bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single nucleotide polymorphisms as markers of bacillus Calmette-Guérin intravesical therapy response in non-muscle invasive bladder cancer.
Authors: Alanee Shaheen , Hamilton Robert James , Joseph Vijai , Ostrovnaya Irina , Garcia-Grossman Ilana Rebecca , Gallagher David J , Pendse Deepa , Regazzi Ashley Marie , Przybylo Jennifer A. , Gaudet Mia , Milowsky Matthew I. , Herr Harry W. , Offit Kenneth , Bajorin Dean F. 
Published: March 2020

e15022 Background: A marker of response to Bacillus Calmette-Guérin (BCG) intravesical therapy in high-risk non-muscle invasive bladder cancer (NMIBC) could help avoid unsuccessful BCG treatment and potentially enhance care. This study examines germline single nucleotide polymorphisms (SNPs) as markers of BCG-refractory NMIBC. Methods: Saliva or blood was prospectively collected from patients treated with BCG for NMIBC between 1991 and 2010, treated either at MSKCC or referring centers prior to MSKCC registration. BCG-refractory disease was defined as the presence of pathologically documented tumor in the bladder six months after BCG administration. SNPs were selected based on either reported associations with BCG response or putative mechanisms of BCG activity. Eighty candidate SNPs were genotyped (using the Sequenom Mass ARRAY iPLEX platform) in a discovery set (n=158) and those significantly associated were analyzed in a validation set (n=168). Univariate logistic regression was used to test the association between refractory disease, selected clinical variables, and SNPs. Because center of treatment was found to be a confounding variable (p=0.02), primary analysis was limited to cases treated at a single center (MSKCC), consisting of 276 patients (108 from discovery set and 168 from validation set). Results: Median age of diagnosis of the 276 cases was 65.7 years, 94% diagnosed with high-grade superficial bladder cancer, 35% stage Ta, 30% stage T1, and 35% stage Tis. At six month follow-up, 37 (13.4%) had BCG–refractory disease. Nine SNPs showed significant associations with outcome in the discovery cohort (two SNPs failed genotyping). In primary analysis, One SNP, rs11615, an intronic variant within the ERCC1 gene, was associated with BCG-refractory disease. Patients with CC genotype were 3.6 times more likely to be refractory to BCG compared to TT genotype (OR for each C allele was 1.8: 95% CI 1.1-3; p=0.01). No other factors were found to be predictive. Conclusions: A single nucleotide polymorphism of ERCC1 may be associated with BCG-refractory disease. Validation in independent datasets is needed.
Complete disappearance of retroperitoneal lymph nodes after induction chemotherapy in advanced nonseminomatous germ cell tumors (NSGCT): Is there a place for adjunctive surgery?
Authors: Tryakin Alexey , Fedyanin Mikhail , Mitin Andrey , Sergeev Urii , Figurin Konstantin , Fainstein Igor , Zakharova Tatiana , Kanagavel Dheepak , Kostjakova Ljudmila , Titov Dmitry , Garin Avgust , Tjulandin Sergei 
Published: March 2020

e15029 Background: The management of patients (pts) with a radiographic complete disappearance of retroperitoneal lymph nodes (CD-RPLN) metastases after chemotherapy (CT) remains controversial. Some authors recommend post-CT retroperitoneal lymph node dissection (PC-RPLND), whereas others omit surgery and observe these pts. In this retrospective study we analyzed outcome of pts with advanced NSGCT who achieved CD-RPLN and did not undergo PC-RPLND. Methods: From 1988 to 2008, 886 CT-naïve pts with advanced NSGCT were treated in our department with first-line cisplatin- and etoposide-based CT. All residual tumors >1cm were resected when it was feasible. Pts who had CD-RPLN (≤1cm by CT-scan) and normalized tumor markers after CT were included into the study. Results: One hundred thirty seven pts were identified. 30% pts had teratoma in primary tumor. Following CT 13 pts underwent resection of extra-retroperitoneal lesions, no viable carcinoma was found. Good, intermediate and poor IGCCCG prognosis had 87 (64%), 33 (24%) and 17 (12%) pts, respectively. After a median f.-up of 72 (6-193) months, 11 (8%) pts relapsed. All but one relapses occurred in the first two years. Only 4 (3%) relapses developed in RPLN and were treated with salvage CT and surgery, all 4 pts died. Relapse rate in RPLN was equal among prognostic groups (good 2(2%), intermediate 1(3%), poor 1(6%) pts). 5-years OS were 94%, 97% and 79%, respectively. Conclusions: Pts obtaining complete disappearance of RPLN after induction CT had low risk of relapse and can be safely observed without surgery.
Macrophage inhibitory cytokine 1 plasma levels in testicular cancer patients during cisplatin combination treatment and their relation to endothelial damage.
Authors: Altena Renske , Fehrmann Rudolf S. N. , Boer Hink , de Vries Elisabeth G. E. , Meijer Coby , Gietema Jourik A. 
Published: March 2020

e15035 Background: Chemotherapy- (CTx) related endothelial damage contributes to cardiovascular morbidity in testicular cancer (TC) patients (pts). We used an unbiased translational approach to identify mechanisms of and potential biomarkers for this damage. Methods: During varying time periods human microvascular endothelial cells (HMEC-1) were in vitro exposed to bleomycin, cisplatin or left untreated. From 18k cDNA microarray expression signals were obtained, and quantified with an Affymetrix GMS428 scanner. Differences were analysed at single gene and pathway level, and validated by qRT-PCR. With ELISA, protein levels of 1 candidate biomarker were measured in TC pt plasma before, during and 1 month after bleomycin etoposide cisplatin CTx. Levels were related to endothelial damage plasma markers (von Willebrand Factor [vWF], high-sensitivity C-Reactive Protein [hs-CRP]). Results: Microarray data from 16k genes identified several genes with highly differential expression; Macrophage Inhibitory Cytokine 1(MIC-1), Activating Transcription Factor 3 (ATF3) and Amphiregulin (AREG) had strong differences in >1 experimental setting. We regarded these plausible candidates, and confirmed changes by qRT-PCR. Pathway analysis showed a strong association with ‘P53’ and ‘Diabetes Mellitus’ gene sets. Based on known function, we chose to validate MIC-1 protein levels in 41 TC pts. Pre-CTx MIC-1 levels did not differ from healthy controls (TC pts median 383 pg/mL [range 187-1935] vs 340 pg/mL [range 213-504], p=0.06). During CTx levels of MIC-1, vWF and hsCRP significantly increased. MIC-1 levels correlated with vWF and hsCRP at baseline (vWF rs= 0.35, P=0.03; hsCRP rs= 0.39, P=0.01), during (hsCRP at cycle 1d 8 rs= 0.44, P=0.01; vWF at cycle 3 d8 rs= 0.40, P=0.02) and after CTx (vWF rs= 0.56; P<0.01). Conclusions: An unbiased approach in a preclinical model revealed a set of genes related to bleomycin- and cisplatin-induced endothelial activation, such as MIC-1. The increases in plasma levels and the association with vWF and hsCRP suggest that MIC-1 may be a biomarker for CTx-related endothelial damage. Supported by Dutch Cancer Society grant 2009-4365.
Effects of nintedanib (BIBF 1120) on QTc interval in previously untreated patients with renal cell cancer (RCC): Results from an open-label, phase II study.
Authors: Eisen Tim , Shparyk Yaroslav , MacLeod Nicholas James , Wallenstein Gudrun , Temple Graham , Khder Yasser , Dallinger Claudia , Studeny Matus , Loembe Arsene Bienvenu , Bondarenko Igor N. 
Published: March 2020

e15037 Background: Nintedanib (BIBF 1120), an angiokinase inhibitor of VEGFR 1–3, PDGFR-α/-β, and FGFR 1–3, has shown clinical activity with a good safety profile in patients (pts) with solid tumors in previous Phase II clinical trials. Several classes of targeted agents are associated with QT prolongation, including the multi-targeted tyrosine kinase inhibitors. Here, we prospectively evaluated the cardiac safety of nintedanib, specifically assessing the QT liability in an open-label, randomized, phase II efficacy and safety study of nintedanib vs sunitinib in pts with previously untreated RCC. Methods: Eligible pts (advanced, measurable, unresectable, recurrent RCC, ECOG PS 0–1, chemo-naïve, life expectancy >3 months) were randomized to receive either nintedanib 200 mg bid or sunitinib 50 mg od in a 2:1 ratio. Time-matched electrocardiograms of patients treated with nintedanib were collected over 12 hrs. Primary endpoint was the time-matched change from baseline (Day –1 prior nintedanib dosing) to Day 15 (steady-state) in the QTcF interval (QT interval corrected for heart rate dependency by the Fridericia formula) observed at each timepoint. PK parameters were determined and AEs were reported until Day 15. Results: 64 pts were treated with nintedanib. Estimated mean time-matched changes in the QTcF interval (ms) from baseline to Day 15 ranged from –1.7 (90% CI: –4.9, 1.6) at 2 hrs to 3.1 (90% CI: –0.2, 6.4) at 7 hrs. Upper CIs at all timepoints were <10 ms, the ICH E14 guideline threshold level of regulatory concern. Changes from baseline to Day 1 and changes in QT interval were also within the threshold of 10 ms. No pts showed a QTcF or a QT value >500 ms at baseline, Day 1 or Day 15, and no patient experienced an increase from baseline in QTcF >60 ms on Days 1 and 15. PK/QTc analyses did not indicate any relationship between exposure to nintedanib and a change from baseline in QTcF or the QT interval. The most frequently reported drug-related AEs were nausea (14.1%), diarrhea (12.5%) and vomiting (6.3%). Conclusions: Single and multiple doses of 200 mg nintedanib administered until steady-state did not prolong the QTcF interval compared with baseline in pts with RCC.
Oncologic kidney surgery in obese patients.
Authors: Safwat Mohab W. , O'Malley Rebecca , Kristopher Attwood , Mehedint Diana , Narayanan Ramkishen , Schwaab Thomas 
Published: March 2020

e15039 Background: Obesity adds significant operative challenge to kidney surgery. Its impact on minimally invasive kidney surgery has not been well defined. We evaluated the impact of obesity on open and minimally invasive kidney surgery (MIS) for kidney tumors. Methods: Patients in our prospectively collected IRB-approved kidney database were divided into 5 groups as determined by the World health organization Body mass index (BMI) classification: less than 25.0, 25.0-30.0, 30.0-35.0, 35.0-40.0, and more than 40.0 Kg/m2. Patient characteristics, and peri-operative data were recorded and compared between the different groups and between surgical approches(open vs. MIS) using the Kruskal Wallis and Chi Square tests for continuous and categorical data, respectively. The potential association between BMI and the continuous measures of OR time, Post op stay and EBL were assessed using spearman Correlations. Results: Of the 620 patients identified, 142 (22.9 %) had healthy weight, 180 (29.0%) were overweight, and 298 (48.1%) were obese. Most had grade 1 obesity (BMI 30-34, 167, 26.9%), grade 2 obesity (BMI 35-40, 76, 12.3%), and grade 3 obesity (BMI > 40, 55, 8.9%). As expected, the ASA score rose with degree of obesity (p=<.001). EBL (estimated blood loss), OR (operative time) time, Room time and post-operative stay differed significantly in the 5 groups of patients (p=0.001, p=0.003, p=<0.002, p= <.001, p=.002), respectively. While intra-operative complications did not differ between the obesity groups, obese patients had a higher rate of high grade Clavien complications (p=0.026). Interestingly, the surgical approach (open vs. MIS) and type of nephrectomy ( radical vs. partial) did not correlate with degree of obesity or complications, even when adjusted for stage. Conversion rates for MIS did not correlate with degree of obesity. Conclusions: Nephrectomy in obese patients results in incresed high grade of postoperative complications. Surgical approach does not appear to have any impact on peri-operative outcomes.
Use of STAT3 polymorphisms to predict overall survival in patients treated with interferon-alpha for metastatic renal cell carcinoma.
Authors: Eto Masatoshi , Kamba Tomomi , Miyake Hideaki , Fujisawa Masato , Kamai Takao , Uemura Hirotsugu , Tsukamoto Taiji , Azuma Haruhito , Matsubara Akio , Nishimura Kazuo , Nakamura Tsuyoshi , Ogawa Osamu , Naito Seiji ,   Japan Immunotherapy SNPs-Study Group for Kidney Cancer
Published: March 2020

e15048 Background: We previously reported that the single nucleotide polymorphisms (SNPs) in signal transducer and activator 3 (STAT3) gene were most significantly associated with better response to interferon (IFN)-α in patients with metastatic renal cell carcinoma (mRCC) in our retrospective analysis (JCO 25:2785, 2007). We conducted this trial to prospectively confirm the results, and reported the significant association between the SNPs of STAT3-2 and clinical benefits (CR, PR, and SD more than 24 weeks) of IFN-α (p = 0.039) (ASCO 2011, abstract No. 4590). In this study, we have further analyzed the correlation between overall survival (OS), progression-free survival (PFS) and the 11 SNPs reported previously. Methods: In this multicenter, prospective study, patients with histologically confirmed RCC that was metastatic, measurable disease, age > 20 years, ECOG PS 0-1 and adequate organ function received 3 dosages of 5 million U per week of IFN-α treatment. We evaluated the correlation between OS, PFS and SNP allele frequencies of STAT3-2, STAT3-0, SOCS3-1, IL4R-34, PTGS1-3, PTGS1-4, PTGS1-5, PTGS2-12, IRF2-67, ICSBP-38, and TAP2-5 (JCO 25:2785, 2007) in mRCC patients treated with IFN-α. Association between OS, PFS and genetic polymorphisms was analyzed using Logrank test for trend. Results: Two hundreds three eligible patients were enrolled between December 2006 and October 2009. All patients had prior nephrectomy, and 88.7% had ECOG PS 0. Ninety-four percent of patients had clear cell RCC, and 5% had papillary RCC. At the time of this analysis the central review assessed response rate was 13.8% (28/203) (9 CR, 19 PR). CR rate of 4.4% (9/203) was more than we expected. PFS was not associated with any of the 11 SNPs examined. However, 2 SNPs of STAT3 gene, STAT3-2 and STAT3-0, were significantly associated with OS, and the correlation of STAT3-2 (p = 0.0347) was stronger than that of STAT3-0. Namely, C/C genotype of STAT3-2 was significantly associated with prolonged OS compared with the other genotypes (C/T and T/T). Conclusions: This is the first prospective study demonstrating that STAT3 polymorphisms can predict OS in mRCC patients treated with IFN-α.
RAD001 and zoledronic acid in renal cell carcinoma patients with bone metastases (RAZOR): A randomized phase II trial.
Authors: Broom Reuben James , Hinder Vicky , Sharples Katrina , Proctor Janie , Duffey Steven , Pollard Stephanie , Fong Peter C.C. , Forgeson Garry , Harris Dean Laurence , Jameson Michael B. , O'Donnell Anne , North Richard T. , Deva Sanjeev , Hanning Fritha J. , Grey Andrew , Findlay Michael P. N. 
Published: March 2020

e15054 Background: Bone metastases (BM) from renal cell carcinoma (RCC) are common, cause major morbidity and have been identified as an adverse prognostic feature. Previous trials have not assessed the effects of modern therapies on BM from RCC. Randomized data has demonstrated that zoledronic acid (ZOL) reduces skeletal-related-events (SRE’s) in RCC patients (pts). Bone turnover markers can identify pts at risk of SREs among those receiving ZOL. We sought to evaluate the effect on BM of RAD001 (everolimus) alone compared to RAD001 plus ZOL in the first-line setting. Methods: 30 treatment naïve pts with RCC and ≥ 1 BM were randomized 1:1 to RAD001 10mg daily (Arm A) vs. RAD001 + ZOL 4mg IV 4-weekly (dose adjusted for creatinine clearance [CrCl], Arm B). Key eligibility criteria were ECOG PS ≤ 2, no bisphosphonates or radiotherapy within 4 weeks and CrCl >35ml/min. Bone-specific assessments were performed at baseline, weeks 1,4,8 and12. Treatment was continued on the allocated arm until progression (RECIST 1.1). The primary objective was to assess the difference in bone turnover markers over the first 12-weeks. The primary endpoint was urine N-telopeptide (uNTX) levels with plasma C-telopeptide (CTX) being secondary. Secondary objectives include comparison of quality of life (QoL) and pain (FACT-BP, BPI scores), SREs, safety and efficacy (PFS, RR). Results: Heng prognostic group was poor, intermediate and favorable-risk in; 40.0%, 46.7%, 13.3% respectively in Arm A and 20.0%, 46.7%, 33.3% (Arm B). 53.3% (Arm A) and 60.0% (Arm B) of pts had prior nephrectomy. Over the first 12 weeks, the reduction in mean CTX on Arm B relative to Arm A was 77% (95% CI (68%, 83%); p<0.0001). Median PFS was 7.5mo (95% CI 3.5, 14.7) in Arm B and 5.5mo (95% CI 3.2, 7.2) in Arm A (p=0.11). Data on uNTX, QoL and SREs will be presented. At data cut off, 8 pts in Arm B had stopped ZOL before progression with either a drop in CrCl or hypocalcaemia. No cases of osteonecrosis of the jaw were seen. Conclusions: The addition of ZOL to RAD001 significantly reduced the bone resorption marker CTX in this treatment-naïve RCC population of pts with the adverse prognostic feature of BM.
Influence of risk factors for renal cell carcinoma (RCC) on outcome of patients (pts) with metastatic disease (mRCC) treated with sunitinib (Su).
Authors: Berger Raanan , Keizman Daniel , Ish-Shalom Maya , Hammers Hans J. , Eisenberger Mario A. , Sinibaldi Victoria J. , Pili Roberto , Boursi Ben , Maimon Natalie , Gottfried Maya , Hayat Henry , Peer Avivit , Kovel Svetlana , Sella Avishay , Carducci Michael Anthony 
Published: March 2020

e15058 Background: Obesity, smoking, hypertension (HTN) and diabetes (DM) are risk factors for RCC development. Their presence has been associated with a worse outcome of therapy (tx) in various metastatic cancers. We sought to determine their influence on the progression free survival (PFS) and overall survival (OS) of Su tx in mRCC. Methods: We performed an international multicenter retrospective study of pts with mRCC, who were treated with Su. We analyzed the pre-tx status of smoking (active vs past vs never), BMI (obese= BMI≥30 vs overweight=BMI 25-29.9 vs normal weight= BMI <25), HTN, DM, and known prognostic factors including past nephrectomy, clear cell vs non clear cell histology, initial diagnosis to Su tx initiation time, ≥ 2 metastasis (mets) sites, lung/liver/bone mets, ECOG performance status, anemia, calcium level > 10, elevated alkaline phosphatase (AP), pre-tx neutrophil to lymphocyte ratio (NLR) >3, Su induced HTN, use of angiotensin system inhibitors (ASIs), past cytokines/targeted tx, and median Su dose/cycle. PFS and OS were determined by the Kaplan-Meier method. Multivariate analyses using Cox Regression model were performed to determine their independent effect. Results: Between 2004-2011, 244 pts with mRCC were treated with Su. 51 pts were active smokers, 58 obese, 62 diabetic, and 145 had pre-tx HTN. In the entire pt cohort, median PFS was 9 months (mos) and OS 21 mos. Factors associated with PFS were active smoking (HR 2.29, p= 0.003, median PFS 4 vs 10 mos in past smokers vs 12 mos in never smokers), non clear cell histology (HR 1.7, p=0.042), pre-tx NLR >3 (HR 1.92, p<0.0001) and the use of ASIs (HR 0.58, p=0.03). Factors associated with OS were were active smoking (HR 1.85, p= 0.018, median OS 11 vs 25 mos in past smokers vs 27 mos in never smokers), AP (HR 1.9, p=0.017), pre-tx NLR >3 (HR 2.5, p<0.0001), and liver mets (HR 1.86, p=0.021). BMI, DM, and pre-tx HTN were not associated with PFS or OS. Conclusions: Active smoking may decrease the PFS and OS of pts with mRCC that are treated with Su. BMI, DM, and pre-tx HTN were not found to be associated with outcome. These results should be investigated prospectively, and if validated applied in clinical practice and clinical trials.
Beyond metastatic renal cell carcinoma (mRCC) clinical trials: Targeted therapy use and overall survival in community oncology clinics.
Authors: Harrison Michael Roger , George Daniel J. , Walker Mark S. , Hudson Lori L. , Chen Connie , Korytowsky Beata , Stepanski Edward J. , Abernethy Amy Pickar 
Published: March 2020

e15061 Background: Targeted therapies are now the standard of care for mRCC with use and expected outcomes defined by clinical trials. What are "real world" patterns of use and survival outcomes in mRCC patients (pts) treated in community oncology (COMM) settings? Methods: We reviewed a retrospective registry of adult mRCC pts from 11 COMM oncology practices, diagnosed since 1/2007 and not enrolled in a trial. Demographics, disease characteristics, treatment patterns and outcomes were recorded from the EMR and supplemented with chart abstraction.Pts were grouped by treatment sequence reflecting up to 3 exposures based on drug mechanism of action (VEGFR TKI [TKI] or mTOR inhibitor [mTOR]). Other pts received a non-TKI, non-mTOR therapy in the 1st three exposures (e.g., bevacizumab, cytokines, combinations, etc.). No Therapy pts received no systemic therapy as of data analysis. Survival analyses included Kaplan-Meier methods and Cox regression. Results: 255 patient/disease characteristics included: age 65±11 yrs; 68% male; 71% Caucasian; 62% clear cell histology (25% unknown); 1.6 ±0.9 metastatic sites. MSKCC risk was: 28% good, 63% intermediate, 10% poor. Median overall survival (OS) was 12.1 mo (95% CI: 8.7-15.4); median OS by sequence was: No Therapy (n=38; 3.7), mTOR (n=28; 5.2), TKI (n=79; 8.7), mTOR/TKI (n=10; 9.3), TKI/mTOR (n=32; 13.7), TKI/TKI (n=24; 20.7), Other (n=20; 22.5), TKI/mTOR/TKI (N=14; 29.8), TKI/TKI/mTOR (N=10; 33.1). Cox regression identified subgroups with differential outcomes. After significant covariates were controlled, compared with No Therapy, all regimens with TKI as 1st exposure had hazard ratios (HR) <1.0 (range=0.14 – 0.51; all p values ≤ 0.02). Other treatment had HR=0.31 (P=0.001), but when mTOR was the only treatment HR=1.04 (p=0.88). MSKCC scores of intermediate (HR=2.4) or poor (HR=4.5) were a significant risk (p<0.001). Conclusions: Only pts treated with two TKI exposures (≥20.7 mo) approached the best OS seen in trials (26 mo). For mTOR only, 1st line treatment in sicker patients, OS (5.2 mo) was shorter than trials (11 mo). Outcome differences between trial and community practice settings offer insights into opportunities to optimize care.
Retrospective data study evaluating resource utilization among metastatic renal cell carcinoma patients receiving oral versus intravenous mTOR inhibitors.
Authors: Bhor Menaka , Hutson Thomas E. , Dhanda Rahul , Liu Zhimei , Vogelzang Nicholas J. 
Published: March 2020

e15063 Background: The purpose of this retrospective study was to compare healthcare resource utilization among metastatic renal cell carcinoma (mRCC) patients (pts) receiving everolimus (oral mTOR inhibitor), relative to pts receiving temsirolimus (intravenous mTOR inhibitor). Methods: Using US Oncology’s iKnowMed EMR in conjunction with claims and pharmacy data, we identified mRCC pts who initiated a treatment regimen of everolimus or temsirolimus from 2009 –2010 with a minimal six month follow-up period. Healthcare encounters were estimated and presented using the per patient per month metric. Poisson regression models were used to examine the impact of treatment on resource use after controlling for covariates including stage, ECOG status, and insurance type, and were stratified by line of therapy (LOT) as LOT was the most significant different baseline characteristic between the two treatment groups. Results: A total of 461 pts were identified: 143 were treated with everolimus, and 318 with temsirolimus. The everolimus group had lower usage of all types of services than the temsirolimus group and the results were statistically significant for most of the categories as per the bivariate analysis. In the multivariate analysis stratified by LOT and adjusted for baseline characteristics, the temsirolimus group had statistically significant more acute care services (1st line), drug usages (1st and 2nd line), lab visits (2nd and 3rd line), radiation treatment and minor services (2nd line), non-drug and other services (1st, 2nd, and 3rd line), than the everolimus group. Conclusions: Results of this retrospective study suggest that overall everolimus is associated with lower patient burden in terms of health care resource utilization relative to temsirolimus.