bluuebunny/crossref_metadata_2025_split huggingface dataset:
Management of cT1 micropapillary bladder cancer.
Authors: Willis Daniel Levi , Fernandez Mario , Dickstein Rian J. , Parikh Sahil , Shah Jay Bakul , Pisters Louis L. , Guo Charles , Czerniak Bogdan , Grossman H. Barton , Dinney Colin P.N. , Kamat Ashish M. 
Published: February 2017

308 Background: We have previously reported that intravesical BCG is ineffective as therapy for micropapillary variant of bladder cancer. Since then, smaller reports have emerged with differing conclusions. Here we report our updated experience and expanded number of patients with micropapillary bladder cancer (MPBC), with emphasis on cT1 MPBC. Methods: An IRB approved institutional review of our bladder cancer database identified 255 patients presenting with MPBC with 72 patients staged as cT1N0M0 at the time of initial diagnosis. Statistical and descriptive analysis was performed using IBM SPSS Statistics version 20 and survival analysis was performed using the Kaplan-Meier estimator and compared using the log-rank test. Results: Of the 72 patients with cT1 MPBC, intravesical BCG was used in 38 patients (53%), while 32 (44%) proceeded directly to radical cystectomy. This included 15 (20%) who received neoadjuvant chemotherapy for lymphovascular invasion (LVI). Kaplan-Meier estimates of overall survival (OS) and disease specific survival (DSS) at 5 and 10 years were 66% and 45%, and 70% and 61%, respectively. Among those receiving BCG, 28 (74%) recurred at a median of 7 mo., and 17 (45%) progressed, including 8 (30%) who developed metastatic disease. Among the 10 post BCG patients who underwent cystectomy after progression, median DSS was 43 mo. (mean=53 mo.) and 5 year DSS was 33%, whereas among those proceeding directly to cystectomy, median DSS was not reached (mean=152 mo.) and the 5 year DSS rate was 92% (p<0.001). For OS, upfront cystectomy conferred a median survival of 170 mo. versus 92 mo. for those receiving BCG as initial therapy (p=0.05). There was no association of OS with the presence of CIS, repeat transurethral resection (TUR), or history of intravesical therapy prior to the diagnosis of MPBC. Interestingly, the extent of micropapillary component in the initial TUR specimen did have prognostic value for those treated with BCG as patients with focal MPBC were 2.3 times less likely to progress (p=0.02). Conclusions: Our updated findings support the use of upfront radical cystectomy prior to progression of disease in patients with cT1 MPBC. BCG therapy should be attempted only in select patients as there is a high risk of disease progression during BCG treatment.
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.