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INCREASING TUMOR SIZE IS ASSOCIATED WITH HIGHER RATES OF HIGH FUHRMAN NUCLEAR GRADE IN PATIENTS WITH RENAL CELL CARCINOMA
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Table 3: Patterns of recurrence, treatment and outcomes after LRC Local Recurrence PLUS No Local Recurrence Distant Metastases Recurred at 19 months. Recurred at 20 months. Treated 1 Treated with nephrectomy. with nephrectomy. Died of NED at 117 months cancer at 29 months Recurred at 30 months. Recurred at 90 months. 2 Treated by radical nephrectomy. Treated with repeat cryo. NED at 97 months Died of cancer at 108 months. Recurred at 40 months. 3 No treatment information. Alive at 96 months. Recurred at 65 months. 4 No treatment offered. Died from non-cancer cause. Patient with multiple tumors. Recurred at 36 months. Treated 5 with repeat cryo. NED at 82 months 6 7
Vol. 179, No. 4, Supplement, Monday, May 19, 2008
598 Distant Metastases Brain mets at 8 months. Died of cancer at 14 months Liver and lung mets at 12 months. Died of cancer at 19 months Lung mets at 24 months. Died of cancer at 31 months Lung, brain and bone mets at 58 months. Died of cancer at 71 months Brain mets at 70 months. Alive at 80 months Liver and bone mets at 89 months. Alive at 113 months Patient with multiple tumors. Lung mets12 months. Died of cancer at 21 months
Source of Funding: None
597 EXPRESSION OF PI3K/AKT/mTOR PATHWAY IN RENAL CELL CARCINOMA METASTASES: CORRELATION WITH PATHOLOGIC FINDINGS AND SURVIVAL Tamer M Abou Youssif*, Simon Tanguay, Mona Alam-Fahmy, Ismael H Koumakpayi, Kanishka Sircar. Montreal, QC, Canada. INTRODUCTION AND OBJECTIVE: PI3K/AKT/mTOR pathway is upregulated in many human cancers. Recently agents targeting this pathway in RCC have shown promising results in terms of diseases free progression and overall survival. In this study we examined the activation status of the PI3K/AKT/mTOR/p70S6 pathway in metastatic RCC as well as its relation to pathologic parameters and survival. METHODS: Tissue microarray containing metastatic specimens form 132 RCC patients was constructed. Immunohistochemical analysis with antibodies against PI3K, p-AKT, p-mTOR and p-70S6 was done. The sites of metastases were adrenal, bone, brain, liver, lymph node, lung, gastrointestinal tract, thyroid and skin. Histologic type was conventional in96%. Pearson correlation analyses were used to determine the correlation of markers with different variables. Survival analyses was carried out and correlated to each marker expression. RESULTS: PI3K/AKT/mTOR/p70S6 pathway is highly expressed in the studied metastatic lesions. p70S6, cytoplasmic mTOR, nuclear mTOR, Cytoplasmic pAKT, nuclear pAKT, and PI3K were expressed in 96, 86, 64, 82, 63, and 98 percent of cases respectively. Generally all PI3K/AKT/mTOR/p70S6 pathway proteins are more expressed in high grade tumors (grade 3 and 4). PI3K expression was inversely correlated with the nuclear grade (p=0.003 Pearson test). ([SUHVVLRQRIF\WRSODVPLFP725SURWHLQZDVVLJQL¿FDQWO\DVVRFLDWHG with high level of other cytoplasmic proteins as pAKT and PI3K (p= 0.000 3HDUVRQ WHVW 1XFOHDU DQG F\WRSODVPLF$&7 ZHUH DOVR VLJQL¿FDQWO\ correlated (p=0.005 Pearson test). Mean and median disease free interval were 43 and 37 months respectively. Patients with short GLVHDVHIUHHLQWHUYDOVKRZHGVLJQL¿FDQWO\KLJKH[SUHVVLRQRI3,. S &\WRSODVPLFP725H[SUHVVLRQZDVVLJQL¿FDQWO\FRUUHODWHGZLWK EHWWHUGLVHDVHVSHFL¿FVXUYLYDOZLWKPHGLDQGLVHDVHVSHFL¿FVXUYLYDO of 33 months for cytoplasmic mTOR positive patients compared to 24 months for cytoplasmic mTOR negative patients. Other protein failed to GHPRQVWUDWHVLJQL¿FDQWFRUUHODWLRQZLWKGLVHDVHVSHFL¿FPRUWDOLW\ CONCLUSIONS: The PI3K pathway is activated downstream to the level of the translational protein p-70S6 in RCC metastases, supporting a therapeutic role for PI3K pathway inhibitors. PI3K and F\WRSODVPLF P725 VKRZHG VLJQL¿FDQW DVVRFLDWLRQV ZLWK SDWKRORJLF features and survival respectively and hence can be used to LGHQWLI\ SDWLHQWV WKDW PD\ EHQH¿W IURP DQWLWXPRU WKHUDS\ ZLWK P725 inhibitors. Source of Funding: None
NEAR INFRARED FLUORESCENCE OF INTRAVENOUS INDOCYANINE GREEN FOR INTRAOPERATIVE IMAGING OF RENAL CORTICAL TUMORS: A COMPLETED FEASIBILITY STUDY Dragan J Golijanin*, Jonah Marshall, Allison Cardin, Eric A Singer, Ralph R Madeb, Ronald W Wood, Jay E Reeder, Guan Wu, Jorge L Yao, Edward M Messing. Rochester, NY. INTRODUCTION AND OBJECTIVE: Successful partial nephrectomy for the treatment of renal cancer is predicated on attaining negative surgical margins while preserving normal parenchyma. To help determine intraoperative margin status, we studied if renal cortical tumors can be safely differentiated from normal parenchyma by near infrared ÀXRUHVFHQFH 1,5) RILQWUDYHQRXVLQRGF\DQLQHJUHHQ ,9,&* METHODS: 17 patients (one had bilateral surgery) underwent radical (2) or partial (16) nephrectomy with NIRF intraoperative imaging of their 18 renal tumors after IV injection of ICG. After kidney exposure, 7-10cc (2.5mg/ml) of ICG was injected IV and shortly after, NIRF was detected using LUNATM system (Novadaq Technologies Inc, Mississauga, Canada), and its uptake and deposition recorded. RESULTS: No immediate allergic or systemic side effects occurred and no postoperative changes in liver or kidney function were observed. All tumor and non-tumorous lesions were clearly delineated E\ 1,5) LQ RXU SDWLHQWV XQGHUJRLQJ SDUWLDO QHSKUHFWRP\7XPRU VL]H averaged 4.1cm (1.1-11). A total of 27 lesions were found in 18 kidneys exposed, 19 solid and 8 cystic. All malignant tumors (clear cell (9), papillary (4), chromophobe (2) and cystic renal cell carcinoma (2) ZHUHVHHQDVK\SRÀXRUHVFHQWDUHDVZKLFKZHUHFOHDUO\GHPDUFDWHG from the surrounding normal parenchyma. Oncocytoma (2) was seen as hypofluorescent area but with minimal difference from normal parenchyma comparing to clear cell renal carcinoma which was nearly QRQÀXRUHVFHQW%HQLJQF\VWV ZHUHFKDUDFWHUL]HGZLWKDQLQFUHDVHG ÀXRUHVFHQFHFRPSDUHGWRWKHQRUPDOSDUHQFK\PD6LPSOHWKLFNZDOOHG cyst (1) had similar characteristics to normal parenchyma. Clear cell FDUFLQRPDVGXULQJUDGLFDOQHSKUHFWRPLHV ZHUHQRWYLVXDOL]HGZHOO VHFRQGDU\WRWKHWKLFNOD\HURISHULQHSKULFIDW1,5)PLFURVFRS\FRQ¿UPHG ,&*SUHVHQFHLQQRUPDOSDUHQFK\PDDQGGHFUHDVHGÀXRUHVFHQFHLQVLGH WKHWXPRURXVWLVVXH+ (ZDVFRUUHODWHGWR1,5)PLFURVFRS\FRQ¿UPLQJ DFFXUDWHO\GLIIHUHQWGHSRVLWLRQRI,&*DQGÀXRUHVFHQFHLQWXPRUYHUVXV normal renal tissue. All margins were negative. CONCLUSIONS: No adverse events were observed related to ICG administration and use of LUNA imaging system. We also observed that NIRF after IV ICG permits accurate intraoperative detection of renal cortical tumors during partial nephrectomy. Source of Funding: Novadaq Technologies, Inc., Mississauga, Canada.
599 INCREASING TUMOR SIZE IS ASSOCIATED WITH HIGHER RATES OF HIGH FUHRMAN NUCLEAR GRADE IN PATIENTS WITH RENAL CELL CARCINOMA Claudio Jeldres*, Nazareno Suardi, Naeem Bhojani, Jean-Jacques 3DWDUG.DULP%HQVDODK5DI¿$YDNLDQ9LQFHQ]R)LFDUUD7RPPDVR Prayer-Galetti, Luca Cindolo, Alexandre de la Taille, Laurent Salomon, Peter F Mulders, Jacques Tostain, Richard Zigeuner, Denis Chautard, Antoine Valeri, Eric Lechevallier, Jean-Luc Descotes, Herve Lang, Arnaud Mejean, Roberto Bertini, Francesco Montorsi, Pierre I Karakiewicz. Montreal, QC, Canada, Rennes, France, Padova, Italy, Benevento, Italy, Creteil, France, Nijmegen, The Netherlands, Saint Etienne, France, Graz, Austria, Angers, France, Paris, France, and Milan, Italy. INTRODUCTION AND OBJECTIVE: Active surveillance as EHHQXVHGLQVHOHFWHGSDWLHQWVZLWKVPDOOORFDOL]HGUHQDOPDVVHV6LQFH KLJK)XKUPDQQXFOHDUJUDGHGH¿QHGDVJUDGH,,,RU,9LVDVVRFLDWHGZLWK XQIDYRUDEOHRXWFRPHVZHDVVHVVWKHHIIHFWRIWXPRUVL]HRQWKHUDWHRI Fuhrman grade III-IV in patients who underwent nephron-sparing surgery (NSS) and radical nephrectomy (RN) for renal cell carcinoma. METHODS: Between 1984 and 2001, 2476 patients were treated for renal cell carcinoma in thirteen academic centers in Europe. Univariable and multivariable logistic regression analyses addressed WKHSUHVHQFHRI)XKUPDQJUDGH,,,,9DW¿QDOSDWKRORJ\DFFRUGLQJWR
Vol. 179, No. 4, Supplement, Monday, May 19, 2008
WKHWXPRUVL]H&RYDULDWHVFRQVLVWHGRIDJH7VWDJHDQGV\PSWRPVDW GLDJQRVLV7XPRUVL]HZDVFRGHGDVFXELFVSOLQHV WRDOORZQRQOLQHDU effect). RESULTS: The age mean and median were 60 years and 61 years, respectively (range 18-93). Of all, 1991 (80.4%) patients were T1 stage and 485 (19.6%) patients were T2 stage tumors. Mean DQGPHGLDQWXPRUVL]HYDOXHVZHUHFPDQGFPUHVSHFWLYHO\ (range 0.5-21.0). Of all, 1625 (65.6%) were male. At diagnosis, 1776 (71.7%) patients were asymptomatic. The rate of Fuhrman grade III-IV LQFUHDVHG ZLWKWXPRUVL]H ZKHUH WXPRUV FP FP FP cm, 4-5 cm, 5-6 cm, 6-7 cm and >7cm were associated with rates of Fuhrman grade III-IV of 0.4%, 3.7%, 11.2%, 14.8%, 15.9%, 12.5%, 11.2%, 30.3%, respectively. In univariable and multivariable analyses LQFUHDVLQJWXPRUVL]HZDVDVVRFLDWHGZLWKKLJKHUULVNRI)XKUPDQJUDGH ,,,,9DW¿QDOSDWKRORJ\7KHPXOWLYDULDEOHFXELFVSOLQHDQDO\VHVVKRZHG that the rate of Fuhrman grade III-IV markedly increased up to a tumor VL]HRIFP S DQGWKHQÀDWWHQHG &21&/86,216 7XPRU VL]H SUHGLFWV WKH UDWH RI )XKUPDQ grade III-IV up to 7 cm and may be used as an indicator of nuclear grade.
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p<0.01). In clinical renal cancer tissue, survivin expression was DVVRFLDWHGVLJQL¿FDQWO\ZLWKGLVWDQWPHWDVWDVLVVWDJH 0 0 S 6XUYLYLQ%JHQHH[SUHVVLRQOHYHOZDVDVVRFLDWHGVLJQL¿FDQW\ with T stage (pT1: pT2: pT3= 1:1.15:4.50, p=0.04). Althrough, not VKRZLQJ VLJQL¿FDQW DVVRFLDWLRQ WKH UDWLR RI VXUYLYLQ %VXUYLYLQ LQ metastasis stage (M1) was lower than that in no metastasis stage(M0) (M0:M1=5.35:1,p=0.23). &21&/86,216 7KHVH¿QGLQJVVXJJHVWHGWKDWVXUYLYLQDQG LWVVSOLFHGLVRIRUPVKDGVLJQL¿FDQWDVVRFLDWLRQVZLWKUHQDOFDQFHUFHOO proliferation and distant metastases. And the elimination of survivin would be a potential candidate for a novel approach to treat renal cancer.
Source of Funding: None
601
Source of Funding: None
600 SURVIVIN AND ITS SPLICED ISOFORMS GENE EXPRESSION IS ASSOCIATED WITH PROLIFERATION OF RENAL CANCER CELLS AND CLINICAL STAGE OF RENAL CANCER Hidekazu Koike*, Keigo Okamura, Yoshitaka Sekine, Kazuhiro Suzuki. Maebashi, Japan. INTRODUCTION AND OBJECTIVE: Survivin has been implicated in both the control of cell division and inhibition of apoptosis. 7RGDWHDOWHUQDWLYHO\VSOLFHGLVRIRUPV6XUYLYLQĮ%([%KDYH been described. We assessed the effect of survivin gene expression on the proliferation of renal cancer cells, and studied the association of suvivin and its spliced isoforms gene expression levels with clinical stage of renal cancer. METHODS: Gene expression of survivin and its spliced isoforms in renal cancer cells, Caki-1 were performed by RT-PCR. We knocked down the gene expression of survivin using small interfering RNA (siRNA), and assessed the cell proliferation by MTS assay. Next, ZHTXDQWL¿HGWKHJHQHH[SUHVVLRQOHYHOVRIVXUYLYLQDQGLWVLVRIRUPV in nephrectomy samples(27 patients) using quantitative real-time PCR method. 5(68/76 ,Q&DNLFHOOVVXUYLYLQDQGVXUYLYLQĮ%ZHUH expressed higher than that of survivin-Ex3. In the cells, gene expression OHYHOV RI VXUYLYLQ P51$ ZHUH VLJQL¿FDQWO\ GHFUHDVHG E\ WUDQVIHFWLRQ of siRNA against survivin. Decrease of survivin gene expression was accompanied by inhibition of cell proliferation of renal cancer cells. ,QFDNLFHOOVYLDEOHFHOOQXPEHUVZHUHVLJQL¿FDQWO\GHFUHDVHGDIWHU 96h of siRNA treatement (36% decrease in Caki-1 cells, respectively.
EARLY AND NONINVASIVE DIAGNOSIS OF RENAL CELL CARCINOMA USING 1H-NMR-BASED METABONOMICS Bai-Jun Dong*, Hong-Chang Gao, Han-Qing Xuan, Xia Liu, Dong-Hai Lin, Yi-Ran Huang. Shanghai, China. INTRODUCTION AND OBJECTIVE: Renal cell carcinoma (RCC) is one of the most lethal urologic malignancies. Prognosis for RCC varies considerably depending on the disease stage at diagnosis. 7KRVHGLDJQRVHGHDUO\ZLWKRUJDQFRQ¿QHGWXPRXUVKDYHDQ 5-yr survival rate but only 5-10% for those with metastatic disease. 7KHUHLVFXUUHQWO\QRELRÀXLGVFUHHQLQJWHVWVH[LVWIRU5&&DQGXSWR one-third of patients are initially diagnosed with advanced disease. 1H NMR based metabonomics has been well-established to be a powerful technique for investigating the metabolic state of various biological ÀXLGVIRUH[SORULQJSDWKRORJLFDOPHWDEROLFDWWKHPROHFXODUOHYHO,QWKLV study, we have undertaken 1H-NMR-based metabonomics on serum VSHFLPHQVWRFKDUDFWHUL]HWKHPHWDEROLFSUR¿OLQJRI5&&IRUHDUO\DQG noninvasive diagnosis. METHODS: The serum samples from the 71 RCC patients including 49 local and 22 advanced cases and 55 healthy volunteers were examined by high-resolution 1H NMR spectroscopy. All NMR VSHFWUDZHUHDQDO\]HGE\WKHPHDQVRISULQFLSDOFRPSRQHQWDQDO\VLV (PCA) for multivariate pattern recognition in order to differentiate local and advanced cases, cases before and after nephrectomy in comparison with healthy humans, and to identify the metabolites responsible for the discrimination. RESULTS: The RCC patients, can be well distinguished from the healthy humans(Figure in addition), even in their early stage. The patients with metastases can be distinctly differentiated from those without metastases. And the patients after nephrectomy can be discriminated from those before nephrectomy. Systemic changes of metabolite concentrations between RCC patients and healthy human are most likely the result of the cells switched to glycolysis to maintain energy homeostasis with a manifestation of higher levels of lipid, lactate, pyruvate, and glycerol, but declined levels of phosphatidylcholine/ choline, glutamine, acetoacetate, and glucose/glycogen. And the systemic changes can be somewhat reversed after nephrectomy. CONCLUSIONS: Serum NMR spectra in combination with
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Table 3: Patterns of recurrence, treatment and outcomes after LRC Local Recurrence PLUS No Local Recurrence Distant Metastases Recurred at 19 months. Recurred at 20 months. Treated 1 Treated with nephrectomy. with nephrectomy. Died of NED at 117 months cancer at 29 months Recurred at 30 months. Recurred at 90 months. 2 Treated by radical nephrectomy. Treated with repeat cryo. NED at 97 months Died of cancer at 108 months. Recurred at 40 months. 3 No treatment information. Alive at 96 months. Recurred at 65 months. 4 No treatment offered. Died from non-cancer cause. Patient with multiple tumors. Recurred at 36 months. Treated 5 with repeat cryo. NED at 82 months 6 7
Vol. 179, No. 4, Supplement, Monday, May 19, 2008
598 Distant Metastases Brain mets at 8 months. Died of cancer at 14 months Liver and lung mets at 12 months. Died of cancer at 19 months Lung mets at 24 months. Died of cancer at 31 months Lung, brain and bone mets at 58 months. Died of cancer at 71 months Brain mets at 70 months. Alive at 80 months Liver and bone mets at 89 months. Alive at 113 months Patient with multiple tumors. Lung mets12 months. Died of cancer at 21 months
Source of Funding: None
597 EXPRESSION OF PI3K/AKT/mTOR PATHWAY IN RENAL CELL CARCINOMA METASTASES: CORRELATION WITH PATHOLOGIC FINDINGS AND SURVIVAL Tamer M Abou Youssif*, Simon Tanguay, Mona Alam-Fahmy, Ismael H Koumakpayi, Kanishka Sircar. Montreal, QC, Canada. INTRODUCTION AND OBJECTIVE: PI3K/AKT/mTOR pathway is upregulated in many human cancers. Recently agents targeting this pathway in RCC have shown promising results in terms of diseases free progression and overall survival. In this study we examined the activation status of the PI3K/AKT/mTOR/p70S6 pathway in metastatic RCC as well as its relation to pathologic parameters and survival. METHODS: Tissue microarray containing metastatic specimens form 132 RCC patients was constructed. Immunohistochemical analysis with antibodies against PI3K, p-AKT, p-mTOR and p-70S6 was done. The sites of metastases were adrenal, bone, brain, liver, lymph node, lung, gastrointestinal tract, thyroid and skin. Histologic type was conventional in96%. Pearson correlation analyses were used to determine the correlation of markers with different variables. Survival analyses was carried out and correlated to each marker expression. RESULTS: PI3K/AKT/mTOR/p70S6 pathway is highly expressed in the studied metastatic lesions. p70S6, cytoplasmic mTOR, nuclear mTOR, Cytoplasmic pAKT, nuclear pAKT, and PI3K were expressed in 96, 86, 64, 82, 63, and 98 percent of cases respectively. Generally all PI3K/AKT/mTOR/p70S6 pathway proteins are more expressed in high grade tumors (grade 3 and 4). PI3K expression was inversely correlated with the nuclear grade (p=0.003 Pearson test). ([SUHVVLRQRIF\WRSODVPLFP725SURWHLQZDVVLJQL¿FDQWO\DVVRFLDWHG with high level of other cytoplasmic proteins as pAKT and PI3K (p= 0.000 3HDUVRQ WHVW 1XFOHDU DQG F\WRSODVPLF$&7 ZHUH DOVR VLJQL¿FDQWO\ correlated (p=0.005 Pearson test). Mean and median disease free interval were 43 and 37 months respectively. Patients with short GLVHDVHIUHHLQWHUYDOVKRZHGVLJQL¿FDQWO\KLJKH[SUHVVLRQRI3,. S &\WRSODVPLFP725H[SUHVVLRQZDVVLJQL¿FDQWO\FRUUHODWHGZLWK EHWWHUGLVHDVHVSHFL¿FVXUYLYDOZLWKPHGLDQGLVHDVHVSHFL¿FVXUYLYDO of 33 months for cytoplasmic mTOR positive patients compared to 24 months for cytoplasmic mTOR negative patients. Other protein failed to GHPRQVWUDWHVLJQL¿FDQWFRUUHODWLRQZLWKGLVHDVHVSHFL¿FPRUWDOLW\ CONCLUSIONS: The PI3K pathway is activated downstream to the level of the translational protein p-70S6 in RCC metastases, supporting a therapeutic role for PI3K pathway inhibitors. PI3K and F\WRSODVPLF P725 VKRZHG VLJQL¿FDQW DVVRFLDWLRQV ZLWK SDWKRORJLF features and survival respectively and hence can be used to LGHQWLI\ SDWLHQWV WKDW PD\ EHQH¿W IURP DQWLWXPRU WKHUDS\ ZLWK P725 inhibitors. Source of Funding: None
NEAR INFRARED FLUORESCENCE OF INTRAVENOUS INDOCYANINE GREEN FOR INTRAOPERATIVE IMAGING OF RENAL CORTICAL TUMORS: A COMPLETED FEASIBILITY STUDY Dragan J Golijanin*, Jonah Marshall, Allison Cardin, Eric A Singer, Ralph R Madeb, Ronald W Wood, Jay E Reeder, Guan Wu, Jorge L Yao, Edward M Messing. Rochester, NY. INTRODUCTION AND OBJECTIVE: Successful partial nephrectomy for the treatment of renal cancer is predicated on attaining negative surgical margins while preserving normal parenchyma. To help determine intraoperative margin status, we studied if renal cortical tumors can be safely differentiated from normal parenchyma by near infrared ÀXRUHVFHQFH 1,5) RILQWUDYHQRXVLQRGF\DQLQHJUHHQ ,9,&* METHODS: 17 patients (one had bilateral surgery) underwent radical (2) or partial (16) nephrectomy with NIRF intraoperative imaging of their 18 renal tumors after IV injection of ICG. After kidney exposure, 7-10cc (2.5mg/ml) of ICG was injected IV and shortly after, NIRF was detected using LUNATM system (Novadaq Technologies Inc, Mississauga, Canada), and its uptake and deposition recorded. RESULTS: No immediate allergic or systemic side effects occurred and no postoperative changes in liver or kidney function were observed. All tumor and non-tumorous lesions were clearly delineated E\ 1,5) LQ RXU SDWLHQWV XQGHUJRLQJ SDUWLDO QHSKUHFWRP\7XPRU VL]H averaged 4.1cm (1.1-11). A total of 27 lesions were found in 18 kidneys exposed, 19 solid and 8 cystic. All malignant tumors (clear cell (9), papillary (4), chromophobe (2) and cystic renal cell carcinoma (2) ZHUHVHHQDVK\SRÀXRUHVFHQWDUHDVZKLFKZHUHFOHDUO\GHPDUFDWHG from the surrounding normal parenchyma. Oncocytoma (2) was seen as hypofluorescent area but with minimal difference from normal parenchyma comparing to clear cell renal carcinoma which was nearly QRQÀXRUHVFHQW%HQLJQF\VWV ZHUHFKDUDFWHUL]HGZLWKDQLQFUHDVHG ÀXRUHVFHQFHFRPSDUHGWRWKHQRUPDOSDUHQFK\PD6LPSOHWKLFNZDOOHG cyst (1) had similar characteristics to normal parenchyma. Clear cell FDUFLQRPDVGXULQJUDGLFDOQHSKUHFWRPLHV ZHUHQRWYLVXDOL]HGZHOO VHFRQGDU\WRWKHWKLFNOD\HURISHULQHSKULFIDW1,5)PLFURVFRS\FRQ¿UPHG ,&*SUHVHQFHLQQRUPDOSDUHQFK\PDDQGGHFUHDVHGÀXRUHVFHQFHLQVLGH WKHWXPRURXVWLVVXH+ (ZDVFRUUHODWHGWR1,5)PLFURVFRS\FRQ¿UPLQJ DFFXUDWHO\GLIIHUHQWGHSRVLWLRQRI,&*DQGÀXRUHVFHQFHLQWXPRUYHUVXV normal renal tissue. All margins were negative. CONCLUSIONS: No adverse events were observed related to ICG administration and use of LUNA imaging system. We also observed that NIRF after IV ICG permits accurate intraoperative detection of renal cortical tumors during partial nephrectomy. Source of Funding: Novadaq Technologies, Inc., Mississauga, Canada.
599 INCREASING TUMOR SIZE IS ASSOCIATED WITH HIGHER RATES OF HIGH FUHRMAN NUCLEAR GRADE IN PATIENTS WITH RENAL CELL CARCINOMA Claudio Jeldres*, Nazareno Suardi, Naeem Bhojani, Jean-Jacques 3DWDUG.DULP%HQVDODK5DI¿$YDNLDQ9LQFHQ]R)LFDUUD7RPPDVR Prayer-Galetti, Luca Cindolo, Alexandre de la Taille, Laurent Salomon, Peter F Mulders, Jacques Tostain, Richard Zigeuner, Denis Chautard, Antoine Valeri, Eric Lechevallier, Jean-Luc Descotes, Herve Lang, Arnaud Mejean, Roberto Bertini, Francesco Montorsi, Pierre I Karakiewicz. Montreal, QC, Canada, Rennes, France, Padova, Italy, Benevento, Italy, Creteil, France, Nijmegen, The Netherlands, Saint Etienne, France, Graz, Austria, Angers, France, Paris, France, and Milan, Italy. INTRODUCTION AND OBJECTIVE: Active surveillance as EHHQXVHGLQVHOHFWHGSDWLHQWVZLWKVPDOOORFDOL]HGUHQDOPDVVHV6LQFH KLJK)XKUPDQQXFOHDUJUDGHGH¿QHGDVJUDGH,,,RU,9LVDVVRFLDWHGZLWK XQIDYRUDEOHRXWFRPHVZHDVVHVVWKHHIIHFWRIWXPRUVL]HRQWKHUDWHRI Fuhrman grade III-IV in patients who underwent nephron-sparing surgery (NSS) and radical nephrectomy (RN) for renal cell carcinoma. METHODS: Between 1984 and 2001, 2476 patients were treated for renal cell carcinoma in thirteen academic centers in Europe. Univariable and multivariable logistic regression analyses addressed WKHSUHVHQFHRI)XKUPDQJUDGH,,,,9DW¿QDOSDWKRORJ\DFFRUGLQJWR
Vol. 179, No. 4, Supplement, Monday, May 19, 2008
WKHWXPRUVL]H&RYDULDWHVFRQVLVWHGRIDJH7VWDJHDQGV\PSWRPVDW GLDJQRVLV7XPRUVL]HZDVFRGHGDVFXELFVSOLQHV WRDOORZQRQOLQHDU effect). RESULTS: The age mean and median were 60 years and 61 years, respectively (range 18-93). Of all, 1991 (80.4%) patients were T1 stage and 485 (19.6%) patients were T2 stage tumors. Mean DQGPHGLDQWXPRUVL]HYDOXHVZHUHFPDQGFPUHVSHFWLYHO\ (range 0.5-21.0). Of all, 1625 (65.6%) were male. At diagnosis, 1776 (71.7%) patients were asymptomatic. The rate of Fuhrman grade III-IV LQFUHDVHG ZLWKWXPRUVL]H ZKHUH WXPRUV FP FP FP cm, 4-5 cm, 5-6 cm, 6-7 cm and >7cm were associated with rates of Fuhrman grade III-IV of 0.4%, 3.7%, 11.2%, 14.8%, 15.9%, 12.5%, 11.2%, 30.3%, respectively. In univariable and multivariable analyses LQFUHDVLQJWXPRUVL]HZDVDVVRFLDWHGZLWKKLJKHUULVNRI)XKUPDQJUDGH ,,,,9DW¿QDOSDWKRORJ\7KHPXOWLYDULDEOHFXELFVSOLQHDQDO\VHVVKRZHG that the rate of Fuhrman grade III-IV markedly increased up to a tumor VL]HRIFP S DQGWKHQÀDWWHQHG &21&/86,216 7XPRU VL]H SUHGLFWV WKH UDWH RI )XKUPDQ grade III-IV up to 7 cm and may be used as an indicator of nuclear grade.
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p<0.01). In clinical renal cancer tissue, survivin expression was DVVRFLDWHGVLJQL¿FDQWO\ZLWKGLVWDQWPHWDVWDVLVVWDJH 0 0 S 6XUYLYLQ%JHQHH[SUHVVLRQOHYHOZDVDVVRFLDWHGVLJQL¿FDQW\ with T stage (pT1: pT2: pT3= 1:1.15:4.50, p=0.04). Althrough, not VKRZLQJ VLJQL¿FDQW DVVRFLDWLRQ WKH UDWLR RI VXUYLYLQ %VXUYLYLQ LQ metastasis stage (M1) was lower than that in no metastasis stage(M0) (M0:M1=5.35:1,p=0.23). &21&/86,216 7KHVH¿QGLQJVVXJJHVWHGWKDWVXUYLYLQDQG LWVVSOLFHGLVRIRUPVKDGVLJQL¿FDQWDVVRFLDWLRQVZLWKUHQDOFDQFHUFHOO proliferation and distant metastases. And the elimination of survivin would be a potential candidate for a novel approach to treat renal cancer.
Source of Funding: None
601
Source of Funding: None
600 SURVIVIN AND ITS SPLICED ISOFORMS GENE EXPRESSION IS ASSOCIATED WITH PROLIFERATION OF RENAL CANCER CELLS AND CLINICAL STAGE OF RENAL CANCER Hidekazu Koike*, Keigo Okamura, Yoshitaka Sekine, Kazuhiro Suzuki. Maebashi, Japan. INTRODUCTION AND OBJECTIVE: Survivin has been implicated in both the control of cell division and inhibition of apoptosis. 7RGDWHDOWHUQDWLYHO\VSOLFHGLVRIRUPV6XUYLYLQĮ%([%KDYH been described. We assessed the effect of survivin gene expression on the proliferation of renal cancer cells, and studied the association of suvivin and its spliced isoforms gene expression levels with clinical stage of renal cancer. METHODS: Gene expression of survivin and its spliced isoforms in renal cancer cells, Caki-1 were performed by RT-PCR. We knocked down the gene expression of survivin using small interfering RNA (siRNA), and assessed the cell proliferation by MTS assay. Next, ZHTXDQWL¿HGWKHJHQHH[SUHVVLRQOHYHOVRIVXUYLYLQDQGLWVLVRIRUPV in nephrectomy samples(27 patients) using quantitative real-time PCR method. 5(68/76 ,Q&DNLFHOOVVXUYLYLQDQGVXUYLYLQĮ%ZHUH expressed higher than that of survivin-Ex3. In the cells, gene expression OHYHOV RI VXUYLYLQ P51$ ZHUH VLJQL¿FDQWO\ GHFUHDVHG E\ WUDQVIHFWLRQ of siRNA against survivin. Decrease of survivin gene expression was accompanied by inhibition of cell proliferation of renal cancer cells. ,QFDNLFHOOVYLDEOHFHOOQXPEHUVZHUHVLJQL¿FDQWO\GHFUHDVHGDIWHU 96h of siRNA treatement (36% decrease in Caki-1 cells, respectively.
EARLY AND NONINVASIVE DIAGNOSIS OF RENAL CELL CARCINOMA USING 1H-NMR-BASED METABONOMICS Bai-Jun Dong*, Hong-Chang Gao, Han-Qing Xuan, Xia Liu, Dong-Hai Lin, Yi-Ran Huang. Shanghai, China. INTRODUCTION AND OBJECTIVE: Renal cell carcinoma (RCC) is one of the most lethal urologic malignancies. Prognosis for RCC varies considerably depending on the disease stage at diagnosis. 7KRVHGLDJQRVHGHDUO\ZLWKRUJDQFRQ¿QHGWXPRXUVKDYHDQ 5-yr survival rate but only 5-10% for those with metastatic disease. 7KHUHLVFXUUHQWO\QRELRÀXLGVFUHHQLQJWHVWVH[LVWIRU5&&DQGXSWR one-third of patients are initially diagnosed with advanced disease. 1H NMR based metabonomics has been well-established to be a powerful technique for investigating the metabolic state of various biological ÀXLGVIRUH[SORULQJSDWKRORJLFDOPHWDEROLFDWWKHPROHFXODUOHYHO,QWKLV study, we have undertaken 1H-NMR-based metabonomics on serum VSHFLPHQVWRFKDUDFWHUL]HWKHPHWDEROLFSUR¿OLQJRI5&&IRUHDUO\DQG noninvasive diagnosis. METHODS: The serum samples from the 71 RCC patients including 49 local and 22 advanced cases and 55 healthy volunteers were examined by high-resolution 1H NMR spectroscopy. All NMR VSHFWUDZHUHDQDO\]HGE\WKHPHDQVRISULQFLSDOFRPSRQHQWDQDO\VLV (PCA) for multivariate pattern recognition in order to differentiate local and advanced cases, cases before and after nephrectomy in comparison with healthy humans, and to identify the metabolites responsible for the discrimination. RESULTS: The RCC patients, can be well distinguished from the healthy humans(Figure in addition), even in their early stage. The patients with metastases can be distinctly differentiated from those without metastases. And the patients after nephrectomy can be discriminated from those before nephrectomy. Systemic changes of metabolite concentrations between RCC patients and healthy human are most likely the result of the cells switched to glycolysis to maintain energy homeostasis with a manifestation of higher levels of lipid, lactate, pyruvate, and glycerol, but declined levels of phosphatidylcholine/ choline, glutamine, acetoacetate, and glucose/glycogen. And the systemic changes can be somewhat reversed after nephrectomy. CONCLUSIONS: Serum NMR spectra in combination with