bluuebunny/crossref_metadata_2025 huggingface dataset:
Contemporary evaluation of urography in diagnosis in patients with urothelial cell carcinoma.
Authors: Leliveld Anna Maria , Doornweerd Benjamin HJ , De Jong Igle
Published: February 2017

312

Background: Upper urinary tract tumors (UUTT) can occur synchronous or metachronous (0.7 – 6%) with bladder tumors. The optimal imaging technique of the upper urinary tract is unclear. Studies on the accuracy of retrograde pyelography (RUP) and comparative studies on detection level are sparse. In this study we evaluated the effectiveness of a first RUP in patients with a first manifestation of urothelial cell carcinoma (UCC) in the urinary tract. Methods: In this retrospective study we evaluated all consecutive patients with pathologic proven UCC who underwent their first RUP between March 1998 and April 2008 in the University Medical Center Groningen, Netherlands. Data regarding patient and tumor characteristics, results from RUPs, use of alternative imaging techniques, treatment and outcome were collected from the electronically patient’s records. Follow up was calculated from the first RUP to the last registrated visit. Descriptive statistics have been used to evaluate the performance of the RUP. Results: A total of 156 patients underwent a first RUP because of a first manifestation of UCC of the bladder or upper urinary tract. A mean follow up of 5.09 years was achieved (range 0-13 years). On 17 RUPs (11%) abnormalities were detected. In 16 patients a malignancy was diagnosed. Except one renal cell carcinoma all tumors were UCC of the renal pelvis, ureters or both. Muscle invasive tumors were diagnosed in 7 of these 17 patients. In 30 patients (19%) no conclusive results were obtained because of failure of the RUP due to technical difficulties. In 19 of 30 patients alternative imaging was performed, with intravenous pyelography in 11 patients, computer tomography urography in 7 patients and with both in 1 patient. No UUTTs were diagnosed in this group. In 109 (70%) patients whit a negative RUP three patients developed a tumor after 8, 52, and 65 months. The latter two we consider as newly developed lesions. Conclusions: RUP in patients with a first manifestation of UCC is a very sensitive and accurate diagnostic tool in detecting UUTT.
Perioperative management of radical cystectomy patients: A questionnaire survey of the American Urological Association members.
Authors: Truong Hong , Nix Jeffrey , Smith Kamal , Mittal Aayush , Agarwal Piyush
Published: February 2017

316

Background: Radical cystectomy (RC) is the standard treatment for patients with muscle invasive bladder cancer. RC is associated with more post-op complications and longer length of stay (LOS) after surgery than other urologic procedures. There is little information about peri-op pathways in the urologic literature. This study investigates practice patterns of urologists in the United States on peri-op management of bladder cancer patients undergoing RC. Methods: All AUA members were invited via email to an online survey from April to August 2012. The 31-items questionnaire of multiple choice and open-ended questions related to training, practice, and peri-op protocols. Results: A total of 375 urologists participated in the survey, 28.9% have oncology fellowship training, 46.4% training in robotic RC, and 30.1% perform robotics or laparoscopy. Of participants, 41.6% follow a clinical pathway however most utilize experience/training rather than an evidence-based protocol. Even with current evidence for enhanced recovery after surgery (ERAS) only 39.5% of respondents perform pre-op nutritional assessment. Most require a prolonged fast, no carbohydrate loading, and give all patients bowel prep pre-op. Most administer antibiotic prophylaxis before incision and continued 24 hrs, however only ~1/3 administer thromboprophylaxis pre-op, 15% give neither pre or post-op. Of respondents only 5% initiate a diet on post-op day (POD) 1 or before. 38.6% routinely send patients to ICU after surgery. Epidural, narcotics, or NSAIDs are commonly used for pain control, narcotics being the most common. Overall first flatus is reported on POD3 to 4, first bowel movement on POD4 to 5. Most patients are discharged on POD6 to 7. Urologists with oncology fellowship stated shorter LOS compared to those without (POD6.19 vs 6.64). Those doing open RC stated longer LOS compared to those doing robotic or laparoscopic RC (POD6.54 vs 6.03). Conclusions: ERAS studies have shown objective parameters that can improve peri-op outcomes. However, this survey shows significant individual differences in peri-op management of bladder cancer with the majority of urologists using personal experience as their primary guide.
A multi-institutional clinical trial of rectal dose reduction via injected polyethylene-glycol hydrogel during IMRT for prostate cancer: Analysis of dosimetric outcomes.
Authors: Song Danny Y. , Herfarth Klaus , Uhl Matthias , Eble Michael J. , Pinkawa Michael , Van Triest Baukelien , Kalisvaart Robin , Weber Damien C. , Miralbell Raymond , DeWeese Theodore L. , Ford Eric
Published: February 2017

35

Background: To characterize the effect of a prostate-rectum spacer on dose to rectum during external beam radiotherapy for prostate cancer, and to assess for factors correlated with rectal dose reduction. Methods: Fifty-two patients at 4 institutions were enrolled onto a prospective pilot clinical trial. Patients underwent baseline scans, then were injected with perirectal spacing hydrogel and re-scanned. IMRT plans were created on both scans for comparison. Objectives were to establish rates of creation of ≥7.5mm of prostate-rectal separation, and decrease in rectal V70 of ≥25%. Multiple regression analysis was performed to evaluate associations between pre- vs. post-injection changes in rectal V70 and changes in plan conformity, rectal volume, bladder volume, bladder V70, PTV volume, as well as post-injection mid-gland separation, gel volume, gel thickness, length of PTV/gel contact, or gel left-to-right symmetry. Results: Hydrogel resulted in > 7.5mm prostate-rectal separation in 95.8% of patients; 95.7% had decreased rectal V70 of > 25%, with mean reduction of 8.0 Gy. There were no significant differences in pre- and post-injection prostate, PTV, rectal, and bladder volumes. Plan conformities were significantly different pre- vs. post-injection (P = 0.02). In multiple regression analysis, change in plan conformity was negatively associated with reduction in V70 (P=0.01); plans with worse conformity indexes post-injection compared to pre-injection (n=13) still had improvements in rectal V70. Reductions in V70 did not significantly vary by institution, despite significant inter-institutional variations in plan conformity. There were no significant relationships between reduction in V70 and the other characteristics analyzed. Conclusions: Injection of hydrogel into prostate-rectal interface resulted in dose reductions to rectum for > 90% of patients treated. Rectal sparing was statistically significant across a range of 10-75 Gy, and was demonstrated within the presence of significant inter-institutional variability in plan conformity, target definitions, and injection results.
Association of mutations in chromatin modifiers with poor survival in clear cell renal cell carcinoma: Analysis of the Cancer Genome Atlas Project.
Authors: Hakimi A. Ari , Ostrovnaya Irina , Voss Martin Henner , Motzer Robert John , Russo Paul , Reuter Victor E. , Hsieh James
Published: February 2017

360

Background: We have previously shown that mutations in the epigenetic modifiers PBRM1, BAP1, SETD2 and KDM5C are associated with adverse tumor characteristics and, in some cases, worse cancer specific survival in clear cell renal cell carcinoma (ccRCC). We analyzed publically available data from the Cancer Genome Atlas Project (TCGA), to assess the impact of mutations in these genes on cancer-specific survival. Methods: We analayzed the genomic and clinical data from the TCGA cohort of 424 patients with primary ccRCC. The Kaplan-Meier method was used to estimate the survival probabilities, and log-rank test was used to test the univariate association between mutation status and overall survival. Cancer specific survival (CSS) was analyzed using the competing risk method. Multivariate Cox proportional hazard regression and competing risk models were also fitted to adjust for the validated Mayo Clinic SSIGN prognostic score. Results: Mutations in these epigenetic modifiers are frequent (PBRM1, 33.7%; SETD2, 11.6%; BAP1, 9.7%, KDM5C, 5.7%). BAP1 (p=0.002, HR 2.21 [1.34-3.62]), SETD2 (p=0.036, HR 1.68 [1.03-2.72]) and KDM5C (p=0.016, HR 2.18 [1.16-4.11]) are associated with worse CSS by competing risk. When adjusting for the prognostic SSIGN score, only mutations in KDM5C remain significant (p<0.0001 HR 4.03 [2.1-7.9]). On the contrary, PBRM1 mutations, the second most common gene mutations of ccRCC, have no impact on CSS. Conclusions: BAP1, SETD2 and KDM5C mutations are associated with worse CSS, suggesting their roles in disease progression. PBRM1 mutations do not impact CSS, implicating its principal role in the tumor initiation. Future efforts should focus on therapeutic interventions and further clinical, pathologic and molecular interrogation of this novel class of tumor suppressors.
Phase I study of high-dose interleukin 2, aldesleukin, in combination with the histone deacetylase inhibitor, entinostat, in patients with metastatic renal cell carcinoma: Safety and tolerability results.
Authors: Pili Roberto , Shen Li , George Saby , Hammers Hans J. , Sandecki Anita , Collins Connie , Carducci Michael Anthony
Published: February 2017

369

Background: Immunosuppressive factors such as regulatory T cells (Tregs) limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors have been shown to have anti-tumor activity in different malignancies and to induce immuno-modulatory effects. We have previously reported that a class I selective HDAC inhibitor, entinostat, has synergistic anti-tumor effects in combination with high dose interleukin-2 (IL-2) in a renal cell carcinoma model (Kato Y, et al. Clinical Cancer Res 2007). Our group has also recently shown that low dose entinostat induces STAT3 acetylation, down-regulates Foxp3 expression in Tregs, and blocks Tregs suppressive function without affecting T effector cells (Shen Li, et al. PLoSONE 2012). Methods: Based on these preclinical evidences, we have initiated a Phase I/II clinical study with entinostat and high dose IL-2 in patients (pts) with metastatic renal cell carcinoma. The primary objective of the phase I portion was to evaluate the safety and tolerability of this combination strategy. The main eligibility criteria were clear cell histology, no prior treatments, and being fit to receive high dose IL-2. Results: The phase I portion consisted of two dose levels of entinostat (3 and 5 mg) and a fixed standard dose of IL-2 (600,000 units/kg every 8 hrs) according to a 3+3 design. To date, dose level one and two have been completed without DLTs. No severe adverse events have been observed during the first 45 days of treatment. The most common transient grade 3/4 toxicities were hypophosphatemia and thrombocytopenia (6 pts), neutropenia and lymphopenia (2 pts). The 5 mg dose level has been expanded. To date we have enrolled eight eligible pts and six have completed one cycle (84 days) treatment with four achieving objective responses by RECIST criteria. Decreased Tregs and increased CD8 numbers have been observed in tumor biopsies following treatment. Conclusions: The results from the phase I portion suggest that entinostat can be given safely in combination with high dose IL-2. Preliminary results also show encouraging biological and efficacy data (R21CA137649; U0-1CA70095). Clinical trial information: NCT01038778.
Novel stratification of the recurrence risk following surgical extirpation of clear cell renal cell carcinoma using tissue biomarkers in the mammalian target of rapamycin pathway.
Authors: Darwish Oussama M. , Raj Ganesh , Youssef Ramy F. , Kapur Payal , Bagrodia Aditya , Belsante Michael , Lotan Yair , Margulis Vitaly
Published: February 2017

372

Background: Aberrant activation of the mammalian target of rapamycin (mTOR) pathway promotes invasiveness and metastatic potential in a variety of malignancies. The aim of the present study was to evaluate the association of altered expression of mTOR pathway components with recurrence outcome in non-metastatic clear cell renal cell carcinoma (ccRCC) patients. Methods: Immunohistochemistry for phos-S6, phos-mTOR, mTOR, phos-AKT, HIF-1α, RAPTOR, PTEN, PI3K, and phos-4EBP1 was performed on tissue microarrays of patients treated for non-metastatic kidney cancer between 1997-2010. Patients were defined as having a low (<) or high risk (≥) of nomogram predicted recurrence (2001 MSKCC RCC post-op) using an 8% cutoff. The relationship between individual marker expression, as well as combined marker score (low, intermediate and high defined as ≤ 3, 4-5, >5 altered biomarkers; respectively) with the actual and predicted relapse rates was assessed. Results: The study included 419 non-metastatic ccRCC patients (pT1-T2 79.5%, pT3-T4 20.5%, Fuhrman nuclear grade 1-2 in 69%, 3-4 in 31%). 219 and 200 patients had low (<8%) and high (≥8%) nomogram-predicted 5-year risk of recurrence respectively. With a median follow-up of 2.2 years, recurrences were detected in 5 (2.3%) of the predicted low risk and 30 (15%) of the predicted high risk patients. mTOR pathway biomarker profiles were not predictive for patients at low predicted risk of recurrences. For patients at high predicted risk of recurrence, low, intermediate and high combined marker scores were found in 84 (42%), 79 (39.5%), and 37 (18.5%), respectively. The actual rates of recurrence were noted for 8.3% of low, 13.9% of intermediate and 32.4% of high combined marker score in a statistically significant distribution (p=0.027). Conclusions: The cumulative number of aberrantly expressed mTOR biomarkers correlates with a higher rate of recurrence. The combined marker score may help further stratify patients with high nomogram predicted risk of recurrence. Our data supports prospective evaluation of these biomarkers to augment current clinico-pathologic predictors of outcomes in ccRCC.
Meta-analysis of hematologic toxicities in patients with cancer treated with sunitinib.
Authors: Funakoshi Tomohiro , Latif Asma , Arasteh Kamyar , Galsky Matt D.
Published: February 2017

373

Background: Sunitinib is a small molecule which inhibits receptor tyrosine kinases involved in cell proliferation and angiogenesis. Though the incidence and risk of unique toxicities associated with sunitinib, such as hypertension and thromboembolic events, have been previously reported, the incidence and risk of hematologic toxicities have been less well characterized. Methods: We searched Medline and the American Society of Clinical Oncology online database of meeting abstracts up to July 2012 for relevant clinical trials. Eligible studies included phase II and III trials and expanded access programs with sunitinib that reported adequate safety data profile reporting neutropenia, thrombocytopenia or anemia. The relative risk (RR), summary incidence and 95% confidence intervals (CI) were calculated. Results: A total of 8,526 patients from 60 trials of sunitinib as a single agent revealed that the incidence of sunitinib-associated all-grade and high-grade (grade 3-4) hematologic toxicities were, respectively: neutropenia: 42.1% and 12.8%; thrombocytopenia: 44.7% and 10.7% and anemia: 50.4% and 6.2%. Sunitinib-treated patients (2,667 subjects from 10 randomized trials) had a significantly increased risk of all-grade (RR = 3.58; 95% CI, 1.71–7.49) and high-grade (RR = 3.32; 95% CI, 1.60–6.90) neutropenia, all-grade (RR = 4.59; 95% CI, 2.76–7.63) and high-grade (RR = 5.84; 95% CI, 2.22–15.41) thrombocytopenia and all-grade anemia (RR = 1.15; 95% CI, 1.00–1.31). Subgroup analysis revealed the significantly higher relative risk of high-grade neutropenia in patients receiving sunitinib monotherapy than in patients receiving concomitant therapy (p = 0.026). There was no statistically significant difference in the incidence of hematologic toxicities between subgroups; renal cell cancer (RCC) versus non-RCC or continuous daily sunitinib dosing versus intermittent dosing. Conclusions: Sunitinib is associated with a significant increase in the risk of developing all-grade and high-grade neutropenia and thrombocytopenia and all-grade anemia compared with control.
Global metabolic profiling of clear cell renal cell carcinoma.
Authors: Hakimi A. Ari , Lee Chung-Han , Cross Justin R. , Li Zhen , Chen Yang , Neri Bruce , Reuter Victor E. , Motzer Robert John , Russo Paul , Hsieh James
Published: February 2017

379

Background: Recent data has suggested that metabolomic profiling in various cancer states may lead to novel biomarkers and innovative therapeutic strategies. We profiled the metabolome of 140 clear cell renal cell carcinomas (ccRCC) and matched normal tissue of various clinical stages. Methods: In collaboration with Metabolon, Inc., 140 clinically annotated tumors were subject to three global metabolic profiling mass spectroscopy platforms. Demographic, clinical, and pathologic data were recorded and patients were grouped into local, locally advanced and metastatic categories using clinical and pathologic criteria. Welch’s paired two sample t tests were used to identify biochemicals that differed significantly between the tumor and normal tissue groups (p value ≤0.001). Supervised clustering using random forest analysis was performed to identify metabolites that differentiated tumors and normals, as well as those associated with tumor progression. Results: A total of 877 biochemicals (including 300 unnamed metabolites) were identified. Several known cancer metabolic pathways were found to be altered consistent with the Warburg effect including accelerated glycolysis and pentose phosphate pathway (PPP), increased lipogenesis, elevated polyamine production, altered nitrogen handling, cell membrane metabolism, inflammation, and oxidative stress. Interestingly, several novel unexpected pathways were found to be altered and associated with disease progression including alterations in the 2-hydroxyglutarate pathway (2HG). 2HG levels were increased over 6 fold in tumors compared to normal and increased further with respect to disease progression (p = 0.019, q = 0.055). Several promising biomarker candidates were identified as well. Conclusions: We provide the first report of large scale metabolomic analysis of ccRCC, revealing several known and novel alterations to cancer-specific metabolic pathways. Investigation of novel pathway biology and biomarker validation in blood and urine samples is currently underway.
A single-center retrospective review of outcomes associated with sunitinib alternative schedule compared to traditional schedule.
Authors: Atkinson Bradley J. , Kalra Sarathi , Wang Xuemei , Tannir Nizar M. , Jonasch Eric
Published: February 2017

381

Background: Sunitinib is a front-line therapy for metastatic renal cell cancer (mRCC). Recommended dose is 50 mg daily; 28 days (d) on/14 d off (traditional schedule; TS). Sunitinib is associated with several adverse events (AEs). An ideal treatment modification algorithm is not known. We sought to identify (1) common AEs, (2) alternative schedules (AS) that maintained dose intensity while decreasing AEs, and (3) the impact of AS on outcomes. Methods: Single-center retrospective review of mRCC pts performed from January 26, 2006 to March 1, 2011. Pts > 18 years of age with mRCC who received first-line antiangiogenic therapy with sunitinib were eligible. A subset of pts were switched at first intolerable AE from TS to a 14 d/7 d, or further adjusted to 7 d /3 d, or other AS. Control group underwent standard dose reduction. Pt characteristics including demographics, disease status, laboratory data, AEs, AS, and treatment outcomes were analyzed. Results: 186 eligible pts were identified. At baseline, 87% received sunitinib 50 mg and 88% were on TS. 99 pts (53%) continued TS and 87 pts (47%) were switched to AS. Baseline characteristics were similar. Median age was 61 yrs; by MSKCC criteria 5% were good, 50% intermediate, and 45% poor prognosis. Pts had median 2 visceral mets and 42% had primary tumor in place. AEs included fatigue (47%), diarrhea (24%), and hand-foot syndrome (26%). Median time to AS was 126 d with 14 d/7 d the most common (82%). Median time on treatment was 14.9 months (mo) (95% CI:10.2 – 17.0 mo) in AS pts vs. 4.2 mo (95% CI: 3.6 – 5.7 mo), respectively (p < 0.0001). Median OS was 32.9 mo (95% CI:28.3-54.1 mo) vs. 18.5 mo (95% CI: 10.3-21.5 mo), respectively (p = 0.0001). ECOG PS > 2 (HR 3.9), elevated LDH (HR 2.04), and > 2 mets (HR 1.79) were associated with decreased OS. MSKCC intermediate vs. poor (HR 0.57) and AS (HR 0.54) were associated with improved OS by multivariate regression analysis (p < 0.05). Conclusions: In our cohort study, AS sunitinib significantly prolonged outcomes and was predictive of OS. Prospective investigations of alternate dosing schemas are warranted.
Impact of chromosomal copy number variation on outcome in metastatic clear cell renal cell carcinoma patients treated with antiangiogenic agents.
Authors: Jonasch Eric , Thakur Suresh , Sircar Kanishka , Tamboli Pheroze , Tannir Nizar M. , Monzon Federico A.
Published: February 2017

393

Background: Antiangiogenic agents (AA) are used to treat metastatic clear cell renal cell carcinoma (ccRCC). Currently there are no biomarkers of therapeutic efficacy with these agents. We have previously shown that chromosome copy number variation (CNV) is associated with poor (14q loss) or more favorable outcomes (5q31-ter gain) in nonmetastatic patients. The purpose of the current study was the impact of CNV on response, progression free survival (PFS) and on overall survival (OS) after AA in patients with metastatic ccRCC. Methods: We obtained archival FFPE or frozen tumor specimens from patients with mRCC treated with sorafenib (after tumor removal), bevacizumab or sunitinib (neoadjuvant treatment). DNA was analyzed with Affymetrix 250K Nsp SNP microarrays. We identified the presence of genomic imbalances and loss of heterozygosity (LOH) to obtain “virtual karyotypes”. We then compared CNV to outcome using Wilcoxon-Gehan statistical analysis. Results: A total of 83 patients were used to analyze CNV after treatment with AA: 22 sorafenib, 29 sunitinib, 31 bevacizumab. Gain of 8q (p = 0.036) and loss of 16q (p = 0.0031), 20p (p = 0.038) or 20q (p = 0.022) were associated with a shorter OS, whereas gain of 1q (p = 0.037) and 5q (p = 0.019) were associated with longer OS in this patient cohort. When 14q loss was combined with 8q gain, median OS was further decreased (p 0.01). Surprisingly, when assessed as a group, no specific CNV was associated with PFS. However, when compared separately, 5q gain was predictive for better PFS in sorafenib or bevacizumab treated patients (p = 0.006), but no such effect was seen in the sunitinib treated cohort. Conclusions: Our results show that chromosomal imbalances are associated with divergent clinical outcome in metastatic ccRCC patients treated with AA, and are predominantly prognostic. Dissecting out driver tumor suppressor or tumor activating genes within these chromosomal regions will guide our understanding of what defines a particularly lethal phenotype. The possibility exists that specific CNV profiles predict for response to therapy, but a larger sample size is required to validate this possibility.
Real-life patterns of use and effectiveness of sunitinib in patients with metastatic renal cell carcinoma: The SANTORIN study.
Authors: Ravaud Alain , Culine Stephane , Grelaud Angela , Chevreau Christine , Lamarque Stephanie , Balestra Aurelie , Bernard Marie-Agnes , Moore Nicholas , Noize Pernelle , Bay Jacques-Olivier , Fourrier-Réglat Annie
Published: February 2017

400

Background: Until 2006, treatment options for metastatic renal cell carcinoma (mRCC) were limited to cytokine therapy and surgery. Sunitinib, an oral antiangiogenic agent, received European marketing authorisation in Jan 2007 for first-line treatment in advanced and/or mRCC. The SANTORIN study was designed to describe patterns of use and estimate survival outcomes in mRCC patients treated with sunitinib in a real-life setting. Methods: SANTORIN was an observational cohort conducted in 36 French centres including patients initiating first-line treatment with sunitinib from Jan 2008-Apr 2010, followed 2 years after treatment onset. Treatment characteristics, response (evaluated by investigator based on RECIST criteria) and survival outcomes were collected from medical files. Overall and progression-free survival (OS and PFS) results were estimated using Kaplan-Meier method. Results: Characteristics of the 302 included patients were: mean age 64.3 years; male 73.2%; clear-cell histological component 83.1%; ECOG ≥2 9.9%, prior nephrectomy 85.4%. Baseline sunitinib dose was 50 mg/day for 83.4% of patients. The median duration of first-line treatment was 10.7 months (median number of cycles: 6). Dose reduction occurred in 65.2% of patients. Reasons for discontinuation of first-line treatment were progressive disease (61.1%), death (31.2%), adverse events (6.8%), and other reasons (1.0%). OS was 70.8% at 1 year (95%CI [65.3;75.5]) and 49.5% at 2 years [43.7;55.0]. Median OS was 23.6 months [19.9;27.4] (not reached in patients with clear-cell component). PFS was 38.2% at 1 year [32.7;43.7] and 16.4% at 2 years [12.5;20.9]. Median PFS was 8.4 months [7.6;9.9] (9.5 months [8.1;11.0] in patients with clear-cell component). Overall best response was 31.1% (2.3% complete, 28.8% partial), 40.1% had stable and 18.5% progressive disease. Conclusions: Despite certain differences regarding severity of cancer, these results demonstrated that effectiveness of sunitinib in mRCC is close to efficacy reported in the pivotal clinical trial (median OS: 26.4 months [95% CI 23.0 ; 32.9], median PFS: 11.0 months [11.0 ; 13.0]), especially in patients with clear-cell component.
Tumor thrombus transection in renal cell carcinoma.
Authors: Klink Joseph C. , Westesson Karin E. , Gao Tianming , Stephenson Andrew J. , Krishnamurthi Venkatesh
Published: February 2017

409

Background: Inferior vena cava (IVC) tumor thrombectomy with radical nephrectomy (RN) for renal cell carcinoma (RCC) is difficult when a large renal mass is present, but completing the RN by transecting the renal vein with tumor thrombus inside can facilitate dissection of the IVC for thrombectomy. We compared the outcomes of patients in whom the thrombus was purposely transected to those in whom the IVC thrombus was removed en bloc with the kidney. Methods: At our institution between 2000-2011, 152 patients with RCC and level II (N =53), III (N =52) or IV (N =47) IVC thrombus underwent RN and IVC thrombectomy. In 92 patients the kidney was removed prior to initiating the IVC thrombectomy. In 60 patients, the tumor thrombus and kidney were removed en bloc. Clinical information was obtained from an institutional database. Since thrombus level greatly affects surgical technique and complications, outcomes were analyzed within each level. Results: Thrombus level and clinical stage were higher in the transected group, but other baseline characteristics did not differ significantly. The primary endpoint, the overall rate of complications including intra-op and post-op events, was not statistically significantly different (all p >0.2) between the en bloc and transected groups for level 2 (8/37 vs. 6/16), level 3 (7/17 vs. 15/35), and level 4 (2/6 vs. 25/41). Operative times were similar within level 2 (300 vs. 300 minutes, p=0.2), level 3 (312 vs. 360, p=0.1), and level 4 (325 vs. 402, p=0.7). Units of blood products transfused were also similar within level 2 (3 vs 5, p=0.3), level 3 (5 vs. 9, p=0.06), and level 4 (6 vs. 14, p=0.4). Due to the low event numbers within each subgroup, multivariable analysis could not be reliably run on these outcomes. Three patients, all in the transected group, experienced intraoperative tumor thrombus embolization to the pulmonary artery requiring surgical embolectomy, but all 3 survived to discharge without any serious sequelae. Conclusions: Complications, operative time, and transfusion rates were similar between the en bloc and transected techniques when stratified by tumor thrombus level. Because of the rarity of this disease, statistical power of these comparisons is low, but our study suggests no evidence of advantage to either technique.
B7H1 expression and association with clinical response to sunitinib therapy in patients with metastatic renal cell carcinoma (mRCC).
Authors: Kim Jenny J. , Xu Haiying , Haddad Housam , Anders Robert , Arslankoz Sehbal , Wang Hang , Zhang Zhe , Rapp Sarah , Wood Laura S. , Netto George J. , Drake Charles G. , Rosner Gary L. , Rini Brian I.
Published: February 2017

416

Background: Preliminary data support that B7H1 expression is associated with objective response (OR) to anti-PD-1 antibody treatment in multiple solid tumors. The aim of this study was to retrospectively evaluate a possible association between B7H1 expression and clinical response to sunitinib therapy in mRCC patients. Methods: mRCC patients receiving sunitinib therapy (50mg 4/2) were identified and data regarding patient characteristics and clinical outcome to sunitinib were recorded. Immunohistochemistry (IHC) staining of B7H1 was done on pretreatment formalin fixed paraffin embedded (FFPE) tissue sections according to available protocol at Hopkins. IHC scorings were done by 2 independent pathologists who were blinded to outcomes and a 3rd pathologist was used if there was a discrepancy between the first 2. Association of B7H1 expression with OR was assessed using Fisher’s exact test. Progression free survivals (PFS) were estimated using the Kaplan-Meier method and compared using log-rank test. Multivariate analyses were performed using logistic regression and Cox regression. Results: 20 cases were identified of which 18 had available FFPE for IHC analysis. 78% were male; median age was 55 (range 35-79); 72% ECOG PS of 0; 94% had prior nephrectomy; 89% were therapy naïve. 50% were intermediate risk category according to Heng criteria and the rest were poor risk. 55.6% (10/18) were positive for B7H1 expression (>5% positive cell membranous staining). 30% of B7H1 positive patients had OR whereas 50% of B7H1 negative patients had OR (p = 0.63). Median PFS were 19.3 and 6.2 mos for B7H1 negative and positive groups, respectively (p = 0.56). In multivariate models, B7H1 expression was neither associated with OR (odds ratio = 0.54, 95% CI = 0.07-4.23, p = 0.56) nor PFS (hazard ratio =1.06, 95% CI = 0.34-3.34, p = 0.92) after adjusting for Heng risk classification. Conclusions: In this study, B7H1 expression was not associated with clinical outcome to sunitinib therapy in metastatic RCC patients.
Survival trends among patients with advanced renal cell carcinoma (RCC) in the United States.
Authors: Shah Binay Kumar , Ghimire Krishna Bilas
Published: February 2017

422

Background: Since approval of sorafenib in December 2005, several targeted therapeutic agents have been approved by the FDA for the treatment of advanced renal cell carcinoma. This study was conducted to find out whether the improvements in survival of advanced RCC patients with targeted agents have translated into survival benefit in population-based cohort. Methods: We analyzed the Surveillance, Epidemiology, and End Results (SEER) 18 registry database to compare 1- and 3-year relative survival rates among advanced RCC patients during 2001-2009, 2001-2004, and 2006-2009. We also evaluated the survival rates by age (<65 and ≥65 years) and sex. We used SEER*Stat software to analyze the data. Results: The total number of advanced RCC patients during 2001-2009, 2001-2004, and 2006-2009 were 7,055, 3,355 and 2,985 respectively. During 2001-2009, the 1- and 3-year relative survival rates were 26.7± 0.6% and 10.0±0.4% respectively. The 1-year relative survival rates during 2001-2004 and 2006-2009 were 27.0±0.8% and 27.1±0.9%, (p value=1.3) respectively. Similarly, the 3-year survival rates during 2001-2004 and 2006-2009 were 10.1±0.6% and 9.6±0.8%, (p value=1.42), respectively. There was no significant difference in survival rates during 2001-2004 and 2006-2009 periods by age and sex. Conclusions: This population based study showed that there was no significant improvement in relative survival rates among advanced RCC patients in the era of targeted agents. As with other database analyses, limitations of this large study may be incomplete reporting practices and lack of data on treatment.
Outcomes of second-targeted therapy for mRCC: A retrospective chart review of community practices in the United States.
Authors: Jonasch Eric , Signorovitch James E. , Lin Peggy L. , Liu Zhimei , Culver Kenneth W. , Pal Sumanta Kumar , Scott Jeffrey A. , Vogelzang Nicholas J.
Published: February 2017

424

Background: Sequential use of targeted therapies has become standard practice for the treatment of metastatic renal cell carcinoma (mRCC). This study describes treatment outcomes of the 2nd-targeted therapy among patients with mRCC treated in the community setting. Methods: A retrospective chart review and survey was conducted during May through June 2012 among community-based oncologists or hematologists. Charts were reviewed for adult mRCC patients initiated on 2nd -targeted therapy on or after January 1, 2010. Abstracted data included patient demographics, disease characteristics, treatment duration, dose adjustment, progression, mortality, and imaging test patterns. Kaplan-Meier analysis was used to estimate treatment duration, overall survival (OS) and progression-free survival (PFS) during 2nd-targeted therapy. Patients were censored at the most recent contact. Results: Charts were reviewed for 433 mRCC patients. Mean age was 63 years at initial mRCC diagnosis and 64% were male. The most commonly used 2nd targeted therapies were everolimus (36% of patients), temsirolimus (17%), pazopanib (15%), and sunitinib (14%). The median duration of 2nd -targeted therapy was 10.5 months (95% CI: 8.8-11.5). The majority of patients (73%) had no dose adjustment on 2nd-targeted therapy; the most common reason for adjustment was drug toxicity (70%). Among the 44% of patients who discontinued 2nd-targeted therapy, disease progression was the most common reason for discontinuation. The proportion of patients who received imaging test within 3, 6, and 12 months after 2nd-line treatment initiation was 57%, 92%, and 99%, respectively. Routine monitoring (83%) was the most common reason for imaging tests. Median durations of OS and PFS after initiation of the 2nd-targeted therapy were 30.4 months (95% CI: 23.5-not reached) and 10.7 months (95% CI: 8.4-12.2), respectively. Conclusions: In this large, retrospective chart review study, median treatment duration of 2nd -targeted therapy was 10.5 months, median OS was 30.4 months, and median PFS was 10.7 months. Median treatment duration in community practice was longer than in clinical trials for targeted therapies in mRCC.
Hypertension and myelosuppression as biomarkers of sunitinib efficacy in Chinese patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Qin Shukui , Jin Jie , Guo Jun , Wang Jin-Wan , Zhou Fang-Jian , Huang Yi-Ran , Ren Xiu-Bao , Ye Ding-Wei , Pan Sharon , Sajben Peter , Wang Qiao
Published: February 2017

426

Background: In an open-label, phase IV study of sunitinib as 1st-line treatment (Tx) in Chinese pts with mRCC, median progression-free survival (PFS) and overall survival (OS) were 61.7 and 133.4 wk, respectively; objective response rate (ORR) was 31.1% (Ann Oncol 2012;23:851P). We retrospectively investigated correlations between on-Tx hypertension (HTN), neutropenia (N), and thrombocytopenia (T) and efficacy endpoints in pts from this trial. Methods: HTN was defined by either maximum systolic blood pressure ≥140 mm Hg (S-HTN) or maximum diastolic blood pressure ≥90 mm Hg (D-HTN). Using CTCAE assessment, N grade ≥2 and T grade >1 were used as cut-points for the analyses. Median PFS and OS were estimated by Kaplan−Meier method. The log-rank test was used to compare PFS and OS between groups with and without HTN, N grade ≥2, or T grade >1. Fisher’s exact test was used for ORR. Results: 102 pts were included in the HTN analyses, 60% with S-HTN versus 40% without S-HTN. Pts with S-HTN had greater ORR and longer PFS and OS than pts without S-HTN (Table). (Results were similar with D-HTN; see Table.) 103 pts were included in the N and T analyses, 67% with N grade ≥2 versus 33% with N grade <2, and 56% with T grade >1 versus 44% with T grade ≤1. Pts with N grade ≥2 had significantly greater ORR and significantly longer PFS and OS than pts with N grade <2 (Table). Pts with T grade >1 had greater ORR and significantly longer PFS and OS than pts with T grade ≤1 (Table). Conclusions: The developments of N grade ≥2 and T grade >1 during Tx with sunitinib were significantly associated with better outcome. Median PFS was more than twice as long for pts with S-HTN as for those without S-HTN, but the association did not reach statistical significance. [Table: see text]
First-line mTOR inhibition in metastatic renal cell carcinoma (mRCC): An analysis from the International mRCC Database Consortium.
Authors: Harshman Lauren Christine , Wood Lori , Srinivas Sandy , Heng Daniel Yick Chin , Choueiri Toni K.
Published: February 2017

430

Background: mTOR inhibitors (mTORi) are an important class of targeted therapies for mRCC that may act through regulation of mTOR as well as hypoxia-inducible factor and its resultant downstream angiogenesis pathways. FDA approval was based on efficacy in poor risk patients in the first-line setting for temsirolimus (T) and in sunitinib- and sorafenib-refractory patients for everolimus (E). Little is known about T’s effectiveness in good and intermediate risk patients and E’s outcomes in the first-line setting. Methods: We evaluated our international mRCC database to evaluate the outcomes of patients who received mTORi as their first-line targeted therapy. Results: Of the 2,370 patients in the database, 49 received a first-line mTORi (7 E, 42 T). Median age was 61 years and median KPS was 80%. 63% had clear cell and 37% had non-clear cell histology. 65% had prior nephrectomy. Of the 38 patients with available Heng prognostic risk criteria, 21%, 21%, and 58% were good, intermediate, and poor risk respectively. Median PFS and OS are detailed below. Objective responses and disease stabilization were achieved in 5% and 58%. Second-line therapy was administered in 21 patients of which 17 received VEGF inhibitors. Conclusions: Outcomes for good and intermediate risk patients treated with first-line mTORi were lower than historically expected for patients treated with VEGF targeted therapies. These results may be due to inclusion of non-clear cell histologies, treatment biases, small sample size, or other undefined confounders that need further exploration. Greater data capture of this important cohort of patients to confirm these results is planned and will be presented. [Table: see text]
Outcomes of RCC patients with venous thrombus presenting with pulmonary embolism: A multicenter analysis of 782 consecutive patients.
Authors: Abel Edwin Jason , Wood Christopher G. , Kenney Patrick , Eickstaedt Nathan , Bagrodia Aditya , Ramirez Daniel , Gayed Bishoy A. , Youssef Ramy F. , Odom Christopher , Margulis Vitaly
Published: February 2017

433

Background: Renal cell carcinoma (RCC) patients who present with pulmonary embolism (PE) and venous thrombus may not be offered surgery because of concerns with anti-coagulation and presumed poor post-surgical outcomes. The objective of this study was to evaluate post-surgical recurrence and disease specific survival (DSS) in RCC patients with venous thrombus who had PE diagnosed at initial presentation. Methods: After IRB approval, we reviewed the records from 2000-2011 at 3 tertiary hospitals (UW, UTMDACC, UTSW) for all consecutive RCC patients who had nephrectomy with thrombectomy. Clinical and pathologic predictive factors for recurrence and survival were collected for each patient. Univariate and multivariate analysis was used to evaluate whether PE at presentation was associated with RCC recurrence or DSS after nephrectomy with thrombectomy. Results: Preoperative PE was diagnosed in 35/782 (0.5%) RCC patients undergoing nephrectomy with thrombectomy with a median follow-up time of 22 months. Patients with PE at initial diagnosis were more likely to have higher level thrombus (p<0.01) but no differences were found between groups for age, gender, race, tumor diameter, Fuhrman grade, sarcomatoid de-differentiation, peri-nephric fat invasion or histologic subtype. In N0M0 patients, there was no difference (p=0.36) in the rate of RCC recurrence for 395/782(50%) or 7/17(41%) patients without PE or with PE respectively. On multivariate analysis, peri-nephric fat invasion, Fuhrman grade, and thrombus height, but not preoperative PE status, were predictive of recurrence risk. Similarly, there was no difference in the rates of lung metastases for 67/123 (53%) N0M0 patients without PE or 3/7 (43%) patients with PE (p=0.71). Preoperative PE diagnosis was not predictive of death from RCC (p=0.58). On multivariate analysis, peri-nephric fat invasion, sarcomatoid de-differentiation, Fuhrman grade, and thrombus height, were independently predictive of risk of death from RCC. Conclusions: PE at initial diagnosis is not associated with worse post-surgical recurrence or survival in RCC patients with tumor thrombus.
Prospective assessment of circulating endothelial cells (CECs) as early markers of clear cell renal cell carcinoma (CCRCC) progression in first-line setting: The Circles study (SOGUG 2011-01).
Authors: Oyarvides Victor , Castellano Daniel , Leon Mateos Luis , Esteban Emilio , Basterretxea Laura , Gonzalez del Alba Aranzazu , Arranz Arija Jose Angel , Mendez Maria Jose , Garcia Del Muro Francisco Javier , Climent Miguel Angel , Virizuela Juan Antonio , POLO Susana Hernando , Garcia-Donas Jesus ,   Spanish Oncology Genitourianry Group
Published: February 2017

436

Background: Angiogenesis inhibitors have become a cornerstone in the management of clear cell renal cell carcinoma (CCRCC). Since circulating endothelial cells (CECs) counts have been proposed as surrogate biomarkers of angiogenesis, they could potentially be used to assess the activity of such drugs. Methods: An observational prospective study is being performed in 11 institutions members of the SOGUG group. Patients with confirmed CCRCC on first-line treatment who have not progressed after 3 months of therapy are considered eligible. CECs (CD 105+,CD 45-, DAPI + cells assessed by the Cell Search system), are determined every 6 weeks for 15 months or radiological tumor progression. Results: Up to 64 of the 75 scheduled patients have already been recruited. Mean age was 64 years, 73% were men and 27% women. Distribution upon MSKCC risk cathegories was: good 30%, intermediate 58%, poor 3% and not available (N/A) 9%. 57 (90%) patients received sunitinib, 3 (5%) pazopanib, 1 (2%) temsirolimus and was N/A in 3 (5%). The CECs counts were determined in 60 patients. At baseline median was 47 cells/4 ml (range 4-480). When comparing patients who experienced tumor progression while on study (11 cases) with patients who did not (28 CECs/4 ml vs. 73 CECs/4ml respectively), a significant difference was found (p = 0.002, t-student). Several exploratory analysis regarding concomitant conditions and patients and tumor characteristics showed that cases with heavily treated hypertension (8 in 60 patients) had lower baseline CECs counts, though without statistical significance (p = 0.068, t-student). Conclusions: Our data point to a different behaviour of CECs counts among CCRCC patients tretated with anitangiogenic drugs that could lead to identify specific subpopulations. Mature results will be presented at the meeting.
Outcomes for a multi-institutional cohort of patients treated with intra-operative radiation therapy for advanced or recurrent renal cell carcinoma.
Authors: Paly Jonathan J. , Hallemeier Christopher Leigh , Biggs Peter J. , Niemierko Andrzej , Roeder Falk , Martinez-Monge Rafael , Whitson Jared Myers , Calvo Felipe A. , Fastner Gerd , Wong William , Ellis Rodney J. , Efstathiou Jason Alexander
Published: February 2017

442

Background: For patients with advanced or locally recurrent (LR) renal cell carcinoma (RCC), the role of intra-operative radiation therapy (IORT) remains controversial. We analyzed outcomes in a multi-institutional cohort of patients with RCC who received IORT. Methods: Between 1985 and 2010, 98 patients were treated with IORT for advanced or LR RCC at 9 institutions. We collected demographic, clinical, treatment, and outcomes data for all patients. Overall (OS), disease specific (DSS), and disease-free survival (DFS) was estimated using the Kaplan-Meier method. A multivariate Cox hazards regression was used to test significance. Results: IORT was delivered at nephrectomy for advanced disease (28%) or during resection of LR RCC in the renal fossa (72%). 69% of patients were male and mean age at RCC diagnosis was 57. At initial nephrectomy, primary T-stage was 17% T1, 12% T2, 55% T3, and 16% T4. Prior to IORT, 87% had visibly complete surgical resection of tumor. Mean IORT dose delivered was 14.7Gy (range 9-20Gy). Average post-op hospitalization was 10.7 days. Median follow-up after IORT was 1.6 years. OS at 1 and 5 years after IORT was 69% and 37% for advanced patients and 94% and 55% for LR patients, respectively. DFS at 1 and 5 years was 72% and 39% for advanced patients and 96% and 52% for LR patients, respectively. DSS at 1 and 5 years was 72% and 41% for advanced patients and 96% and 60% for LR patients, respectively. For the entire cohort, higher IORT dose (HR 1.3, p < 0.001), positive initial node status (HR 2.9-3.6, p < 0.01), and presence of sarcomatoid features (HR 3.7-6.9, p < 0.05) had a significant association with decreased OS, DFS and DSS. Patients who received adjuvant systemic therapy after IORT showed decreased DSS (HR 2.4, p = 0.03). When analyzing LR tumors alone, positive margin (HR 2.6, p = 0.01) was associated with decreased OS. Conclusions: We report on the largest known cohort of patients with RCC managed with IORT and we have identified factors associated with survival. Outcomes in our cohort with LR RCC treated with local resection and IORT compare favorably to similar groups treated with resection alone suggesting improved DSS may be possible with IORT.