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RCC
Kinds of RCC Terms modified by RCC Selected AbstractsFine needle aspiration of renal cortical lesions in adultsDIAGNOSTIC CYTOPATHOLOGY, Issue 10 2010Adebowale J. Adeniran M.D. Abstract The role of fine needle aspiration (FNA) biopsy of renal cortical lesions was controversial in the past because the result of the FNA did not affect clinical management. All renal cortical lesions, except metastasis, were subject to surgical resection. However, with the advances in neoadjuvant targeted therapies, knowledge of the renal cortical tumor histological subtype is critical for tailoring clinical trials and follow-up strategies. At present, there are clinical trials involving the use of novel kinase inhibitors for conventional (clear cell) and papillary renal cell carcinoma. We studied 143 consecutive cases of renal cortical lesions, evaluated after radical or partial nephrectomies over a 2-year period. An air-dried smear and a Thinprep® slide were prepared in all cases. The slides were Diff-Quick and Papanicolaou stained, respectively. The cytology specimens were reviewed and the results were then compared with the histologic diagnosis. Cytology was highly accurate to diagnose conventional RCC, while the accuracy for papillary RCC, chromophobe RCC, and papillary urothelial carcinoma was much lower. Our results indicate that ancillary studies might have an important role in the subclassification of renal cortical neoplasms for targeted treatment. Diagn. Cytopathol. 2010;38:710,715. © 2009 Wiley-Liss, Inc. [source] Papillary thyroid carcinoma with metastasis to the frontal skullDIAGNOSTIC CYTOPATHOLOGY, Issue 7 2009Dian Feng M.D., Ph.D. Abstract Papillary thyroid carcinoma with metastasis to the frontal skull is extremely rare. We report a case of unsuspected papillary thyroid carcinoma with frontal skull metastasis. The patient was a 62-year-old African American woman with presentation of a 4-cm firm, painless, immobile, ill-defined mass at the right forehead. Ultrasound and computer tonography detected a hypervascular and osteolytic tumor involving the skull and overlying skin. Fine-needle aspiration was performed followed by surgical biopsy. Cytologic examination revealed the presence of hypercellular and bloody material. The neoplasm showed glandular features and was composed of clusters of round to oval cells with pinkish squamoid cytoplasm, oval nuclei and inconspicuous nucleoli on smears and sections of cell block. With immunocytochemical stain, the neoplastic cells were positive for pancytokeratin and vimentin and focally positive for EMA, while they were negative for S100, HMB45, Melan-A, CD34, GFAP, CD10, LCA, RCC and CD138. The diagnosis was a metastatic carcinoma. Clinical follow up with surgical biopsy was recommended. Surgical biopsy demonstrated histological and cytological features of papillary thyroid carcinoma including prominent papillae, nuclear overlapping, grooves, and intranuclear pseudoinclusions. Thus, a diagnosis of metastatic papillary thyroid carcinoma was rendered. Though skull metastasis of thyroid carcinoma is rare, it should be considered in the differential diagnosis when a skull mass lesion is encountered. Diagn. Cytopathol. 2009. © 2009 Wiley-Liss, Inc. [source] Characterization of t(6;11)(p21;q12) in a renal-cell carcinoma of an adult patientGENES, CHROMOSOMES AND CANCER, Issue 5 2007Lorenza Pecciarini Renal-cell carcinoma (RCC) constitutes a heterogeneous group of tumors with specific chromosome aberrations. Recently, a new small group of RCC, occurring in children and young adults, has been described as characterized by t(6;11)(p21;q12). It has been shown that this translocation results in the fusion of the 5, portion of the ALPHA gene (11q12) with the transcription factor gene TFEB (6p21). Herewith, we report the first complete cytogenetic and molecular characterization of a t(6;11)-positive RCC of an adult patient, a 54-year-old woman. The tumor was histologically defined as RCC with peculiar features and it was negative for epithelial markers and positive for melanocytic markers. Chromosome QFQ banding analysis of short-term cultured cells from the RCC showed t(6;11)(p21;q12) as the sole cytogenetic abnormality. The translocation was confirmed by FISH analysis. RT-PCR analysis, performed on total RNA isolated from both neoplastic and normal tissue samples, revealed an ALPHA,TFEB chimeric transcript in the tumor sample; sequencing of the RT-PCR product defined a novel TFEB gene breakpoint cluster region, broader than the one reported thus far. Western blot analysis showed a band at the expected size of wild-type TFEB in the neoplastic tissue compared to the normal sample, supporting that the fusion gene does not encode for a chimeric protein but it causes an upregulation of the wild-type TFEB. Our data contribute to define better this rare RCC type, which is typical not only of childhood but can also be found in adulthood. © 2007 Wiley-Liss, Inc. [source] Characterization of a 3;6 translocation associated with renal cell carcinomaGENES, CHROMOSOMES AND CANCER, Issue 4 2007Rebecca E. Foster The most frequent cause of familial clear cell renal cell carcinoma (RCC) is von Hippel,Lindau disease and the VHL tumor suppressor gene (TSG) is inactivated in most sporadic clear cell RCC. Although there is relatively little information on the mechanisms of tumorigenesis of clear cell RCC without VHL inactivation, a subset of familial cases harbors a balanced constitutional chromosome 3 translocation. To date nine different chromosome 3 translocations have been associated with familial or multicentric clear cell RCC; and in three cases chromosome 6 was also involved. To identify candidate genes for renal tumorigenesis we characterized a constitutional translocation, t(3;6)(q22;q16.1) associated with multicentric RCC without evidence of VHL target gene dysregulation. Analysis of breakpoint sequences revealed a 1.3-kb deletion on chromosome 6 within the intron of a 2 exon predicted gene (NT_007299.434). However, RT-PCR analysis failed to detect the expression of this gene in lymphoblast, fibroblast, or kidney tumor cell lines. No known genes were disrupted by the translocation breakpoints but several candidate TSGs (e.g., EPHB1, EPHA7, PPP2R3A RNF184, and STAG1) map within close proximity to the breakpoints. © 2007 Wiley-Liss, Inc. [source] Molecular cytogenetic characterization of early and late renal cell carcinomas in Von Hippel-Lindau disease ,GENES, CHROMOSOMES AND CANCER, Issue 1 2001John L. Phillips Deletions of 3p25, gains of chromosomes 7 and 10, and isochromosome 17q are known cytogenetic aberrations in sporadic renal cell carcinoma (RCC). In addition, a majority of RCCs have loss of heterozygosity (LOH) of the Von Hippel-Lindau (VHL) gene located at chromosome band 3p25. Patients who inherit a germline mutation of the VHL gene can develop multifocal RCCs and other solid tumors, including malignancies of the pancreas, adrenal medulla, and brain. VHL tumors follow the two-hit model of tumorigenesis, as LOH of VHL, a classic tumor suppressor gene, is the critical event in the development of the neoplastic phenotype. In an attempt to define the cytogenetic aberrations from early tumors to late RCC further, we applied spectral karyotyping (SKY) to 23 renal tumors harvested from 6 unrelated VHL patients undergoing surgery. Cysts and low-grade solid lesions were near-diploid and contained 1,2 reciprocal translocations, dicentric chromosomes, and/or isochromosomes. A variety of sole numerical aberrations included gains of chromosomes 1, 2, 4, 7, 10, 13, 21, and the X chromosome, although no tumors had sole numerical losses. Three patients shared a breakpoint at 2p21,22, and three others shared a dicentric chromosome 9 or an isochromosome 9q. In contrast to the near-diploidy of the low-grade lesions, a high-grade lesion and its nodal metastasis were markedly aneuploid, revealed loss of VHL by fluorescence in situ hybridization (FISH), and contained recurrent unbalanced translocations and losses of chromosome arms 2q, 3p, 4q, 9p, 14q, and 19p as demonstrated by comparative genomic hybridization (CGH). By combining SKY, CGH, and FISH of multiple tumors from the same VHL kidney, we have begun to identify chromosomal aberrations in the earliest stages of VHL-related renal cell tumors. Our current findings illustrate the cytogenetic heterogeneity of different VHL lesions from the same kidney, which supports the multiclonal origins of hereditary RCCs. Published 2001 Wiley-Liss, Inc. [source] The angiogenic makeup of human hepatocellular carcinoma does not favor vascular endothelial growth factor/angiopoietin-driven sprouting neovascularization,,HEPATOLOGY, Issue 5 2008Wenjiao Zeng Quantitative data on the expression of multiple factors that control angiogenesis in hepatocellular carcinoma (HCC) are limited. A better understanding of the mechanisms underlying angiogenesis in HCC will improve the rational choice of anti-angiogenic treatment. We quantified gene and protein expression of members of the vascular endothelial growth factor (VEGF) and angiopoietin systems and studied localization of VEGF, its receptors VEGFR-1 and VEGFR-2, Angiopoietin (Ang)-1 and Ang-2, and their receptor, in HCC in noncirrhotic and cirrhotic livers. We employed real-time reverse transcription polymerase chain reaction (RT-PCR), western blot, and immunohistology, and compared the outcome with highly angiogenic human renal cell carcinoma (RCC). HCC in noncirrhotic and cirrhotic livers expressed VEGF and its receptors to a similar extent as normal liver, although in cirrhotic background, VEGFR-2 levels in both tumor and adjacent tissue were decreased. Ang-1 expression was slightly increased compared with normal liver, whereas Tie-2 was strongly down-regulated in the tumor vasculature. Ang-2 messenger RNA (mRNA) levels were also low in HCCs of both noncirrhotic and cirrhotic livers, implying that VEGF-driven angiogenic sprouting accompanied by angiopoietin-driven vascular destabilization is not pronounced. In RCC, VEGF-A levels were one order of magnitude higher. At the same time, endothelially expressed Ang-2 was over 30-fold increased compared with expression in normal kidney, whereas Ang-1 expression was decreased. Conclusion: In hepatocellular carcinoma, tumor vascularization is not per se VEGF/angiopoietin driven. However, increased CD31 expression and morphological changes representative of sinusoidal capillarization in tumor vasculature indicate that vascular remodeling is taking place. This portends that therapeutic intervention of HCC at the level of the vasculature is optional, and that further studies into the molecular control thereof are warranted. (HEPATOLOGY 2008.) [source] Immunohistochemical and molecular genetic profiling of acquired cystic disease-associated renal cell carcinomaHISTOPATHOLOGY, Issue 2 2009Chin-Chen Pan Aims:, Acquired cystic disease-associated renal cell carcinoma (ACD-associated RCC) is a unique neoplasm that specifically develops in the background of acquired cystic disease of the kidney. The aim was to analyse nine ACD-associated RCCs from three patients to determine their immunohistochemical and molecular characteristics using immunohistochemistry, comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH). Methods and results:, ACD-associated RCC preferentially expressed proximal nephron phenotype (CD10+/RCC marker+/,-methylacyl-CoA racemase+/glutathione S-transferase-,+/BerEP4+/cytokeratin 7,/E-cadherin,/high-molecular-weight cytokeratin,/MOC31,). CGH combined with FISH demonstrated non-random chromosomal gains clustering on chromosomes 3 (8/9), 7 (6/9), 16 (7/9), 17 (4/9) and Y (5/9). Chromosomal losses were uncommon. The chromosomal aberrations in all multifocal tumours were not identical for the same kidney or for the same patient, indicating a ,field effect' that induces multiple independent clones. Conclusions:, Although the genetic profiles of ACD-associated RCC showed some similarity to those of papillary RCC, ACD-associated RCC distinctly revealed frequent gains on chromosomes 3 and Y. ACD-associated RCC is characterized not only by its particular clinical setting and histology, but also by its unique immunohistochemical and molecular genetic profiles. [source] Renal cell carcinoma marker reliably discriminates central nervous system haemangioblastoma from brain metastases of renal cell carcinomaHISTOPATHOLOGY, Issue 6 2008B Ingold Aims:, The distinction between central nervous system (CNS) metastases of clear cell renal cell carcinoma (RCC) and CNS haemangioblastoma still poses a challenge to the pathologist. Since both entities occur in von Hippel,Lindau disease, this aggravates the issue. The antibody renal cell carcinoma marker (RCC-ma) has been suggested to identify primary RCCs specifically, but its value for diagnosing metastases of RCC is controversial. The aim was to assess two distinct clones of the RCC-ma for their potential to: (i) identify primary RCCs and (ii) differentiate between CNS metastases of clear cell RCC and CNS haemangioblastomas. Methods and results:, Using tissue microarrays, 77% (n = 363; PN-15) and 66% (n = 355; 66.4C2) of clear cell RCCs, and 93% (PN-15) and 74% (66.4C2) of papillary RCCs (n = 46) were immunopositive for RCC-ma, whereas none of the investigated chromophobe RCCs (n = 22) or any of the oncocytomas (n = 15) showed immunoreactivity. Importantly, 50.9% of CNS metastases of clear cell RCCs (n = 55) exhibited RCC-ma expression, whereas all CNS haemangioblastomas (71) were negative. Conclusions:, Both RCC-ma clones, despite some variation in their sensitivity to detect clear cell and papillary RCCs, are of value in differentiating subtypes of primary RCC and are excellent markers for discriminating clear cell lesions in the brain. [source] The diagnostic utility of MOC31, BerEP4, RCC marker and CD10 in the classification of renal cell carcinoma and renal oncocytoma: an immunohistochemical analysis of 328 casesHISTOPATHOLOGY, Issue 5 2004C-C Pan Aims:, To demonstrate the diagnostic utility of MOC31, BerEP4, renal cell carcinoma marker (RCC Ma) and CD10 in the classification of RCC and renal oncocytoma, based upon a comprehensive immunohistochemical analysis. Methods and results:, Immunohistochemistry was performed on 328 samples consisting of 256 clear cell/conventional, 27 papillary, 28 chromophobe, five collecting duct, five unclassified RCCs and seven renal oncocytomas using antibodies MOC31, BerEP4 and antibodies against cytokeratins (KL-1, CAM5.2, 34,E12, cytokeratin 7), RCC Ma, epithelial membrane antigen, E-cadherin, CD10, CD15 and vimentin. Multivariate analysis showed that MOC31, BerEP4, RCC Ma and CD10 have discriminatory value. MOC31 and BerEP4 chiefly labelled distal tubules of normal kidney while RCC Ma and CD10 labelled the proximal tubules. Twenty-three chromophobe RCCs (82%) were reactive for MOC31, while only four clear cell RCCs and three papillary RCCs were positive for this marker. Clear cell RCCs were characterized by a high positive rate for CD10 (82%) and a low positive rate for BerEP4 (27%). Papillary RCCs frequently coexpressed RCC Ma and BerEP4 (51%). All renal oncocytomas were negative for MOC31 and CD10. Conclusions:, MOC31 has diagnostic merit in discerning chromophobe RCC. The CD10+/BerEP4, profile and RCC Ma+/BerEP4+ profile achieve moderate sensitivity and good specificity for clear cell RCC and papillary RCC, respectively. The non-reactivity for both MOC31 and CD10 is helpful in distinguishing renal oncocytoma from RCC. When properly selected, antibodies have immunohistochemical diagnostic utility for the classification of renal cortical epithelial tumours. [source] Microsatellite allelotyping differentiates chromophobe renal cell carcinomas from renal oncocytomas and identifies new genetic changesHISTOPATHOLOGY, Issue 6 2004A Nagy Aims:, The diagnosis of renal oncocytomas (ROs) and chromophobe renal cell carcinomas (RCCs) based on histological features is often uncertain. To assess the value of genetic analysis in their differential diagnosis we analysed 27 ROs and 21 chromophobe RCCs by microsatellite allelotyping. Methods and results:, Markers at the short and long arms of chromosomes specifically involved in the genetic changes of the four main types of renal cancers were selected. Allelic changes were identified by automated sequencing. Allelic changes at chromosome 1p occurred in 8/26 (31%) and at chromosome 14q in 4/27 (15%) ROs. Loss of heterozygosity (LOH) at chromosomes 1, 2, 6, 10, 13, 17 and 21 were seen in 90%, 90%, 96%, 86%, 85%, 90% and 72% of the chromophobe RCCs, respectively. Alterations of at least three of these chromosomal sites were detected in each chromophobe RCC. In addition, we found recurrent LOH at chromosomes 9p23 (43%), 18q22 (30%), 5q22 (28%) and 8p (28%) in chromophobe RCCs. Conclusions:, Chromophobe RCCs can be differentiated from ROs by analysing specific chromosomal regions with microsatellites. [source] Refining indications for contemporary surgical treatment of renal cell carcinoma metastatic to the pancreasHPB, Issue 2 2009Aram N. Demirjian Abstract Background:, The pancreas is a rare location for metastatic disease, with only 2,11% of all pancreatic tumours being of non-primary origin. It is also uncommon for renal cell carcinoma (RCC) to metastasize to the pancreas (1,3% of cases) and, when it does, it typically occurs substantially after index nephrectomy. It is not known whether all pancreatic metastases need be resected because today's chemo- and biological therapies are increasingly effective in controlling advanced disease. Methods:, Six patients with a variety of symptoms are discussed. Four patients presented with recurrent gastrointestinal bleeding, ranging from occult to life-threatening in severity. Results:, The four patients with gastrointestinal bleeding had RCC metastases that had eroded into the duodenum and were successfully controlled by palliative pancreaticoduodenectomy or completion pancreatectomy. The other two patients were treated using different chemotherapeutic or biological agents. Conclusions:, Renal cell carcinoma metastases to the pancreas typically occur long after index nephrectomy. Although clinical presentation is variable, palliative resection should be reserved for those who develop complications, such as upper gastrointestinal bleeding, and, in other series, obstructive jaundice. Routine debulking resections do not appear to be indicated because current biological therapies effectively and reliably control disease over long periods. [source] Resection of renal metastases to the pancreas: a surgical challengeHPB, Issue 3 2003D Zacharoulis Background Metastasis to the pancreas from renal cell carcinoma (RCC) is distinctly uncommon. Most cases are detected at an advanced stage of the disease and are thus unsuitable for resection. A solitary RCC metastasis to the head of pancreas is rarely encountered and, although it is potentially amenable to surgical resection, surgeons may be hesitant to perform pancreatoduodenectomy. Cases outlines Two patients with a solitary RCC metastasis to the head of pancreas were treated by pancreatoduodenectomy, while a third with multiple RCC metastases declined any treatment. Two of the patients were asymptomatic, and one presented with anaemia and mild abdominal pain. Computed tomography (CT) and angiography were used to exclude other metastases and to assess resectability of the pancreatic tumour. All three patients are still alive, those with resectable disease at 2 years and 9 years and the one with irresectable disease at 4 years. Discussion Isolated RCC metastasis to the pancreas is a rare event. Patients present either on follow-up imaging or with symptoms such as mild abdominal pain, weight loss, jaundice, anaemia or gastrointestinal bleeding (whether occult or overt). Dynamic spiral CT can visualise the tumour and exclude distant metastasis. Angiography often reveals a highly vascularised tumour and will help to assess resectability. In the absence of widespread disease, pancreatic resection can provide long-term survival in metastatic RCC, although few cases have been reported with lengthy follow-up. The prognosis is better than for pancreatic adenocarcinoma. [source] Gene signatures of pulmonary metastases of renal cell carcinoma reflect the disease-free interval and the number of metastases per patientINTERNATIONAL JOURNAL OF CANCER, Issue 2 2009Daniela Wuttig Abstract Our understanding of metastatic spread is limited and molecular mechanisms causing particular characteristics of metastasis are largely unknown. Herein, transcriptome-wide expression profiles of a unique cohort of 20 laser-resected pulmonary metastases (Mets) of 18 patients with clear-cell renal cell carcinoma (RCC) were analyzed to identify expression patterns associated with two important prognostic factors in RCC: the disease-free interval (DFI) after nephrectomy and the number of Mets per patient. Differentially expressed genes were identified by comparing early (DFI , 9 months) and late (DFI , 5 years) Mets, and Mets derived from patients with few (,8) and multiple (,16) Mets. Early and late Mets could be separated by the expression of genes involved in metastasis-associated processes, such as angiogenesis, cell migration and adhesion (e.g., PECAM1, KDR). Samples from patients with multiple Mets showed an elevated expression of genes associated with cell division and cell cycle (e.g., PBK, BIRC5, PTTG1) which indicates that a high number of Mets might result from an increased growth potential. Minimal sets of genes for the prediction of the DFI and the number of Mets per patient were identified. Microarray results were confirmed by quantitative PCR by including nine further pulmonary Mets of RCC. In summary, we showed that subgroups of Mets are distinguishable based on their expression profiles, which reflect the DFI and the number of Mets of a patient. To what extent the identified molecular factors contribute to the development of these characteristics of metastatic spread needs to be analyzed in further studies. © 2009 UICC [source] Targeted therapy of renal cell carcinoma: Synergistic activity of cG250-TNF and IFNgINTERNATIONAL JOURNAL OF CANCER, Issue 1 2009Stefan Bauer Abstract Immunotherapeutic targeting of G250/Carbonic anhydrase IX (CA-IX) represents a promising strategy for treatment of renal cell carcinoma (RCC). The well characterized human-mouse chimeric G250 (cG250) antibody has been shown in human studies to specifically enrich in CA-IX positive tumors and was chosen as a carrier for site specific delivery of TNF in form of our IgG-TNF-fusion protein (cG250-TNF) to RCC xenografts. Genetically engineered TNF constructs were designed as CH2/CH3 truncated cG250-TNF fusion proteins and eucariotic expression was optimized under serum-free conditions. In-vitro characterization of cG250-TNF comprised biochemical analysis and bioactivity assays, alone and in combination with Interferon-, (IFN,). Biodistribution data on radiolabeled [125J] cG250-TNF and antitumor activity of cG250-TNF, alone and in combination with IFN,, were measured on RCC xenografts in BALB/c nu/nu mice. Combined administration of cG250-TNF and IFN, caused synergistic biological effects that represent key mechanisms displaying antitumor responses. Biodistribution studies demonstrated specific accumulation and retention of cG250-TNF at CA-IX-positive RCC resulting in growth inhibition of RCC and improved progression free survival and overall survival. Antitumor activity induced by targeted TNF-based constructs could be enhanced by coadministration of low doses of nontargeted IFN, without significant increase in side effects. Administration of cG250-TNF and IFN, resulted in significant synergistic tumoricidal activity. Considering the poor outcome of renal cancer patients with advanced disease, cG250-TNF-based immunotherapeutic approaches warrant clinical evaluation. © 2009 UICC [source] DNA methylation and histone modifications cause silencing of Wnt antagonist gene in human renal cell carcinoma cell linesINTERNATIONAL JOURNAL OF CANCER, Issue 3 2008Ken Kawamoto Abstract Secreted frizzled-related protein 2 (sFRP2) is a negative modulator of the Wingless-type (Wnt) signaling pathway, and shown to be inactivated in renal cell carcinoma (RCC). However, the molecular mechanism of silencing of sFRP2 is not fully understood. Our study was designed to elucidate the silencing mechanism of sFRP2 in RCC. Expression of sFRP2 was examined in 20 pairs of primary cancers by immunohistochemistry. Kidney cell lines (HK-2, Caki-1, Caki-2, A-498 and ACHN) were analyzed for sFRP2 expression using real-time RT-PCR and Western blotting. The methylation status at 46 CpG sites of the 2 CpG islands in the sFRP2 promoter was characterized by bisulfite DNA sequencing. Histone modifications were assessed by chromatin immunoprecipitation (ChIP) assay using antibodies against AcH3, AcH4, H3K4 and H3K9. sFRP2 was frequently repressed in primary cancers and in RCC cells. The majority of sFRP2 negative cells had a methylated promoter. Meanwhile, sFRP2 expression was repressed by a hypomethylated promoter in Caki-1 cells, and these cells had a repressive histone modification at the promoter. In Caki-1 cells, sFRP2 was reactivated by trichostatin A (TSA). Repressive histone modifications were also observed in RCC cells with hypermethylated promoters, but sFRP2 was reactivated only by 5-aza-2,-deoxycytidine (DAC) and not by TSA. However, the activation of the silenced sFRP2 gene could be achieved in all cells using a combination of DAC and TSA. This is the first report indicating that aberrant DNA methylation and histone modifications work together to silence the sFRP2 gene in RCC cells. © 2008 Wiley-Liss, Inc. [source] Eradication of established renal cell carcinoma by a combination of 5-fluorouracil and anti-4-1BB monoclonal antibody in miceINTERNATIONAL JOURNAL OF CANCER, Issue 12 2008Seong-A Ju Abstract Renal cell carcinoma (RCC), one of the most incurable malignancies, is highly resistant to chemotherapy and radiotherapy. Cytokine immunotherapy has been the standard approach, but the overall response rate is still very low. Administration of agonistic anti-4-1BB monoclonal antibody (mAb) has been shown to induce regression of several animal tumors but its effect on RCC is unknown. We show here that monotherapy with either anti-4-1BB mAb or the cytotoxic drug, 5-fluorouracil (5-FU), has little effect on established RCC, Renca tumors, but combination therapy with anti-4-1BB mAb and 5-FU eradicates the tumors in more than 70 % of mice. The regressing tumor tissues from mice receiving the combination therapy contained more apoptotic tumor cells and tumor infiltrating lymphocytes than tumor tissues from mice receiving 5-FU or anti-4-1BB mAb monotherapy. The number of lymphocytes in the spleens and tumor- draining lymph nodes (TDLNs) of the combination therapy mice was greatly increased compared to that of control or 5-FU monotherapy mice. Mice that had recovered due to the combination therapy rapidly rejected rechallenge with the tumor, pointing to the establishment of long-lasting tumor-specific memory. Our results indicate that targeting tumors with 5-FU, and immune cells with 4-1BB stimulation, could be a useful strategy for treating incurable RCC. © 2008 Wiley-Liss, Inc. [source] Folate metabolism genes, vegetable intake and renal cancer risk in central EuropeINTERNATIONAL JOURNAL OF CANCER, Issue 8 2008Lee E. Moore Abstract In a multicenter case-control study of renal cell carcinoma (RCC) conducted in central and eastern Europe, we reported a strong inverse association with high vegetable intake and RCC risk. The odds ratio (OR) for high compared to the lowest tertile of vegetable intake was OR = 0.67; (95% confidence interval (CI): 0.53,0.83; p -trend < 0.001). We hypothesized that variation in key folate metabolism genes may modify this association. Common variation in 5 folate metabolism genes (CBS: Ex9+33C > T (rs234706), Ex13 +41C > T (rs1801181), Ex18 ,391 G > A (rs12613); MTHFR: A222V Ex5+79C > T (rs1801133), Ex8,62A > C (rs1801131); MTR: Ex26 20A > G (rs1805087), MTRR: Ex5+136 T > C (rs161870), and TYMS:IVS2,405 C > T (rs502396), Ex8+157 C > T (rs699517), Ex8+227 A > G (rs2790)) were analyzed among 1,097 RCC cases and 1,555 controls genotyped in this study. Having at least 1 variant T allele of MTHFR A222V was associated with higher RCC risk compared to those with 2 common (CC) alleles (OR = 1.44; 95% CI: 1.17,1.77; p = 0.001). After stratification by tertile of vegetable intake, the higher risk associated with the variant genotype was only observed in the low and medium tertiles (p -trend = 0.001), but not among those in the highest tertile (p -interaction = 0.22). The association remained robust after calculation of the false discovery rate (FDR = 0.05). Of the 3 TYMS SNPs examined, only the TYMS IVS2 ,405 C (rs502396) variant was associated with a significantly lower risk compared to the common genotype (OR = 0.73; 95% CI: 0.57,0.93). Vegetable intake modified the association between all 3 TYMS SNPs and RCC risk (p -interaction < 0.04 for all). In summary, these findings suggest that common variation in MTHFR and TYMS genes may be associated with RCC risk, particularly when vegetable intake is low. © 2007 Wiley-Liss, Inc. [source] Modulation of p21-activated kinase 1 alters the behavior of renal cell carcinomaINTERNATIONAL JOURNAL OF CANCER, Issue 9 2007Gerald C. O'Sullivan Abstract The p21-activated kinase 1 (Pak1) is a serine/threonine kinase whose activity is regulated by both Rho GTPases and AGC kinase family members. It plays a role in cytoskeletal remodeling and cell motility as well as cell proliferation, angiogenesis, tumorigenesis and metastasis. An involvement of Pak1 in renal cell carcinoma (RCC), which remains highly refractory to chemotherapy and radiotherapy, remains to be investigated. Pak1 expression, phosphorylation and kinase activity were examined in RCC cell lines and human tissue from normal and renal carcinoma. We report increased Pak1 expression and constitutive activity in the membrane and nucleus but not the cytoplasm of resected human RCC. To study a role for Pak1 in RCC, we developed 786-0 clones that expressed either a kinase-active Pak1L83,L86 2 different Pak1 dominant negative mutants, Pak1R299 and Pak1L83,L86,R299 or Pak1 siRNA. The expression of Pak1L83,L86 increased 786-0 proliferation, motility and anchorage independent growth, while the dominant negative mutants and Pak1 siRNA abrogated these effects. In addition, Pak1L83,L86 conferred resistance to 5-fluorouracil with a 40% ± 10% increase in cell viability. Conversely, Pak1L83,L86,R299, Pak1R299 and Pak1 siRNA conferred sensitivity with a 65.2% ± 5.5%, 69.2% ± 3.3% and 73.0% ± 8.4% loss in viability, respectively. Finally, Pak1 plays a role in renal tumor growth in vivo. Only 33% of mice developed tumors in the Pak1L83,L86,R299 group and no tumors developed from Pak1R299 cell challenge. Together these findings point to Pak1 as an exciting target for therapy of renal cancer, which remains highly refractory to existing treatments. © 2007 Wiley-Liss, Inc. [source] Fibre intake and renal cell carcinoma: A case-control study from ItalyINTERNATIONAL JOURNAL OF CANCER, Issue 8 2007Carlotta Galeone Abstract Only 2 previous studies, conducted in Australia, United States and northern Europe, considered the role of dietary fibre intake on renal cell carcinoma (RCC) risk, and both showed a modest, inverse association. Therefore, we investigated in depth the topic of fibres and RCC, using data from a multicenter case-control study conducted in Italy from 1992 to 2004, including 767 cases with incident, histologically confirmed RCC and 1,534 controls admitted to the same network of hospitals as cases with acute nonmalignant conditions. Multivariate odds ratios (OR) and 95% confidence intervals (CI) were obtained after allowance for major identified confounding factors, including total energy intake. The continuous OR for an increase in intake equal to the difference between the 80th and the 20th percentile were 0.94 (95% CI: 0.82,1.08) for total dietary fibre, 0.98 (95% CI: 0.85,1.13) for soluble noncellulose polysaccharides, 0.92 (95% CI: 0.80,1.05) for total insoluble fibre, 0.90 (95% CI: 0.78,1.04) for cellulose, 0.95 (95% CI: 0.84,1.06) for insoluble noncellulose polysaccharides and 1.06 (95% CI: 0.93,1.21) for lignin. With reference to the sources of fibre, we found an inverse association with vegetable fibre (OR = 0.84, 95% CI: 0.73,0.97), but no association with fruit (OR = 0.98, 95% CI: 0.86,1.12) and grain fibre (OR = 1.05, 95% CI: 0.95,1.15). The inverse association with vegetable fibre may reflect a real favorable effect, or be an indicator of a beneficial role of a diet rich in vegetable on RCC risk. © 2007 Wiley-Liss, Inc. [source] DOK4/IRS-5 expression is altered in clear cell renal cell carcinomaINTERNATIONAL JOURNAL OF CANCER, Issue 5 2007Nael Al-sarraf Abstract The insulin-receptor substrate family plays important roles in cellular growth, signaling, and survival. We have previously shown the dysregulation of the IGF-axis in clear cell renal cell carcinoma. In this manuscript, we examine the expression of the insulin receptor substrate family in clear cell RCC, and demonstrate that the expression of 2 members of this family are significantly altered in tumors. The most striking finding is that expression of the new IRS family member IRS-5 is significantly upregulated in 90% of examined clear cell RCCs. Studies on this gene has shown that it is regulated through chromatin remodeling in kidney cells. © 2007 Wiley-Liss, Inc. [source] Low adiponectin levels are associated with renal cell carcinoma: A case-control studyINTERNATIONAL JOURNAL OF CANCER, Issue 7 2007Themistoklis N. Spyridopoulos Abstract Adiponectin is a novel endogenous insulin sensitizer, secreted by mature adipocytes. Circulating levels of adiponectin are inversely associated with obesity and insulin resistance. Because obesity is a risk factor for renal cell carcinoma (RCC), we hypothesized that low adiponectin levels are associated with RCC. To evaluate this hypothesis, we conducted a case- control study of 70 patients with histologically confirmed RCC and 280 healthy controls matched by gender, age and county of residence. Study subjects were interviewed and blood samples were collected during a 32-month period in Athens, Greece. Serum adiponectin levels were statistically, significantly and inversely associated with RCC when compared with controls (OR = 0.76, p = 0.05) and this association remained practically unchanged after controlling for BMI; the introduction of waist to hip ratio along with adiponectin in the multiple logistic regression analysis model rendered the association between adiponectin and RCC risk insignificant, indicating that altered levels of adiponectin may mediate the effect of central or intra-abdominal obesity on RCC. Prospective studies as well as studies exploring underlying mechanisms are needed to fully explore the role of adiponectin in predicting future risk of RCC in humans. © 2006 Wiley-Liss, Inc. [source] Micronutrients and the risk of renal cell cancer: A case-control study from ItalyINTERNATIONAL JOURNAL OF CANCER, Issue 4 2007Cristina Bosetti Abstract The role of various micronutrients on the risk of renal cell cancer (RCC) was examined in a multicentric case-control study from Italy, in which information on dietary habits were collected using a validated food-frequency questionnaire. Cases were 767 patients (494 men and 273 women) with incident, histologically confirmed RCC; controls were 1,534 subjects (988 men and 546 women) admitted to the same hospitals as cases for a wide spectrum of acute, nonneoplastic conditions. After allowing for energy and other major covariates, a significant inverse association was found for vitamin E (odds ratio, OR, for the highest quintile of intake versus the lowest one 0.56, 95% confidence interval, CI 0.41,0.75), and vitamin C (OR = 0.72, 95% CI = 0.54,0.96), although the trend in risk for vitamin C was of borderline significance. No significant trend of decreasing risk was found for other micronutrients analyzed, although for most of them the risk estimates were below unity for intakes above the lowest. The ORs for the upper quintile of intake when compared with the lowest one were 0.80 (95% confidence interval, CI = 0.59,1.08) for retinol, 0.82 (95% CI = 0.61,1.10) for ,-carotene, 0.90 (95% CI = 0.68,1.20) for ,-carotene, 0.94 (95% CI = 0.73,1.21) for ,-criptoxanthin, 0.85 (95% CI = 0.63,1.14) for lutein/zeaxanthin, 0.76 (95% CI = 0.57,1.01) for vitamin D, 0.75 (95% CI = 0.55,1.01) for thiamine, 0.88 (95% CI = 0.66,1.19) for riboflavin, 0.85 for vitamin B6 (95% CI = 0.64,1.13), 0.85 (95% CI = 0.64,1.12) for folate and 0.80 (95% CI = 0.60,1.07) for niacin. No meaningful associations emerged for lycopene (OR = 1.11). The present findings support a possible beneficial effect of vitamin E and C on RCC. © 2006 Wiley-Liss, Inc. [source] Alteration of subcellular and cellular expression patterns of cyclin B1 in renal cell carcinoma is significantly related to clinical progression and survival of patientsINTERNATIONAL JOURNAL OF CANCER, Issue 4 2006Stephen O. Ikuerowo Abstract Cyclin B1, identified as a regulator of late cell cycle, is involved in the development and progression of a variety of human malignancies. To clarify the role of cyclin B1 in the pathogenesis and prognosis of renal cell carcinoma (RCC), protein expression was compared with clinicopathological characteristics of patients as well as the long-term survival after surgical therapy. Expression analysis was carried out by immunohistochemistry and tissue microarray analysis. The microarrays that represented the primary tumors, their invasion front and normal peritumoral renal parenchyma contained 753 tissue cores obtained from 251 randomly selected nephrectomy specimens. Immunopositivity within the primary tumors was significantly associated with tumor stage (pT) (p < 0.01), lymph node status (pN) (p < 0.01) as well as the presence of systemic metastatic disease (p = 0.01). Subcellular expression in the cytoplasm of tumor cells significantly correlated with pT (p = 0.02) and pN (p = 0.03). When peritumoral tissue samples exhibited a relative amount of <10% of positively reacting epithelial cells, cyclin B positivity was identified to predict long-term survival of patients in univariate analysis (p < 0.01) whereas borderline significance was observed in multivariate statistical analysis (p = 0.05). Increased intratumoral cyclin B1 positivity and aberrant localization of signals within the cytoplasm of tumor cells is positively correlated with the tendency towards tumor progression, indicating the significant role of cyclin B1 in the development and pathogenesis of RCC. The result of uni- and multivariate statistical analysis suggests the prognostic value of cyclin B1 for RCC patients. © 2006 Wiley-Liss, Inc. [source] Analysis of fumarate hydratase mutations in a population-based series of early onset uterine leiomyosarcoma patientsINTERNATIONAL JOURNAL OF CANCER, Issue 2 2006Sanna K. Ylisaukko-oja Abstract Germline mutations in fumarate hydratase (FH) gene at 1q43 predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. In HLRCC, the most common clinical features are leiomyomas of the skin and uterus, and in a subset of the families, renal cell cancer (RCC) and uterine leiomyosarcoma (ULMS) occur frequently at young age. This study was conducted to evaluate the possible contribution of FH mutations in a population-based series of early onset (,45 years) ULMSs. Eighty-one cases were identified through the national cancer registry, and samples from 67 cases (83%) were available for FH mutation screening and analysis of allelic imbalance (AI) at the FH locus. Seventeen percent of tumors showed AI. In the mutation analysis, a novel missense mutation K424R was found. The mutation was also found from the patient's normal tissue. To study whether this variant has functional consequences, FH enzyme activity assay was performed in a cell model. The activity of the mutated protein was significantly reduced as compared to wild type (p = 0.009). This study shows that FH germline mutations can occur in seemingly nonsyndromic cases of ULMS (1/67, 1.5%). It appears that on the population level hereditary FH defects do play a role in pathogenesis of sporadic early onset ULMSs, albeit rarely. © 2006 Wiley-Liss, Inc. [source] Fruits and vegetables and renal cell carcinoma: Findings from the European prospective investigation into cancer and nutrition (EPIC)INTERNATIONAL JOURNAL OF CANCER, Issue 12 2006Steffen Weikert Abstract We examined the association between fruits and vegetables and risk of renal cell carcinoma (RCC) in the European Prospective Investigation into Cancer and Nutrition (EPIC). Dietary intake data and complete follow-up information on cancer incidence were available for 375,851 participants recruited in EPIC centers of 8 countries. During an average follow-up of 6.2 years, 306 incident cases of RCC were identified. The associations of consumption of total vegetables, total fruits, combined total fruits and vegetables and specific subtypes of vegetables with RCC risk were analyzed using Cox proportional hazards, stratified by centre and adjusted for potential confounders. No significant associations between fruit and vegetable consumption and RCC risk were observed despite a wide range of intake. The estimated relative risks (95% confidence intervals [CI]) in men and women combined were 0.97 (0.85,1.11) per 40 g increase in vegetable intake, 1.03 (0.97,1.08) per 40 g increase in fruit intake and 1.02 (0.93,1.11) per 80 g increase in fruit and vegetable intake combined. Among the vegetable subtypes, an inverse association was observed for root vegetables (RR per 8 g increase: 0.88; 95% CI: 0.78,0.99). These results suggest that total consumption of fruits and vegetables is not related to risk of RCC, although we cannot exclude the possibility that very low consumption is related to higher risk. The relationship of specific fruit and vegetable subgroups with RCC risk warrant further investigation. © 2006 Wiley-Liss, Inc. [source] Intrinsic chemotherapy resistance to the tubulin-binding antimitotic agents in renal cell carcinomaINTERNATIONAL JOURNAL OF CANCER, Issue 1 2005Roisean E. Ferguson Abstract Renal cancer is one of the most chemoresistant tumor types. Using a panel of 10 established renal cancer cell lines that have not been subjected to prior drug selection, the range of functional resistance phenotypes to the tubulin-binding agents paclitaxel, vinblastine, vincristine and patupilone (epothilone B, EPO906) was determined, together with expression of P-glycoprotein (PgP), multidrug resistance associated protein-2 (MRP2) and major vault protein (MVP) proteins. The IC50 values for vincristine correlated positively with PgP expression (r = 0.73; p = 0.031), with values for paclitaxel and vinblastine just failing to reach significance. A significant positive correlation was observed for sensitivity to paclitaxel and MRP2 expression only (r = 0.8; p = 0.013). MVP expression did not correlate with sensitivity to any of the drugs examined. All cell lines exhibited much greater sensitivity to patupilone, demonstrating for the first time the potential use of patupilone in this cancer. In tissue samples from chemotherapy-naive renal cell carcinoma (RCC) patients, marked downregulation or absence of PgP in many tumor cells with expression levels more similar to sensitive cell lines rather than the resistant lines was seen. Similarly, MRP2 was absent or only weakly present in tumor cells, whereas MVP was very strongly upregulated in most tumor samples. This study illustrating discrepancies between results exclusively based on studies in cell lines and findings in vivo suggests that the role of PgP and MRP2 in intrinsic resistance in RCC in vivo may be less than expected from the in vitro findings and supports a potential role for MVP on the basis of in vivo expression studies. © 2004 Wiley-Liss, Inc. [source] Molecular pathology of chromophobe renal cell carcinoma: A reviewINTERNATIONAL JOURNAL OF UROLOGY, Issue 7 2010Maria V Yusenko Abstract The recognition of chromophobe renal cell carcinoma (RCC) among other distinct types of renal cell tumors (RCT) based on light-microscopic features, such as cytoplasmic and nuclear characteristics, might pose a dilemma in some cases because of morphological pattern overlapping with renal oncocytoma or conventional RCC. The present article reviews chromophobe RCC with focus on aspects of its molecular pathology, which was shown using ancillary modern microarray-based technology that can distinguish it from its mimics and therefore be helpful for its correct diagnosis. Although the high resolution DNA-microarray analyses excluded with all certainty the occurrence of small specific alterations, the loss of entire chromosomes 2, 10, 13, 17 and 21 occurs exclusively in chromophobe RCC and therefore probes localized at these chromosomes might be used to establish the diagnosis of chromophobe RCC in cases with uncertain histology. The usefulness of proposed candidate genes selected by the global gene expression analyses in the diagnostic pathology is far below expectations. The conflicting staining patterns, together with the poor specificity of used antibodies, leads us to believe that these candidate immunomarkers might not help in the separation of chromophobe RCC, with the exception of CD82, which has recently been suggested to be used for routine histological diagnosis. [source] A case of renal mucinous tubular and spindle cell carcinomaINTERNATIONAL JOURNAL OF UROLOGY, Issue 8 2009Manabu Kato Abstract A 33-year-old man was hospitalized for treatment of a left renal tumor. The radiological findings were consistent with those of a left renal cell carcinoma (RCC). Subsequently, a radical nephrectomy was carried out. Macroscopic examination showed that a well-demarcated tumor measuring 2.9 × 2.6 × 2.5 cm was present in the middle portion of the resected kidney. The cut surface of the tumor was grayish-white in color. Pathological examination of the resected specimen showed a mucinous tubular and spindle cell carcinoma of the kidney (MTSCC-K). MTSCC-K is a low-grade renal epithelial neoplasm that has recently been recognized as a specific entity in the World Health Organization 2004 classification of RCC. To our knowledge, 17 cases of MTSCC-K in Japan have been reported by Japanese investigators. To avoid administration of excessive adjuvant treatment to patients, pathologists and urologists should consider this newly recognized low-grade malignancy when diagnosing renal tumors. [source] Renal cell carcinoma with a huge solitary metastasis to the contralateral adrenal gland: A case reportINTERNATIONAL JOURNAL OF UROLOGY, Issue 12 2008Takanobu Utsumi Abstract Renal cell carcinoma (RCC) is capable of metastasizing to several organs. Synchronous isolated contralateral adrenal metastasis of the primary RCC is, however, very rare. Herein we report a case of RCC with a huge solitary metastasis to the contralateral adrenal gland that was surgically treated. We scheduled nephrectomy for the left primary RCC and adrenalectomy for the right adrenal tumor. However, at surgery we found a huge right adrenal tumor that had invaded the right kidney, right renal vein, and inferior vena cava. Therefore right nephrectomy was performed simultaneously with resection and reconstruction of the inferior vena cava. Pathological findings demonstrated that the left renal tumor and right adrenal tumor had the same histology. Although the patient required hemodialysis, he remains well at six months postoperatively. So far, there have been only two cases of a solitary contralateral metastatic adrenal tumor that was larger than the primary RCC, thus the present case is the third one. [source] Comparison of transperitoneal and retroperitoneal laparoscopic nephrectomy for renal cell carcinoma: A single-center experience of 100 casesINTERNATIONAL JOURNAL OF UROLOGY, Issue 11 2008Takatsugu Okegawa Objectives: To report our experience with the retroperitoneal and transperitoneal approaches of laparoscopic nephrectomy for renal cell carcinoma (RCC). Methods: Between July 2001 and December 2007, 100 patients with RCC underwent laparoscopic radical nephrectomy at our institution for clinically localized RCC. Fifty-three patients received a retroperitoneal procedure and 47 received a transperitoneal procedure. The perioperative and oncological outcomes of these groups were reviewed retrospectively. Results: Mean follow up was 34 months. No statistically significant difference was found between the two approaches in terms of pathological stage, operative time, need for additional procedures such as adrenalectomy and/or lymph node sampling, estimated blood loss, need for blood transfusions, analgesic requirement, length of hospital stay, or the incidence of minor or major complications. The 5-year disease-free survival rate was 90% for both the retroperitoneal and transperitoneal procedures. The 5-year overall survival rates were 98% and 96%, respectively. Therefore, no significant difference was observed in the long-term oncological outcome between the two groups. Conclusions: Tumor control and surgical morbidity in laparoscopic radical nephrectomy seem not to be significantly influenced by the approach. [source] | ||||||||||||||||||||||||||||||||||