bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I/II trial of combined BRAF and EGFR inhibition in patients (pts) with BRAF V600E mutated (BRAFm) metastatic colorectal (mCRC): The EViCT (Erlotinib and Vemurafenib in Combination Trial) study.
Authors: Desai Jayesh , Markman Ben , Ananda Sumitra , Tebbutt Niall C. , Michael Michael , Solomon Benjamin J. , McArthur Grant A. , Tie Jeanne , Gibbs Peter , Ritchie David , Koldej Rachel , Herschtal Alan , Columbus Ruth , Ashley David M. , Lundy Joanne , Kwan Edmond Michael , Waring Paul Michael , Tran Ben 
Published: September 2018

3557 Background: Pts with BRAFm mCRC have an exceedingly poor prognosis. Unlike melanoma, BRAF inhibitor monotherapy has limited activity in BRAFm mCRC. Preclinically, BRAF inhibition results in rapid feedback activation of EGFR and ongoing tumor proliferation, which can be readily overcome by combining BRAF and EGFR inhibition. EViCT examined the safety and efficacy of combining two oral agents targeting BRAF with Vemurafenib (Vem) and EGFR with Erlotinib (Erl), in BRAFm mCRC pts. Herein, we report safety and preliminary efficacy data. Methods: EViCT had 2 parts: a Phase I dose escalation of Erl (cohort 1: 100mg qd; cohort 2: 150mg qd) together with Vem 960mg bd, to determine the maximum tolerated dose (MTD). The Phase II component involved dose expansion at MTD using a Simon 2-stage design to treat 9 pts in stage 1 and 15 pts in stage 2. Cycles were 28 days. Eligible pts had ECOG < 1, < 2 lines of systemic therapy for metastatic disease, and acceptable organ function. Staging CT scans were performed every 2 cycles, response assessed using RECIST 1.1. Primary endoint was clinical benefit rate (CR, PR and SD). A number of pharmacodynamics correlates were assessed including serial ctDNA, FDG-PET and optional tumour biopsies. Pts were treated until disease progression or toxicity requiring discontinuation. Results: Between Jul-2014 and Oct-2016, 30 BRAFm mCRC pts were enrolled. The Phase I Lead-in enrolled 4 pts in cohort 1 and 7 pts in cohort 2. There was 1 DLT (grade 3 hand-foot syndrome) in cohort 2. MTD/Recommended Phase 2 Dose was Erl 150mg qd and Vem 960mg bd, the full dose for each agent. The Phase II expansion enrolled 19 pts. Overall, 23 pts are evaluable for this interim analysis. Median age was 61 years, 11 (48%) pts were male. Most pts had 1(50%) or 2 (41%) lines of prior treatment. Overall response rate was 39% (95%CI = [20%, 61%]), including 5 (22%) confirmed PR, 4 (17%) unconfirmed PR, 3 (13%) stable disease and 11 (48%) progressive disease. Conclusions: Vem and Erl can both be given safely at their individual full doses when used in combination. In BRAFm mCRC, this combination resulted in clear clinical activity. Clinical trial information: ACTRN12614000486628.
Primary tumor sidedness associates with prognosis of patients with brain metastases of colorectal cancer.
Authors: Berghoff Anna Sophie , Ferreira Pedro , Plazer Hanna , Widhalm Georg , Birner Peter , Bartsch Rupert , Prager Gerald W. , Zielinski Christoph , Preusser Matthias 
Published: September 2018

3562 Background: Brian metastases (BM) are a rare but devastating complication of colorectal cancer. We aimed to analyse prognostic factors in patients suffering from colorectal cancer (CRC) BM. Methods: Patients with histological proven CRC and BM were identified from the brain metastasis database of the Comprehensive Cancer Center Vienna. Clinical characteristics including established prognostic factors were retrieved by chart review. Established clinical prognostic scores for BM patients including the graded prognostic assessment (GPA) and the GPA for gastrointestinal tumours (GI-GPA) were calculated based on clinical characteristics as previously published. Results: 215 (male: 125/215 (58.1%); female 90/215 (41.9%)) patients with CRC BM were available for this study. The following established clinical prognostic factors showed a significant association with median overall survival (OS) times from BM diagnosis: number of brain metastases (n = 1: 6 months; n = 2-3: 4 months; n > 3: 3 months; p = 0.001), age at BM diagnosis ( < 65 years: 6 months; > 65 years: 4 months; p = 0.047), extracranial disease (present: 4 months; absent: 8 months; p = 0.002) and Karfnofsky performance score (KPS < 70%: 3 months; KPS > 70%: 5 months; p = 0.002), graded prognostic assessment (GPA) class (class I: 15 months; class II: 13 months; class III: 4 months; class IV: 4 months) and the gastro-intestinal disease-specific GI-GPA (class I: 11 months; class II: 6 months; class III: 6 months; class IV: 3 months; p < 0.001). In addition, the location of the primary tumour in the left colon (n = 176 (81.9%); 5 months) was associated with significantly longer median overall survival times from diagnosis of BM than primary tumour location in the right colon (n = 39 (18.1%); 3 months; p = 0.010). Primary tumor sidedness (HR 0.577; 95% CI 0.397-0.841; p = 0.004) remained a strong prognostic factor at multivariate analysis independently of GI-GPA (HR 0.718; 95% CI 0.612-0.842). Conclusions: Primary tumor sidedness is an independent prognostic factor in patients with CRC BM and should be included in disease-specific prognostic scores.
Robotic procedure versus open surgery for simultaneous resection of colorectal cancer with liver metastases: Short-term outcomes of a randomized controlled study.
Authors: Xu Jianmin , Wei Ye , Ye Qinghai , Wang Xiaoying , Chang Wenju , Jian Mi , Ren Li , Zhu Dexiang , Feng Qingyang , Qin Xinyu , Fan Jia 
Published: September 2018

3575 Background: The simultaneous resecting both colorectal cancer and liver metastases is a safety and efficacy surgical procedure for treating colorectal cancer patients with liver metastases (CRCLM).The safety and efficacy of robot-assisted simultaneous resection of CRCLM is unclear. Furthermore, what kind of selective CRCLM patients would obtain benefits from robotic procedure need identify. The aim of this study was designed to compare robotic procedure with open surgery, and establish robotic surgery indications to identify benefit population of CRCLM. Methods: CRCLM patients were evaluated and confirmed with surgical indication by multidisciplinary team (MDT), and randomized to two groups, robotic arm (n = 58) and open arm (n = 57). The primary endpoint is 3-year DFS, the second endpoints include short-term surgical outcomes, complications and safety. Results: A total of 115 patients were randomized between September 2013 and September 2016. Despite longer operating time, patients assigned to robot-assisted surgery had less blood loss (100ml vs. 150ml, P < 0.001), a shorter time to pass first flatus (3 d vs. 4 d, P < 0.001) and return to diet (3 d vs. 5 d, P = 0.002), shorter hospital stay with improved sexual function. Furthermore, followed benefits were observed in robotic arm versus open arm: lower serum C reactive protein (CRP) level on postoperative day 1 (POD1) (16 mg/L vs. 37 mg/L,P < 0.001), and POD3 (112 mg/L vs. 160 mg/L, P < 0.001), lower level of liver transaminase on POD5, and lower liver-related complication morbidity(10.3% vs 28.1%, p = 0.016). In addition, we identified and recommended selective CRCLM patients with the number of liver metastases < 3, maximal tumor size < 5cm, tumor not located in segment I to accept robotic procedure. Conclusions: We identified and recommended selective CRCLM patients to accept robotic surgery for treating liver metastases. Robotic surgery result in similar safety as open procedure, with shorter recovery time, decreased morbidity, and improved sexual function. Clinical trial information: NCT02642978.
Not all RAS mutations created equal: Functional and clinical characterization of 80 different KRAS and NRAS mutations.
Authors: Loree Jonathan M. , Miron Ben , Holla Vijaykumar , Overman Michael J. , Pereira Allan Andresson Lima , Lam Michael , Morris Van Karlyle , Raghav Kanwal Pratap Singh , Routbort Mark , Shaw Kenna Rael , Burck Nitza , Sharivkin Revital , Edelheit Oded , Meric-Bernstam Funda , Vidne Michael , Tarcic Gabi , Kopetz Scott 
Published: September 2018

3589 Background: Mutations (mts) in RAS predict lack of response to anti-EGFR therapy in colorectal cancer. Outside the “typical RAS” mts ( KRAS/NRAS Codons 12, 13, 59, 61, 117, 146) cited in guidelines and anti-EGFR labeling, clinical impact of other “atypical RAS” mts is uncertain. Methods: Available literature and databases were surveyed to identify 80 KRAS/NRAS mts. We used the NovellusDx Functional Annotation for Cancer Treatment (FACT) to transfect these RAS mts (repeated a mean of 5.5 times/mt) in a cell-based assay that quantifies nuclear ERK localization as a measure of MAPK pathway activation, and normalized to wild type (WT) transfection. In 963 metastatic colorectal cancer patients (pts) with BRAF WT/ KRAS mutant tumors, overall survival (OS) was evaluated by level of RAS signaling activity. Results: Of the surveyed mutations,96% (45/47) of typical mts and 39% (13/33) of atypical mts increased MAPK pathway activation above WT (range: 107%-211% of WT activity). Within the typical RAS mts, mts in NRAS or exon 3, 4 of KRAS had higher activity than mts in exon 2 (codons 12/13) of KRAS, reaffirming the biologic relevance of expanded RAS testing (median activity of 130% vs 178%, P < 0.001). The median activity of atypical RAS mts was lower than typical RAS mts (110% vs 159%, P < 0.001). Several notable exceptions in atypical RAS mts with high activity levels were KRAS V14I, Q22K, D33E, N116S, and F156L (all > 165% of WT activity). Conversely, within the typical RAS mts in the guidelines, KRAS G13C and K117R were not shown to increase activity significantly above WT. Pts with any RAS mt with MAPK activity above the median of typical mts had a worse OS compared to pts below the median in univariate (HR 1.45, 95% CI 1.04-2.32, P = 0.033) and multivariate models (HR 1.96, 95% CI 1.13-3.42, P = 0.017) that controlled for age, gender, sidedness, and synchronous vs metachronous presentation. Conclusions: Functional characterization confirmed activity of RAS mts in the current guidelines, but also suggested that a subset of atypical RAS mutations have similar levels of activation of the MAPK pathway. Within the subset of pts with RAS mts, those mts resulting in high MAPK activity are associated with notably shorter OS.
Impact of patient age on molecular alterations in left-sided colorectal tumors.
Authors: Weinberg Benjamin Adam , Poorman Kelsey , Arguello David , Marshall John , Salem Mohamed E. 
Published: September 2018

3592 Background: The incidence of colorectal cancer (CRC) in younger patients (pts) is rising. This increase is most pronounced in tumors arising from the distal colon and rectum. Since tumor sidedness has emerged as an important prognostic and predictive biomarker in CRC, we aim to explore the impact of age on the tumor biology of left-sided colon cancer (LCC). Herein, we compare profiles of LCC from younger (≤ 45 years) and older pts (≥ 65 years). Methods: LCCs (splenic flexure to rectum; n = 1,602) were examined by NextGen sequencing, protein expression, gene amplification, and microsatellite instability fragment analyses. Tumor mutational load (TML) was calculated using only somatic nonsynonymous missense mutations. Chi-square tests were used for comparisons. Results: LCCs from younger (median age 40, range 22-45 years, n = 229) and older (median age 71, range 65-89, n = 503) pts were studied. The most frequently mutated genes included APC, TP53, KRAS, PIK3CA, ARID1A, FBXW7, SMAD4, ATM, BRAF, and NRAS. Comparing younger v. older pts, there were no significant differences in the rates of APC (75.3% v. 82.9%, P = 0.139), TP53 (79.5% v. 73.1%, P = 0.261), KRAS (37.6% v. 43.0%, P = 0.403), PIK3CA (9.4% v. 14.6%, P = 0.234), ARID1A (14.3% v. 13.2%, P = 0.884), FBXW7 (11.4% v. 10.5%, P = 0.830), SMAD4 (13.1% v. 7.4%, P = 0.129), BRAF (4.8% v. 5.7%, P = 0.762), or NRAS (3.5% v. 2.6%, P = 0.680) mutations. Additionally there were no significant differences in protein overexpression. However, there was a trend towards increased HER2 amplification in younger pts (5.7% v. 2.1%, P = 0.05). MSH6 (4.8% v. 0.5%, P = 0.015), MSH2 (2.4% v. 0%, P = 0.032), POLE (2.4% v. 0%, P = 0.032), and NF1 (7.9% v. 0%, P < 0.001) mutations were observed at higher rates in younger pts. High TML (≥ 17 mutations per megabase) was seen more frequently in younger pts (8.2% v. 2.6%, P = 0.02). Conclusions: The molecular differences between LCC in younger and older pts are mostly due to mutations in mismatch repair genes. Higher TML may predict a higher response rate to checkpoint inhibitors in younger pts with LCC. The differences in tumor biology observed here warrant further study and may eventually be used to tailor therapy.
Robotic vs. laparoscopic vs. open abdominoperineal resection for low rectal cancer: Short-term outcomes of a single-center prospective randomized controlled trial.
Authors: Wei Ye , Xu Jianmin , Ren Li , Feng Qingyang , He Guodong , Chen Jingwen , Chang Wenju , Zhu Dexiang , Yi Tuo , Lin Qi 
Published: September 2018

3603 Background: Currently, robotic surgery for rectal cancer using da Vinci System is common. However, there is almost no clinical trial reported. This randomized controlled trial aims to compare the safety and efficacy of robotic, laparoscopic and open abdominoperineal resection (APR) for low rectal cancer. Methods: From September 2013 to August 2016, patients aged from 18 to 75 years, with low rectal cancer within 5 cm from anal verge, clinical T1 to T3, no distant metastases, were randomly assigned to receive either robotic procedures (RAP), laparoscopic procedures (LAP) or open surgery (OS) for APR in 1:1:1 ratio. The primary endpoint was postoperative complication rate. This study is registered with ClinicalTrials.gov (NCT01985698). Results: Totally 406 patients were randomly assigned. Actually, 135 finished RAP, 131 finished LAP, and 137 finished OS (including 4 convert from LAP to OS). RAP had significantly lower postoperative complication rate (11.1%) than both LAP (21.4%, P = 0.023) and OS (27.7%, P = 0.001). Also, RAP reduced intraoperative hemorrhage (median [interquartile range], 100 [90-110] ml) than LAP (130 [100-150] ml, P < 0.001) and OS (150 [120-260] ml, P < 0.001). And RAP promoted postoperative recovery, with shorter days to first flatus (1.0 [1.0-2.0] day) than LAP (2.0 [2.0-3.0] day, P < 0.001) and OS (3.0 [2.0-4.0] day, P < 0.001), shorter days to first automatic urination (2.0 [2.0-3.0] day) than LAP (3.0 [2.0-4.0] day, P < 0.001) and OS (3.0 [2.0-4.0] day, P < 0.001), and shorter days to discharge (5.0 [5.0-6.0] days) than LAP (6.0 [5.0-7.0] days, P < 0.001) and OS (6.0 [5.0-7.0] day, P = 0.005). There was no significant difference in open conversion rate, resection margin involvement (including circumferential resection margin), number of lymph node harvested and pathological tumor stage. Conclusions: Robotic APR was safer, and reproduce equivalent surgical quality of conventional laparoscopic and open surgery. Also, it provided less injury and faster functional recovery. Clinical trial information: NCT01985698.
Randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) vs AG in patients (Pts) with untreated, metastatic pancreatic ductal adenocarcinoma (mPDA).
Authors: Hingorani Sunil R. , Bullock Andrea J. , Seery Tara Elisabeth , Zheng Lei , Sigal Darren , Ritch Paul S. , Braiteh Fadi S. , Zalupski Mark , Bahary Nathan , Harris William Proctor , Pu Jie , Aldrich Carrie , Khelifa Sihem , Wu Xionghua W. , Baranda Joaquina , Jiang Ping , Hendifar Andrew Eugene 
Published: September 2018

4008 Background: Hyaluronan (HA) accumulation in the tumor microenvironment produces elevated tumor pressure, vascular compression, and reduced drug delivery. PEGPH20 degrades HA, increasing the access and therapeutic index of anticancer agents. Methods: In Stage 1 of this phase II study, pts with untreated mPDA were randomized 1:1 to PAG (P; 3 µg/kg IV 2x/wk x 3 wks in C1, then 1x/wk x 3 wks in C2+, plus AG) vs AG every 28 days. An imbalance in thromboembolic (TE) events in the PAG arm led to a clinical hold (~40% of pts discontinued PEGPH20), exclusion of pts at high risk for TE events and enoxaparin prophylaxis in both study arms. In Stage 2, randomization was 2:1 to PAG vs AG. Tumor HA was tested using a novel assay (VENTANA HA RxDx). Primary endpoints were PFS (evaluable pts) and TE event rate (Stage 2). Secondary endpoints were PFS by HA level and ORR. Results: 279 pts were randomized; 231 are evaluable for efficacy. Of 246 pts with HA data, 84 (34%) were HA-High. As of December 16, 2016, the primary PFS endpoint was statistically significant for PAG vs AG (HR 0.73, 95% CI 0.53-1.00; p = 0.048) (Table). PFS in HA-High pts was also statistically significant in the PAG vs AG arm (HR 0.51; 95% CI 0.26-1.00; p = 0.048). ORR in HA-High pts was 46% (PAG) vs 34% (AG). Overall survival in HA-High pts (exploratory) was 11.5 months (mo) (PAG) and 8.5 mo (AG) (HR 0.96, 95% CI 0.57-1.61). TE events were similar (PAG 14% vs AG 10%) following enoxaparin initiation. All grade treatment-related AE included peripheral edema (PAG 63% vs AG 26%), muscle spasms (56% vs 3%), neutropenia (34% vs 19%), and myalgia (26% vs 7%). Conclusions: Randomized Phase II study met both primary endpoints (PFS and TE event rate), with the largest improvement in the secondary endpoint of PFS in HA-High pts. These data support HA as a potential predictive biomarker for patient selection of PEGPH20, currently investigated in the ongoing global Phase III HALO 301 study with PFS and OS as co-primary endpoints. Clinical trial information: NCT01839487. [Table: see text]
Phase I study of AG-120, an IDH1 mutant enzyme inhibitor: Results from the cholangiocarcinoma dose escalation and expansion cohorts.
Authors: Lowery Maeve Aine , Abou-Alfa Ghassan K. , Burris Howard A. , Janku Filip , Shroff Rachna T. , Cleary James M. , Azad Nilofer Saba , Goyal Lipika , Maher Elizabeth A. , Gore Lia , Hollebecque Antoine , Beeram Muralidhar , Trent Jonathan C. , Jiang Liewen , Ishii Yuko , Auer Julia , Gliser Camelia , Agresta Samuel V. , Pandya Shuchi Sumant , Zhu Andrew X. 
Published: September 2018

4015 Background: Mutations in the metabolic enzyme isocitrate dehydrogenase 1 (mIDH1) occur in patients (pts) with cholangiocarcinoma (CC) and are detected in up to 25% of intrahepatic CC. mIDH1 produce the oncometabolite, D-2-hydroxyglutarate (2-HG), resulting in epigenetic and genetic dysregulation and oncogenesis. AG-120 is a first-in-class, potent, oral inhibitor of mIDH1 tested in this phase I study in mIDH1 solid tumors, including CC. Methods: AG-120 was escalated in a 3+3 design from 100 mg twice daily to 1200 mg once daily (QD) in 28-day cycles (N = 60, mIDH1 advanced solid tumors). Key eligibility for CC: recurrence of progressive mIDH1 CC following standard therapy (dose escalation) or at least a prior gemcitabine-based regimen (expansion cohort). Response (RECIST 1.1) was assessed every 8 weeks. Plasma and tumor tissue were collected for exploratory analyses. Results: Based on the safety, pharmacokinetic, and pharmacodynamic data from dose escalation, the 500 mg QD dose was selected for expansion in mIDH1 CC and other mIDH1 solid tumors. As of Dec 16, 2016, 73 pts with mIDH1 CC had been dosed in the dose escalation (n = 24) and expansion (n = 49) cohorts. Demographics: M/F = 24/49, median number of prior therapies = 2 (range 1–5), ECOG 0–1 = 26/47. There were no dose-limiting toxicities. Treatment-related adverse events (AEs) in ≥5% pts: fatigue (21%), nausea (18%), vomiting (12%), diarrhea (10%), decreased appetite (8%), dysgeusia (5%), QT prolongation (5%). Two (3%) pts experienced related grade 3 AEs: fatigue and low phosphorus. There were no AG-120-related AEs leading to discontinuation. Among the 72 efficacy evaluable (≥1 post baseline response assessment or discontinued prematurely) mIDH1 CC pts (24 in escalation and 48 in expansion cohort), 6% (n = 4) had a confirmed partial response and 56% (n = 40) experienced stable disease. The progression-free survival rate at 6 months was 40%, and 8 pts have been treated with AG-120 for ≥1 year. Conclusions: In this pretreated mIDH1 CC population, AG-120 was associated with a favorable safety profile and prolonged stable disease. A global, phase III, randomized, placebo-controlled study of AG-120 in mIDH1 CC has been initiated (ClarIDHy). Clinical trial information: NCT02073994.
Impact of chemoradiotherapy on PD1/PDL1 expression and clinical outcomes in gastroesophageal cancers.
Authors: Osipov Arsen , Li Quanlin , Thomassian Shant , Annamalai Lakshmanan , Yearley Jennifer Holmes , Rutgers Joanne K , Hendifar Andrew Eugene , Tuli Richard 
Published: September 2018

4031 Background: Expression of the immune modulating proteins, programmed death receptor-1 (PD1) and its ligand (PDL1), in gastrointestinal malignancies is associated with poor prognosis. PD1/PDL1 expression levels have also been identified as predictors of response to checkpoint inhibition. Minimal data is available on how expression of PD1 and PDL1 is influenced by chemoradiotherapy (CRT). In this study, we investigated the relationship between PDL1/PD1 expression, CRT, and clinical outcomes in gastroesophageal (GE) cancer. Methods: With IRB approval, we identified 28 patients with gastric cardia or GE junction tumors who underwent neoadjuvant standard CRT followed by surgical resection. Pre-CRT biopsies and post-CRT surgical specimens were analyzed using quantitative immunohistochemistry for the expression of PDL1 and PD1. Samples were categorized as trace-low (TL) or moderate-high (MH) expressors of PDL1 and PD1. The impact of these and other clinical and pathologic variables on overall survival (OS) was assessed using multivariate cox proportional hazards modeling. Co-expression of PDL1 and PD1 in matched samples was determined by regression analysis. Results: Following CRT, PDL1 and PD1 expression increased in 54% and 32% of patients, respectively. On multivariate analysis, patients with MH expression of PD1 after CRT irrespective of pre-CRT expression levels had a significant decrease in OS compared to those with TL expression (median survival 23.1 vs 74.1 months; HR,3.31; CI,1.05-10.35; p = 0.039). In patients with gastric confined tumors, an increase in PD1 expression from TL to MH after CRT was associated with significantly lower OS rates (p = 0.003). Regression analysis of PD1 to PDL1 was significant (p < 0.01) both before and after CRT, with a correlation coefficient of 0.34 in pre-CRT and 0.49 in post-CRT specimens. Conclusions: Elevated expression of PD1 is associated with poor OS in patients with GE cancer. Neoadjuvant CRT upregulates both PDL1 and PD1. In gastric cancer patients, this led to significantly worse survival. These data identify potential mechanisms of resistance and suggest a role for checkpoint inhibitors in combination with CRT.