Toshiro Terachi

Constitutive Activation of Mitogen-activated Protein (MAP) Kinases in Human Renal Cell Carcinoma

Mitogen-activated protein kinases (MAPKs) play a pivotal role in the mitogenic signal transduction pathway and are essential components of the MAPK cascade, which includes MEK (also known as MAP kinase kinase), Raf-1, and Ras. In this study, we examined whether constitutive activation of the MAPK cascade was associated with the carcinogenesis of human renal cell carcinomas in a series of 25 tumors and in corresponding normal kidneys. Constitutive activation of MAPKs in tumor tissue, as determined by the appearance of phosphorylated forms, was found in 12 cases (48%), and this activation was confirmed by a direct in vitro kinase assay of immunoprecipitate using myelin basic protein as the substrate. The phosphorylation of MEK and of Raf-1, as monitored by a mobility shift in SDS-PAGE, which is reportedly associated with the activation of these kinases, occurred in 9 of 18 cases (50%) and in 6 of 11 cases (55%) respectively. The activation of MAPKs was correlated with MEK activation (P = 0.0045) and with Raf-1 activation (P = 0.067). Furthermore, overexpression of MEK was found in 13 of 25 cases (52%) by Western blot analysis, and this overexpression was associated significantly with MAPK activation (P = 0.034). No mutations were noted in H-,K-, or N-ras genes by PCR direct sequencing in any of the 25 tumor samples. Of the patients studied, 8 of 18 (44%) stage pT2 patients and four of six (67%) stage pT3 patients showed MAPK activation. The single stage pT1 patient did not evidence MAPK activation. Furthermore, one of seven (14%) grade 1 patients, 9 of 13 (69%) grade 2 patients, and two of five (40%) grade 3 patients showed MAPK activation (grade 1 versus grades 2 and 3, P = 0.046). Our results suggest that constitutive activation of MAPKs may be associated with the carcinogenesis of human RCCs.

Prognosis of Japanese Metastatic Renal Cell Carcinoma Patients in the Cytokine Era: A Cooperative Group Report of 1463 Patients

BACKGROUND Incidence rate of renal cell carcinoma (RCC) differs among countries. The rates of Asian countries are lower than those of countries in North America or Europe but are exceptionally high in Japanese males. Approximately 30% of patients with RCC have metastasis at initial diagnosis, and another 30% have metastasis after nephrectomy. Clinical studies of risk factors in patients with metastatic RCC (mRCC) are mainly based on data from non-Asian patients. OBJECTIVES We aimed to investigate the prognosis of Japanese patients and their prognostic factors. DESIGN, SETTING, AND PARTICIPANTS The subjects of this study were 1463 patients who were clinically diagnosed with RCC with metastasis in 40 Japanese hospitals between January 1988 and November 2002. MEASUREMENTS The primary end point was overall survival calculated from first diagnosis of mRCC to death or last follow-up. We also investigated the relationship between survival and clinical features. RESULTS AND LIMITATIONS The median overall survival time was 21.4 mo. The estimated survival rates at 1, 3, 5, and 10 yr were 64.2%, 35.2%, 22.5%, and 9.1%, respectively; they contrasted with data from the United States of 54%, 19%, 10%, and 6%, respectively for the same periods. A high percentage of patients had undergone nephrectomy (80.5%) and metastasectomy (20.8%), both of which were shown to prolong survival. CONCLUSIONS The median survival time in the present study was approximately twice as long as that of previous studies from North America or Europe. Early diagnosis of metastasis, nephrectomy, metastasectomy, and cytokine-based therapy seemed to improve the prognosis of RCC patients in the present study.

Radical retropubic prostatectomy: time trends, morbidity and mortality in Japan

Objectives To assess the time trends, morbidity and mortality of contemporary anatomical radical retropubic prostatectomy (RRP) in a multi‐institutional study in Japan, where RRP has become more popular in the last decade.

Urinary Calculi as a Late Complication of the Indiana Continent Urinary Diversion: Comparison with the Kock Pouch Procedure

PURPOSE Although urinary calculi have been frequent late complications of the Kock continent urinary diversion, they have not been regarded as significant problems in patients with the Indiana pouch because of the lack of foreign material present. However, stones developed in a significant percentage of our patients with an Indiana pouch. We investigated the characteristics of stone formation in patients with the Indiana pouch and compared them to those with a Kock pouch. MATERIALS AND METHODS Detailed clinical courses regarding stone formation were reviewed in 72 patients with a Kock pouch and 54 with an Indiana pouch who had a minimum followup of 12 months. RESULTS Stones developed in 7 of 54 patients (12.9%) with an Indiana pouch compared to 31 of 72 (43.1%) with a Kock pouch. The incidence gradually increased with longer followup but it was lower in the Indiana than in the Kock pouch group (5-year stone-free rate 84% versus 66%, respectively). Although the stones consisted principally of a mixture of struvite, carbonate apatite and ammonium hydrogen urate, variable amounts of calcium oxalate were identified in 50% of the Indiana pouch calculi. CONCLUSIONS Not only urinary infections but also metabolic factors were considered to be involved in stone formation within the Indiana pouch. However, the substantially higher rate of stone formation in our Kock and Indiana pouch groups than has been reported in the United States suggested that no or infrequent pouch irrigations in our patients were important risk factors for urinary calculi.

Psychosocial Aspects in Long-Term Survivors of Testicular Cancer

PURPOSE We assessed the psychosocial well-being in cured testicular cancer patients who had undergone chemotherapy with or without retroperitoneal lymph node dissection, radiotherapy or surveillance therapy. MATERIALS AND METHODS The sample consisted of 83 cured testicular cancer patients of whom 34 had undergone cisplatin-based combination chemotherapy with or without retroperitoneal lymph node dissection (chemotherapy group), 42 had received infradiaphragmatic radiotherapy (radiotherapy group) and 7 had received surveillance therapy (surveillance group). The questionnaire reported demographic data, psychosocial well-being, working ability, satisfaction with life, relationships, and general health and fitness. RESULTS For questions dealing with psychological distress there were no differences among the groups. However, a significant number of patients in all groups reported greater feelings of anxiety about health and future since treatment. Working ability was significantly better in the chemotherapy and radiotherapy groups than in the surveillance group (p < 0.05 and p < 0.01, respectively). Interestingly, the patients who received the most extensive treatment (chemotherapy plus retroperitoneal lymph node dissection) reported the best working ability. Using the satisfaction with life scale, patients in the chemotherapy and radiotherapy groups showed significantly higher scores than those in the surveillance group (p < 0.05). The majority of the patients reported no significant change in long-term relationships with family, friends and spouse. CONCLUSIONS The development of psychosocial problems during long-term adjustment seems to be low regardless of treatment received. Although a significant number of patients reported a higher incidence of anxiety and depression since the illness, the overall attitude was positive toward life. With regard to treatment type, patients in the chemotherapy and radiotherapy groups had better working ability and greater satisfaction with life than the surveillance group.

Complications of laparoscopic and retroperitoneoscopic adrenalectomies in 370 cases in Japan: a multi-institutional study

A total of 370 laparoscopic adrenalectomies, including 311 transperitoneal (TP) and 59 retroperitoneal (RP) approaches, were performed in nine urologic centers, where the laparoscopic adrenalectomy was first begun independently in Japan, and their affiliated hospitals between January 1992 and September 1996. The clinical diagnoses of those 370 adrenal diseases were primary aldosteronism in 155 patients, Cushings syndrome in 61. preclinical Cushings syndrome in 21. pheochromocytoma in 16, nonfunctioning adenoma in 87, complicated cyst in ten, myelolipoma in nine, adrenal cancer in four and other diagnoses in eight (table 1). There was no mortality in this series. Intraoperative complication rate was 33/370 (9%) in total: 26/311(8%) in the TP procedures and 7/59 (12%) in the RP procedures (table 11). Postoperative complication rate was 24/370 (6%) in total: 22/311 (7%) in the TP procedures and 2/59 (3%) in the RP ones (table 111). Conversion rates to open surgery in total, in the TP and in the RP procedures were 13/370 (3.5%), 10/311 (3.2%) and 3/59 (5.1 %). respectively (table IV). Although the RP procedure has a lower morbidity rate compared to the TP procedure, more skill is required to overcome the drawback of the narrow working space and fewer anatomical landmarks.

Long-term followup of the Kock and Indiana pouch procedures.

Between 1984 and 1991, 115 consecutive patients underwent cutaneous continent urinary diversion comprising 76 Kock and 39 Indiana pouch procedures. The 2 different forms of achieving continent urinary diversion were subsequently compared in a long-term followup that evaluated complications, including pouch function and the need for revisions. In the Kock pouch group there were 14 (18.4%) early postoperative complications (3 months), which required 4 subsequent reoperations (5.3%). The Indiana pouch group had a similar incidence of early complications (17.9%) but there were no reservoir related problems. The long-term study group comprised 68 Kock and 37 Indiana pouch patients who were observed for 12 months or longer (mean followup 53 and 34 months, respectively). Of 9 efferent nipple valve malfunctions observed in the Kock pouch group 5 required surgical revision. Of 16 complications related to afferent limb function 15 were caused by the use of polyester fiber fabric for the anchoring collar and 8 of these 15 complications required surgical revision. The first 2 Indiana pouch patients had pouch deformities due to incomplete detubularization of the cecum that required surgical repair. Overall, surgical revisions, including minor repairs, were performed on 15 Kock pouch patients (22.1%) and 4 Indiana pouch patients (10.8%). Both forms of the procedure preserved continence to a satisfactory degree. Urinary tract stones developed in 18 patients (26.5%) from the Kock pouch group, usually on the exposed staples or the eroded, nonabsorbable collar used to construct the nipple valves. Stone formation was rare (5.4%) in the Indiana pouch group. The incidence of ureteral implantation stricture was low in both procedures. There was no significant difference in the incidence of bacteriuria between the 2 methods of urinary diversion. These data demonstrate that the Kock pouch and Indiana pouch procedures can be accomplished with the same early postoperative complication rate. Our 8-year experience showed a high incidence of Kock afferent nipple valve malfunction. However, most of these malfunctions were due to the use of a nonabsorbable collar and can be avoided. When taking this into account, therefore, it can be concluded that the Indiana pouch functions as well as the Kock pouch with roughly the same incidence of late complications and the same reoperation rate but with a lower incidence of stone formation.

Allelic Frequency of p53 Gene Codon 72 Polymorphism in Urologic Cancers

Alterations in the p53 tumor suppressor gene appear to be important in the development of many human tumors. The wild‐type p53 gene has a polymorphism at codon 72 that presents the arginine (CGC) or proline (CCC) genotype, which recently has been reported to be associated with genetically determined susceptibility to smoking‐related lung cancers. To determine whether this p53 genotype influences individual risk of urologic cancer and/or its progression, we used polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) analysis to assay the allelic frequencies of this polymorphism in 85 renal cell carcinoma patients, 151 urothelial cancer patients, 33 testicular cancer patients, 28 prostatic cancer patients and 56 patients without neoplastic disease. The allelic distributions of the three genotypes (Arg/Arg, Arg/Pro, Pro/Pro) in patients with renal cell carcinoma (29.4%, 55.3%, 15.3%), urothelial cancers (45.7%, 39.7%, 14.6%), testicular cancer (45.4%, 48.5%, 6.1%) or prostate cancer (42,9%, 50.0%, 7.1%) did not differ significantly from those in the normal controls. However, Pro/Pro genotype in renal cell carcinoma and urothelial cancer (smoking‐related cancers) was more frequent than that in prostate cancer and testicular cancer (smoking‐unrelated cancers) with borderline significance (P=0.0881). There was no particular correlation between frequency of the three genotypes and grade or stage of each type of tumor. The association of genetic predisposition to urologic cancers with p53 gene codon 72 polymorphism is not so clear as the previous study of Japanese lung cancer patients, but this polymorphism may play some role in urothelial cancers and renal cell carcinoma, in which smoking is an epidemiological risk factor.

Quality of life following high-intensity focused ultrasound for the treatment of localized prostate cancer: a prospective study.

Objectives:  To report our health‐related quality of life (QOL) and functional outcomes following high‐intensity focused ultrasound (HIFU) for localized prostate cancer.

Improved Outcomes with Advancements in High Intensity Focused Ultrasound Devices for the Treatment of Localized Prostate Cancer

PURPOSE We evaluated the association between long-term clinical outcomes and morbidity with high intensity focused ultrasound. MATERIALS AND METHODS We included patients with stage T1c-T3N0M0 prostate cancer who were treated with Sonablate® (SB) devices during 1999 to 2012 and followed for more than 2 years. Risk stratification and complication rates were compared among the treatment groups (ie SB200/500 group, SB500 version 4 group and SB500 tissue change monitor group). Primary study outcomes included overall, cancer specific and biochemical disease-free survival rates determined using Kaplan-Meier analysis (Phoenix definition). Secondary outcomes included predictors of biochemical disease-free survival using Cox models. RESULTS A total of 918 patients were included in the study. Median followup in the SB200/500, SB500 version 4 and the SB500 tissue change monitor groups was 108, 83 and 47 months, respectively. The 10-year overall and cancer specific survival rates were 89.6% and 97.4%, respectively. The 5-year biochemical disease-free survival rate in the SB200/500, SB500 version 4 and SB500 tissue change monitor group was 48.3%, 62.3% and 82.0%, respectively (p < 0.0001). The overall negative biopsy rate was 87.3%. On multivariate analysis pretreatment prostate specific antigen, Gleason score, stage, neoadjuvant androgen deprivation therapy and high intensity focused ultrasound devices were significant predictors of biochemical disease-free survival. Urethral stricture, epididymitis, urinary incontinence and rectourethral fistula were observed in 19.7%, 6.2%, 2.3% and 0.1% of cases, respectively. CONCLUSIONS Long-term followup of patients with high intensity focused ultrasound demonstrated improved clinical outcomes due to technical, imaging and technological advancements.