Clinical response to sodium glucose co-transporter 2 inhibitor ipragliflozin in a patient with metastatic renal cell carcinoma.

INTRODUCTION: Sodium glucose co-transporter 2 inhibitors constitute a new class of antidiabetic medication. Sodium glucose co-transporter 2 inhibitors have been shown to exert anticancer effects. However, the clinical value of these drugs as anticancer agents is yet to be evaluated. CASE PRESENTATION: A 72-year-old man presented to our hospital with frequent cough and dyspnea. Contrast-enhanced computed tomography revealed renal cell carcinoma cT3bN0M1. Ipragliflozin, a sodium glucose co-transporter 2 inhibitor, treatment was initiated to control blood glucose levels. Two years after diagnosis, computed tomography revealed remarkable tumor regression without any systemic therapy other than ipragliflozin. CONCLUSION: Sodium glucose co-transporter 2 inhibitors are potentially applicable as anticancer agents among patients with metastatic renal cell carcinoma.

Renal function after radical nephrectomy: development and validation of predictive models in Japanese patients.

OBJECTIVES: To develop and validate predictive models for postoperative estimated glomerular filtration rate and risk of chronic kidney disease after radical nephrectomy in Japanese patients. METHODS: The present retrospective study included a development cohort of 209 patients without preoperative chronic kidney disease who underwent radical nephrectomy between 1994 and 2008, and were followed up for longer than 3 years, and a validation cohort of 144 similar such patients. Univariate and multivariate linear regression or logistic regression analyses were carried out to identify the independent predictors of estimated glomerular filtration rate or chronic kidney disease 3 years after radical nephrectomy. Incorporating all independent predictors, predictive models for postoperative renal function were developed and externally validated. RESULTS: Age, the presence of diabetes mellitus, and preoperative estimated glomerular filtration rate were independent predictors of both postoperative estimated glomerular filtration rate and chronic kidney disease. A formula for predicting the postoperative estimated glomerular filtration rate and a nomogram for predicting the risk of postoperative chronic kidney disease were developed. The adjusted R(2) of the formula and area under the receiver operating characteristic curves of the nomogram were 0.446 and 0.865 in the development cohort, and 0.396 and 0.787 in the validation cohort, respectively. CONCLUSIONS: We developed and validated novel predictive models for the postoperative renal function 3 years after radical nephrectomy in Japanese patients.

Longitudinal change in renal function after radical nephrectomy in Japanese patients with renal cortical tumors.

PURPOSE: We investigated the longitudinal change in renal function after radical nephrectomy in Japanese patients with renal cortical tumors and compared it with that after partial nephrectomy. MATERIALS AND METHODS: This retrospective study included 416 Japanese patients who underwent radical (341) or partial (75) nephrectomy between 1994 and 2009. We investigated the postoperative duration of freedom from new onset of an estimated glomerular filtration rate of less than 60 and 45 ml/minute/1.73 m(2), and the longitudinal change in renal function after surgery. RESULTS: The 3-year probability of freedom from new onset of an estimated glomerular filtration rate of less than 60 ml/minute/1.73 m(2) after radical and partial nephrectomy was 63% and 89%, respectively (p <0.001). The corresponding incidence of an estimated glomerular filtration rate of less than 45 ml/minute/1.73 m(2) was 89% and 95%, respectively (p = 0.247). The estimated glomerular filtration rate decreased by 36% and 13% 1 year after radical and partial nephrectomy, respectively. During the next 5-year followup the estimated glomerular filtration rate after radical nephrectomy slightly but significantly increased by 5% but after partial nephrectomy it did not change significantly. CONCLUSIONS: Radical nephrectomy is an independent risk factor for new onset of an estimated glomerular filtration rate of less than 60 ml/minute/1.73 m(2) in Japanese patients. However, relatively few patients have new onset of an estimated glomerular filtration rate of less than 45 ml/minute/1.73 m(2) even after radical nephrectomy. In Japanese patients renal function deteriorates immediately after radical nephrectomy but improves slightly but significantly thereafter.

Young age as favorable prognostic factor for cancer-specific survival in localized renal cell carcinoma.

OBJECTIVES: To evaluate the prognostic effect of age in patients with localized renal cell carcinoma (RCC) and investigate the incidence of Xp11 translocation RCC in young patients who developed recurrence. METHODS: From 1990 to 2007, 2403 Japanese patients underwent nephrectomy for presumed RCC at 9 institutions. Of those, 1143 patients had localized RCC (Stage pT1-2N0M0). Their clinical data were retrospectively reviewed. In the present study, 131 patients (11%) were considered young (≤45 years at diagnosis). In the young patients with recurrence, the nephrectomy specimens were immunostained with TFE3 to determine the incidence of Xp11 translocation RCC. RESULTS: During the median follow-up of 47 months, 3 cancer deaths (2.2%) occurred among young patients and 51 (5.0%) among older patients. The 5-year cancer-specific survival (CSS) rate was significantly better for the younger patients than for the older patients (P = .049). Multivariate analysis showed that age was significantly associated with CSS, as were the pathologic T stage, tumor grade, and symptoms at diagnosis. The hazard ratio of young age was 0.31 (95% confidence interval 0.077-0.87). The recurrence-free survival curves revealed no difference between these 2 groups. Of the 74 patients with recurrence, the CSS after recurrence was significantly better in the younger patients than in the older patients (P = .0010). Of the 8 young patients with recurrence, 4 had Xp11 translocation RCC, and 3 survived for >5 years after recurrence. CONCLUSIONS: Compared with the older patients, the young patients with RCC had similar recurrence-free survival rates but better CSS rates. This might have been because significant numbers of the young patients had Xp11 translocation RCC.

Phase-II trial of combination treatment of interferon-α, cimetidine, cyclooxygenase-2 inhibitor and renin-angiotensin-system inhibitor (I-CCA therapy) for advanced renal cell carcinoma.

We have recently reported favorable responses to a combination treatment comprising cimetidine, a cyclooxygenase-2 inhibitor and a renin-angiotensin-system inhibitor in metastatic renal cell carcinoma (RCC). In view of the potential synergistic effects of these three agents and interferon-α (I-CCA therapy), we conducted a phase-II trial to examine the efficacy and toxicity of I-CCA as first-line treatment. Fifty-one patients with advanced RCC received natural interferon-α (3-6 million U thrice/week) and cimetidine (800 mg), cyclooxygenase-2 inhibitor meloxicam (10 mg), and renin-angiotensin-system inhibitor candesartan (4 mg) or perindopril (4 mg) orally daily. Memorial Sloan-Kettering Cancer Center prognostic categories were favorable, intermediate and poor in 10 (20%), 31 (61%) and 10 (20%) patients, respectively. The primary end-point was the objective response rate (ORR) and the secondary end-points included clinical benefit, progression-free survival (PFS), overall survival (OS) and safety. Median follow-up was 19 months. Complete response (CR) was observed in four patients (8%) and partial response in seven (14%), yielding an ORR of 22%. None of the four patients who achieved CR relapsed during the 16- to 81-month follow up. The ORR were 17% in the favorable- or intermediate-risk group and 40% in the poor-risk group. The other 24 patients (45%) had stable disease for at least 6 months, resulting in a clinical benefit rate of 67%. The median PFS and OS were 12 and 30 months, respectively. Grade 3/4 toxicities were never observed. The I-CCA therapy, providing favorable responses and low toxicity profiles, is worthy of further consideration as a first-line therapy for metastatic RCC.

[Case of infective endocarditis diagnosed with renal infarction].

A 46-year-old woman with sudden on set strong right flank pain was transferred to our hospital with the diagnosis of right renal infarction. Cardiac ultrasonography revealed a vegetation on the posterior cusp of the mitral valve, and the renal infarction was thought to be caused by renal artery embolism from infective endocarditis. Since the vegetation remained after antimicrobial therapy as conservative management, the patient was surgically treated by mitral annuloplasty. It has been known that infective endocarditis can cause renal infarction. Infective endocarditis requires immediate and adequate treatment because of high mortality. Therefore, the appropriate diagnosis of infective endocarditis is needed for patients with renal infarction without any other disorder causing renal infarction.

Development and external validation of a new outcome prediction model for patients with clear cell renal cell carcinoma treated with nephrectomy based on preoperative serum C-reactive protein and TNM classification: the TNM-C score.

PURPOSE: C-reactive protein has been shown to be a prognostic factor for renal cell carcinoma. We developed a new prediction model including C-reactive protein in patients with clear cell renal cell carcinoma. MATERIALS AND METHODS: This study is based on 2 cohorts of Japanese patients with clear cell renal cell carcinoma, including 249 for evaluating prognostic factors and developing the prediction model, and 290 for external validation. Analyzed factors included TNM classification, tumor size, Fuhrman nuclear grade, tumor necrosis and preoperative serum C-reactive protein (cutoff 0.5 mg/dl). We developed a scoring model based on multivariate analysis to predict cancer specific survival. Predictive ability of the model was evaluated using the concordance index. RESULTS: Multivariate analysis showed that pT stage, lymph node involvement, distant metastasis, tumor necrosis and C-reactive protein were independent predictors of cancer specific survival. A new scoring model was developed, consisting of C-reactive protein and the TNM classification. The 5-year cancer specific survival rate in patients with a score of 0, 1 and 2, 3 and 4, and 5 or more was 99%, 89%, 69% and 18%, respectively. Cancer specific survival rates were clearly discriminated by the stratification according to the scoring model (p <0.001). The concordance index of the new model was 0.820, which was externally validated as a concordance index of 0.865. CONCLUSIONS: In patients with clear cell renal cell carcinoma a new simple scoring model based on serum C-reactive protein and the TNM classification is a useful and easy to use tool for predicting outcome.

Impact of C-reactive protein kinetics on survival of patients with metastatic renal cell carcinoma.

BACKGROUND: Pretreatment C-reactive protein (CRP) level has been shown to be prognostic for metastatic renal cell carcinoma (mRCC). OBJECTIVES: To demonstrate that CRP would be a biomarker for mRCC, we evaluated the impact of CRP kinetics on survival. DESIGN, SETTING, AND PARTICIPANTS: One hundred eight patients with mRCC were treated from 1994 to 2007 with a median follow-up period of 18 mo (interquartile range: 7-40 mo). INTERVENTION: All patients underwent multimodal therapeutic intervention. MEASUREMENT: Patients were divided into three groups according to CRP kinetics. Patients whose pretreatment CRP levels were <5mg/l, patients whose pretreatment CRP levels were >5mg/l and normalized (<5mg/l) at least one time during treatment, and patients whose pretreatment CRP levels were >5mg/l and never normalized were assigned to nonelevated, normalized, and non-normalized CRP groups, respectively. The prognostic impact of CRP kinetics and the correlation between normalized CRP period and overall survival period were determined. RESULTS AND LIMITATIONS: In 61 of the 108 patients (56%), CRP levels were elevated at the diagnosis of mRCC. During treatment, CRP levels were normalized in 30 of 61 patients (49%), whereas CRP levels remained elevated in the remaining 31 patients. Overall survival rates were significantly different between nonelevated, normalized, and non-normalized CRP groups (p<0.001) with 2-yr survival rates of 69%, 55%, and 4%, respectively. In multivariate analysis, CRP kinetics was an independent significant factor for overall survival. Normalized CRP period was significantly correlated with overall survival period in 78 patients who died of disease. Since this is a small retrospective study on patients within the past era of immunotherapy, larger confirmatory studies in the current era of targeted therapy are needed. CONCLUSIONS: CRP can be a novel, widely available biomarker for patients with mRCC.

External validation of the Mayo Clinic cancer specific survival score in a Japanese series of clear cell renal cell carcinoma.

PURPOSE: We validated the Mayo Clinic SSIGN (stage, size, grade and necrosis) score in an independent Japanese sample of patients. MATERIALS AND METHODS: Between 1985 and 2006, 406 consecutive Japanese patients underwent nephrectomy for clear cell renal cell carcinoma. The prognostic value of pathological features for disease specific survival was evaluated using the Cox proportional hazards regression model. The predictive ability of the SSIGN score was evaluated using the concordance index. RESULTS: Median followup in the 406 patients was 56 months. Of the patients 100 died of renal cell carcinoma and the 5-year cancer specific survival rate was 78.4%. All features comprising the SSIGN score were significantly associated with death from renal cell carcinoma on univariate analysis. Primary tumor classification, regional lymph node involvement, distant metastasis and Fuhrman nuclear grade were significantly associated with death from renal cell carcinoma in a multivariate setting. The median SSIGN score in the 406 patients was 3 (range 0 to 15). The concordance index of the SSIGN score was 0.814. The 5-year cancer specific survival rate in patients with a score of 0 to 2, 3 or 4, 5 or 6, 7 to 9 and 10 or more was 96.8%, 92.5%, 78.8%, 57.7% and 18.1%, respectively. The survival rate in the latter 3 groups was higher than reported rates in American and European patients. CONCLUSIONS: The Mayo Clinic SSIGN score can be applicable to Japanese patients with renal cell carcinoma with a high degree of prognostic accuracy. Future studies are needed to determine whether Japanese patients with moderate and high SSIGN scores survive longer than their American and European counterparts.

Incidence of benign pathologic lesions at partial nephrectomy for presumed RCC renal masses: Japanese dual-center experience with 176 consecutive patients.

OBJECTIVES: To determine the incidence of benign pathologic findings at elective partial nephrectomy for renal masses thought to be renal cell carcinoma (RCC) on preoperative imaging in Japanese patients. METHODS: From 1993 to 2007, 176 patients (46 women and 130 men) underwent elective partial nephrectomy for presumed RCC masses in 2 Japanese centers. The mean size of the resected lesions was 2.3 cm (range 0.3-5.8). Overall, 97 and 79 patients had a renal mass of < or = 2 cm and > 2 cm, respectively. Of the 176 patients, 100%, 89%, and 32% had preoperatively undergone computed tomography, ultrasonography, and magnetic resonance imaging, respectively. RESULTS: Of the 176 masses resected, the pathologic examination revealed benign findings in 19 (11%), angiomyolipoma in 10 (5.7%), oncocytoma in 5 (2.8%), complicated cysts in 2 (1.1%), and a solitary fibrous tumor and scar of the kidney 1 each (0.6%). Of the 46 women, 12 (26.1%) had benign lesions compared with 7 of the 130 men (5.3%; P = .0003). Of the 10 angiomyolipomas diagnosed, 8 were diagnosed in women (P = .0004). Tumor size was not associated with benign histologic findings. The incidence of benign lesions was equivalent (10% and 12%) between the 2 centers. CONCLUSIONS: The present incidence (11%) of benign lesions in presumed RCC masses at surgery in Japanese patients was lower than the incidence of 20%-30% previously reported from Western countries, probably because of the low incidence of oncocytomas in Japanese patients. Women had almost 5 times the likelihood of having a benign lesion compared with men, because of the high incidence of angiomyolipomas in women.

Prognostic impact of postoperative C-reactive protein level in patients with metastatic renal cell carcinoma undergoing cytoreductive nephrectomy.

PURPOSE: We explored the prognostic impact of C-reactive protein status in patients with metastatic renal cell carcinoma undergoing cytoreductive nephrectomy. MATERIALS AND METHODS: The oncological outcome of 40 patients with metastatic renal cell carcinoma (TxpN1M0, TxNxM1) who underwent cytoreductive nephrectomy was analyzed. The C-reactive protein level was measured before and 1 month after cytoreductive nephrectomy. The normal value of C-reactive protein was considered less than 0.5 mg/dl. RESULTS: During the median followup of 14 months 31 patients (78%) died of the disease. The preoperative C-reactive protein level was not increased in 17 of the 40 patients (nonelevated group). Of the remaining 23 patients with a preoperatively increased C-reactive protein level, after cytoreductive nephrectomy the C-reactive protein level normalized in 17 (normalized group). However, in the remaining 6 patients the C-reactive protein level did not normalize and remained high during followup (nonnormalized group). All of the patients in nonnormalized group died of the disease within 1 year. The overall survival rate of the nonnormalized group was significantly worse than that of the other 2 groups (p <0.0001). No significant difference was found in terms of overall survival rate between the normalized and nonelevated groups (p = 0.22). Multivariate analysis demonstrated that nonnormalized C-reactive protein (p <0.0001), absence of metastatectomy (p = 0.005), poorer performance status (p = 0.006) and bone metastases (p = 0.023) were independent factors for predicting poorer overall survival. CONCLUSIONS: The current study indicated that C-reactive protein kinetics would predict the clinical course of patients with metastatic renal cell carcinoma who underwent cytoreductive nephrectomy. Larger confirmatory studies would be warranted to validate the current results.

Oncological outcome of minimum incision endoscopic radical nephrectomy for pathologically organ confined renal cell carcinoma.

OBJECTIVE: To date, follow-up after minimum incision endoscopic radical nephrectomy (MIES radical nephrectomy) for renal cell carcinoma (RCC) has not been reported. Minimum incision indicates an incision that narrowly permits the extraction of the specimen. To evaluate the oncological outcome of the patients with pathologically organ confined (pT1-2N0M0) RCC treated with this operation, the results in those patients were analyzed. METHODS: From 1998 to 2006, 154 consecutive patients underwent MIES radical nephrectomy under diagnosis of clinical T1-2N0M0 RCC in our hospital. Of the patients, 127 patients with pathologically confirmed organ confined (pT1-2N0M0) RCC constituted the current study population. Overall, the recurrence-free and cancer-specific survival rates of the patients treated with MIES radical nephrectomy were calculated using the Kaplan-Meier method and compared with those of the patients treated with open radical nephrectomy using the log rank test. RESULTS: The median follow-up period was 34 months (range: 3-98 months). Of the 127 pT1-2N0M0 patients treated with MIES radical nephrectomy, the disease recurred in nine patients and four patients died of the cancer during follow-up. The five-year overall, recurrence-free and cancer-specific survival rates were 95.0%, 90.8% and 95.8%, respectively. Overall, the recurrence-free and cancer-specific survival rates were not different from those of patients treated with open radical nephrectomy. CONCLUSION: MIES radical nephrectomy has the validity in adequate cancer control and is one of the recommendable options as a minimally invasive surgery for patients with organ confined RCC.

Transplantation of an autologous mesothelial cell sheet prepared from tunica vaginalis prevents post-operative adhesions in a canine model.

Post-operative adhesions often cause severe complications such as bowel obstruction and abdominopelvic pain. Previously, we reported that transplantation of a mesothelial cell sheet is effective for preventing adhesion in rat model. We also proposed a new technique for harvesting autologous mesothelial cells from tunica vaginalis without intra-abdominal maneuvers. In this study, we examined whether an autologous mesothelial cell sheet can prevent post-operative peritoneal adhesions in a canine adhesion model. Mesothelial cells were isolated from the tunica vaginalis of male beagles. Isolated cells were cultured on fibrin gel. We named this construct the "mesothelial cell sheet." Animals underwent surgery to induce peritoneal adhesion formation and were then transplanted with the mesothelial cell sheets (sheet group, n = 4), fibrin gel (fibrin group, n = 4), or no materials (sham group, n = 4). Four weeks after the transplantation, we evaluated adhesion formation and scored adhesion levels. The abdominal wall transplanted with the mesothelial cell sheet was covered with mesothelium. The total adhesion score of the sheet group was significantly lower than that of the fibrin group and the sham group. These results indicated that transplantation of an autologous mesothelial cell sheet is effective for preventing post-operative adhesion formation in the canine adhesion model. Our mesothelial cell sheet has the potential to be a powerful adhesion prophylactic material in surgery.