bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activity of cabozantinib (XL184) in patients (pts) with metastatic, refractory renal cell carcinoma (RCC).
Authors: Choueiri Toni K. , Pal Sumanta Kumar , McDermott David F. , Ramies David A. , Morrissey Stephanie , Lee Yihua , Miles Dale , Holland Jaymes S. , Dutcher Janice P. 
Published: February 2017

364 Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2 that is currently undergoing clinical efficacy evaluation in several oncology indications. Renal cell carcinoma (RCC) was chosen as an indication in this drug-drug interaction (DDI) study based on involvement of the MET and VEGFR signaling pathways in this disease. The primary objective of this study is to determine the effect of cabo on single dose PK of the CYP2C8 substrate rosiglitazone (rosi). The exploratory objective of this study is to evaluate the preliminary antitumor activity of cabo in pts with RCC. Methods: Eligible pts were required to have RCC with clear cell components with metastases, Karnofsky performance status of ≥70 and measurable disease by RECIST. Pts needed to have experienced PD following standard therapies. Method for DDI study: Day 1, 4 mg rosi; Days 2 - 22, cabo given daily at a dose of 175 mg; Day 22, 4 mg rosi to complete PK assessment for DDI. Cabo continued until PD. On Day 57 and every 8 weeks thereafter subjects underwent tumor assessments by mRECIST. Results: Enrollment is complete at 25 RCC pts with a median of 2 prior regimens; 17/25 (68%) RCC pts had received ≥ 2 lines of prior therapy and 13/25 (52%) with at least 1 VEGF pathway inhibitor and 1 mTOR inhibitor. All pts were intermediate (24/25) or poor (1/25) risk category per Heng et al prognostic strata (JCO 2009). Related AEs ≥ Grade 3 severity: hypophosphatemia 8 (32%), PE 3 (12%; all were incidental / resolved) and diarrhea 3 (12%). Preliminary PK data suggest that clinically relevant doses of cabo do not markedly alter the Cmax or AUC0-24h of rosi consistent with lack of inhibition of CYP2C8. RCC pts with confirmed PR by mRECIST: 6/25 (24%). Additionally, 1 pt had an unconfirmed PR. Disease control rate (PR + SD): 68% at 16 weeks; 18/21 (86%) pts with ≥1 post-baseline scan experienced tumor regression (range: 4 – 63% reduction in measurements). 14/25 (56%) remain on cabo with a median follow-up of 4 months. Median PFS and OS have not been reached. Conclusions: Cabo demonstrates encouraging anti-tumor activity in heavily pretreated pts with RCC with a toxicity profile similar to that of other TKIs. Preliminary data suggest no DDI between cabo and rosi (CYP2C8 substrate).
A prospective trial assessing the effects of clamp ischemia during partial nephrectomy on renal function, biomarkers, and structure.
Authors: Ercole Barbara , Torkko Kathleen , Hilton William , Devarajan Prasad , Venkatachalam Manjery A. , Weinberg Joel M. , Parekh Dipen J. 
Published: February 2017

367 Background: Tolerance of the human kidney to clamp ischemia (CI) during partial nephrectomy (PN) has been considered to be limited to 20–30 min. We determined the utility of new biomarkers for following renal injury in this setting. Methods: 40 patients undergoing open PN without ( N=27, avg clamp time 32.3 min, range 15–53 min., 74% > 30 min.) or with cooling ( N=13 avg clamp 48 min. range 30–61 min.) had biopsies of uninvolved areas of the kidney preclamp, during clamping and 5 min. after clamp release, along with serial measurements of standard renal functional parameters plus measurement of serum cystatin C and NGAL, and of urine NGAL, cystatin C, NAG, LFABP, NGAL, KIM-1 and IL-18. Results: Serum creatinine transiently increased at 24 hours by 21.9±6.4% after warm CI and 27.2±7.9% after cold CI (Ps < .001), but serum cystatin C did not change and plasma NGAL was minimally affected. Urine biomarkers increased irrespective of whether they were factored for creatinine, with particularly large changes in KIM-1 and LFABP, but did not correlate with duration of CI, the change in creatinine at 24 hours, or the use of cold or warm CI. Ultrastructure and staining for actin, phosphotyrosine, B1 integrin, and ICAM-1 showed changes consistent with CI, but much milder than predicted from animal models. Creatinine has remained stable in the patient cohort at up to 18 months of follow-up. Conclusions: The data indicate that the insult to the clamped kidney from 30–60 minutes of CI under conditions of open partial nephrectomy is well tolerated despite increases of urinary biomarkers, which may in part reflect local effects of the surgery itself, expand indications for PN in the management of renal cancers, and support the use of CI as opposed to more complex procedures for PN.
What is the best treatment option for second line in long responders to the first-line TKI in metastatic renal cell carcinoma (mRCC) patients (pts): TKI-TKI or TKI-mTORi? A European retrospective study.
Authors: Elaidi Reza-Thierry , Beuselinck Benoit , Maj-HES Agnes , Carmier Delphine , Bamias Aristotelis , Debruyne Philip R. , Porta Camillo , Roca Sophie , Oudard Stephane 
Published: February 2017

375 Background: The question regarding the benefit of a TKI rechallenge versus switch to an mTOR inhibitor (mTORi) in mRCC pts who responded to a previous line of TKI remains unanswered and is a common dilemma in clinical practice. We report results of a retrospective study to address this question. Methods: This study retrospectively investigated Duration of Treatment (DT), best radiological response (OR) and predictive factors in pts treated with either TKI-TKI or TKI-mTORi sequences for clear-cell mRCC. Eligibility criteria: 1 TKI in 1st line (L1) followed by another TKI or mTORi as 2nd line (L2). Prior immunotherapy was allowed but not intermediate lines with other drugs. Pts characteristics and Heng’s prognostic factors were collected at each line initiation. Response (resp) was classified with regard to DT and OR using 2 different definitions: def1 = Non Responders (NR): < 4months (m) + PD; Short-Term responders (STR): [4–6]m + SD/PR, Long-term Responders (LTR): >6m + SD/PR, and def2 = NR: < 4m + PD, STR: [4–12]m + SD/PR, LTR: >12m + SD/PR. Results: 127 pts from 7 European centers were retrospectively analyzed. Based on def1, resp to L1 was: LTR=93, STR=20, NR=14; among LTR pts, 54 received a L2=TKI and 39 a L2=mTORi. Based on def2, resp to L1 was: LTR=59, STR=53, NR=15; among LTR pts, 35 received a L2=TKI and 24 a L2=mTORi. Whether def1 or def2, resp (L1 and L2) was never related to Heng’s score. Among LTR pts at L1, 26 out of 54 were LTR after L2=TKI vs 18 out of 39 after L2=mTORi (p=0.85, Z-test) for def1 and 9 out of 35 were LTR after L2=TKI vs 6 out of 24 after L2=mTORi (p=0.95) for def2 (see table). For both def1 and def2, median DT was 7.2m and 6.9m for L2=TKI and L2=mTORi, respectively (p=0.86 and p=0.95, Log-Rank). Conclusions: Results suggest that long-term responders on 1st line TKI could benefit both from TKI and mTORi as 2nd line and there is no evidence to favor one sequence over the other. [Table: see text]
Everolimus in patients with metastatic renal cell carcinoma refractory to VEGF-targeted therapy: REACT subgroup analysis of prior therapy.
Authors: Larkin James M. G. , Blank Christian U. , Bono Petri , Gogov Svetozar , Panneerselvam Ashok , Garay Carlos A. , Grünwald Viktor ,   on behalf of the REACT Study Group
Published: February 2017

391 Background: Efficacy of everolimus (EVE) in metastatic renal cell carcinoma (mRCC) refractory to vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI) therapy is well established. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to provide patients with VEGFR-TKI-refractory mRCC access to EVE in advance of regulatory approval. Methods: REACT, an open-label, international, expanded-access clinical trial (Clinicaltrials.gov: NCT00655252 ) enrolled patients with measurable or nonmeasurable mRCC of any histology who were intolerant of, or progressed while on, VEGFR-TKI therapy. Long-term safety of EVE 10 mg/day in patients with mRCC, as determined by overall incidence of grade 3/4 and serious adverse events (AEs) was documented. RECIST-defined tumor response was also assessed by local investigator. Subgroup analyses evaluated effect of prior treatment on safety and efficacy of EVE. Results: Of 1367 patients enrolled, most (92.7%) had progressed on prior VEGFR-TKI therapy, and some (24.4%) were VEGFR-TKI intolerant. Across patient subgroups by prior VEGFR-TKI treatment, median EVE treatment duration was similar (Table). Best overall response rates were similar in the VEGFR-TKI-intolerant subgroup and overall populations: respectively, 1.8% and 1.7% had partial response (PR) while 53.5% and 51.6% had stable disease (SD). Incidence of grade 3/4 AEs across all prior treatment subgroups were similar to those of the overall population. (See table.) Conclusions: Patients enrolled in REACT derived benefit from EVE irrespective of prior VEGFR-TKI therapy, including VEGFR-TKI-intolerant patients. EVE is well tolerated and affords disease stabilization in the majority of patients with VEGFR-TKI-refractory mRCC, and is the standard of care in this patient population. [Table: see text]
A phase II study of S-1 for the treatment of cytokine and/or tyrosine-kinase inhibitor (TKI) refractory metastatic renal cell carcinoma: Updated results.
Authors: Tomita Yoshihiko , Shinohara Nobuo , Mizokami Atsushi , Fujisawa Masato , Hashine Katsuyoshi , Nishikido Masaharu , Nakagawa Masayuki , Akaza Hideyuki , Tsukamoto Taiji , Naito Seiji 
Published: February 2017

393 Background: S-1 is an oral anticancer agent combining tegafur, a prodrug of 5-fluorouracil (5-FU), with 5-chloro-2,4-dihydroxypyridine and potassium oxonate. S-1 has shown efficacy for cytokine and/or tyrosine-kinase inhibitor (TKI) refractory metastatic renal-cell carcinoma (mRCC). We report the final results of a phase II study and evaluate 5-FU-related enzymes as a predictor of the response to S-1. Methods: 45 patients received S-1 at a dose of 40 mg/m2 twice daily for 28 days, followed by 14 days of rest. The primary endpoint was the objective response rate (ORR). The secondary endpoints of progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Formalin-fixed, paraffin-embedded specimens obtained by radical nephrectomy were used for mRNA expression assay, performed by reverse-transcriptase polymerase chain reaction. Results: 45 patients including 6 were progressed after TKI were enrolled from April 2006. 24 patients received more than 5 cycles, and 2 continued to receive S-1 as of October 2011. Two (4.4%) of the 45 patients had complete responses to S-1, 9 (20.0%) had partial responses, and 28 (62.8%) had stable disease. The final PFS and OS were 9.2 and 42.8 months, respectively, and the PFS of TKI refractory patients was approximately two times of final PFS (18.0 months). The most common grade 3-4 adverse events according to CTCAE v.3.0 were similar to the previous report except for hemoglobin decreased and fatigue. On mRNA expression analysis, the expression level of thymidylate synthase correlated with ORR and PFS. On the other hand, OS did not differ significantly between patients with low expression and those with high expression of 5-FU-related enzymes. Conclusions: S-1 is effective and well tolerated in patients with cytokine and/or TKI refractory mRCC. Moreover, long-term treatment with S-1 is safe in mRCC patients enabling long-term disease control, especially in TKI refractory patients. Clinical trial with large number of TKI refractory patients is warranted to determine the efficacy of S-1.
The usefulness of serum X-linked inhibitor of apoptosis protein (XIAP) for predicting recurrence of renal cell carcinoma.
Authors: Hongo Fumiya , Toiyama Daisuke , Ueda Takashi , Kimura Yasunori , Nakamura Terukazu , Mikami Kazuya , Takaha Natsuki , Miki Tsuneharu 
Published: February 2017

396 Background: The X-linked Inhibitor of Apoptosis protein (XIAP) is associated with cell survival by blocking caspase-mediated apoptosis. We have reported the expression and prognostic value of XIAP in human prostate cancer using prostate tissue microarrays (Clin Cancer Res 2007). The expression and prognostic significance of XIAP in renal cell cancer (RCC) has been rarely studied. To our knowledge, no report on the serum XIAP levels from RCC patients has been published. In this study, we examined serum XIAP levels of RCC patients and normal individuals and evaluated its utility as biomarker. Methods: Peripheral blood samples were obtained from 99 patients (68 men and 31 women, median age; 60.7 years [36–85]) with RCC before surgery. All the patients underwent radical or partial nephrectomy. Blood samples were also collected from 52 healthy controls. The histological grade was as follows: Grade1; n= 5, Grade2; n=72, Grade3; n= 22. The serum XIAP levels were measured by a sandwich enzyme-linked immunosorbent assay. Cut off value was calculated by ROC analysis. Results: The serum XIAP levels in patients with RCC were higher than those of normal control individuals (328.3 pg/ml vs 156.2 pg/ml, P<0.001). At a median follow up of 33 months (1-105M), tumor with low serum XIAP showed significantly longer progression free survival (PFS) than those with high serum XIAP in Grade 1-2 group (P<0.001). Conclusions: Serum XIAP level is associated with recurrence and prognosis. These results suggest that it may be used as a novel prognosticator and a potential target for renal cell cancer diagnosis and therapy.
Patients with metastatic renal cell carcinoma treated with everolimus in REACT: Hyperglycemia and hypercholesterolemia and associated outcomes.
Authors: Bono Petri , Gogov Svetozar , Panneerselvam Ashok , Garay Carlos A. , Grünwald Viktor ,   on behalf of the REACT Study Group
Published: February 2017

407 Background: Correlation between specific adverse events (AEs) and clinical efficacy of targeted therapies in the treatment of patients with metastatic renal cell carcinoma (mRCC) has been noted. Subanalyses of REACT (RAD001 Expanded Access Clinical Trial in RCC) evaluated potential association of hyperglycemia and hypercholesterolemia with outcomes in patients with mRCC treated with everolimus (EVE). Methods: The open-label, international, expanded-access clinical trial REACT (Clinicaltrials.gov: NCT00655252 ) evaluated long-term safety and efficacy of EVE 10 mg/day in patients with mRCC who were intolerant of, or progressed while on, VEGFR-TKI therapy. Based on Common Toxicity Criteria AE v3.0 criteria, all grade 3/4 AEs and any grade 1/2 AEs resulting in study drug modification, temporary interruption, or treatment discontinuation were collected. Subgroup analyses of patients who developed hyperglycemia or hypercholesterolemia of any grade were performed. Results: There were 1364 patients enrolled in REACT, of whom 78 developed hyperglycemia and 14 developed hypercholesterolemia. Median EVE treatment duration was longer for patients who developed hyperglycemia or hypercholesterolemia than for the overall population (19.14, 19.71, and 14.0 weeks, respectively). Overall, 30.3% of REACT patients remained on EVE for ≥6 months compared with 42.3% and 35.7% of patients with hyperglycemia and hypercholesterolemia, respectively. Best overall response was stable disease in 51.6% (overall) compared with 65.4% of patients with hyperglycemia and 71.4% of patients with hypercholesterolemia. Conclusions: Most patients with hyperglycemia and hypercholesterolemia remained on EVE longer than the overall REACT population, suggesting these AEs do not lead to permanent EVE treatment discontinuations. Hyperglycemia and especially hypercholesterolemia were observed in low numbers of patients, but may be associated with improved response to EVE treatment and should be further explored as putative biomarkers for mTOR inhibition.
Assessment of a cell-line-derived HIF1α gene signature in tumor tissue from a metastatic renal cell carcinoma (RCC) trial of pazopanib.
Authors: Gagnon Robert C. , Liu Yuan , Choueiri Toni K. , Martin Anne-Marie , Rosenberg Jonathan E. , Signoretti Sabina , Pandite Lini N. 
Published: February 2017

408 Background: Microarray and clinical data from a randomized phase II RCC clinical trial were evaluated to examine the HIF1α kidney cancer gene signature developed from cell lines by Shen et al (Cancer Discovery 2011). Methods: Archival FFPE tumor samples were collected from patients (pts) enrolled in a Phase II RCC study of pazopanib (Hutson, JCO 2009). RNA was isolated and microarray analysis was performed at Response Genetics, Inc. (Los Angeles, CA) using the Affymetrix (Affy) U133 plus Array. Affy data were normalized using the MAS5 algorithm. Genes (n=69) identified from experiments in 10 cancer cell lines were mapped to genes on the U133 array. Patterns of expression (exp) among the mapped genes were assessed using multivariate analyses. Putative patterns were assessed for association with HIF1α gene exp levels, and both patterns and HIF1α levels were assessed for association with response rate (RR) (RECIST), and PFS, using nonparametric and Kaplan-Meier analyses. Gene set enrichment analysis (GSEA) was applied to determine if mapped genes were enriched for HIF1α gene exp. Results: RNA was available for 46 of 225 patients; baseline characteristics were similar to the overall study. 41/46 patients had VHL heterozygous mutations; 5/46 patients were VHL wild type. HIF1a gene expression was detected in all 46 patients. 64/69 genes were mapped to the Affy platform. For genes which mapped to multiple probes, the probe closest to the 3` end was used. A potential 4 cluster pattern was identified. These clusters were associated with HIF1α gene exp, but neither clusters nor HIF1α gene exp were associated with clinical response to pazopanib. Conclusions: The observed pattern of gene exp among 46 pts with available data from a Phase II RCC study of pazopanib is consistent with the cell line derived gene set proposed by Shen et al. Patterns are associated with HIF1α exp; neither patterns nor HIF1α exp are associated with clinical response in this small subset of pts. These data support the on-going efforts in bench-to-bedside research.
Time to ADT and chemotherapy initiation for treatment of metastatic prostate cancer (mPC).
Authors: Perlroth Daniella J. , Thompson Stephen F. , Luna Yesenia , Goldman Dana P. , Mozaffari Essy , Lakdawalla Darius N. 
Published: February 2017

41 Background: ADT and chemotherapy use in men with mPC may differ across regions in community practice. The extent of variation could indicate whether men with mPC have appropriate access to effective treatments. Methods: We identified 16,024 men diagnosed with mPC in the Surveillance, Epidemiology, and End Results (SEER) database from 2000-2005 linked to their Medicare claims. Patients were excluded if they had a second cancer or disenrolled from Medicare Parts A or B (n=6,155), or failed to initiate therapy with ADT (n=3,400). We identified demographic and clinical information from SEER and treatments and comorbidities from J-codes and ICD-9 codes in the Medicare claims. We used regression models to estimate the probability of advancement to chemotherapy, the time from diagnosis to first ADT use, and time from first ADT to chemotherapy. Then the patient-level predicted results from these models were used to generate summary statistics by hospital service area (HSA). Results: There were 6,469 patients remaining after exclusion who were treated with ADT, and 1,198 of those received chemotherapy (19%). The median age was 76 years old, most were white (77%), married (62%), and 50% had 1 other major comorbidity (most frequent was diabetes, 21%). Men who were younger, married, with fewer comorbidities, and higher Gleason scores were statistically more likely to both receive chemotherapy and use it earlier. After adjusting for clinical and sociodemographic factors, the average time to ADT by referral region was 2.7 months but varied from 1.3 to 5.6; probability of progression to chemotherapy averaged 19% but varied from 6% to 30%, and the time from first ADT to chemotherapy averaged 19.7 months but varied from 12.9 to 25.7 months. The difference in time to ADT between regions in the 10th and 90th percentiles of use was 2.6 months, whereas for chemotherapy initiation, it was 12.4 months. Conclusions: Our results suggest that living in different parts of the country has a substantial impact on how clinically similar patients are treated. There was substantial variation across regions in use of and time to initiation of chemotherapy for men with mPC, but not in ADT use.
The effect of cytoreductive radiofrequency ablation (cRFA) on results of therapy with sunitinib or interferon-alpha (IFN) in metastatic renal cell carcinoma (RCC) patients with a small primary tumor.
Authors: Tsimafeyeu Ilya , Chung Bin , Zart Janie S. ,   KCRB Group
Published: February 2017

414 Background: At least 5% of the patients (pts) with small primary RCC initially present with metastasis. The main objective of this trial was to evaluate the role of cRFA in metastatic RCC pts with small primary tumor treated with immuno- or targeted therapy. Methods: Three parallel single-arm prospective studies were conducted. Eligibility criteria were nearly identical for all trials, and included histopathologically confirmed RCC; metastatic measurable disease; size of primary tumor ≤5 cm; good prognosis by MSKCC model; no previous therapy. Study 1: Pts were treated with percutaneous cRFA under CT guide and following IFN, 9 MIU, s.c, 3 tiw. Study 2: Pts received cRFA and following sunitinib in repeated 6-week cycles of 50 mg/day for 4 weeks, followed by 2 weeks off. Study 3: Pts with unresected primary RCC received sunitinib alone. The primary endpoint was a 33% increase in progression-free survival (PFS) over expected 5 months in study 1 and over expected 11 months in studies 2-3 (power 80%; significance .05). Sample size was 38 pts for each study. Results: Studies were comparable by baseline patient characteristics (age, gender, histology, ECOG PS, number of metastatic sites, primary tumor size). Efficacy data for 114 evaluable pts showed an objective response rate (ORR) of 8% (95% CI 4.5, 10.5) for study 1, 28.9% (95% CI 15.2, 34) for study 2, and 31.6% (95% CI 20.3, 38.9) for study 3; median PFS of 9.1 (95% CI 6.9, 10.2), 13.4 (95% CI 9.8, 14), and 12.7 (95% CI 11.3, 13.5) months for studies 1-3, respectively. ORR and PFS were significantly higher in sunitinib trials comparing with study 1 (P<.01 all differences); no differences were found between studies 2 and 3 (ORR, P=.1; PFS, P=.6). The study 1 met its primary end point, showing that PFS was significantly increased. There were no unexpected toxicities of medical treatment and complications of cRFA. Conclusions: cRFA is a safe and effective approach for select patients with metastatic RCC treated with immunotherapy. Cytoreductive ablative technique did not improve PFS in pts treated with sunitinib. Sunitinib was effective in metastatic RCC pts with unresected small primary tumor.