- Email: [email protected]
PI-08 COMBINING URINE PCA3 AND TMPRSS2: ERG TESTS TO REFINE PROSTATE CANCER DETECTION – VALIDATION STUDY AND HEALTH ECONOMIC ANALYSIS
e982
THE JOURNAL OF UROLOGYâ
Source of Funding: Genitourinary SPORE in Bladder Cancer P50CA091846
Vol. 193, No. 4S, Supplement, Tuesday, May 19, 2015
score) and disease features (symptoms, laterality, tumor size, thrombus level). RESULTS: Surgical-site related complications (39%), postoperative fever (11%), adynamic ileus (9%), pneumothorax (4%), coagulopathy (4%), pancreatitis (2.3%), and pulmonary embolism (2%) were the most frequently seen complications. Major postoperative complications (Clavien-Dindo grades III-V) were seen in 46 patients in this series (22%). The in-hospital mortality was 4%. Surgical variables influencing the rise of perioperative complications were: type of incision (.000), surgical approach (.000), regional lymphadenectomy (.021), IVC resection (.033), IVC replacement (.006) and use of extracorporeal circulation (.000). Overall and major postoperative complication rates were lower in the transplant-based surgical approach group; OR¼0.19, 95%CI (0.096-0.374); p¼.000 and OR¼0.21, 95%CI (0.099-0.480); p¼.000, respectively. CONCLUSIONS: A tailored surgical approach based on different maneuvers derived from transplant surgery may improve complication rates after radical nephrectomy and tumor thrombectomy by increasing the exposure in the operative field, facilitating tumor and thrombus removal and avoiding the use of ancillary techniques in the excision. Source of Funding: none
PI-08 PI-07 A TRANSPLANT-BASED SURGICAL APPROACH MAY IMPROVE POSTOPERATIVE COMPLICATIONS IN CASES OF RENAL CELL CARCINOMA AND TUMOR THROMBUS s, Javier Gonza lez*, Juan I. Martínez-SalaEstefania Linares Espino manca, Madrid, Spain; Giacomo Novara, Padua, Italy; Roberto Bertini, Milan, Italy; Joaquín Carballido, Madrid, Spain; Thomas Chromecki, Graz, Germany; Gaetano Ciancio, Miami, FL; Siamak Daneshmand, Los Angeles, CA; Christopher Evans, Sacramento, CA; Paolo Gontero, Turin, Italy; Alex Haferkamp, Frankfurt, Germany; Markus Hohenfellner, Heidelberg, Germany; William C. Huang, New York, NY; Theresa Koppie, Portland, OR; Danny Lascano, New York, NY; Adam Lorentz, Atlanta, GA; Alon Y. Mass, New York, NY; Viraj Master, Atlanta, GA; James McKiernan, New York, NY; Carmen Mir, Miami, FL; Carrie Mlynarczyk, New York, NY; Francesco Montorsi, Milan, Italy; Hao Nguyen, Sacramento, CA; Sascha Pahernik, Heidelberg, Germany; Juan Palou, Barcelona, Spain; Raj Pruthi, Chapel Hill, NC; Oscar Rodríguez-Faba, Barcelona, Spain; Paul Russo, Douglas S. Scherr, New York, NY; Shahrokh Shariat, Vienna, Austria; Martin Spahn, Wuzburg, Germany; Carlo Terrone, Novara, Italy; Derya Tilki, Sacramento, CA; Daniel Vergho, Wuzburg, Germany; Eric Wallen, Chapel Hill, NC; Richard Zigeuner, Graz, Austria; John A. Libertino, Burlington, MA INTRODUCTION AND OBJECTIVES: Radical nephrectomy and tumor thrombectomy remains the only potential cure in renal cell carcinoma (RCC) with intravenous tumor thrombus. However, postperative complication (PC) rates are still far from optimal after this procedure. Surgical technique may influence the rise of PCs in this setting. The aims of this study were to identify operative variables influencing the rise of PCs, and to compare two different surgical approaches in terms of PC in this setting. METHODS: A central database was created by an international consortium of 22 Institutions, including data of patients who underwent radical nephrectomy and tumor thrombectomy for RCC from 19712012. A total of 189 cases were included, and grouped according to the surgical approach used: transplant-based vs. no transplant-based. Transplant-based approach (n¼89) included the use of a trirradiate Chevron incision, Rochard retractor and posterior access to the renal artery, together with a set of visceral mobilization maneuvers derived from the field of transplant surgery. A propensity score matched analysis was performed for the selection of non transplant-based cases (n¼100). Covariates for paired analysis included patient demographics (sex, age, race), comorbid status (Charlson Comorbidity Index, ASA
COMBINING URINE PCA3 AND TMPRSS2: ERG TESTS TO REFINE PROSTATE CANCER DETECTION e VALIDATION STUDY AND HEALTH ECONOMIC ANALYSIS Martin Sanda*, Atlanta, GA; Ziding Feng, Houston, TX; John Wei, Ann Arbor, MI; David Howard, Atlanta, GA; Mark Rubin, New York, NY; Jack Groskopf, San Diego, CA; Lori Sokoll, Daniel Chan, Baltimore, MD; Meredith Regan, Boston, MA; Dattatraya Patil, Atlanta, GA; Simpa Salami, Manhasset, NY; Javed Siddiqui, Ann Arbor, MI; Douglas Scherr, New York, NY; Jacob Kagan, Sudhir Srivastava, Bethesda, MD; Ian Thompson, San Antonio, TX; Aaron Joon, Houston, TX; Arul Chinnayian, Scott Tomlins, Ann Arbor, MI INTRODUCTION AND OBJECTIVES: To evaluate the performance of urinary RNA testing as a strategy to reduce unnecessary prostate biopsy and over-detection while enhancing detection of aggressive prostate cancer (PCa), and to assess potential health economic impact of such a strategy to improve selection of men to undergo prostate biopsy to detect cancer. METHODS: A prospective multi-center study was conducted to develop a strategy for combining urinary assays detecting TMPRSS2:Erg fusion (T:Erg) and PCA3 to refine detection of aggressive PCa (Gleason score 7 or higher). Multivariable models using 10fold cross validation were constructed to identify optimal cut-points for urine RNA assays to optimize specificity while maintaining at least 95% sensitivity for detecting aggressive PCa. Findings were validated in a separate multi-center cohort. Economic impact of the urinary RNA testing strategy for selecting men to undergo prostate biopsy was evaluated by cost modeling. RESULTS: The primary cohort had 516 subjects from 3 clinical sites; the validation cohort was comprised of 561 subjects from 10 clinical sites(total N ¼ 1077). Prostate biopsy in the primary cohort showed 262 (50.8%) of the men had no PCa; 98 (19%) had PCa with Gleason score ¼ 6; and 156 (30%) had Gleason score 7 or higher. Urinary PCA3 and TMPRSS2:Erg scores were significantly associated with presence of aggressive PCa (Gleason >7; Figure). When sensitivity in detecting aggressive PCa was set to 95%, the optimal cutpoints for urinary T;erg and PCA3 were 7.6 and 19.1, respectively, and this combination improved specificity for detection of aggressive prostate cancer from 18% to 39%, and enables avoiding 49% of unnecessary biopsies. Validation cohort analysis confirmed improvement of specificity from 16% to 33% (p¼ 0.04) while retaining high sensitivity (93%). Cost impact analysis showed reduction of lifetime healthcare costs by use of this urinary testing to refine selection of men for prostate biopsy among men 55 to 64 years of age (Table).
THE JOURNAL OF UROLOGYâ
Vol. 193, No. 4S, Supplement, Tuesday, May 19, 2015
CONCLUSIONS: Use of combined urinary testing for TMPRSS2:Erg and PCA3 to determine who should undergo prostate biopsy can avert unnecessary biopsy in 49% of men while retaining 95% sensitivity in detecting aggressive PCa with consequent lifetime cost savings evident among men less than 65 years of age.
e983
METHODS: We treated VHL-/-mutant zebrafish that recapitulate aspects of human VHL disease with HIF2a inhibitors and score their effect on erythrocytosis, vascular proliferation and survival. In addition, we treated mice xenografted subcutaneously or orthotopically with human ccRCC cell lines with HIF2a inhibitors. Tumor growth and HIF2a activity were monitored by chemiluminescence. Finally, we tested the effect of HIF2a inhibitors on the metastatic potential of human ccRCC implanted orthotopically in mice. RESULTS: Treatment of VHL-/- zebrafish embryos with the small molecule HIF-2a inhibitor 76 potently down-regulated the expression of HIF-target genes, decreased erythrocytosis, inhibited vascular proliferation and improved early survival. Treatment of mice with compound 76 (15mg/kg three times daily) significantly decreased HIF2a activity in human ccRCC lines implanted subcutaneously as well as their growth as tumors. The effect of HIF2a inhibitors on the growth and metastasis of human ccRCC cells after orthotopic injection in mice is currently investigated and the results will be presented. CONCLUSIONS: Our data demonstrate that IRP1-based HIF2a inhibitors are active in vivo both in the zebrafish model of human VHL disease and mouse model of ccRCC. Current studies will further evaluate the effect of HIF2a inhibitors on the growth and metastasis of ccRCC in preclinical animal models. Source of Funding: none
PI-10 DECLINING RATES OF RETROPERITONEAL LYMPH NODE DISSECTION FOR STAGE I NON-SEMINOMATOUS GERM CELL TUMORS: RESULTS FROM THE NATIONAL CANCER DATABASE
Cost Impact of Urinary TMPRSS2:erg and PCA3 Testing on Lifetime Cost of Care among Men with Abnormal Prostate Screening* Level of Access to Health Care
Lifetime Health Care Cost Differential PCA3+T:Erg Urine Test Compared to PSA-prompted Biopsy
Lifetime Health Care Cost Differential PCA3+T:Erg Urine Test Compared to No Biopsy (USPSTF Standard)
55-64
Poor Access to Care
-$1500
+$7900
55-64
Effective Access to Care
-$800
-$2800
65-74
Poor Access to Care
-$1700
+$11700
65-74
Effective Access to Care
-$1200
+$4500
Age (Yrs)
* Men being considered for prostate biopsy due to abnormal PSA or DRE
Source of Funding: NCI EDRN U01
PI-09 PRECLINICAL TESTING OF SMALL MOLECULE HIF2a INHIBITOR IN ZEBRAFISH AND MOUSE MODELS OF VHL-DEFICIENT RENAL CELL CARCINOMA. Meike Schneider*, Ana Metelo, Haley Noonan, Xiang Li, Jing Youngnam, Nick Olson, Rania Baker, Charlestown, MA; Lee Kamentsky, Cambridge, MA; Yiyun Zhang, Charlestown, MA; Anne Carpenter, Cambridge, MA; Jing-Ruey Yeh, Randall Peterson, Othon Iliopoulos, Charlestown, MA INTRODUCTION AND OBJECTIVES: Hypoxia inducible factor 2a (HIF2a) target genes promote angiogenesis, metabolism and stem cell proliferation. The von Hippel-Lindau (VHL) tumor suppressor protein targets HIF2a for degradation under normoxic conditions. Loss-ofVHL leads to constitutive expression of HIF2a and it is the earliest molecular lesion of 90% of clear cell Renal Cell Carcinoma (ccRCC). We discovered small molecules that repress HIF2a translation by enhancing the binding of Iron-Regulatory Protein 1 to the IronResponsive Element within the 50 -UTR of HIF-2a mRNA. These small molecules specifically down-regulate HIF-2a expression in vitro as well as in the VHl-/- zebrafish model in vivo. Our objective was to test the effect of HIF2a inhibitors in the VHL-/- zebrafish phenotype and in the xenograft mouse model of RCC.
Mohammed Haseebuddin*, Elizabeth Handorf, Alexander Kutikov, Nikhil Wainganker, Yu-Ning Wong, Elizabeth Plimack, Robert Uzzo, Marc Smaldone, Philadelphia, PA INTRODUCTION AND OBJECTIVES: Per existing best practice guidelines, careful observation with serial imaging (active surveillance) or primary chemotherapy have supplanted primary retroperitoneal lymph node dissection (RPLND) for stage I non-seminomatous germ cell tumors (NSGCT). Hypothesizing that rates of primary RPLND have declined over the past decade, our objective was to assess temporal trends in primary treatment for stage I NSGCT using a large national cancer registry. METHODS: The National Cancer Database (NCDB) was queried for all patients diagnosed with stage I NSGCT from 1998-2011. Temporal trends for receipt of primary RPLND, chemotherapy, or observation (defined as no treatment) were assessed. Adjusting for patient, demographics (age, ethnicity, race, insurance status, education, income, geographic location), and clinicopathologic characteristics (stage), multivariable logistic models were used to examine the association between available covariates and receipt of primary RPLND. RESULTS: Of 15,822 patients identified over the study period, 9001 (56.9%), 2937 (18.6%), and 3884 (24.5%) underwent observation, RPLND, and chemotherapy respectively. While rates of observation minimally changed over time (56.3 to 55.0%, p¼0.85), a significant decrease in utilization of RPLND (23.0 to 12.4%, p<0.001) was matched by a significant increase in receipt of primary chemotherapy (20.7 to 32.5%, p<0.001). Rates of RPLND declined across all age groups-age < 30 (24.3% to 12.1%, P<0.0001), age 30-39 (21.6% to 13.8%, p <0.0001), age 40-49 (23.1% to 11.4%, p<0.0001), age>50 (20.0% to 11.7%, p ¼ 0.02). Following adjustment, stage T2 (OR 0.79 [CI 0.72-0.87]) and T3 (OR 0.33 [CI 0.24-0.96]), and age categories 4049 years (OR 0.83 [CI 0.72-0.94]) and 50 years (OR 0.66 [CI 0.520.82]) were associated with decreased utilization of RPLND. CONCLUSIONS: In hospitals reporting to the NCDB, utilization of primary RPLND for stage I NSGCT has significantly decreased over the last decade, while receipt of primary chemotherapy has increased over the same period. While employed in more than 50% of patients, rates of observation remain unchanged. Source of Funding: None
THE JOURNAL OF UROLOGYâ
Source of Funding: Genitourinary SPORE in Bladder Cancer P50CA091846
Vol. 193, No. 4S, Supplement, Tuesday, May 19, 2015
score) and disease features (symptoms, laterality, tumor size, thrombus level). RESULTS: Surgical-site related complications (39%), postoperative fever (11%), adynamic ileus (9%), pneumothorax (4%), coagulopathy (4%), pancreatitis (2.3%), and pulmonary embolism (2%) were the most frequently seen complications. Major postoperative complications (Clavien-Dindo grades III-V) were seen in 46 patients in this series (22%). The in-hospital mortality was 4%. Surgical variables influencing the rise of perioperative complications were: type of incision (.000), surgical approach (.000), regional lymphadenectomy (.021), IVC resection (.033), IVC replacement (.006) and use of extracorporeal circulation (.000). Overall and major postoperative complication rates were lower in the transplant-based surgical approach group; OR¼0.19, 95%CI (0.096-0.374); p¼.000 and OR¼0.21, 95%CI (0.099-0.480); p¼.000, respectively. CONCLUSIONS: A tailored surgical approach based on different maneuvers derived from transplant surgery may improve complication rates after radical nephrectomy and tumor thrombectomy by increasing the exposure in the operative field, facilitating tumor and thrombus removal and avoiding the use of ancillary techniques in the excision. Source of Funding: none
PI-08 PI-07 A TRANSPLANT-BASED SURGICAL APPROACH MAY IMPROVE POSTOPERATIVE COMPLICATIONS IN CASES OF RENAL CELL CARCINOMA AND TUMOR THROMBUS s, Javier Gonza lez*, Juan I. Martínez-SalaEstefania Linares Espino manca, Madrid, Spain; Giacomo Novara, Padua, Italy; Roberto Bertini, Milan, Italy; Joaquín Carballido, Madrid, Spain; Thomas Chromecki, Graz, Germany; Gaetano Ciancio, Miami, FL; Siamak Daneshmand, Los Angeles, CA; Christopher Evans, Sacramento, CA; Paolo Gontero, Turin, Italy; Alex Haferkamp, Frankfurt, Germany; Markus Hohenfellner, Heidelberg, Germany; William C. Huang, New York, NY; Theresa Koppie, Portland, OR; Danny Lascano, New York, NY; Adam Lorentz, Atlanta, GA; Alon Y. Mass, New York, NY; Viraj Master, Atlanta, GA; James McKiernan, New York, NY; Carmen Mir, Miami, FL; Carrie Mlynarczyk, New York, NY; Francesco Montorsi, Milan, Italy; Hao Nguyen, Sacramento, CA; Sascha Pahernik, Heidelberg, Germany; Juan Palou, Barcelona, Spain; Raj Pruthi, Chapel Hill, NC; Oscar Rodríguez-Faba, Barcelona, Spain; Paul Russo, Douglas S. Scherr, New York, NY; Shahrokh Shariat, Vienna, Austria; Martin Spahn, Wuzburg, Germany; Carlo Terrone, Novara, Italy; Derya Tilki, Sacramento, CA; Daniel Vergho, Wuzburg, Germany; Eric Wallen, Chapel Hill, NC; Richard Zigeuner, Graz, Austria; John A. Libertino, Burlington, MA INTRODUCTION AND OBJECTIVES: Radical nephrectomy and tumor thrombectomy remains the only potential cure in renal cell carcinoma (RCC) with intravenous tumor thrombus. However, postperative complication (PC) rates are still far from optimal after this procedure. Surgical technique may influence the rise of PCs in this setting. The aims of this study were to identify operative variables influencing the rise of PCs, and to compare two different surgical approaches in terms of PC in this setting. METHODS: A central database was created by an international consortium of 22 Institutions, including data of patients who underwent radical nephrectomy and tumor thrombectomy for RCC from 19712012. A total of 189 cases were included, and grouped according to the surgical approach used: transplant-based vs. no transplant-based. Transplant-based approach (n¼89) included the use of a trirradiate Chevron incision, Rochard retractor and posterior access to the renal artery, together with a set of visceral mobilization maneuvers derived from the field of transplant surgery. A propensity score matched analysis was performed for the selection of non transplant-based cases (n¼100). Covariates for paired analysis included patient demographics (sex, age, race), comorbid status (Charlson Comorbidity Index, ASA
COMBINING URINE PCA3 AND TMPRSS2: ERG TESTS TO REFINE PROSTATE CANCER DETECTION e VALIDATION STUDY AND HEALTH ECONOMIC ANALYSIS Martin Sanda*, Atlanta, GA; Ziding Feng, Houston, TX; John Wei, Ann Arbor, MI; David Howard, Atlanta, GA; Mark Rubin, New York, NY; Jack Groskopf, San Diego, CA; Lori Sokoll, Daniel Chan, Baltimore, MD; Meredith Regan, Boston, MA; Dattatraya Patil, Atlanta, GA; Simpa Salami, Manhasset, NY; Javed Siddiqui, Ann Arbor, MI; Douglas Scherr, New York, NY; Jacob Kagan, Sudhir Srivastava, Bethesda, MD; Ian Thompson, San Antonio, TX; Aaron Joon, Houston, TX; Arul Chinnayian, Scott Tomlins, Ann Arbor, MI INTRODUCTION AND OBJECTIVES: To evaluate the performance of urinary RNA testing as a strategy to reduce unnecessary prostate biopsy and over-detection while enhancing detection of aggressive prostate cancer (PCa), and to assess potential health economic impact of such a strategy to improve selection of men to undergo prostate biopsy to detect cancer. METHODS: A prospective multi-center study was conducted to develop a strategy for combining urinary assays detecting TMPRSS2:Erg fusion (T:Erg) and PCA3 to refine detection of aggressive PCa (Gleason score 7 or higher). Multivariable models using 10fold cross validation were constructed to identify optimal cut-points for urine RNA assays to optimize specificity while maintaining at least 95% sensitivity for detecting aggressive PCa. Findings were validated in a separate multi-center cohort. Economic impact of the urinary RNA testing strategy for selecting men to undergo prostate biopsy was evaluated by cost modeling. RESULTS: The primary cohort had 516 subjects from 3 clinical sites; the validation cohort was comprised of 561 subjects from 10 clinical sites(total N ¼ 1077). Prostate biopsy in the primary cohort showed 262 (50.8%) of the men had no PCa; 98 (19%) had PCa with Gleason score ¼ 6; and 156 (30%) had Gleason score 7 or higher. Urinary PCA3 and TMPRSS2:Erg scores were significantly associated with presence of aggressive PCa (Gleason >7; Figure). When sensitivity in detecting aggressive PCa was set to 95%, the optimal cutpoints for urinary T;erg and PCA3 were 7.6 and 19.1, respectively, and this combination improved specificity for detection of aggressive prostate cancer from 18% to 39%, and enables avoiding 49% of unnecessary biopsies. Validation cohort analysis confirmed improvement of specificity from 16% to 33% (p¼ 0.04) while retaining high sensitivity (93%). Cost impact analysis showed reduction of lifetime healthcare costs by use of this urinary testing to refine selection of men for prostate biopsy among men 55 to 64 years of age (Table).
THE JOURNAL OF UROLOGYâ
Vol. 193, No. 4S, Supplement, Tuesday, May 19, 2015
CONCLUSIONS: Use of combined urinary testing for TMPRSS2:Erg and PCA3 to determine who should undergo prostate biopsy can avert unnecessary biopsy in 49% of men while retaining 95% sensitivity in detecting aggressive PCa with consequent lifetime cost savings evident among men less than 65 years of age.
e983
METHODS: We treated VHL-/-mutant zebrafish that recapitulate aspects of human VHL disease with HIF2a inhibitors and score their effect on erythrocytosis, vascular proliferation and survival. In addition, we treated mice xenografted subcutaneously or orthotopically with human ccRCC cell lines with HIF2a inhibitors. Tumor growth and HIF2a activity were monitored by chemiluminescence. Finally, we tested the effect of HIF2a inhibitors on the metastatic potential of human ccRCC implanted orthotopically in mice. RESULTS: Treatment of VHL-/- zebrafish embryos with the small molecule HIF-2a inhibitor 76 potently down-regulated the expression of HIF-target genes, decreased erythrocytosis, inhibited vascular proliferation and improved early survival. Treatment of mice with compound 76 (15mg/kg three times daily) significantly decreased HIF2a activity in human ccRCC lines implanted subcutaneously as well as their growth as tumors. The effect of HIF2a inhibitors on the growth and metastasis of human ccRCC cells after orthotopic injection in mice is currently investigated and the results will be presented. CONCLUSIONS: Our data demonstrate that IRP1-based HIF2a inhibitors are active in vivo both in the zebrafish model of human VHL disease and mouse model of ccRCC. Current studies will further evaluate the effect of HIF2a inhibitors on the growth and metastasis of ccRCC in preclinical animal models. Source of Funding: none
PI-10 DECLINING RATES OF RETROPERITONEAL LYMPH NODE DISSECTION FOR STAGE I NON-SEMINOMATOUS GERM CELL TUMORS: RESULTS FROM THE NATIONAL CANCER DATABASE
Cost Impact of Urinary TMPRSS2:erg and PCA3 Testing on Lifetime Cost of Care among Men with Abnormal Prostate Screening* Level of Access to Health Care
Lifetime Health Care Cost Differential PCA3+T:Erg Urine Test Compared to PSA-prompted Biopsy
Lifetime Health Care Cost Differential PCA3+T:Erg Urine Test Compared to No Biopsy (USPSTF Standard)
55-64
Poor Access to Care
-$1500
+$7900
55-64
Effective Access to Care
-$800
-$2800
65-74
Poor Access to Care
-$1700
+$11700
65-74
Effective Access to Care
-$1200
+$4500
Age (Yrs)
* Men being considered for prostate biopsy due to abnormal PSA or DRE
Source of Funding: NCI EDRN U01
PI-09 PRECLINICAL TESTING OF SMALL MOLECULE HIF2a INHIBITOR IN ZEBRAFISH AND MOUSE MODELS OF VHL-DEFICIENT RENAL CELL CARCINOMA. Meike Schneider*, Ana Metelo, Haley Noonan, Xiang Li, Jing Youngnam, Nick Olson, Rania Baker, Charlestown, MA; Lee Kamentsky, Cambridge, MA; Yiyun Zhang, Charlestown, MA; Anne Carpenter, Cambridge, MA; Jing-Ruey Yeh, Randall Peterson, Othon Iliopoulos, Charlestown, MA INTRODUCTION AND OBJECTIVES: Hypoxia inducible factor 2a (HIF2a) target genes promote angiogenesis, metabolism and stem cell proliferation. The von Hippel-Lindau (VHL) tumor suppressor protein targets HIF2a for degradation under normoxic conditions. Loss-ofVHL leads to constitutive expression of HIF2a and it is the earliest molecular lesion of 90% of clear cell Renal Cell Carcinoma (ccRCC). We discovered small molecules that repress HIF2a translation by enhancing the binding of Iron-Regulatory Protein 1 to the IronResponsive Element within the 50 -UTR of HIF-2a mRNA. These small molecules specifically down-regulate HIF-2a expression in vitro as well as in the VHl-/- zebrafish model in vivo. Our objective was to test the effect of HIF2a inhibitors in the VHL-/- zebrafish phenotype and in the xenograft mouse model of RCC.
Mohammed Haseebuddin*, Elizabeth Handorf, Alexander Kutikov, Nikhil Wainganker, Yu-Ning Wong, Elizabeth Plimack, Robert Uzzo, Marc Smaldone, Philadelphia, PA INTRODUCTION AND OBJECTIVES: Per existing best practice guidelines, careful observation with serial imaging (active surveillance) or primary chemotherapy have supplanted primary retroperitoneal lymph node dissection (RPLND) for stage I non-seminomatous germ cell tumors (NSGCT). Hypothesizing that rates of primary RPLND have declined over the past decade, our objective was to assess temporal trends in primary treatment for stage I NSGCT using a large national cancer registry. METHODS: The National Cancer Database (NCDB) was queried for all patients diagnosed with stage I NSGCT from 1998-2011. Temporal trends for receipt of primary RPLND, chemotherapy, or observation (defined as no treatment) were assessed. Adjusting for patient, demographics (age, ethnicity, race, insurance status, education, income, geographic location), and clinicopathologic characteristics (stage), multivariable logistic models were used to examine the association between available covariates and receipt of primary RPLND. RESULTS: Of 15,822 patients identified over the study period, 9001 (56.9%), 2937 (18.6%), and 3884 (24.5%) underwent observation, RPLND, and chemotherapy respectively. While rates of observation minimally changed over time (56.3 to 55.0%, p¼0.85), a significant decrease in utilization of RPLND (23.0 to 12.4%, p<0.001) was matched by a significant increase in receipt of primary chemotherapy (20.7 to 32.5%, p<0.001). Rates of RPLND declined across all age groups-age < 30 (24.3% to 12.1%, P<0.0001), age 30-39 (21.6% to 13.8%, p <0.0001), age 40-49 (23.1% to 11.4%, p<0.0001), age>50 (20.0% to 11.7%, p ¼ 0.02). Following adjustment, stage T2 (OR 0.79 [CI 0.72-0.87]) and T3 (OR 0.33 [CI 0.24-0.96]), and age categories 4049 years (OR 0.83 [CI 0.72-0.94]) and 50 years (OR 0.66 [CI 0.520.82]) were associated with decreased utilization of RPLND. CONCLUSIONS: In hospitals reporting to the NCDB, utilization of primary RPLND for stage I NSGCT has significantly decreased over the last decade, while receipt of primary chemotherapy has increased over the same period. While employed in more than 50% of patients, rates of observation remain unchanged. Source of Funding: None