Futoshi Sano

Early assessment by FDG-PET/CT of patients with advanced renal cell carcinoma treated with tyrosine kinase inhibitors is predictive of disease course

BackgroundWe reported previously that 18F-2-fluoro-2-deoxyglucose positron emission tomography/ computed tomography (FDG PET/CT) had potential for evaluating early response to treatment by tyrosine kinase inhibitors (TKIs) in advanced renal cell carcinoma (RCC). This time we investigated the relation of the early assessment by FDG PET/CT to long-term prognosis with an expanded number of patients and period of observation.MethodsPatients for whom TKI treatment for advanced RCC was planned were enrolled. FDG PET/CT was performed before TKI treatment and after one month of TKI treatment. The relations of the FDGPET/CT assessment to progression free survival (PFS) and overall survival (OS) were investigated.ResultsThirty-five patients were enrolled (sunitinib 19 cases, sorafenib 16 cases). The patients with RCC showing high SUVmax in pretreatment FDG PET/CT demonstrated short PFS (P =0.024, hazard ratio 1.137, 95% CI 1.017-1.271) and short OS (P =0.004, hazard ratio 1.210 95% CI 1.062-1.379). Thirty patients (sunitinib 16 cases, sorafenib 14 cases) were evaluated again after 1 month. The PFS of the patients whose SUVmax decreased<20% was shorter than that of the patients whose SUVmax decreased<20% (P = 0.027, hazard ratio 3.043, 95% CI 1.134-8.167). The PFS of patients whose tumor diameter sum increased was shorter than that of the patient with tumors whose diameter sum did not (P =0.006, hazard ratio 4.555, 95% CI 1.543-13.448).The patients were classified into three response groups: good responder (diameter sum did not increase, and SUVmax decreased ≥ 20%), intermediate responder (diameter sum did not increase, and SUVmax decreased<20%), and poor responder (diameter sum increased, or one or more new lesions appeared). The median PFS of good, intermediate, and poor responders were 458 ± 146 days, 131 ± 9 days, and 88 ± 26 days (good vs. intermediate P = 0.0366, intermediate vs. poor P = 0.0097, log-rank test). Additionally the mean OSs were 999 ± 70 days, 469 ± 34 days, and 374 ± 125 days, respectively (good vs. intermediate P = 0.0385, intermediate vs. poor P = 0.0305, log-rank test).ConclusionsThe evaluation of RCC response to TKI by tumor size and FDG uptake using FDG PET/CT after 1 month can predict PFS and OS.

A three-gene expression signature model to predict clinical outcome of clear cell renal carcinoma.

Renal cell carcinomas (RCCs) are morphologically and genetically heterogeneous tumors and present diverse clinical courses. We developed a scoring system using levels of gene expression to predict the outcome for clear cell RCC patients. We selected differentially expressed genes from the DNA microarray data of 27 clear cell RCCs; 16 were metastasis phenotypes and 11 were not. We compared the selected gene set with previously published data and identified 33 overlapping genes closely associated with patient outcome. We selected the 12 top‐ranked genes and confirmed the level of expression using quantitative reverse transcriptase PCR. Multivariate Cox analysis revealed that 3 genes—vascular cell adhesion molecule 1 (VCAM1), endothelin receptor type B (EDNRB), and regulator of G‐protein signaling 5 (RGS5)—were the most tightly associated with cancer‐specific survival and that higher expression of the 3 genes correlated with better outcome. A formula for an outcome predictor was generated from integration of the measurements of the expression levels of the 3 genes. Multivariate Cox models combined with a split‐sample cross‐validation method in a cohort of 386 clear cell RCC patients demonstrated that the derived score for outcome prediction was an independent predictor in cancer‐specific survival tests. The accuracy of the prediction of cancer death after nephrectomy was improved by the inclusion of this score in receiver operating characteristic analysis from multivariate logistic regression models, suggesting that a scoring system based on the expression levels of these 3 genes is useful in the prediction of survival for patients with clear cell RCC.

Identification and characterization of Birt-Hogg-Dubé associated renal carcinoma.

The Birt–Hogg–Dubé (BHD) gene is responsible for BHD syndrome, a rare autosomal dominant disease, characterized by benign hair follicle tumours, spontaneous pneumothorax and renal neoplasms with diverse histology. To elucidate its involvement in the development of renal neoplasms, we examined a total of 100 sporadic renal tumours with various histological subtypes for BHD mutation by SSCP‐sequencing analyses. We found one germline insertion mutation in the C8 hotspot of exon 11 (c.1733insC), which is known to have a strong association with renal tumour occurrence. The germline‐mutated patient suffered from solitary renal cell carcinoma (RCC) but did not have any other BHD manifestations or family history. The tumour revealed heterogeneous cytomorphology, mainly a mixture of eosinophilic and focally clear cells with tubulopapillary architecture. In this tumour, both BHD alleles were inactivated by germline mutation concomitant with loss of heterozygosity, and the amount of BHD mRNA detected by real‐time quantitative PCR (RQ‐PCR) was very low. Renal tumour subtype/nephron segment‐specific gene expression detected by RQ‐PCR demonstrated that the tumour expressed relatively high amounts of α‐methylacyl‐CoA racemase (AMACR) and the KIT oncogene, but relatively low amounts of carbonic anhydrase IX (CA9), aquaporin 1 (AQP1), claudin 7 (CLDN7), parvalbumin (PVALB), chloride channel Kb (CLCNKB) and 11‐β‐hydroxysteroid dehydrogenase 2 (HSD11B2), suggesting diverse mRNA signatures. Further clustering analysis of 88 renal tumours based on expression of these eight genes sub‐classified the tumour as close to oncocytomas and chromophobe RCCs, which are considered distal nephron‐associated tumours. These data suggest that somatic mutation of BHD is relatively rare in Japanese patients. The BHD‐mutated RCC identified in this study, which exhibits heterogeneous biological features in both morphology and gene expression signatures, seems to deviate from our current understanding of renal tumour classification. Copyright

Vascular cell adhesion molecule 1 predicts cancer-free survival in clear cell renal carcinoma patients

Purpose: Vascular cell adhesion molecule 1 (VCAM1) is a cell surface glycoprotein implicated in various pathophysiologic conditions. We measured VCAM1 expression levels in tumor tissues and evaluated its significance and prognostic use in renal cell carcinoma (RCC). Experimental Design: We used real-time quantitative PCR to examine the VCAM1 expression levels of a total of 485 sporadic renal tumors, including 429 clear cell, 21 papillary, 17 chromophobe, 11 oncocytomas, and 7 collecting duct carcinomas. We retrospectively examined the relationship of this expression to various clinicopathologic variables and the von Hippel-Lindau alteration status. We evaluated its significance with respect to patient survival rates using the Cox regression model combined with the split-sample method. Results: Compared with normal kidney samples (n = 43), VCAM1 was significantly up-regulated in clear cell RCC and papillary RCC, whereas it was down-regulated in chromophobe RCC and oncocytoma. In clear cell RCC, VCAM1 expression levels were apparently high in patients asymptomatic at presentation and in patients with small tumor size, low-stage, low-grade, microvascular invasion–negative, and von Hippel-Lindau alteration-positive tumors. Univariate analyses showed that VCAM1 high expression is strongly associated with better outcomes in clear cell and papillary RCCs. Further, Cox multivariate analysis models combined with the split-sample method revealed that this association is significant only in cancer-free survival for patients with clear cell RCC after curative surgical resection. Conclusions:VCAM1 expression levels were found to be histologically subtype specific in renal tumors. Determination of the VCAM1 expression level as a biomarker can provide useful prognostic information for patients with clear cell RCC.

Contrast-enhanced ultrasonography of the prostate: various imaging findings that indicate prostate cancer

Study Type – Diagnostic (non‐consecutive case series) 
Level of Evidence 3b

Expression of aquaporin 1 in primary renal tumors: a prognostic indicator for clear-cell renal cell carcinoma.

BACKGROUND Aquaporin 1 (AQP1) is a water channel expressed in many epithelial tissues and endothelium, including the proximal nephron of the kidney. OBJECTIVE We measured AQP1 expression in primary renal cell carcinomas (RCCs) and evaluated its significance and prognostic utility. DESIGN, SETTING, AND PARTICIPANTS We examined AQP1 expression in 559 sporadic renal tumors as well as in 43 normal kidney tissue samples and collected clinicopathologic and prognostic data. MEASUREMENTS AQP1 expression was measured by using real-time quantitative polymerase chain reaction (PCR). RESULTS AND LIMITATIONS All normal kidney samples presented substantial AQP1 expression. Among tumor subtypes, AQP1 expression was significantly higher in clear-cell and papillary RCCs, whereas it was lower in chromophobe RCCs, oncocytomas, and collecting-duct carcinomas. In clear-cell RCC, AQP1 was significantly higher in patients without symptomatic presentation or whose tumors were smaller, lower grade, or either lower stage or lacking in microvascular invasion. Von Hippel-Lindau (VHL) tumor suppressor gene mutational status did not affect expression level. Cox univariate and multivariate analyses strongly associated high AQP1 expression with better prognosis in cancer-specific and cancer-free survival tests in all patient cohorts, as well as in cancer-specific survival in a cohort of patients with advanced metastatic RCC. The time-dependent receiver operation characteristic (ROC) analyses, combined with logistic regression models, revealed that the addition of the AQP1 parameter to the University of California Los Angeles Integrated Staging System (UISS) prognostic score can improve the accuracy of predictions of both cancer death and recurrence for all patient cohorts as well as of cancer death for advanced cases within a 5-yr follow-up period in clear-cell RCC. High AQP1 expression was also associated with better outcome in a univariate cancer-specific survival test in papillary RCCs. CONCLUSIONS AQP1 shows RCC subtype-specific expression, and its expression level provides useful prognostic information for patients with clear-cell RCC.

Risk Factors for Metastatic Castration-Resistant Prostate Cancer (CRPC) Predict Long-Term Treatment with Docetaxel

Purpose For patients with metastatic castration-resistant prostatic cancer (mCRPC), docetaxel plus prednisone leads to superior survival and a higher response rate compared with mitoxantrone plus prednisone. We analyzed the efficacy of long-term treatment with ≥10 cycles of docetaxel, and validated the risk group classification in predicting overall survival (OS) in Japanese patients with mCRPC. Patients and Methods Fifty-two patients with mCRPC were administered 55 mg/m2 docetaxel and 8 mg dexamethasone, every 3 or 4 weeks, simultaneously with hormonal therapy and daily oral dexamethasone. They were divided into two groups, short-term (9 or fewer cycles) and long-term (10 or more cycles). Four risk factors including the presence of anemia, bone metastases, significant pain and visceral metastases were utilized for the risk group classification. Results Fourteen patients (27%) had an elevation of PSA in spite of docetaxel treatment, while 23 patients (44%) had a decline in PSA level, including 9 patients (17%) whose PSA level declined by ≥50%. The median duration of OS after the initiation of this therapy was 11.2 months in the short-term group and 28.5 months in the long-term group. The good risk group showed a significant difference in OS compared with the intermediate and poor risk groups (P<0.001). The median number of cycles of treatment was 14, 4 and 3 for each risk group, respectively (p<0.01). Conclusions The present study indicated that ≥10 cycles of this docetaxel therapy can significantly prolong survival in Japanese men with CRPC. This risk group classification for men with mCRPC at the initiation of this chemotherapy is useful.

Gallbladder Metastasis from Renal Cell Carcinoma

A 73-year-old female was operated with radical nephrectomy and cholecystectomy for renal cell carcinoma and suspected gallstones after 9 courses of sunitinib treatment. Gallbladder specimen showed gallbladder metastasis originating from the renal cell carcinoma. Gallbladder metastasis from renal cell carcinoma is rare. Here, we discuss a case of gallbladder metastasis from renal cell carcinoma.

C-reactive protein in patients with advanced metastatic renal cell carcinoma: Usefulness in identifying patients most likely to benefit from initial nephrectomy

ObjectiveC-reactive protein (CRP) is considered a useful serum marker for patients with RCC. However, its clinical utility in advanced metastatic renal cell carcinoma (AM-RCC), particularly in deciding whether to perform nephrectomy at the onset, is not well studied.Patients and methodsWe retrospectively evaluated 181 patients with AM-RCC, including 18 patients underwent potentially curative surgery, 111 underwent cytoreductive nephrectomy, and 52 received medical treatment only. CRP cutoff points were determined by receiver operating characteristic (ROC) curve analysis. Kaplan-Meier and Cox regression analyses were used for survival tests.ResultsROC analysis suggested that grouping patients according to 3 CRP ranges was a rational model. Patients with highly elevated CRP (≥67.0 mg/L) presented remarkably poor prognosis despite treatment (nephrectomy or medical treatment only). Cox regression models demonstrated that risk factors of overall survival for patients who underwent nephrectomy were the CRP ranges defined in this study (≤18.0 mg/L, >18.0 and <67.0 mg/L, and ≥67.0 mg/L), ECOG PS (0, 1, and ≥2), and number of metastatic organ sites (0–1 and ≥2). The retrospective design is a limitation of this study.ConclusionOur study demonstrated that the serum CRP level is a statistically significant prognostic parameter for patients with AM-RCC. The data also indicated that pretreatment serum CRP level provides useful prognostic information that helps in deciding whether to perform initial nephrectomy for patients with AM-RCC.

The Utility and Limitations of Contrast-Enhanced Ultrasound for the Diagnosis and Treatment of Prostate Cancer

In association with the widespread use of prostate specific antigen (PSA) screening, the numbers of men identified with early-stage prostate cancer (PCa) are increasing in the developed countries, including Japan. However, the accurate localization of PCa lesions in diagnostic imaging is still difficult because PCa has a tendency to be multifocal in the prostate gland. Contrast-enhanced ultrasound (CEUS) improves the detection of PCa by visualizing cancerous lesions in order to target a needle biopsy. CEUS has the potential to enable not only accurate diagnoses but also novel treatments such as focal therapy. The combination of CEUS and other modalities is expected to improve the diagnosis of PCa and its treatment.