bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comorbidity and other predictors of survival in veterans with metastatic renal cell carcinoma (RCC).
Authors: Cho Michael , Wang Trent P , Gonzalez Melanie L. , Chang Victor T , Zhong Fengming , Srinivas Shanthi , Crump Barbara , Paz-Querubin Emma R , McPherson Monica , Blumenfrucht Marvin , Kasimis Basil 
Published: March 2020

e15561 Background: Comorbidity as a prognostic marker has been reported in several solid tumors. We examined whether co-morbidity indices predict survival in Veterans with metastatic renal cell carcinoma (RCC) who were treated with signal transduction inhibitors. Methods: In an IRB-approved protocol, we reviewed the records of patients (Pts) diagnosed with RCC at a VA Medical Center from 1/1/2000 to 12/31/2011. Age, ECOG Performance Status (ECOG PS), Hemoglobin (Hgb), Albumin (Alb), Corrected Calcium (CCa), history of Nephrectomy, and histology (clear cell (CC) vs. non clear cell (NCC)) were abstracted. Co-morbidity was assessed with Charlson Comorbidity Index (CCI), and the Kaplan-Feinstein Index (KFI). We developed a survival model with age, ECOG PS, Hgb, Alb, CCa, history of nephrectomy, and histology. Co-morbidity indices were tested by determining if they were independent predictors of survival after inclusion in this model. Cox regression analyses were performed with SAS V9.2. Results: There were 24 Pts;6 (25%) are alive. The Median (M) age when seen at VA was 64 years (54-85). The M Hgb level was 12.1g/dL (6.7-16.5), Alb was 4.1g/dL (2.8-5.0), and CCa was 9.19mg/dL (7.9-12.5). The M CCI was 4.2 (1.4-12.0) and KFI was 2.0 (1-3). The M Survival was 823 days (24-3482). 17(68%) pts had clear cell carcinoma and 18(72%) had nephrectomies Median ECOG PS was one range(0-4). The median number of treatments was 2, range 1-7. Results of univariate analyses with co-morbidity indices were significant for age (p < ,029) and history of nephrectomy p< .068). There were no multivariate predictors of survival. Conclusions: In the univariate analysis, ECOG PS as well as Nephrectomy status were significant predictors for M survival. CCI and KFI did not predict M survival. In distinction to other solid tumor histologies where chemotherapy is used, KFI and CCI in RCC may not be associated with overall survival due to either RCC histology or use of signal transduction inhibitors as treatment. Confirmatory studies should be done in larger populations. This was supported by the New Jersey Commission for Cancer Research.
Renal cell carcinoma with a novel germ-line mutation in isocitrate dehydrogenase 1 (IDH1) and its functional study.
Authors: Takayama Tatsuya , Kitagawa Mitsuhiro , Takaoka Naohisa , Sugiyama Naoyuki , Igarashi Kaori , Miyazaki Miki , Sugiyama Takayuki , Kai Fumitake , Soga Tomoyoshi , Ozono Seiichiro 
Published: March 2020

e15568 Background: Recently, omics study such as metabolome analysis and whole genome sequencing has been applied to various disorders. We predicted the dysfunction of isocitrate dehydrogenase 1 (IDH1) in renal cell carcinoma (RCC) using metabolome analysis and identified a novel mutation of IDH1. In addition, we examined its function. Methods: We determined the global-scale metabolome profiling of human RCC by capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS), and compared the metabolite levels of tumors and paired normal tissues in 10 patients with RCC. We performed the genotyping of IDH1 and von Hippel-Lindau (VHL) gene. We also performed transfection experiments by using Lipofectamine and measured the enzymatic activity of IDH1 in RCC cell lines. All protocols were performed by the Institutional Review Board (IRB) of Hamamatsu University School of Medicine and Keio University. Informed consent was obtained from the patient in accordance with the IRB of Hamamatsu University School of Medicine. Results: The acceleration of glycolysis with low level of NADPH and citrate in one patient led to IDH1 dysfunction followed by identifying a novel missense mutation, V178I. In transfection experiment, the reductive activity of IDH1 variant (V178I) increased 2.5 times than that of IDH1 wild type while the oxidative activity of IDH1 variant oxidative activity was as well as that of IDH1 wild type. Furthermore, in the metabolome analysis using labeling glutamine, RCC cell lines deficient in the von Hippel-Lindau (VHL) protein preferentially use reductive glutamine metabolism. On the other hand, this patient with V178I mutation of IDH1 had no VHL mutation. Conclusions: Metabolome analysis led to the identification a novel IDH1 missense mutation in RCC. This mutation might be involved with acceleration of reductive reaction in tricarboxylic acid cycle. Metabolome analysis using CE-TOFMS could be a powerful tool for the global-scale exploration of disease-specific metabolism.
Inadequate data availability on clinical trial accrual and its effect on progress in cancer research.
Authors: Mitchell Aaron Philip , Hirsch Bradford Richard , Abernethy Amy Pickar 
Published: March 2020

e15572 Background: Participant accrual is a critical benchmark in clinical research, predicting study completion and reflecting the perceived value of the clinical question and study designed to answer it. Timely accrual data can be used prospectively to inform the design of new clinical trials. Accrual statistics are available within research networks, such as the cancer cooperative groups, but comprehensive data reflecting the overall portfolio of cancer clinical trials are lacking. As a demonstration case, we tested the availability of accrual data across all recent renal cell carcinoma (RCC) studies. Methods: The database for the Aggregate Analysis of ClinicalTrials.gov (CTG) summarizes all trials registered between 10/2007-9/2010. 137 RCC trials were included, of which 108 focused on pharmacologic therapy. Accrual data on these trials were gathered from CTG, online surveys sent to principle investigators, trial coordinators, and/or industry sponsors, review of resulting publications, and follow up phone calls to non-responders. Results: 20 of 76 (26%) trials listing a government, academic, or cooperative group (GAC) sponsor responded to the survey vs 0 of 32 (0%) of those listing only industry (I) sponsors. Across all methods, accrual data were collected for 43 trials (40%), including 28 of 76 (37%) GAC trials and 15 of 32 (47%) I trials. 87% of GAC trials which were ongoing (open, actively recruiting, or of unknown status) vs 75% of I trials. 10 of 108 trials (9%) were closed prematurely. Conclusions: Despite extensive efforts (surveys, phone calls, CTG abstraction, publication searches), accurate accrual data remained inaccessible for 60% of the RCC trial cohort. While CTG reports trial results, ongoing accrual data are also critically needed. Poor access to accrual data will continue to limit attempts to develop a national summary of clinical trials metrics and to optimize the cancer clinical research portfolio. [Table: see text]
Efficacy and toxicity of sunitinib in renal insufficiency patients with metastatic renal cell carcinoma.
Authors: Kim Ki Hyang , Rha Sun Young , Kim Ho Young , Kim Hye Ryun , Sun Jong-Mu , Lim Ho Yeong , Lee Hyo Jin , Lee Suee , Bae Woo Kyun 
Published: March 2020

e15573 Background: We investigated the efficacy and toxicity of sunitinib in renal insufficiency patients with metastatic renal cell carcinoma (mRCC). Methods: From Korean Renal Cell Cancer Registry (KRCCR, http://kcsg-rcc.or.kr), we searched renal insufficiency patients with mRCC treated with sunitinib as a first-line treatment between January 2008 and May 2012. The Crockcroft-Gault formula was used for calculation of glomerular filtration rate and selected patients with chronic renal failure not requiring dialysis. Patients characteristics, clinical outcomes, toxicities were evaluated. The patients were divided by 2 groups based on the National Kidney Foundation definition of renal impairment and overall survival (OS) and progression-free survival (PFS) were obtained. Results: From total 997 enrolled from KRCCR, 34 patients were evaluated. Patients characteristics included: median age 66 years, ECOG performance status of 0 and 1 were 90%, and median GFR 46.5 ml/min/1.73m2 (range, 21.1-59.5). The starting dose of sunitinib was 50 mg for 22 patients and 37.5 mg for 12 patients. A schedule of sunitinib was 4 weeks on-2 weeks off for 31 patients, 2 weeks on-2 weeks off for 1 patient and daily for 2 patients. Best response was partial response (N=8) or stable disease (N=12). The median OS and PFS was 26.3 (95% CI: 17.1-35.3) and 12.2 (95% CI: 10.2-13.2) months, respectively. Log rank analysis revealed that severity of renal impairment was significantly associated with PFS but not with OS. Most common adverse events (AEs) of non-hematologic toxicities were stomatitis, rash, general edema and fatigue. The most common grade ≥3 AEs were fatigue, neutropenia and thrombocytopenia. Conclusions: Renal insufficiency patients with metastatic RCC did not impact on the efficacy of sunitinib and did not increased toxicities. Clinicians should not hesitate to treat renal insufficiency patients with metastatic renal cell carcinoma.
Effect of targeted therapy on renal cell carcinoma with rapid progression.
Authors: Wu Shenhong , Ranpura Vishal Navnitray 
Published: March 2020

e15578 Background: Seven targeted agents so far have been approved for the treatment of advanced renal cell carcinoma (RCC). However, it is not clear whether these agents are effective in patients with rapid progressive disease, which is characterized by progression within three months and associated with poor prognosis. Therefore, we conducted a systematic review and meta-analysis of published randomized controlled clinical trials (RCTs) to assess the effect of targeted therapy on rapid progressive RCC. Methods: Databases from PUBMED, the Web of Science, and abstracts presented at the American Society of Clinical Oncology (ASCO) conferences until October, 2012 were searched to identify relevant studies. Rapid progression was defined as progressive disease or death within 3 months after the initiation of clinical trial. Eligible studies included prospective RCTs in which a targeted therapy was compared to a placebo or cytokine control in RCC patients. Summary incidence, relative risk (RR), and 95% confidence interval (CI) were calculated based on the heterogeneity of included studies. Results: A total of 4,628 patients (targeted therapy: 2,461, control: 2,167) with RCC from 10 RCTs were included for analysis. When compared to controls, the targeted therapy significantly reduced the overall risk of rapid progression (23.6%, 95% CI: 19.2-28.6% versus 54.5%, 95% CI: 44.6-64.1%) with an overall RR of 0.46 (95% CI: 0.38-0.54, P<0.001). The effect did not vary significantly with prior therapies (P=0.67), but varied with different prognostic groups (P=0.025). In addition, the effect varied significantly among different agents (p<0.001), with the highest reduction seen in patients treated with pazopanib (RR=0.27; 95% CI: 0.21-0.35). There was no significant difference between mTOR and VEGF inhibitors (P=0.25) in the risk reduction. Furthermore, the targeted therapy significantly reduced the risk of 3-month mortality (RR 0.58, P=0.002) from 10.0% (95% CI: 5.3-18.1%) to 5.5% (95% CI: 3.3-8.9%) in comparison with controls. Conclusions: The targeted therapy may significantly reduce the risk of rapid progression and early death in patients with renal cell carcinoma. Early application of these agents is recommended.
Meta-analysis of hematologic toxicities in patients with solid tumors treated with everolimus.
Authors: Funakoshi Tomohiro , Latif Asma , Galsky Matt D. 
Published: March 2020

e15580 Background: Everolimus is an orally administered targeted agent that inhibits mammalian target of rapamycin (mTOR) signaling involved in tumor growth and proliferation. Hematologic toxicities associated with everolimus have been reported with a substantial variation in the incidences among clinical studies without a systematic attempt to synthesize these data. We performed a systemic review and meta-analysis of published clinical trials to evaluate the overall risk of everolimus-related hematologic toxicities. Methods: We searched Medline and the American Society of Clinical Oncology online database of meeting abstracts up to December 2012 for relevant clinical trials. Eligible studies included phase II and III trials in patients with solid tumors treated with everolimus that reported adequate safety data profile reporting neutropenia, thrombocytopenia or anemia based on the CTCAE of the NCI. The relative risk (RR), summary incidence and 95% confidence intervals (CI) were calculated. Results: For the incidence analysis, we included a total of 1,090 patients from 14 studies (three phase III and 11phase II trials) considering only arms with everolimus as a single agent. The incidence of everolimus -associated all-grade and high-grade (Grade 3-4) hematologic toxicities were, respectively: neutropenia: 21.7% and 3.7%; thrombocytopenia: 36.0% and 4.7% and anemia: 61.2% and 4.4%. For the RR calculation, seven randomized trials with everolimus in only one of the arms in addition to similar therapy in both arms were available (five phase III and two phase II trials, representing 2,462 patients). Everolimus -treated patients had a significantly increased risk of all-grade neutropenia (RR = 2.24; 95% CI, 1.51–3.32), all-grade (RR = 9.19; 95% CI, 4.51–18.70) and high-grade (RR = 7.46; 95% CI, 2.58–21.61) thrombocytopenia and all-grade (RR = 1.58; 95% CI, 1.25–1.99) and high-grade (RR = 3.92; 95% CI, 1.46–10.52) anemia. RR of high-grade neutropenia was 1.40 (95% CI: 0.70-2.78; p=0.34). Conclusions: Everolimus is associated with a significant increase in the risk of developing all-grade and high-grade thrombocytopenia and anemia and all-grade neutropenia compared with control.
Brain metastases (BM) of nonseminomatous germ cell tumors (NSGCT): What population of patients should be screened?
Authors: Tryakin Alexey , Fedyanin Mikhail , Aleshin Vladimir , Mikhina Zoja , Zakharova Tatiana , Sergeev Urii , Garin Avgust , Tjulandin Sergei 
Published: March 2020

e15583 Background: BM from NSGCT present in 5-15% of pts with metastatic disease. There is no uniform consensus what population of pts with NSGCT should be screened for BM. Methods: Among 1700 pts with metastatic GCT who were treated in our center from 1990 to 2009 we identified 20 (1.1%) pts with BM: 11 pts had BM at initial presentation. No pts with BM of seminoma were identified. The minimal f.-up time after the end of treatment was 24 months. None of 9 pts with BM at relapse had brain imaging initially and 6 (67%) had BM as the only site of relapse. Since 2005 we have started routine brain MRI for all new pts with hCG level above 50000 IU/l. BM were found in 4 (14%) of 28 those pts, incl. 3 pts with asymptomatic BM. Before 2005 there were 38 pts with hCG level above 50000 IU/l and BM were seen in only 3 (7,9%) pts, who had specific symptoms. For further analysis we combined pts with initially presented BM (n=11) and pts who had BM as the only site of relapse (n=6), because in later group BM were obviously missed before 1-st line of chemotherapy. Results: Factors associated with BM were multiple (n>3) pulmonary mets >2cm - all 17 pts, IGCCCG poor prognosis -13 (76%) pts, initial hCG > 50000 IU/l - 9(53%) pts. Among 43 pts with multiple pulmonary mets and hCG > 50000 IU/l 9 (21%) pts had BM: sensitivity 53%, specificity 93%, PPV 21%, NPV 98%. Screening of BM in this population would miss 47% of them. Among 142 pts with multiple pulmonary mets and intermediate or poor IGCCCG prognosis 17 (12%) pts had BM: sensitivity 100%, specificity 76%, PPV 12%, NPV 100%. Conclusions: Pts with elevated hCG level above 50000 IU/l and multiple (n>3) pulmonary mets >2cm have high incidence (21%) of BM. Brain imaging of pts with multiple (n>3) pulmonary mets >2cm and intermediate or poor IGCCCG prognosis is recommended.
Retrospective, correlative study of BRAF mutation V600E in testicular cancer patients.
Authors: Satpute Shailesh R. , Koster Roelof , Nathanson Katherine L. , Vaughn David J. , Albany Costantine , Einhorn Lawrence H. , Hanna Nasser H. 
Published: March 2020

e15584 Background: Presence of BRAF V600E mutation forms the basis of a successful targeted therapy against malignant melanoma. While this mutation is also demonstrated in various other tumor types, its presence in germ cell tumor (GCT) is inconsistent across various studies. In one study, 9 out of 35 (26%) platinum-refractory GCTs were positive for BRAF V600E mutation (Honecker et al, JCO 2009 May 1; 27(13):2129-36). In the current study we tested tumor tissue of patients for BRAF V600E mutation in order to correlate it with known tumor subtypes and treatment outcomes. Methods: We obtained tumor specimen of 59 patients with GCT that were treated at either Indiana University or University of Pennsylvania from 2000 to 2011 and tested them for presence of BRAF V600E mutation by Sanger sequencing with exon 15 specific primers. Out of 59 tumors, 12 (20%) were seminomas and 47 (80%) were non-seminomas. 26 (44%) patients had no recurrence after first line cisplatin-based chemotherapy whereas 33 (56%) patients had either platinum-refractory disease or had a disease recurrence within 2 years of completing chemotherapy. Tumors from 10 patients contained only mature teratoma after chemotherapy. 31 (52%) patients were classified at the time of diagnosis as good risk, 8 (14%) patients as intermediate risk and 20 (34%) patients as poor risk according to international germ cell consensus classification. Results: We found that all 59 tumor tissue were wild-type or lacked BRAF V600E mutation. Appropriate positive and negative controls were used for the assay. Conclusions: BRAF V600E mutation is not a feature of GCT. In our study, we failed to observe any correlation of the mutation with tumor subtypes or with treatment outcomes. Based on this study, BRAF inhibiting drugs may not be beneficial in germ cell tumors.
Effect of CTCAE v4 grading of hypertension on reported toxicity in advanced cancer patients receiving vascular endothelial growth factor (VEGF)-targeting agents.
Authors: Akhtar Naveed Hassan , Singh Beerinder , Ocean Allyson J. , Karpenko Irene , Beltran Himisha , Popa Elizabeta C. , Nanus David M. , Shah Manish A. , Tagawa Scott T. 
Published: March 2020

e15600 Background: The NCI Common Terminology Criteria for Adverse Events (CTCAE) system changed to version 4 in 2009, and several AE categories underwent changes in grading (Gr), including HTN. As many anti-neoplastic agents, particularly those targeting VEGF are associated with HTN, changing in the grading system may result in changes to maximum tolerated or recommended phase II doses in early dose-escalation studies or overall HTN AE reporting across all studies. Methods: We initially reviewed individual patient data of a multicenter phase I/II trial of sorafenib plus gemcitabine and capecitabine for advanced renal cell carcinoma (RCC), which graded AE’s using CTCAE v3. Individual patient (pt) data was reviewed and HTN AE’s were re-graded using CTCAE v4 criteria for up to 12 cycles of therapy on study. A separate (confirmatory) data set in pts with metastatic colorectal cancer (CRC) treated on a phase IIIb study of regorafenib was subsequently analyzed. Results: In the RCC study, only 1 of 23 pts with complete source documents available had stable highest HTN Gr across both CTCAE versions. In the CRC study, 0 of 8 pts had stable Gr. Table 1 compares each individual’s highest CTCAE v3 versus v4 grading of HTN in each study. Across both studies, all pts had HTN AE’s using CTCAE v4. Only 1 pt maintained grading using both versions (Gr 3), with 30 (96.8%) changing grades. Four (12.9%) moved from Gr 0 to Gr 1, fifteen (48.4%) from Gr 0 to Gr 2, five (16.1%) from Gr 1 to Gr 2, one from Gr 1 to Gr 3, and six (19.4%) from Gr 2 to Gr 3. Conclusions: Re-classification of grading in this study demonstrates that only 3.2% maintained stable grading of HTN across systems, with 51.6% increasing by 2 grades. The change in AE reporting criteria has the potential to significantly impact results of clinical trials. This may be particularly important with VEGF-targeted agents, with emerging data pointing towards HTN as a pharmacodynamic marker in pts with RCC, and may affect dosing and AE reporting of other drugs with blood pressure effects. Clinical trial information: NCT00121251, NCT01538680. [Table: see text]
High-dose interleukin-2 therapy for metastatic renal cell carcinoma: A contemporary experience.
Authors: Aboumohamed Ahmed A. , Yarlagadda Naveen , Creighton Terrance , Mehedint Diana , Attwood Kristopher , Kauffman Eric , George Saby , Khushalani Nikhil I. , Pili Roberto , Schwaab Thomas 
Published: March 2020

e15604 Background: Despite recent advances in targeted treatment options, high dose interleukin-2 (HDIL-2) remains an important therapeutic option for metastatic renal cell carcinoma (mRCC). We present a contemporary experience of HDIL-2 in a high-volume, National Cancer Institute (NCI)-designated cancer center. Methods: Patients with mRCC who received HDIL-2 monotherapy as a first- or second-line therapy during 2004-2011 were identified. Patients’ demographics, pathologic variables, renal function, time until start of HDIL-2 therapy, number of cycles given (1-3), best responses (complete response; CR, partial response; PR, stable disease; SD, and progressive disease; PD), and primary RCC treatment were analyzed. Progression free survival (PFS) and overall survival (OS) were determined. Results: Of 176 mRCC patients, 91 patients were treated with HDIL-2 (59 as a primary treatment). Median age was 51 years and 73.9% were males. Median Follow-up was 44.9 months. Majority (92%) of tumors showed clear cell histology, and 14.8% had impaired renal function (creatinine >1.5 mg/dL) prior to treatment. Patients with impaired initial renal function were more likely to get more treatment cycles (2-3) than those with adequate initial kidney function (92.3% vs.50.6%, respectively; p=0.002). Eighteen (20.5%) patients underwent cytoreductive nephrectomy. Lower tumor stage at diagnosis correlated with better treatment response (p=0.023), but with longer time from diagnosis to initiation of HDIL-2 (p=0.011). Prominent therapy complications included hypotension (67.4%), renal impairment (63%), impaired liver function (42.4%), and thrombocytopenia (31.5%). None needed hemodialysis for IL-2 induced renal toxicity, and all regained their pre-treatment baseline kidney functions after therapy. Four patients (4.5%) had CR, 11.4% had PR, and 31.8% had SD. Median PFS and OS were 8.6 and 35.5 months, respectively. Estimated 2-year OS rate was 60.6%. Conclusions: Incorporating HDIL-2 therapy in treatment strategies of patients with mRCC added to the patients’ survival in this contemporary series. HDIL-2 therapy appears to be well tolerated in patients with preexisting renal impairment with no long term renal toxicity.