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Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder caused by germline mutations in the folliculin gene (FLCN). It is characterized by skin tumors, multiple lung cysts, and renal tumors. Active genetic testing and appropriate periodic examinations of family lines of patients with BHD syndrome have not been widely performed. In this report, we present our experience regarding the diagnosis of asymptomatic family members with BHD syndrome. The proband was a 65-year-old female with a family history of colorectal cancer and spontaneous pneumothorax that affected her father. Computed tomography revealed an approximately 10 cm-sized tumor protruding from the upper pole of the left kidney, a buried tumor approximately 1.5 cm in length in the right kidney, and multiple pulmonary cysts. The patient underwent laparoscopic radical left nephrectomy. Pathological examination indicated that the resected tumor was a chromophobe renal cell carcinoma. After the surgery, there was no evidence of local recurrence or metastasis. The size of the tumor in the right kidney was monitored, but it did not increase. On FLCN genetic examination, targeted next generation sequencing revealed a partial deletion of exon 14, thus confirming the diagnosis of the patient to be BHD syndrome that caused the previously unreported pathogenic variant. Three years after the surgery, we conducted genetic counseling for the proposita and her three children. Genetic examination, performed at the request of the second daughter, confirmed that she carried the same genetic variant as her mother. This diagnosis prompted the second daughter to begin managing her health via periodic imaging tests.

Objectives: In our multicenter study evaluating metastatic papillary renal cell carcinoma (PRCC), 29% of tumors diagnosed as PRCC in collaborative institutes were finally diagnosed as other RCCs under central review. In those tumors, mucinous tubular and spindle cell carcinoma (MTSCC) was the leading histology, followed by unclassified RCC (ucRCC). We focused on those patients with MTSCC or ucRCC., Methods: We reviewed the processes for the pathological diagnoses of nine tumors and reviewed their clinical features., Results: All of the MTSCCs and ucRCCs were positive for AMACR, which is frequently positive in PRCC. Mucin was demonstrated in 80% of the MTSCCs, and its presence is important for their diagnoses. One MTSCC was diagnosed as a mucin-poor variant. The presence of spindle cells with low-grade nuclei was suggestive of MTSCC, but the diagnosis of high-grade MTSCC was difficult. Four tumors were diagnosed as ucRCC by histological and immunohistochemical findings. Three of the four tumors were suspicious of ucRCC in the initial review due to atypical findings as PRCC. Sunitinib and interferon-α were effective for one MTSCC patient who survived for >5 years. Two MTSCC patients who were Memorial Sloan-Kettering Cancer Center poor risk had unfavorable prognoses. One patient with mucin-poor MTSCC had an indolent clinical course. Two of four ucRCC patients showed durable stable disease with targeted agents (TAs) and survived >3 years., Conclusion: Some MTSCC metastases progressed very slowly and poor-risk tumors progressed rapidly. Systemic therapies including TAs showed some efficacies. Some patients who have metastatic ucRCC with microscopic papillary architecture can benefit from TAs., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Standard treatments have not been established in metastatic papillary renal-cell carcinoma (PRCC). We aimed to investigate treatment outcomes in patients with mPRCC., Patients and Methods: This study included 51 patients who were diagnosed with PRCC at 14 institutions. Pathologic slides were reviewed by pathologists. The associations between clinical factors and overall survival (OS) were analyzed., Results: Final pathologic diagnoses could be determined in 50 patients. Thirty-five tumors were diagnosed as PRCC (type 2 PRCC, 91.4%), and 15 were diagnosed as other histologic types. Targeted therapies (TTs) were provided to 25 mPRCC patients. Patients treated with TT survived significantly longer than those treated before the era of TT (median OS, 22.5 vs. 6.3 months; P = .0035). Median OS of patients who experienced stable disease for ≥ 9 months using single TT was 43.1 months. Patients treated with a tyrosine kinase inhibitor (TKI) as first-line TT survived longer after TT initiation than those treated with an mTOR inhibitor (median, 22.4 vs. 11.7 months; P = .2684). Patients treated with TKIs in both first- and second-line settings had significantly better survival after TT initiation than those treated with a TKI in one therapy line and an mTOR inhibitor in the other (31.4 vs. 12.9 months, P = .0172). Patients treated with a TKI as second-line TT survived significantly longer after second-line TT initiation than did those treated with an mTOR inhibitor (16.2 vs. 7.4 months, P = .0016)., Conclusion: Prognoses of patients with mPRCC were improved by TT, and TKIs appeared to be the treatment of choice in both the first- and second-line settings., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To assess the efficacy of cytoreductive nephrectomy for Japanese patients with primary metastatic renal cell carcinoma in the cytokine and targeted therapy era., Methods: The present retrospective study evaluated 330 Japanese patients with renal cell carcinoma who had synchronous metastases at diagnosis between 2001 and 2010. The characteristics of patients who did and did not undergo cytoreductive nephrectomy were compared., Results: Of the 330 patients, 254 (77.0%) underwent cytoreductive nephrectomy. Patients who underwent cytoreductive nephrectomy were younger; had better Karnofsky Performance Status; higher rates of lung metastases only and systemic therapy; lower rates of increased lactate dehydrogenase concentration and liver and multiple metastases; and a lower Memorial Sloan Kettering Cancer Center risk score. Independent predictors of poorer overall survival included clinical stage T3/4; poorer Memorial Sloan Kettering Cancer Center risk and Karnofsky Performance Status; increased C-reactive protein concentration; and absence of cytoreductive nephrectomy and systemic therapy. Median overall survival was significantly longer in the patients who did rather than did not undergo cytoreductive nephrectomy, irrespective of systemic treatment. In patients without cytoreductive nephrectomy, median overall survival was significantly longer in those who received targeted (15.5 months; hazard ratio 0.45; 95% confidence interval 0.21-0.94), but not by cytokine (8.2 months; hazard ratio 0.72; 95% confidence interval 0.36-1.46) compared with no systemic treatment (4.4 months)., Conclusions: Overall survival seems to be significantly longer in patients undergoing cytoreductive nephrectomy. However, prospective trials are required to confirm our results, as targeted therapy might improve the survival even in the absence of cytoreductive nephrectomy., (© 2015 The Japanese Urological Association.)

Background: Although the percentage of patients with renal cell carcinoma (RCC) extending into venous systems is unexpectedly high, the prognostic impact and independency of venous tumor thrombus-related factors on overall survival (OS) remain controversial. Furthermore, the prognostic impact of various clinicopathologic factors including tumor thrombus-related factors on OS may change with elapsed years after the intervention and also with follow-up duration of participants. The aim of the study is to explore independent and universal predictive preoperative and intraoperative clinicopathologic factors on OS in patients with RCC extending into venous systems using subgroup analysis in terms of restricted follow-up duration and yearly-based survivors., Methods: Between 1980 and 2009, 292 patients diagnosed with RCC with venous tumor thrombus were retrospectively registered for this study. The prognostic impacts of various clinicopathologic and surgical treatment factors including levels of venous thrombus, venous wall invasion status and likelihood of aggressive cytoreductive operation, were investigated using Kaplan-Meier method and following multivariate Cox proportional hazards model for all patients and those still alive at 1, 2, and 3 years of follow-up. To investigate the impact of follow-up duration on the statistical analyses, multivariate logistic regression analyses were used to explore prognostic factors using restricted data until 1, 2, and 3 years of follow-up., Results: The median follow-up duration was 40.4 months. The 5-year OS was 47.6%. Several independent predictive factors were identified in each subgroup analysis in terms of yearly-based survival and restricted follow-up duration. The presence of tumor thrombus invading to venous wall was independently related to OS in the full-range follow-up data and in survivors at 2 and 3 years of follow-up. Using restricted follow-up data until 1, 2, and 3 years of follow-up, many independent predictive factors changed with follow-up duration, but surgical category could be universal and independent predictive factors., Conclusion: The most universal factors affecting improvement both in short-term and long-term survivals could be cytoreductive surgery and absence of venous wall invasion. It may mean that feasible aggressive cytoreductive operation following more reliable preoperative imaging for predicting venous wall invasion status would improve OS for patients with RCC extending into venous systems.

Background: The prophylactic effect of postoperative interferon on recurrence and distant metastasis in stage II or III renal cell carcinoma is unclear. In most studies, interferon has been administered for 6 months or less. Therefore, we performed a clinical study of the efficacy of 1-year postoperative administration of natural interferon α, which is generally used in Japan., Methods: The subjects were patients diagnosed with stage II or III renal cell carcinoma who underwent radical nephrectomy. The subjects were randomly allocated to receive an intramuscular injection of natural interferon α (3 million to 6 million units) 3 times a week for 1 year or to receive follow-up observation until recurrence or metastasis occurred. Chest and abdominal CT were performed once yearly for all patients. The primary endpoint was progression-free survival., Results: From September 2001 to August 2006, a total of 107 patients were registered, but 7 subsequently withdrew from the study. Therefore, 100 patients were included in the analysis. The primary endpoint of progression-free survival did not differ significantly between the groups that received natural interferon α or follow-up observation (p = 0.456, log-rank test). However, peak hazards of progression in the interferon group were delayed for about 6-10 months compared with the observation group., Conclusion: Progression-free survival showed no improvement after administration of natural interferon α to patients with stage II or III renal cell carcinoma for 1 year after radical nephrectomy. The peak hazards of progression might be delayed by about 6 months by interferon administration.

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., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objectives: We retrospectively review patients treated for renal cell carcinoma at 19 institutes in collaboration with the Japanese Society of Renal Cancer, to clarify the risk factors for ipsilateral adrenal involvement (IADI)., Methods: The clinicopathologic factors of the 30 patients with IADI were compared with those of the 926 control patients without IADI, and independent predictors for IADI were identified by multivariate analysis., Results: Preoperative computed tomography (CT) could detect 83.3% of the instances of synchronous ipsilateral adrenal metastasis. Patients with IADI had significantly larger primary tumors, higher pT stages and histologic grades, and higher percentages of upper pole involvement, microvascular invasion, spindle-cell-type tumors, lymph node metastasis (LNM), and distant metastasis (DM) outside the ipsilateral adrenal gland (IAd) than in control patients. Multivariate logistic regression analysis of clinical factors revealed that tumor size greater than 5.5 cm, pT stage of 3 or higher, LNM, and DM outside IAd, but not upper pole involvement, were significant predictors of IADI., Conclusions: Tumor size greater than 5.5 cm, clinical T stage of 3 or higher (tumor for which pT stage of 3 or higher is suspected), LNM, and DM outside IAd seemed to be important preoperative indicators of IADI. These factors and CT findings would be useful preoperative indicators for ipsilateral adrenalectomy. Moreover, patients with renal cell carcinoma who have normal adrenal on CT, have a T1 tumor extending less than 5.5 cm, and have neither LNM nor DM are good candidates for adrenal-sparing nephrectomy.

Objective: A joint study was undertaken by the Japanese Society of Renal Cancer to investigate the present status of partial nephrectomy in Japan and to speculate about what may be the indications for partial nephrectomy in patients with renal cell carcinoma., Methods: Data were tabulated for 469 patients from participating medical institutions and various clinical factors were investigated with regard to disease progression (local recurrence and distant metastasis)., Results: Disease progression was observed in 21 patients (4.5%). No significant relation to disease progression was observed for sex, laterality, tumor histology, grade and tumor size. Although patients with solitary tumors displayed excellent prognosis irrespective of tumor diameter, patients with multiple tumors displayed a high likelihood of disease progression. Patients older than 77 years old and patients with imperative indication were found to have a poorer prognosis., Conclusion: In patients with solitary tumors, partial nephrectomy can be actively performed, even if the patient displays elective indications and the tumor is >4 cm in diameter. In patients displaying multiple tumors with imperative indications, the decision whether to perform partial nephrectomy should be made by the patients and their physicians after considering the impact on curability and the quality of life.

Purpose: We performed Tc-mercaptoacetyltriglycine (MAG3) renal scintigraphy in patients with renal malignancy to evaluate the function of each renal unit before and after nephrectomy to see if postoperative functional deterioration could be predicted based on scintigraphy results and creatinine clearance., Materials and Methods: A total of 22 men and 13 women with renal malignancy, including 32 with renal cell carcinoma and 3 with urothelial cancer, were prospectively enrolled in this study. Average patient age was 64.3 years (median 65, range 43 to 88). All patients underwent MAG3 renal scintigraphy before and after unilateral nephrectomy. At the same time serum creatinine and endogenous creatinine clearance were determined., Results: Mean serum creatinine was 0.93 mg/dl before and 1.31 after nephrectomy (p <0.0001). Preoperative endogenous creatinine clearance was 70.8 ml per minute per 1.73 m, which decreased to 49.0 ml per minute per 1.73 m after nephrectomy (p <0.0001). Mean MAG3 clearance of the remaining kidney increased 35.1% above baseline from 156.5 to 211.5 ml per minute per 1.73 m following nephrectomy. Spearman rank core analysis revealed that preoperative MAG3 clearance of the remaining kidney significantly correlated with postoperative creatinine clearance (r = 0.596, p = 0.0005). Preoperative MAG3 clearance of the remaining kidney more than 130 ml per minute per 1.73 m coincided with postoperative creatinine clearance above 40 ml per minute per 1.73 m., Conclusions: MAG3 renal scintigraphy may be useful for predicting renal insufficiency after nephrectomy. The findings in this study suggest that preoperative MAG3 clearance of the remaining kidney less than 130 ml per minute per 1.73 m is a risk factor for postoperative renal insufficiency.

Aim: A retrospective analysis was performed involving patients who had undergone radical nephrectomy for renal cell cancer to determine the long-term outcome of this surgery on renal status., Materials and Methods: Between 1977 and 2001, 172 patients having undergone radical nephrectomy for renal cell cancer were followed for a period of more than one year at the Department of Urology Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan. The preoperative and postoperative serum creatinine values of these individuals were reviewed. Long-term effects of radical nephrectomy on renal function and factors influencing postoperative renal dysfunction were analyzed., Results: Six (3.5%) of the 172 individuals progressed to hemodialysis. Eleven (6.4%) patients displayed serum creatinine values of > or =1.6 mg/dL. The remaining 155 patients (90.1%) demonstrated postoperative serum creatinine values of <1.6 mg/dL. The present study suggests that aging, a high degree of proteinuria, hypertension and diabetes mellitus were the predominant risk factors for renal deterioration following nephrectomy., Conclusions: We have primarily selected radical nephrectomy for cases exhibiting smaller renal tumors with a normal contralateral kidney. We encourage nephron-sparing surgery where possible in patients displaying risk factors, including a high degree of proteinuria, hypertension, or diabetes mellitus.

Objectives: To evaluate the function of the remaining kidney after nephrectomy for renal cell cancer by technetium-99m-mercaptoacetyltriglycine (99mTc-MAG3) renal scintigraphy., Methods: We evaluated 30 consecutive patients who were undergoing unilateral radical nephrectomy by 99mTc-MAG3 scintigraphy. All patients underwent three consecutive 99mTc-MAG3 scintigraphy studies. The first study was performed before nephrectomy, the second 1 month after surgery, and the third 1 year after surgery. At these times, the serum creatinine levels were also evaluated., Results: The mean preoperative MAG3 clearance of the remaining kidney of the 30 patients was 155.4 mL/min/1.73 m2. The mean MAG3 clearance of the remaining kidney had increased to 209.2 mL/min/1.73 m2 by 1 month after nephrectomy, and the average percentage increase was 39.5%. After 1 year, it had increased to 211.3 mL/min/1.73 m2, with a 40.5% average percentage increase. The preoperative MAG3 clearance of the remaining kidney was inversely correlated with the percentage of increase in MAG3 clearance of the remaining kidney. Abnormal serum creatinine levels (greater than 1.3 mg/dL) were more common after nephrectomy, occurring in 6 patients at 1 month and in 5 patients at 1 year postoperatively. In all 6 patients with elevated creatinine levels, the preoperative MAG3 clearance of the remaining kidney was less than 150 mL/min/1.73 m2., Conclusions: Adaptive hyperfunction occurs soon after nephrectomy that is not associated with age or sex and continues for at least 1 year. A greater compensatory response is produced in patients with more severe renal deterioration. Using 99mTc-MAG3 scintigraphy, we may be able to predict postoperative renal function.

Objectives: To report our development of a new application of the inter-Alu long polymerase chain reaction (PCR) for genomic scanning to screen for tumor-specific alterations in tumor DNA. Using this method, we detected a rearranged chromosomal region in renal cell carcinomas (RCCs). We then examined tumor-specific allelic loss in this region using microsatellite markers and determined whether a relationship was present between this allelic loss and the clinicopathologic features of the patients., Methods: The inter-Alu long PCR genomic scan method was performed using RCC DNA samples and primers specific for a minor subset of the human repeat sequence Alu. We analyzed DNA samples from 42 pairs of matched normal and nonpapillary RCC tissues with seven microsatellite markers., Results: The inter-Alu long PCR genomic scan method revealed an altered DNA region on chromosome 14q24-31, which is the location of several putative tumor suppressor genes. At least one of seven microsatellite markers on chromosome 14q24-31 showed loss of heterozygosity in 23 (54.8%) of 42 informative cases of RCC. The prevalent loss region was confined to a 2-Mb region around D14S67. We found a positive correlation between the presence of the loss of heterozygosity on 14q24-31 and tumor stage (P <0.05). We also found that cases with allelic loss at 14q24-31 had a poor prognosis (P = 0.045)., Conclusions: Our inter-Alu long PCR genomic scan method is a powerful method for the screening of DNA alterations, and our data suggest that the chromosome 14q24-31 region contains likely tumor suppressor genes associated with the progression of RCC.

Objectives: To evaluate the clinical outcome of nephroureterectomy with endoscopically assisted transurethral ureteral stripping for transitional cell carcinoma of the renal pelvis in a comparative study., Methods: Sixty patients with localized renal pelvic cancer were enrolled in a prospective comparative nonrandomized study. Of these, 28 patients underwent nephroureterectomy with endoscopically assisted transurethral ureteral stripping and 32 underwent conventional nephroureterectomy with a bladder cuff. Both short-term and long-term results were analyzed in this series., Results: The operating time for patients with ureteral stripping was significantly shorter than for those with a standard two-incision nephroureterectomy (median 183 versus 250 minutes, P = 0.0231), and the amount of blood loss was significantly less (median 150 versus 390 mL, P = 0.0002). Intravesical recurrence was detected in 10 (35.7%) of the 28 patients with ureteral stripping, and the 1-year and 3-year recurrence-free rate was 68.0% and 57.7%, respectively. Seven patients treated by the standard two-incision nephroureterectomy (21.9%) experienced intravesical recurrence, with a 1-year and 3-year recurrence-free rate of 96.8% and 75.0%, respectively. The recurrence rate was significantly greater in the group with ureteral stripping (P = 0.0287)., Conclusions: Compared with conventional nephroureterectomy with a bladder cuff, nephroureterectomy with transurethral stripping is a minimally invasive procedure with a shorter operating time and less blood loss, but a statistically significantly greater intravesical recurrence rate. Greater consideration should be taken before selecting this procedure.

Purpose: We examined the expression of REIC/Dkk-3, a possible candidate for a tumor suppressor gene, in human renal clear cell carcinoma (RCCC) cell lines and sporadic RCCC surgical specimens., Materials and Methods: Human RCCC cell lines (Caki-1, Caki-2, ACHN and KPK-1) and several control cell lines were used to examine the expression of REIC/Dkk-3 mRNA and characterize a newly raised antibody specific for REIC/Dkk-3 protein. Pairs of cancerous and adjacent noncancerous tissues were obtained from 20 patients with RCCC. Of them 17 and 7 cases were analyzed by real-time quantitative reverse transcriptase-polymerase chain reaction, and by Western blot analysis and/or immunohistochemical analysis, respectively., Results: The decreased expression of REIC/Dkk-3 mRNA and protein in human RCCC cell lines, and the specificity of the new antibody were confirmed. In a real-time quantitative reverse transcriptase-polymerase chain reaction study using 17 pairs of RCCC and adjacent normal tissues REIC/Dkk-3 mRNA levels were significantly decreased in carcinoma tissues (by 25% to approximately 95% in 15 pairs). Western blot analysis and immunohistochemistry revealed a significant decrease in REIC/Dkk-3 protein levels in 6 of the 7 and 13 of the 14 RCCC cases analyzed, respectively., Conclusions: The decrease in REIC/Dkk-3 mRNA and protein levels was observed irrespective of tumor grade and stage, indicating the involvement of REIC/Dkk-3 in an initial step of malignant conversion. Consequently REIC/Dkk-3 could be a new molecular target for therapeutic measures against RCCC.

Objective: This study was conducted to examine the natural history of renal cell carcinoma (RCC)., Methods: Inclusion criteria were the following: (1) patients who received diagnostic imaging of the kidney (CT, MRI) at two points in time before the diagnosis of RCC or patients who were followed, without treatment, after a diagnosis of RCC; and (2) patients in whom changes in tumor size were followed by the same modality of diagnostic imaging and who did not receive any treatment which could exert anti-tumor activity on the primary or metastatic lesions. The tumor doubling time (DT) and the growth rate of maximum tumor diameter (R) were determined. DT was calculated using the equation DT = (T - T(0)) x log2/logV - logV(0) (where T - T(0) indicates the length of time between two measurements and V(0) and V denote the tumor volume at two points of measurement). R was calculated using the equation R = (phi - f(0))/(T - T(0)) x 100 (where phi(0) and f indicate the maximum diameter at two points). Fifty-six cases registered with the Japanese Society of Renal Cancer were included in the evaluation., Results: DT was 603.1 +/- 510.1 days, which did not correlate with V(0). R was 0.263 +/- 0.346 cm/day x 100. In cases where the tumor diameter was >/=4 cm, a significant correlation was noted between f(0) and R., Conclusions: Elucidation of the natural history of RCC will contribute to facilitation of differential diagnosis and determination of optimum therapeutic strategy.

The purpose of this study was to compare the MR characteristics of renal cell carcinomas against histologic findings and to assess the correlations among signal intensity, tumor enhancement, and pathologic findings. Fifty-four patients (56 lesions) were examined by MR imaging and then underwent partial or radical nephrectomy. The pathologic diagnosis of all lesions was renal cell carcinoma. All MR examinations were performed as dynamic studies using the same 1.5-T scanner. MR characteristics were compared against pathologic findings after resection, and the correlations among signal intensity, tumor enhancement, and pathologic findings were then assessed. A significant correlation was observed between tumor grade and tumor enhancement, with G3 lesions tending to show little enhancement. Regardless of the histologic classification, G3 tumors were found to contain highly heterotypic cancer cells and very few vessels by histopathologic examination. No significant correlations were noted between the other MR characteristics and pathologic findings. Renal cell carcinomas showing little enhancement tend to be highly malignant lesions based on the pathologic findings. Special consideration is required for these tumors with regard to the selection of surgical intervention and follow-up observation.

Background: The present study was conducted to investigate the incidence of renal cell carcinoma by sex, age group and different regions in Japan., Methods: The survey was conducted from the beginning of January 1997 to the end of December 1997. A total of 1306 Institutions in all 47 prefectures throughout Japan were requested to register cases., Results: There were 6358 persons with renal cell carcinoma, consisting of 4372 men and 1986 women. The age-specific incidence rates showed a peak in the age group of 65-70 years in both men and women. The crude incidence rates per 100 000 population for men and women were 7.1 and 3.1, respectively, and age-standardized incidence rates per 100 000 population for men and women were 4.9 and 1.8, respectively. The incidence rates in the Hokkaido region were significantly higher than in other regions (P < 0.05), among which there was no significant difference in incidence rates., Conclusions: The present study showed that the incidence rates of renal cell carcinoma in Japan were approximately the same as among Japanese in Los Angeles. The rates were, however, lower than North American and European countries, but higher than China, Central or South American countries and African countries. The reasons for the high incidence of renal cancer in the Hokkaido region are not entirely clear. Further epidemiologic research is required.

Viral-mediated transfer of the herpes simplex virus thymidine kinase (HSV-tk) gene has been demonstrated by several investigators to confer sensitivity to nucleoside analogs such as ganciclovir (GCV) in a variety of tumor cells including brain, prostate, bladder, kidney, ovary, head and neck, lung, pancreas, and liver cancers. Fourteen suicide gene clinical protocols using adenovirus vectors have been conducted, including four in prostate cancer. Two additional protocols for prostate cancer are in preparation in Japan and the Netherlands. A study conducted at Baylor College of Medicine was the first to demonstrate the safety of HSV-tk plus GCV therapy for human prostate cancer and the anticancer activity of gene therapy in this disease. However, it is still in the early stage of its development, with a number of problems to be overcome. Systemic delivery, specific introduction, and specific expression of the target gene are the major issues to be managed in order to establish a clinically relevant treatment strategy.

Objectives: Recent clinical trials have implied the cytotoxic and antiproliferative effects of combining 5-fluorouracil and interferon-alpha in the treatment of metastatic renal cell cancer. We therefore conducted an open multicenter trial to test the efficacy of such a combination on this cancer., Methods: Human lymphoblastoid interferon (3 MIU per patient) was administered subcutaneously three times weekly for 12 weeks, while 5-fluorouracil was administered (600 mg/m2/day) as a continuous infusion for the first 5 days, followed by an intravenous bolus infusion of 600 mg/m2 once a week from the 3rd week until the 12th week., Results: Of the 63 patients entered into the trial, 55 were eligible and evaluable for systemic toxicities, and 53 were evaluable for their response. All patients had undergone a prior nephrectomy, and their European Cooperative Oncology Group (ECOG) performance status ranged from 0 to 3 (median 0). Three complete and eight partial responses were induced, with an overall response rate of 20.0%. The median time to progression and the median survival time were 11 and 33 months, respectively. World Health Organization grade 3 toxicities were observed in 8 patients; however, no grade 4 toxicities or toxicity-related deaths were noted., Conclusions: Combination therapy of interferon-alpha plus 5-fluorouracil at the above-described dosage and schedule produced no better responses than interferon monotherapies. Prolongation of survival could be attributable to the fair performance status of the patients. This regimen has limited value for the treatment of patients with advanced renal cell cancer.

A 60-year-old man with renal cell carcinoma was treated of right nephrectomy and high dose administration of Interferon-alpha (IFN) in 1990. Three and half years after operation, he complained of cough and hemoptysis. Chest X-ray showed a abnormal shadow (5.5 x 3.5 cm) in the upper lung field. On chest CT, a tumor mass with small cavity was located at S2, attended with the speculation and pleural indentation. A rough nodule suspected daughter tumor was pointed out near the tumor mass. Laboratory investigation revealed mild leucocytosis, an elevated ESR and C reactive protein. On lymphocyte subset, CD 4/8 ratio was 0.8 and NK cell activity was 11%. Immunosuppressive acid protein (IAP) in serum was 1,137 ng/ml. No organisms or malignant cells could be demonstrated in the biopsy materials or sputum. Right thoracotomy and upper lobectomy was carried out. Postoperative pathological diagnosis was inflammatory pseudotumor. Namely, the lesion was occupied with variable admixture of lymphocytes, plasma cells, histiocytes, phagocytes included hemosiderin, foam cells and whorled fibrosis. Daughter tumor was scar tissue. Now, he is well without recurrence and his immune response is within normal level. Some discussion of the literature was mentioned.

To investigate the role of basic fibroblast growth factor (FGF) in renal cell carcinoma growth, we have analyzed the expression of mRNA of basic FGF. In 7 of 15 cases, basic FGF mRNA level in renal cell carcinoma tissues was higher than that in corresponding normal tissues. However, the tumor-to-normal ratios of expression levels are chiefly less than 2.0 and, in 5 cases, are even less than 1.0. Furthermore, there was no correlation between the ratio and the clinical stage. In protein analysis, we could not find any difference between basic FGF extracted from renal cell carcinomas and that from normal kidney tissues in bioactivity, immunoreactivity, molecular weight and affinity to heparin. On the other hand, anti-basic FGF monoclonal antibody inhibited the growth of a renal cell carcinoma cell line, VMRC-RCW, and this inhibition was reversed by an extraphysiological amount of exogenous basic FGF (100 ng./ml.). These results suggest that basic FGF itself may have no pivotal role in renal cell carcinoma etiology but is involved in the growth of renal cell carcinomas in an autocrine manner.

Metallothionein (MT) is a low molecular-metal binding protein with multiple biological functions. Recently, MT has been implicated as a factor involved in resistance to anticancer drugs, which presumably inactivates anticancer drugs, including cisplatin, and doxorubicin. In this report, we investigated the relationship of MT expression with the clinical features in bladder cancer and renal cell carcinoma. In 35 cases of bladder cancer, 10 cases of renal cell carcinoma and 3 cases of normal mucosa of bladder, the expression of MT was immunohistologically examined by avidinebiotin-peroxidase (ABC) staining of paraffin-embedded tissue specimens with anti-MT antibody. Intense MT expression was noted in all cases of normal mucosa of bladder. MT was detected in 10 of 35 cases of bladder cancer, with the incidence of MT expression being significantly higher increases with lower pathological tumor grade. MT was detected in 8 of 10 cases of renal cell carcinoma, and all of the their normal renal tubules showed more intense staining. A number of hypotheses can be proposed from these observations. First, our observation of decreased MT expression in poorly differentiated carcinomas, which are the more proliferating tumors, this suggests correlation of MT expression with proliferative status of cancer. Second, the higher incidence of MT expression in renal cell carcinoma than in bladder cancer may suggest that it is a factor responsible for the lower efficacy of chemo-therapy in renal cell carcinoma than in bladder cancer.