a ratio of less than 2.7 (64.4% vs 83.7%, p = 0.0004). When combined with the postoperative ratio, patients with a preoperative ratio of 2.7 or greater could be further divided into 2 groups with a significantly different prognosis. The 10-year recurrence-free survival rate for patients with a preoperative neutrophil-to-lymphocyte ratio of 2.7 or greater and postoperative ratio of less than 2.7 was significantly lower than that for those with a preoperative and postoperative ratio of 2.7 or greater (52.0% vs 83.5%, p = 0.0487). The latter was similar to the 83.7% for patients with a preoperative ratio of less than 2.7. In patients with recurrence the ratio at recurrence was significantly increased compared with the postoperative ratio (mean ± SD 2.82 ± 1.63 vs 2.00 ± 0.90, p = 0.0090). Multivariate analysis showed that tumor size, pathological tumor stage and the neutrophil-to-lymphocyte ratio change (a combination of the preoperative and postoperative ratios) were independent predictors of recurrence. Using these 3 significant variables patients were stratified into low, intermediate and high risk groups, among which the recurrence-free survival rate significantly differed. CONCLUSIONS The posttreatment neutrophil-to-lymphocyte ratio change was a significant prognostic factor for recurrence as well as tumor size and pathological tumor stage in patients with clear cell renal cell carcinoma.

Expression of Estrogen Receptor (ER–α and ER–β) mRNA in Human Prostate Cancer

Objective: The distribution of the two estrogen receptors (ER–α, ER–β) in human prostate tissue have not been fully clarified, so the present study investigated the mRNA expression of the receptors to explain the broad spectrum of estrogen activity in prostate cancer. Materials and Methods: Four human prostate cancer cell lines (LNCap, JCA–1, DU–145 and PC–3) and 24 pairs of untreated prostate cancer tissue and noncancerous tissue from resected prostate glands were subjected to RT–PCR testing. Results: Both LNCap and JCA–1 expressed the mRNA of both receptors, but DU–145 and PC–3 only expressed ER–β mRNA. In the human prostate tissue samples, 20 of the 24 prostate cancer tissues expressed ER–α, and 23 of the 24 expressed ER–β. Of the 24 noncancer tissues, 14 expressed ER–α mRNA and 17 expressed ER–β mRNA. The incidence of ER–β mRNA expression between the paired cancer and noncancer tissues was statistically significantly different (p<0.05). Conclusions: A higher incidence of ER–β mRNA expression in untreated prostate cancer tissues was observed. Furthermore, the absence of ER–α mRNA and the presence of ER–β mRNA expression in hormone–independent and/or untreated prostate cancer cells leads to a tentative speculation of the mechanism of the hormone refractory feature of prostate cancer.

Effects of a KiSS-1 peptide, a metastasis suppressor gene, on the invasive ability of renal cell carcinoma cells through a modulation of a matrix metalloproteinase 2 expression

Although effects of a metastasis suppressor gene, KiSS-1, have been postulated to be mediated by its receptor, hOT7T175, the mechanism of such effects remains unknown. This study was designed to evaluate the mechanism of how KiSS-1 works and to assess effects of a synthesized truncated KiSS-1 protein on the invasive ability of renal cell carcinoma (RCC) cells. Four RCC cell lines, Caki-1, KU19-20, RSP and RSM, were investigated to determine mRNA expressions of KiSS-1, its receptor, hOT7T175, matrix metalloproteinases (MMPs) and MMP inhibitors. While all cell lines demonstrated hOT7T175 mRNA expressions, only Caki-1 had KiSS-1 transcripts. A synthesized truncated KiSS-1 peptide, metastin (45-54), produced a marked suppression of the invasive ability in KU19-20 cells, which were deficient for KiSS-1 transcripts, but not in Caki-1 cells. Metastin (45-54) also increased the ability of KU19-20 cells to attach to collagen 4. Both MMP-2 mRNA levels and protein production were significantly decreased only in KU19-20 cells by metastin (45-54). In conclusion, metastin (45-54) may have potential therapeutic use by suppressing the motility and invasive ability of RCC cells which possess hOT7T175 with either a negative expression or very low expression level of KiSS-1 through, at least in part, the down-regulation of MMP-2.

Adenovirus-mediated gene transduction of truncated IκBα enhances radiosensitivity in human colon cancer cells

Nuclear factor kappa B (NF‐κB) is a transcription factor that is known to regulate apoptosis when cells are exposed to DNA‐damaging agents such as ionizing radiation and cytotoxic drugs. We sought to determine if inhibition of NF‐κB could enhance radiosensitivity in human colon cancer cells in vitro and in vivo. To inhibit NF‐κB activation specifically, we constructed a recombinant adenovirus vector expressing a truncated form of the inhibitor protein lκβα (lκBαΔN) that lacks the phosphorylation sites essential for activation of NF‐κB, and transfected two human colon cancer cell lines (HT29 and HCT15) with this vector. In vitro colony‐forming assays revealed that the overexpression of the stable IκBα by AxIκBαΔN infection significantly suppressed cell growth after irradiation in both cell lines as compared to infection with a control vector, AxLacZ. Treatment with AxIκBαΔN and irradiation successfully inhibited the growth of HT29 xenografted subcutaneous tumors in nude mice with an 83.8% volume reduction on day 38 as compared to the untreated tumors. Furthermore, it was demonstrated that apoptosis was increased by adenovirus‐mediated gene transduction of IκBaLΔN in vitro and in vivo. These results indicated that inhibition of NF‐κB could enhance radiosensitivity through an increase in radiation‐induced apoptosis. We believe that radio‐gene therapy using adenovirusmediated gene transduction of IκBαΔN could be an attractive candidate as a treatment strategy for colorectal cancer.

Impact of Tumor Size on Renal Function and Prediction of Renal Insufficiency After Radical Nephrectomy in Patients With Renal Cell Carcinoma

PURPOSE From the perspective of oncological and functional outcomes partial nephrectomy is considered standard surgery for small renal tumors 4 cm or less. However, radical nephrectomy is commonly done for small tumors. It is important to predict postoperative renal function in patients to choose the most optimal surgical procedure. MATERIALS AND METHODS We retrospectively reviewed the records of 271 patients treated with radical nephrectomy for renal cell carcinoma. Associations of tumor size and clinical variables with renal function were analyzed. RESULTS Preoperatively the mean ± SD glomerular filtration rate was 74.38 ± 17.70 ml per minute/1.73 m(2) and 56 patients (20%) had renal insufficiency (glomerular filtration rate less than 60 ml per minute/1.73 m(2)). The mean decrease in the glomerular filtration rate after radical nephrectomy was 24.2 ± 12.40 ml per minute/1.73 m(2) (31.5% ± 15%). Of 215 patients with a preoperative glomerular filtration rate of 60 ml per minute/1.73 m(2) or greater 165 (77%) had new onset renal insufficiency. Age, tumor size, preoperative glomerular filtration rate and hypertension were significantly associated with new onset renal insufficiency. Multivariate analysis revealed that age 60 years or greater, tumor size 7 cm or less and the preoperative glomerular filtration rate were independent risk factors for new onset renal insufficiency (p <0.05). Finally, we developed a predictive model for new onset renal insufficiency after radical nephrectomy. CONCLUSIONS Tumor size 7 cm or less, age 60 years or greater and a decreased preoperative glomerular filtration rate were significant risk factors for new onset renal insufficiency in patients treated with radical nephrectomy. Partial nephrectomy might be considered an option according to the risk of postoperative renal insufficiency, especially in elderly patients with a tumor of 7 cm or less.

Hiding in plain view: Genetic profiling reveals decades old cross contamination of bladder cancer cell line ku7 with hela

PURPOSE KU7 is a popular urothelial carcinoma cell line that was isolated from the bladder of a patient at Keio University in 1980. It has subsequently been widely used in laboratories around the world. We describe how routine cell line authentication revealed that KU7 was cross contaminated almost 30 years ago with HeLa, a cervical carcinoma cell line. MATERIALS AND METHODS Presumed KU7 clones dating from 1984 to 1999 were provided by M.D. Anderson Cancer Center, Vancouver Prostate Centre, Kyoto University, Tokyo Medical University and Keio University. HeLa was obtained from ATCC. Genomic DNA was isolated and short tandem repeat analysis was performed at the M.D. Anderson Cancer Center Characterized Cell Line Core Facility, Johns Hopkins University Fragment Analysis Facility and RIKEN BioResource Center, Ibaraki, Japan. Comparative genomic hybridization was performed on a platform (Agilent Technologies, Santa Clara, California) at Vancouver Prostate Centre. RESULTS The short tandem repeat profile of all KU7 clones was an exact match with that of HeLa. Comparative genomic hybridization of all samples revealed an abundance of shared chromosomal aberrations. Slight differences in some genomic areas were explained by genomic drift in different KU7 clones separated by many years. CONCLUSIONS Our analysis identified that cross contamination of KU7 with HeLa occurred before 1984 at the source institution. All KU7 clones in the urological literature should be considered HeLa and experimental results should be viewed in this light. Our results emphasize the need to authenticate cell lines in oncological research.

The powerful impact of double-layered posterior rhabdosphincter reconstruction on early recovery of urinary continence after robot-assisted radical prostatectomy

BACKGROUND AND PURPOSE The usefulness of posterior rhabdosphincter reconstruction (PR) during robot-assisted radical prostatectomy (RARP) has still been controversial. We investigated the association of several factors, including the Rocco original double-layered PR, with early recovery of urinary continence after RARP. PATIENTS AND METHODS Between August 2006 and April 2011, a single surgeon at Tokyo Medical University Hospital performed 206 RARPs. Of these 206 patients, 199 eligible patients were enrolled in this study. We retrospectively analyzed the correlation of several perioperative factors, including surgical techniques, with early recovery of urinary continence 1 month after catheter removal. Continence was defined as no use or the use of only one safety pad. RESULTS Univariate analysis showed that surgeon experience, lateral approach of bladder neck preservation, bladder neck reconstruction, anterior reconstruction, and the Rocco double-layered PR were significantly associated with early recovery of urinary continence 1 month after catheter removal. Preoperative prostate-specific antigen level, body mass index, and attempted nerve-sparing (NS) procedures, however, were not significantly associated with early recovery of urinary continence. Multivariate logistic regression analysis showed that the Rocco PR and attempted NS were the only independent predictive factors of urinary continence recovery 1 month after catheter removal (odds ratio [OR], 15.01; 95% confidence interval [CI], 3.413-66.67; P=0.0003 and OR, 2.248; 95% CI, 1.048-4.975; P=0.0402, respectively). When we applied NS as well as the Rocco PR, the recovery rates of continence at 1 month after catheter removal was 85.3%. CONCLUSIONS The Rocco double-layered PR and attempted NS and not surgeon experience were the significant independent predictive factors of early recovery of urinary continence after RARP. NS procedures positively influenced early recovery of urinary continence only when they were applied with the PR technique.

M1 prostate cancer with a serum level of prostate-specific antigen less than 10 ng/mL

Abstract Background: M1 prostate cancer, which is invasive, is usually associated with a serum level of prostate‐specific antigen (PSA) greater than 10 ng/mL, but cases are occurring where the serum PSA level is less than this. The present study investigated the clinical and pathologic characteristics of these cases of M1 prostate cancer.