Tatsuo Igarashi

Strategies for asymptomatic microscopic hematuria : a prospective study of 1,034 patients

To establish strategies for treatment of asymptomatic microscopic hematuria we conducted a prospective study of 1,034 patients with this disease. The patients were examined by cystoscopy, urine cytology, abdominal ultrasound and excretory urography. On initial examination 30 highly significant lesions, including 24 cases of urological malignancies, 195 moderately significant lesions and 246 insignificant lesions were detected. In the remaining 563 patients no underlying lesion could be found. Of the 246 patients with insignificant lesions and 563 with unexplained asymptomatic microscopic hematuria followup was done in 421 at 6-month intervals for more than 1 year. A diagnosis became clear within 3 years in 22 patients, including 3 cases of bladder carcinoma and 1 of prostatic carcinoma.

Collecting Duct (Bellini Duct) Renal Cell Carcinoma: A Nationwide Survey in Japan

PURPOSE Collecting duct carcinoma, a rare type of renal cell carcinoma, remains poorly understood. To analyze the nature of collecting duct carcinoma a retrospective survey was performed in Japan. MATERIALS AND METHODS This survey was done from August 2001 to April 2003. A total of 281 institutions throughout Japan were requested to document all cases of collecting duct carcinoma. All pertinent clinical information was compiled, including patient age, sex, mode of presentation, evaluation modality, preoperative laboratory data, surgery type, macroscopic and microscopic findings, and survival data. Two urological pathologists reviewed microscopic slides of all tumor specimens to confirm collecting duct carcinoma. RESULTS Two pathologists confirmed collecting duct carcinoma in 81 of the 120 cases documented as collecting duct carcinoma. Mean patient age was 58.2 years and males comprised 71.6% of all patients. The mode of presentation was classified as symptomatic in 65.4% of cases, incidental in 24.7% and not available in 9.9%. Regional lymph node metastasis was histologically detected in 44.2% of patients who underwent lymph node dissection, while 32.1% of the population had distant metastasis at presentation. Although postoperative adjuvant therapy against metastasis or recurrence was performed in 25 patients, no obvious responses were identified except in 1 with lung metastases, who showed a partial response to combined gemcitabine and carboplatin therapy. At a median followup of 15 months 1, 3, 5 and 10-year disease specific survival was 69.0%, 45.3%, 34.3% and 13.7%, respectively. CONCLUSIONS We report what is to our knowledge the largest known series of collecting duct carcinoma. Since advanced or recurrent collecting duct carcinoma is resistant to standard treatment modalities, new treatment strategies are needed for advanced collecting duct carcinoma.

Usefulness of intraoperative fluorescence imaging to evaluate local anatomy in hepatobiliary surgery.

BACKGROUND/PURPOSE One of the major complications encountered in hepatobiliary surgery is the incidence of bile duct and blood vessel injuries. It is sometimes difficult during surgery to evaluate the local anatomy corresponding to hepatic arteries and bile ducts. We investigated the potential utility of an infrared camera system as a tool for evaluating local anatomy during hepatobiliary surgery. METHODS An infrared camera system was used to detect indocyanine green fluorescence in vitro. We also employed this system for the intraoperative fluorescence imaging of the arteries and biliary system in a pig. Further, we evaluated blood flow in the hepatic artery, portal vein, and liver parenchyma during a human liver transplant and we investigated local anatomy in patients undergoing cholecystectomy. RESULTS Fluorescence confirmed that indocyanine green was distributed in serum and bile. In the pig study, we confirmed the fluorescence of the biliary system for more than 1 h. In the liver transplant recipient, blood flow in the hepatic artery and portal vein was confirmed around the anastomosis. In most of the patients undergoing cholecystectomy, fluorescence was observed in the gallbladder, cystic and common bile ducts, and hepatic and cystic arteries. CONCLUSIONS Intraoperative fluorescence imaging in hepatobiliary surgery facilitates better understanding of the anatomy of arteries, the portal vein, and bile ducts.

Late recurrence of renal cell carcinoma: retrospective and collaborative study of the Japanese Society of Renal Cancer.

OBJECTIVES To evaluate in collaboration the clinical features of late recurrence of renal cell carcinoma (RCC). Late recurrence is one of the specific biologic behaviors of RCC; however, the clinical and pathologic features of the late recurrence of RCC are not fully understood. METHODS A total of 470 patients who had undergone curative treatment of RCC and had not developed recurrence within 10 years of follow-up were documented from 13 institutions of the board members of the Japanese Society of Renal Cancer. Multivariate analysis with Cox proportional hazards model was used to determine the pathologic and clinical factors affecting the late recurrence and survival of patients with RCC ≥10 years after surgery. Survival analysis was performed using the Kaplan-Meier method. RESULTS During the 10-28-year (median 13.2) observation period, 30 patients (6.4%) developed a late recurrence. The disease-free survival rate at 15 and 20 years was 89.5% and 78.4%, respectively. Multivariate analysis showed that lymph node metastasis was the only factor to predict for late recurrence (P = .0334). Age at nephrectomy was the only prognostic factor for overall survival on multivariate analysis (P < .0001). Of the 470 patients, 30 had developed late recurrence in 44 sites, including the lung (36.4%), kidney (25%), and bone (13.6%), followed by the brain, pancreas, adrenal gland, lymph nodes, and liver. Late recurrences in the lung or kidney were observed at any time ≥10 years after nephrectomy. CONCLUSIONS Late recurrence of RCC after initial treatment is not a rare event, and lifelong follow-up is necessary.

THE IMPACT OF A 4 CM. CUTOFF POINT FOR STRATIFICATION OF T1N0M0 RENAL CELL CARCINOMA AFTER RADICAL NEPHRECTOMY

PURPOSE The 1997 TNM classification defines T1 tumors as those smaller than 7 cm. Recently, a cutoff point of 4 cm. has been proposed to create a subclass of T1 tumors. We evaluated the validity of this cutoff point by assessing the pathological findings and prognoses of patients with T1N0M0 renal cell carcinoma following radical nephrectomy. MATERIALS AND METHODS We reviewed the hospital charts of 333 patients with T1N0M0 tumors, followed as long as 282 months (median 63) after radical nephrectomy. The validity of tumor size cutoff point for predicting survival outcome was tested in relation to other prognostic factors, including patient age, tumor position, nuclear grade, tumor histopathology and degree of microscopic venous invasion. RESULTS During followup 32 patients (9.6%) had tumor recurrence and 21 (6.3%) died of renal cell carcinoma. A 5 cm. cutoff point maximized the differences in cancer specific survival rates and a 4 cm. cutoff point maximized the differences in disease-free survival rates. Tumor size was directly related to microscopic venous invasion and nuclear grade, which are significant prognostic factors, and a 4 cm. cutoff point enhanced these relationships. CONCLUSIONS Tumor size is an important prognostic factor for patients with T1N0M0 renal cell carcinoma. A cutoff point of 4 cm. is practical for dividing the T1N0M0 classification into T1a and T1b subclasses.

Microsatellite Instability and Other Molecular Abnormalities in Human Prostate Cancer

Microsatellites are highly polymorphic, short‐tandem repeat sequences dispersed throughout the genome. Instability of these repeat sequences at multiple genetic loci may result from mismatch repair errors, and occurs in hereditary nonpolyposis colorectal carcinoma and certain sporadic cancers. To examine microsatellite instability during the pathogenesis of human prostate cancer, we screened 48 prostate cancer cases (20 stage B, 10 stage C and 18 endocrine therapy‐resistant cancer‐death cases) for replication error at 17 microsatellite marker loci on 9 chromosomes. Microsatellite instabilities were found in 7 of 48 cases (14.6%), and all 7 cases showing the instability were poorly differentiated adenocarcinomas. Moreover, microsatellite instabilities were more frequently observed in cancer‐death cases (6/18, 33%) than in stage B+C cases (1/30, 3.3%). These data suggest that micro‐satellite instability is an important genetic change related to the progression of a subset of human prostate cancer cases. It is suggested to be associated with extensive, concurrent molecular changes including androgen receptor gene mutations, as well as frequent loss of heterozygosity at chromosomal regions 8p, 10q, and 16q.

State of Adenomatous Polyposis Coli Gene and ras Oncogenes in Japanese Prostate Cancer

Genetic alterations of ras oncogenes (K‐, H‐ and N‐ras) and adenomatous polyposis coli (APC) gene in tissues of prostate cancer from Japanese patients were examined using PCR‐SSCP (polymerase chain reaction‐single strand conformation polymorphism) analysis and direct sequencing. Tissues from 8 cases of untreated stage B prostate cancer surgically removed and from 10 cases of endocrine therapy‐resistant metastatic disease obtained at autopsy were used in the present study. In four out of 18 cases (22%), ras point mutations were found, two in either codon 12 or 61 of K‐ras and two in either 13 or 61 of H‐ras. These point mutations were detected in one of the stage B cases (13%) and in three of the autopsy cases (30%). All these cases were poorly differentiated adenocarcinoma. In autopsy cases showing ras mutation in cancerous prostate, the same alteration was observed in metastatic tissues. No APC gene mutation was detected in any sample, although polymorphism was found in some cases. These results indicate that ras oncogene mutations are related to the progression of prostate cancer, whereas APC gene alteration is not involved in tumorigenesis and development of this cancer.

Identification of a 1‐cM region of common deletion on 13q14 associated with human prostate cancer

Frequent allelic losses on chromosome arm 13q are observed in carcinomas of the head and neck, breast, ovary, and pituitary gland. We analyzed 59 primary prostate tumors (stage B, 18 patients; C, 12 patients; D1, 4 patients; and endocrine therapy‐resistant cancer death, 25 patients), as well as 18 metastatic tissues from 14 of the 25 cancer death patients for loss of heterozygosity (LOH) using 35 microsatellite markers on chromosome arm 13q. Of the 59 primary tumors, 31 (53%) showed LOH involving at least one locus. Detailed deletion mapping identified a distinct commonly deleted region in the 1‐cM interval flanked by D13S153 and D13S273 on 13q14 and this region overlapped a part of the RB1 gene. Paired DNAs were available from both primary and metastatic tumors in the 14 cases of cancer death; among those pairs, we detected LOH on 13q in seven (50%) primary tumors, and in all metastatic foci (P = 0.0029). Moreover, the regions lost in metastatic tissues were more extensive than those seen in the corresponding primary tumors. These results suggest that inactivation of a putative tumor suppressor gene(s) including the RB1 gene on 13q14 plays an important role in human prostate cancer. Genes Chromosomes Cancer 24:183–190, 1999.

Prevalence of renal cell carcinoma: A nation-wide survey in Japan, 2002

Objective:  To investigate the incidence of renal cell carcinoma, classified by sex, age group and region in Japan, following a 5‐year interval after a previous survey performed in 1997.

Epigenetic Regulation of the KAI1 Metastasis Suppressor Gene in Human Prostate Cancer Cell Lines

Expression of the KAI1 gene, a metastasis‐suppressor for prostate cancer, is reduced in all foci of prostatic metastasis. The altered regulatory mechanism is not strongly related to mutations or allelic losses of the KAI1 gene in prostate tumors. Since transcriptional silencing of genes has been found to be caused by epigenetic mechanisms, we have investigated the involvement of this epigenetic regulation of KAI1 expression in prostate cancers. The methylation status of the KAI1 promoter region was examined by restriction‐enzyme digestion and sequencing, after amplifying a 331‐bp fragment in the GC‐rich promoter region from 4 human prostate cancer cell lines treated with bisulfite. The same 4 cell lines were also exposed to various concentrations of the demethylating agent, 5‐aza‐2‐deoxycytidine (5‐AzaC) and/or the histone deacetylase inhibitor, trichostatin A (TSA). To clarify the influence of epigenetic modification on reduced KAI1 mRNA expression in the tumor cells, RT‐PCR and northern‐blot analyses were performed. Bisulfite‐sequencing data showed a few methylated CpG islands in the promoter. RT‐PCR analysis of 5‐AzaC and/or TSA‐treated cells indicated reversal of suppression of KAI1 transcription in two cell lines (PC‐3 and DU‐145), although the expression could not be detected by northern blots. From these results, it is suggested that epigenetic change is not the main mechanism of KAI1 down‐regulation, though there remains a possibility that methylation in a more upstream region might be associated with this regulation.