bluuebunny/crossref_metadata_2025_split huggingface dataset:
An evaluation of abemaciclib activity in combination with sunitinib in renal cell carcinoma.
Authors: Holder Sheldon L. , Small Jeffrey 
Published: March 2017

452 Background: The majority of therapeutic agents used in renal cell carcinoma (RCC) target the vascular endothelial growth factor and mammalian target of rapamycin pathway. Exceptions include the immunotherapy agents interleukin-2 and nivolumab. To change the natural history of RCC and improve upon current treatment regimens we believe new therapeutic targets are necessary. CDK4/6 and PIM1 kinase have both been identified as possible therapeutic targets in RCC. Abemaciclib is a potent inhibitor of both CDK4/6 and PIM1 kinases. We have demonstrated that abemaciclib causes increased apoptosis and decreased cellular viability in RCC cell lines and tumor responses in mice (submitted). Here we report the results of an additional pre-clinical study of the effects of abemaciclib alone and in combination with sunitinib. Methods: Tumors were established in nude mice by subcutaneous flank injection of 786-O cells. Tumors were allowed to establish and grow to about 1 cm. Mice were treated by oral gavage with vehicle, sunitinib, abemaciclib, or combination. Tumors were measured with calipers to determine response. Mice that received sunitinib were subsequently treated with combination therapy and response determined by caliper measurement. At the conclusion of the course of treatment mice were euthanized and the tumors removed, weighed, fixed, and embedded in paraffin. Results: Mice treated with vehicle had continued tumor growth during the course of therapy. Mice treated with sunitinib showed mostly disease stabilization, paralleling the response seen in clinic. Mice in the abemaciclib cohort showed gradual decline in tumor size over the course of treatment. Mice in the combination therapy cohort exhibited a rapid reduction in tumor size with sustained response. Interestingly mice in the sunitinib cohort experiencing stable disease or growing tumor had rapid decrease in tumor size with the initiation of combination therapy. Conclusions: Abemaciclib is active in a mouse model of RCC. The combination of abemaciclib/sunitinib causes rapid reduction in tumor size in treatment naïve and sunitinib pre-treated mice. These data support the use of combination abemaciclib/sunitinib therapy in a human clinical trial.
Development of a prognostic nomogram for liver toxicity in patients treated with pazopanib.
Authors: Kattan Michael W. , Van Der Graaf Winette T.A. , Powles Thomas , Lam Simon , Ahmad Qasim , Dezzani Luca , Han Jackie , Sternberg Cora N. 
Published: March 2017

455 Background: Potential liver toxicity associated with pazopanib treatment has provided a challenge for decision-making regarding patient selection and monitoring. The goal of this study was to develop a tool for predicting liver toxicity for patients receiving pazopanib. Methods: Data was pooled from several clinical trials in patients with renal cell carcinoma, soft tissue sarcoma, or ovarian carcinoma; the dataset consisted of 2,051 patients treated with pazopanib in these trials. Liver toxicity was defined as an ALT level > 3 times the upper limit of normal (ULN) and a bilirubin level > 2 times ULN. Predictors of hepatotoxicity included were age, gender, race, hypertension, performance status, indication (tumor type), prior antineoplastic treatment, concomitant treatment with CYP450, P-gp, or BCRP inhibitors, and baseline clinical characteristics of weight, ALT, AST, ALP, and bilirubin. The statistical modeling was performed using logistic regression. Continuous predictors were modeled with restricted cubic splines to permit potentially nonlinear effects. The performance of the model was evaluated using discrimination (measured by concordance index) and calibration (assessed graphically). Results: Calibration plots suggested adequate congruence between predicted probabilities and actual proportions of liver toxicity. The model had a bootstrap corrected concordance index of 0.739. The calibration of the model was excellent for predicted probabilities up to 30% (Table). The prediction model was represented as a nomogram. Conclusions: This appears to be the first nomogram that predicts, with reasonable accuracy, liver toxicity in patients receiving pazopanib based on their baseline clinical characteristics. Although nomograms are limited by the degree of uncertainty that is inherent in the estimates of probability, the findings may aid clinicians in selecting patients for treatment and monitoring. Validation in a separate dataset is needed to confirm the nomogram’s accuracy. [Table: see text]
Clinicopathologic characterization and outcomes for patients with renal medullary carcinoma: Results from the National Cancer Database.
Authors: Zaid Harras B. , Thompson Robert Houston , Leibovich Bradley C. , Parker William P. , Costello Brian Addis , Pagliaro Lance C. , Boorjian Stephen A. 
Published: March 2017

456 Background: Renal medullary carcinoma (RMC) is a rare, aggressive malignancy for which relatively limited characterization exists to date. We evaluated clinicopathologic features, treatment patterns, and variables associated with outcomes for patients with RMC. Methods: We reviewed the National Cancer Database to identify patients diagnosed with RMC between 1998-2012. Overall survival (OS) was estimated using the Kaplan-Meier method. Clinicopathologic features associated with all-cause mortality (ACM) were assessed using Cox regression analysis. Results: We identified 153 patients with RMC, comprising approximately 0.04% of renal malignancies during this time period. Median age at diagnosis for RMC was 24 years (IQR 20, 31). The majority of RMC patients were black (135; 88%), male (108; 71%), and presented with unilateral, right-sided tumors (101; 66%). Notably, nearly half (72; 48.9%) presented with metastatic disease. A total of 92 (64.3%) patients underwent radical nephrectomy (RN), and 2 (1.3%) were treated with partial nephrectomy. Pathologic stage at nephrectomy was ≤pT2 in 30 patients (32.6%), pT3 in 43 (46.7%), pT4 in 7 (7.6%), and N+ in 50 (55.6%). Of the patients who underwent RN, 60 (65.2%) received multimodal therapy (MMT), including radiation (3; 3.3%), systemic therapy (49; 53.3%), and radiation + systemic therapy (8; 8.7%). Of the 59 patients who did not undergo surgical resection, the majority (46; 77.8%) presented with M1 disease. Median OS was 7.8 months for the entire RMC cohort, with 1- and 3-year OS of 34% and 11%, respectively. Notably, median OS for patients presenting with M1 and M0 disease was 5.2 months versus 11.2 months, respectively (p< 0.01). On multivariable analysis, treatment with RN (HR 0.40; p=0.003) or RN+MMT (HR 0.44; p<0.001) were associated with decreased ACM, whereas the presence of metastatic disease at diagnosis remained associated with an increased risk of ACM (HR 1.74; p=0.02). Conclusions: The prognosis for patients with RMC is dismal, with a median OS under 8 months. Further studies, including the development of novel therapies, are needed to establish the optimal multimodal management approach for these patients.
Dose adjustment of axitinib based on AUC in sunitinib-pretreated metastatic renal cell carcinoma.
Authors: Miura Yuji , Imamura Chiyo K. , Uchino Keita , Kishida Takeshi , Matsubara Nobuaki , Shinojima Toshiaki , Kondo Keiichi , Hongo Fumiya , Yoshimura Kenichi , Tanigawara Yusuke , Takano Toshimi 
Published: March 2017

457 Background: Axitinib is one of the standard second-line therapies after sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC). The previous study showed that higher exposure and diastolic blood pressure (dBP) were independently associated with better clinical outcomes. However, many factors, such as antihypertensive agents use, usually affect dBP. Therefore, axitinib dose adjustment based on its exposure could be more adequate than that based on dBP. Methods: We conducted a prospective phase II trial of axitinib dose adjustment for Japanese pts with mRCC previously treated with sunitinib. Starting dose of axitinib was 5 mg BID. We assayed blood axitinib levels on day 1 and calculated the area under concentration-time curve from 0 to 12 hours (AUC0-12). We determined the individual sufficient dose (SD) to reach AUC0-12 value at the steady state of 150 ng*hr/mL. After day 15, axitinib dose was adjusted to keep over SD according to adverse drug reaction for each patient. The primary endpoint is 6-month progression-free survival (6m-PFS) rate. Secondary endpoints include toxicity and objective response rate. With power of 80% and one-sided alpha of 10%, thirty-two pts were required to reject 48% of 6m-PFS rate under expected 69% 6m-PFS rate. Results: Between May 2013 to March 2015, 26 pts were enrolled when the trial closed for poor accrual. Pts’ characteristics were: median age 71 years, male 20 (77%), PS 0 19 (73%), and International Metastatic RCC Database Consortium intermediate risk 24 (92%). Median SD of axitinib was 3 mg BID (range 1-16). SD was given at a median of 78% (range 0-100) of total administration day until 6 months. Two pts did not receive the planned SD because their SD was over 10 mg BID. Therefore, the two pts were excluded from safety analysis; meanwhile all pts were included in efficacy analysis. The 6m-PFS rate was 85% (95% CI 66-94, p < 0.01). The median PFS was 10.6 months (95% CI 7.2-16.7). The most common grade 3 to 4 adverse events during the first 6 months were hypertension (79%), decrease appetite (29%), fatigue (13%), and hand-foot syndrome (13%). Conclusions: The individual dose adjustment of axitinib to keep over 150 ng*hr/mL of AUC0-12 on day 1 for sunitinib-pretreated mRCC is feasible. Clinical trial information: UMIN000009579.
Impact of antibiotics on outcome in patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors.
Authors: Derosa Lisa , Routy Bertrand , Enot David , Baciarello Giulia , Massard Christophe , Loriot Yohann , Fizazi Karim , Escudier Bernard J. , Zitvogel Laurence , Albiges Laurence 
Published: March 2017

462 Background: Preclinical data demonstrated that microbiota modulates activity of immune checkpoint inhibitors (ICB) and broad-spectrum antibiotics (ATB) damper their efficacy. However, the impact of ATB in patients (pts) treated with ICB remains unknown. Our study evaluates the effect of ATB use in metastatic renal cell carcinoma (mRCC) pts treated with ICB. Methods: We conducted a retrospective analysis of mRCC pts treated in prospective trials at Gustave Roussy with PD1/PD-L1 inhibitors alone or in combination. ATB (+)/(-) group were defined as pts treated or not with ATB at baseline (up to 1 month prior to the 1st injection of ICB). Progression-Free survival (PFS), Objective Response Rate (ORR), and Overall Survival (OS) were compared in each group (ATB (+) vs ATB (-)). Statistical analyses were performed using Kaplan-Meier method and Cox regression adjusted for risk factors. Results: We enrolled 80 mRCC pts treated with anti-PD-1/PD-L1 monotherapy (n=67), anti-PD-1 plus CTLA-4 (n=10) or anti-PD-L1 plus bevacizumab (n=3) with available data on ATB. Majority of pts were male (65%), clear-cell histology (88%), and had prior nephrectomy (80%). With regard to IMDC risk groups, 21%, 57%, and 22% had favorable, intermediate, and poor-risk disease, respectively. Sixteen (20%) pts belonged to the ATB (+) group (mostly receiving beta-lactamases and fluoroquinolones). ATB (+) had decreased PFS compared to ATB (-), 2.3 vs. 8.1 months, p<0.001. This statistical association was maintained after multivariate analysis adjusted for age, gender, IMDC risk groups, tumour burden and proton pomp inhibitors. In addition, ORR was lower in ATB (+) compared with ATB (-) (p<0.002). Even though it is too early to conclude on OS (median follow-up <6 months), there was already a negative trend driven in ATB (+). Conclusions: This is the first analysis evaluating the impact of ATB in mRCC pts treated in the era of ICB. Recent use of ATB prior to ICB, negatively influences responses even after multivariable analysis for prognostic risk factors. Further studies are warranted to investigate whether the alteration of gut microbiota compositions is responsible for this different outcome.
Individualized treatment with sunitinib versus standard dosing with sunitinib or pazopanib in patients with metastatic renal cell carcinoma (mRCC): Results from the Canadian Kidney Cancer information system (CKCis).
Authors: Basappa Naveen S. , Lalani Aly-Khan A. , Li Haocheng , Kalirai Austin , Wood Lori , Kollmannsberger Christian K. , Sim Hao-Wen , Kapoor Anil , Hotte Sebastien J. , Czaykowski Piotr , Canil Christina M. , Reaume M. Neil , Bjarnason Georg A. , Vanhuyse Marie , Soulieres Denis , Levesque Eric , North Scott A. , Heng Daniel Yick Chin 
Published: March 2017

468 Background: Recent analysis using CKCis, a prospective database, showed that mRCC patients receiving first-line sunitinib (S) had better survival than patients receiving pazopanib (P) and greater than expected absolute survival in the real world setting. We conducted further analyses to see if an individualized approach (treatment starting at standard dose/schedule with subsequent schedule/dose alterations based on toxicity) using S results in better outcomes in mRCC patients. Methods: Patients within CKCis diagnosed with clear cell mRCC treated with first-line S or P between January 2011 to December 2015 were analyzed by three treatment groups: 1) S as per individualized approach (SI), 2) S as per product monograph (SS), or 3) P as per product monograph (PS). Overall survival (OS) and time-to-treatment failure (TTF) were calculated. Cox regression analysis allowed for adjustment of International Metastatic RCC Database Consortium (IMDC) criteria with age as a continuous variable. Results: A total of 573 patients were identified, 261 patients in SI, 201 patients in SS, and 111 patients in PS. Differences in baseline characteristics were noted (Table). Median OS was improved in SI vs. SS (40.8 vs. 22.6 months (m), p<0.001) and SI vs. PS (40.8 vs. 20.3 m, p<0.001). TTF was better in SI vs. SS (16.6 vs. 5.4 m, p<0.001) and SI vs. PS (16.6 vs. 7.0 m, p<0.001). SS vs. PS showed no difference in median OS (22.6 vs. 20.3 m, p=0.76) or TTF (5.4 vs. 7.0 m, p=0.11). Adjusted hazard ratio showed significance in SS vs. SI (OS 1.81, p=0.004 TTF 2.42, p<0.001) and PS vs. SI (OS 3.16, p<0.001; TTF 2.03, p<0.001). Conclusions: Significant improvement in OS and TTF is seen using an individualized approach to mRCC patients, further supporting the growing body of evidence endorsing this practice. Further prospective validation awaits from the NCT01499121 study. [Table: see text]
Acute and late toxicity in high-risk prostate cancer patients treated with androgen suppression and hypofractionated pelvic radiotherapy.
Authors: Faria Sergio , RUO Russel , Cury Fabio , Duclos Marie , Souhami Luis 
Published: March 2017

47 Background: Two recent large randomized trials confirm that 60Gy in 20 fractions is an effective regimen compared to conventionally fractionated escalated doses in localized prostate cancer. However, in these two trials the prostate was the only target volume irradiated. The purpose of this study is to report acute and late toxicity in patients with high-risk prostate cancer treated with the same moderate hypofractionated radiotherapy (HypoRT) to two target volumes at the same time: prostate and pelvic nodes. Methods: High-risk prostate cancer patients received 60Gy/20 fractions (4 weeks) to the prostate while the pelvic-nodes received 44Gy delivered with intensity modulated radiation therapy (IMRT) with a simultaneous integrated boost (SIB) during the same 20 fractions. ADT started 2-3 months before HypoRT. Acute and late toxicity were prospectively assessed according to CTCAE.v3. Results: 105 patients treated between September/2010 and November/2013 were reviewed. Median follow up is 41 months. Median ADT duration was 18 months. Acute grade > 2 gastrointestinal (GI) or genitourinary (GU) toxicity was seen in 17% and 17% respectively, with only 1 and 3 patients experiencing GI and GU acute grade 3 toxicity, respectively. The worst grade > 2 late GI and GU toxicity was seen in 7% and 8% of patients, respectively. There was no grade 4-5 toxicity. At the last follow-up, the rates of grade = 2 GI and GU toxicity were 5% and 3%, respectively with no residual grade > 3 toxicity. The 48-month actuarial progression free survival is 82%. We found only 8 publications on this topic, all delivered the HypoRT in 25-28 fractions, but only one has long-term toxicity. Conclusions: ADT with HypoRT delivered with IMRT and SIB to the prostate (60Gy) and pelvic nodes (44Gy) in 20 fractions is feasible and well tolerated after 41months of median follow-up. Our approach shortens treatment duration, is convenient and its results support a needed randomized trial. Clinical trial information: NCT02107287.
The role of microRNAs (miRNAs) as predictive biomarker in advanced renal cell carcinoma (mRCC) patients (pts) with “extreme response” to tyrosine kinase inhibitors (TKIs) treatment.
Authors: Garrigos Carmen , Molina-Pinelo Sonia , Montano Marta Espinosa , Lerma Antonio , Osman Ignacio , Ávila Rainiero , Medina Rafael , Melendez Ricardo , Salinas Ana , Garcia-Donas Jesus , Rodriguez-Antona Cristina , Duran Ignacio 
Published: March 2017

470 Background: MiRNAs play an important role as modulators of gene expression in a multitude of biological processes, being closely linked to the regulation of development and cell differentiation. Promising results about their value as predictors of drug response have been published in lung, colorectal cancer [Molina-Pinelo] and RCC [García-Donas]. This study aims to determine whether miRNAs can predict TKIs “extreme responses” in mRCC pts. Methods: RNA from formalin fixed paraffin embedded tumor and non-tumor samples from 15 pts with mRCC was extracted with mirVana miRNA isolation kit (Ambion). We defined as TKI “extreme responders” those pts that either had a long-term response (LR) (PFS˃11 months, n=7) or that were primary refractory (PR) (progression as best response, n=8). The expression of 754 miRNAs was analyzed with TaqMan Low Density Array Human MicroRNA Panel (TLDA) (ThermoFisher). QPCR was carried out in the System of Gene Expression and Genotyping Arrays module ViiA7. A qPCR ThermoFisher software specifically designed was used to calculate the ΔCt, cluster analysis, comparison between groups and primary analysis of the results. MiRNAs differentially expressed were analyzed independently by individual qPCR assays in the same cohort. A validation in an external cohort is being currently conducted. Results: Four miRNAs were significantly associated with patient response and differentially expressed in PR vs. LR (up-regulated in PR: miR-425-5p, down-regulated in PR: miR-139-3p, let-7d, and let-7e). Validation in our cohort was successful with let-7d and let-7e (p<0.05). Regarding differential expression in tumor vs non-tumor samples 14 miRNAs were identified by TLDA. Seven of those were validated in our series (tumor up-regulated: miR-146b, miR-21, miR-155, miR-122; tumor down-regulated: miR135a, miR-200c, miR-187) (p<0.05). These miRNAs were located in genes related with apoptosis, proliferation, metastasis, migration, and oncogenic pathways. Conclusions: MiRNAs could represent a valid predictive biomarker in mRCC treatment. These results need further validation in an independent cohort [work in progress].
The genomic landscape of metastatic non-clear cell renal cell carcinoma.
Authors: Carlo Maria Isabel , Khan Nabeela , Chen Yingbei , Hsieh James , Hakimi A. Ari , Lee Chung-Han , Feldman Darren R. , Motzer Robert J. , Voss Martin Henner 
Published: March 2017

474 Background: Non-clear cell renal cell carcinoma (nccRCC) encompasses about 20% of RCC cases and includes a number of subtypes that vary clinically and molecularly. Compared to ccRCC, these tumors have more limited sensitivity to conventional anti-VEGF agents and mTOR inhibitors, and there is clear need for better therapies. Analysis of genomic alterations in potentially targetable pathways may lead to novel therapeutic development strategies. Methods: We retrospectively analyzed tumors from 112 patients with metastatic nccRCC with targeted next-generation sequencing (NGS) across a panel of >340 cancer-relevant genes. Matched tumor and normal was used to facilitate somatic calling. We report on recurrent alterations observed for nccRCC variants. Results: Median age was 53 years (range 12-77), 67% were male; 47% presented with metastatic disease and 53% with localized disease that later metastasized. NGS was performed on tissue from primary tumors (57%) or metastatic sites (43%). Subtype classifications included unclassified (44%), papillary (21%), chromophobe (13%), translocation (12%), and other (9%). The most frequently altered genes by subtype are included in table. 36% of unclassified or papillary tumors had a mutation in a putative driver gene amenable to targeted therapies, including MET, NOTCH1, SMARCB1, TSC1, TSC2, PIK3CA, and FGFR3. 3 chromophobe tumors and 1 translocation tumor had a mutation in a potentially targetable pathway. Conclusions: The mutation profiles of metastatic nccRCC vary by papillary, chromophobe, and translocation subtype, with unclassified tumors most approximating papillary subtype. Unclassified and papillary subtypes harbor frequent mutations in potentially targetable pathways that merit further investigation. [Table: see text]
The efficacy and safety in elderly patients with advanced renal cell carcinoma: Real-world use of sorafenib in Japan.
Authors: Tatsugami Katsunori , Oya Mototsugu , Kabu Koki , Akaza Hideyuki 
Published: March 2017

476 Background: Multiple treatment options are available for patients with advanced renal cell carcinoma (RCC). However, the safety and efficacy data of these agents in elderly patients are limited. In this study, the data, which prospectively collected practical use of sorafenib amongst all RCC patients as a nationwide post-marketing surveillance, were analyzed using propensity-matched cohorts. Methods: A total of 3,255 patients with advanced RCC were enrolled and 772 patients selected by propensity score were matched for <75 (n=386) and ≥75 year old patients (n=386). Progression free survival (PFS), tumor response, adverse events (AEs), doses of sorafenib, and estimated glomerular filtration rate (eGFR) were analyzed. Results: The median PFS in <75 and ≥75 year old patients was 233 days (194, 274) vs. 219 days (190, 263), respectively. The mean starting dose (702 mg vs. 688 mg) and median treatment duration (222 days vs. 175 days) were similar in two groups, but mean dose intensity (70.3% vs. 61.4%, p<0.001) was lower in ≥75 year old patients than that in <75 year old patients. Complete response rates were 0.9% and 3.7%, partial response rates were 27.9% and 27.1%, stable disease rates were 58.4% and 55.6%, progressive disease rates were 12.8% and 12.8% in <75 and ≥75 year old patients, respectively. Objective response rate (CR+PR) was comparable in both groups (28.8% and 30.8%). Safety was analyzed for 772 patients, and any grade AEs observed ≥20% were hand-foot skin reaction (HFSR) (55.8%), hypertension (36.7%), rash (27.4%), and increase in lipase / amylase (26.2%), and diarrhea (21.8%). The common serious AEs were rash (7.4%), HFSR (6.0%), hepatic dysfunction (5.6%), cytopenia (4.9%), and hypertension (2.8%). The incidence of these common AEs was similar between the two groups. The discontinuation due to AE and drug related death rates were 65.3% vs. 74.9% (p<0.01) and 3.4% vs. 4.9% in <75 and ≥75 year old patients, respectively. In both groups, the eGFR value did not change from the baseline, and even slightly increased after 12 months of sorafenib treatment. Conclusions: This study indicated that sorafenib provides clinical benefits and is tolerable amongst patients with advanced RCC regardless of age.