bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of a high-response patient population to S-1 via predictive enrichment strategy analysis of the S-CUBE phase III trial.
Authors: Kudo Masatoshi , Okusaka Takuji , Kaneko Shuichi , Furuse Junji , Takeuchi Madoka , Fang Xuemin , Date Yoshito , Takeuchi Masahiro 
Published: February 2017

229 Background: S-CUBE was a randomized, double-blind, phase III trial evaluating the efficacy and safety of S-1 in patients with sorafenib-refractory advanced hepatocellular carcinoma (HCC). The study’s primary outcome was presented at the 2015 ASCO Annual Meeting. Although S-1 did not significantly improve overall survival (OS) in all cohort (hazard ratio [HR] = 0.86; confidence interval [CI] = 0.67–1.10; P = 0.2201), we conducted predictive enrichment strategy analysis (PESA) to identify a patient population with a better response to S-1. Methods: Predictive enrichment strategy is a newly introduced concept proposed by the United States Food and Drug Administration, “to select a study population in which detection of a drug effect (if one is in fact present) is more likely than it would be in an unselected population. (Temple R. [2012] )” Therefore, in our study, PESA provides robust results and identifies advanced HCC patients who are more likely to respond to S-1. Clinically meaningful baseline characteristics were selected to create a scoring system; patients were ranked based on their scores, and the population with a better response was identified. Patient mapping was used to further characterize the population. Results: The full S-CUBE analysis set consisted of 333 patients, including 222 in the S-1 arm and 111 in the placebo. PESA and patient mapping identified 219 patients (65.8% of the total population) as the high-response patient population. High-response patients are classified as those with the following criteria; 1) TNM stage III, IVa, or IVb, 2) Child-Pugh class A, and 3) Levels of both the tumor markers are not high (AFP ≥ 400 ng/mL and PIVKA-II ≥ 10000 mAU/mL). In this population, the median OS of S-1 group was significantly longer than that of placebo group (426.0 days vs. 375.5 days; HR, 0.69; 95% CI, 0.51 to 0.93; P = 0.0156). Conclusions: PESA and patient mapping identified a high-response patient population to S-1. This statistically robust analysis demonstrated S-1 showed survival benefit for identified clinically-important population of sorafenib-refractory advanced HCC patients. Clinical trial information: JapicCTI-090920.
Next-generation sequencing (NGS) in advanced well differentiated pancreatic neuroendocrine tumors (WD pNETs): A study using MSK-IMPACT.
Authors: Raj Nitya Prabhakar , Soumerai Tara , Valentino Emily , Hechtman Jaclyn Frances , Berger Michael F. , Reidy Diane Lauren 
Published: February 2017

246 Background: Whole exome sequencing in WD pNETs demonstrated an increased number of mutations in chromatin modeling genes (MEN1, DAXX, and ATRX), and in the mTOR pathway. NGS brings this technology to the clinic but its relevance in practice has been questioned. In this prospective, IRB-approved study (NCT01775072), we used the MSK-IMPACT assay to perform NGS on WD pNETs in a routine practice setting. MSK-IMPACT, performed in a CLIA-compliant laboratory, is a multiplexed assay (Illumina HiSeq) providing full exon coverage of 410 cancer related genes, detecting base substitutions, small indels, copy number and select gene rearrangements. Methods: After written consent, tumor and germline DNA were analyzed. Genomic alterations were catalogued. Results: MSK-IMPACT results are available in 39 patients (pts). Actionable alterations were identified in 13/39 pts (33.3%). These actionable alterations included BRAF V600E (2 pts; 5.1%), and mutations in TSC1 (1 pt; 2.6%), TSC2 (5 pts; 12.8%), PTEN (4 pts; 10.3%), CDKN1B (2 pts; 5.1%), CDKN2A (2 pts; 5.1%), CDKN2B (2 pts; 5.1%), CDKN2C (1 pt; 2.6%), and ARID1A (5 pts; 12.8%). Other recurrently altered genes included MEN1 (23 pts, 59.0%), DAXX (13 pts, 33.3%), and ATRX (10 pts, 25.6%). Notably, 7 pts (17.9%) had alterations in the histone methyltransferase SETD2. All 7 pts presented with metastatic liver disease. No tumors were low grade; 6/7 (85.7%) were intermediate grade and 1/7 (14.3%) were high grade. All 7 pts received capecitabine/temozolomide (cape/tem); 6 pts (85.7%) had disease shrinkage and 1 pt (14.3%) had stable disease. Conclusions: The mutational landscape in our study was in line with prior work in pNET whole exome sequencing. In one-third of our cohort, potentially actionable alterations were identified through NGS but have not yet been shown to be therapeutically relevant. An exploratory analysis to identify responses to different therapies is ongoing. In addition, we report a novel finding of SETD2 alterations in pNETs. All pts with SETD2 alterations had intermediate to high grade tumors that responded to cape/tem. The clinical significance of SETD2 in pNETs is unknown, and evaluation using tissue microarrays is ongoing.
Tumor profiling of 431 pancreatic tumors from elderly patients.
Authors: Xiu Joanne , Rakszawski Kevin , Reddy Sandeep K. , Jia Yuxia 
Published: February 2017

257 Background: Pancreatic cancer (PC) is frequently a disease of the elderly and controversy exists as to whether these patients benefit from aggressive treatments. We aimed to investigate biomarker features from tumors taken from elderly PC patients to identify therapeutic implications. We also compared the results to those from younger patients to assess differences. Methods: PC tumors were tested at Caris Life Sciences between 2009 and 2015 by immunohistochemistry, fluorescent/chromogenic in-situ hybridization and sequencing. De-identified biomarker data were analyzed. Results: A total of 431 tumors from PC patients aged > = 75 were analyzed: 50% were samples from pancreas, 50% were from metastatic sites. 26 of 47 genes sequenced carried mutations with frequencies ranging from 0.6% to 84%. The highest mutation rates were seen in KRAS (84%), TP53 (55%), BRCA2 (21%), SMAD4 (12%), ATM (4.4%), BRCA1 (4.2%) and PIK3CA (3.8%). Overexpression of TOPO1 and low expression of ERCC1, RRM1 and TS were seen in 45%, 73%, 86% and 79%, respectively, indicating potential benefit from irinotecan, platinums, gemcitabine and fluoropyrimidine, respectively. Tumor expression of PD-L1 was seen in 14% and tumor-infiltrating lymphocyte expression of PD-1 was seen in 45%. Overexpression of EGFR and cMET were seen in 91% and in 62%, respectively. When compared to 470 tumors from PC patients aged < = 50, KRAS mutations were significantly more common in the elderly than in younger patients (84% vs. 74%, p = 0.0018), while MLH1 mutations were seen exclusively in younger patients (0% vs. 4%, p = 0.0241). Moreover, expression of TOP2A (53%vs. 45%), ERCC1 (36% vs. 27%), RRM1 (20% vs. 14%), SPARC (20% vs. 14%) and PR (5% vs. 1%) were significantly more prevalent in the younger group (all p < 0.05). Conclusions: Tumor profiling of 431 tumors from elderly PC patients suggests therapeutic opportunities including cytotoxic, biological as well as targeted agents for this patient group. A comparison with younger patients indicated that irinotecan, fluoropyrimidine and taxanes may provide equal benefit to elderly and younger patients, while platinums and gemcitabine may be more likely to benefit elderly patients.
Role of MEK inhibition in improving anti-tumor responses in xenograft models of BRAF-mutated metastatic colorectal cancer.
Authors: Morris Van Karlyle , Wu Ji , Adam Liana , Tian Feng , Gagea Mihai , Hong David S. , Menter David , Kopetz Scott 
Published: February 2017

265 Background: BRAFV600E mutations occur in fewer than 10% of all patients with metastatic colorectal cancer (mCRC) and are associated with poor survival outcomes. Addition of anti-EGFR therapy improves responses when combined with BRAF inhibition, yet acquired resistance to targeted therapies invariably develops. Novel therapeutic approaches to deepen anti-tumor activity are warranted for patients with this subset of mCRC. Methods: Patient-derived xenograft (PDX) models of BRAFV600E mCRC were established and treated with vemurafenib (V) +/- cetuximab (C) until acquired resistance. DNA from resistant tumors was sequenced and compared to that of untreated controls. BRAFV600E mCRC tumors from PDX mice with acquired mutations in MAPK signaling were reimplanted into another generation of nude mice and treated with V +C or trametinib (T) + cetuximab. Results: Twelve resistant models were developed in BRAFV600E mCRC PDX models treated with V +/- C, with nine models demonstrating acquired mutations resulting in MAPK pathway re-activation, including codons 12 or 13 KRAS mutations. While sensitivity to V + C was observed in BRAFV600E /KRASwild-type mCRC tumors, this combination demonstrated no anti-tumor response in BRAFV600E models with acquired KRASG12R or KRASG12D mutations. In these PDX models harboring dual BRAF/KRAS mutations, the combination of T + C generated sustained tumor regression not observed with V+C (P <.001 for both BRAFV600E / KRASG12R and BRAFV600E /KRASG12D models). Addition of T following resistance to V+C restored sensitivity in both models. Conclusions: Dual blockade of BRAF + EGFR has shown promise in early-phase clinical trials for patients with BRAFV600E mCRC, and MAPK pathway reactivation appears to be a critical mechanism of resistance. These results suggest that use of a MEK inhibition may reverse such acquired resistance. While MEK + EGFR targeting has been associated with excessive skin toxicity in humans, these data provide rationale for the pursuit of triple BRAF + MEK + EGFR inhibition in patients with BRAFV600E mCRC.
Development of a multidisciplinary program for evaluation and treatment of pancreatic cancer in a community healthcare system.
Authors: Hermann Robert C. , Early Scott , Goel Sachin , Hart Justin , Huertas Magali , Khulman Chad , Webb Leigh , Wilson Barbara J , Shroff Sahir 
Published: February 2017

303 Background: The incidence and mortality of pancreas cancer is rising in the United States. Only patients who are able to have complete (R0) resection have the potential of cure. Optimal surgical outcomes are influenced by local center volume and multidisciplinary support. We describe the development of a multidisciplinary approach to the evaluation and treatment of pancreas cancer in a community health care system. Methods: This project was initiated by the WellStar Cancer Program, encompassing 5 hospitals. An Institutional Guideline was developed, based upon NCCN, with refinements related to local capabilities and preferences. The Guideline emphasized the review of cases at a weekly tumor board for multidisciplinary coordination of care. Standards for staging evaluations, medical imaging, chemotherapy choices, radiation therapy, and surgical approach were included. A GI Nurse Navigator attended the conferences and assisted in the coordination of care. Specific outcomes were tracked by the Nurse Navigator and the Cancer Registry. Here we describe the program impact related to staging, treatment, nurse navigation, volume and outcomes during the 2011-2014 development phase of the program. Results: A total of 308 cases of pancreas cancer were captured by the registry in 2011-2014. 131 were diagnosed with stage IV disease and offered palliative therapy. 30 Stage I and 139 Stage II-III underwent staging evaluation and consideration of multidisciplinary care, summarized in the table below, and compared to a baseline registry cohort of the 4 preceding years. Conclusions: The development of a Multidisciplinary Team approach to pancreas cancer within a 5 hospital community system has led to improvement in treatment outcomes, including R0 resection rate. Full 2-year results to be updated at the meeting. [Table: see text]
Prognostic influence of clinical biomarkers in patients (pts) with advanced hepatocellular carcinoma (HCC) receiving sorafenib: A single institution experience.
Authors: Abdel-Rahman Omar , Lamarca Angela , Salu Ismail , McNamara Mairead G , Valle Juan W. , Hubner Richard 
Published: February 2017

304 Background: Identification of HCC pts with higher probability of benefit from sorafenib warrants investigation. Hypertension (HTN) and hand foot syndrome (HFS) are sorafenib-specific toxicities; the development of these toxicities is prognostic in pts with renal cell cancer receiving sorafenib, their significance in HCC remains uncertain. Methods: HCC pts treated with sorafenib at the Christie NHS Foundation Trust (Nov-09-Feb-15) were identified. The primary end-point was overall survival (OS). Kaplan-Meier and Cox regression models were employed for identification of prognostic factors. Results: Eighty-five eligible pts were identified [median follow-up 6.2 months (range: 0.4-31.4)].Median age 68 yrs (range 29-89); 87% male; 80% background liver cirrhosis ;88% ECOG performance score 0/1; Child-Pugh (CP) A5 (64%), A6 (29%) and B (7%); 41% baseline AFP > 400 IU/L; 45% previous liver-directed therapy. Sorafenib (400mg BD),was started in 68% (median dose intensity 49.9% (range 0.7-100)), remaining patients started at reduced dose. Fifty-one percent had pre-existing HTN (91% treated).The most common grade ≥ 3 treatment-related toxicities were HTN (42% no prior history of HTN), fatigue (8%), and HFS (8%);59% of pts developed any grade HFS and/or worsening HTN (HFS/HTN). Toxicity-related dose reduction/cessation was required in 46 (54%) pts (15% due to HFS, 7% due to HTN). Estimated median progression-free (PFS) and OS were 5.5 (95% CI 4.1-7.0) and 6.5 (95% CI 4.9-8.0) months, respectively. Age at diagnosis, previous liver-directed therapy, CP score, baseline AFP and development of HFS/HTN were included in multivariable analysis: CP-A (vs. B; p-value < 0.001) and development of HFS/HTN (vs. no; HR 0.4 [95% CI 0.2-0.7] p-value 0.001) were independent prognostic factors. The prognostic influence of HFS/HTN was preserved when limiting analysis to pts developing worst grade HFS/HTN in the first 3 months of treatment (53 pts; HR 0.5 [95% CI 0.3-0.9] p-value 0.030) making time-on-treatment bias unlikely. Conclusions: The development of sorafenib-specific toxicities, HFS and HTN, are prognostic factors associated with prolonged OS.
Sunitinib (SU) in patients with advanced, progressive pancreatic neuroendocrine tumors (pNET): Final overall survival (OS) results from a phase III randomized study including adjustment for crossover.
Authors: Raymond Eric , Niccoli Patricia , Castellano Daniel , Valle Juan W. , Hammel Pascal , Raoul Jean-Luc , Vinik Aaron , Bang Yung-Jue , Lee Se-Hoon , Borbath Ivan , Lombard Bohas Catherine , Metrakos Peter , Smith Denis Michel , Chen Jen-Shi , Seitz Jean Francois , Patyna Shem , Huang Xin , Ishak Jack , Faivre Sandrine J. , Ruszniewski Philippe B. 
Published: February 2017

309 Background: In 2010, the pivotal double blind Phase III study met its primary endpoint with a median progression-free survival (PFS) of 11.4 months (mo) for sunitinib vs. 5.5 mo for placebo (PBO) (HR=0.42; 95% CI 0.26-0.66; P <0.001) in patients (pts) with advanced, progressive pNET. This trial showed an OS difference favouring sunitinib (HR=0.41; 95% CI 0.19-0.89; P = 0.02). At 2 years since study closure, median OS was 33.0 mo for SU and 26.7 mo for PBO (HR=0.71; 95% CI 0.47-1.09; P = 0.115). Methods: A total of 171 pts were randomly assigned 1:1 to SU 37.5 mg continuous daily dose (n = 86) or PBO (n = 85). The primary end-point was investigator assessed PFS. Pts receiving PBO could crossover to SU at disease progression. Final OS at 5 years follow-up since study closure was analyzed using the Kaplan-Meier method and Cox proportional hazards model in the intent-to-treat (ITT) population. In addition, a series of methods were used to adjust for cross-over including rank-preserving structural failure time (RPSFT). Clinical trial information: NCT00428597 . Results: At 5 years follow-up since study closure, the median OS was 38.6 mo for those randomized to SU and 29.1 mo for those randomized to PBO (HR=0.73, 95% CI 0.50-1.06; P = 0.094). In total, 59 pts randomized to PBO (69%) crossed over to SU. OS results obtained applying methods to adjust for cross-over are shown in Table 1. Conclusions: The 5-year OS difference (9.5 mo) between SU and PBO is confirmed. Correction for crossover yielded a stronger OS advantage with SU, confirming that crossover likely confounded the OS results. Clinical trial information: NCT00428597. [Table: see text]
Safety and feasibility of enhanced recovery after surgery in the patients underwent pancreaticoduodenectomy for hepatobiliary and pancreatic malignancy.
Authors: Kazama Keisuke , Aoyama Toru , Murakawa Masaaki , Yamaoku Koichiro , Atsumi Yosuke , Kanazawa Amane , Higuchi Akio , Shiozawa Manabu , Yukawa Norio , Oshima Takashi , Yoshikawa Takaki , Rino Yasushi , Masuda Munetaka , Morinaga Soichiro 
Published: February 2017

338 Background: Pancreaticoduodenectomy (PD) remains the mainstay of surgical treatment for hepatobiliary and pancreatic malignancy and offers the only chance of long term survival. However, the morbidity and mortality after PD has been reported to be high. Therefore, it is important to determine the most appropriate perioperative care. This study assessed whether enhanced recovery after surgery (ERAS) program is safe and feasible in patients who underwent pancreaticoduodenectomy Methods: The subjects were patients who underwent consecutive PD between 2012 and 2014 at the Department of Gastrointestinal Surgery, Kanagawa Cancer Center. They received perioperative care according to ERAS program. All data were retrieved retrospectively. Outcome measures included postoperative mortality, morbidity, hospitalization and 30-day readmission rate. Key ERAS program targets were: nasogastric tube (NGT) removal [postoperative day (POD) 1]; resumption of oral fluids (POD 2); urinary catheter removal (POD 3); tolerating diet (POD 5); drain removal (POD 7). Results: A total of 109 patients were studied. The overall incidence of morbidity was 51.4%, the incidence of mortality was 1.8%, and the incidence of readmission was 1.8%. The median postoperative hospital stay was 23 days. The proportions of patients achieving key targets were: 93.6% for NGT removal; 94.5% for resumption of oral fluids; 31.2% for urinary catheter removal; 79.8% for tolerating diet; 80.7% for meeting mobility targets, and 37.6% for drain removal. Conclusions: ERAS program is safe and feasible in patients who undergo PD. However, achieving compliance on some targets, especially the removal of catcher and drain, were more challenging.
Overall survival and resection margin after hepatectomy for intrahepatic cholangiocarcinoma at academic cancer centers versus community cancer centers.
Authors: Berger Nicholas Gerard , Hammad Abdulrahman Y , Miura John Thomas , Johnston Fabian McCartney , Christians Kathleen K. , Tsai Susan , Turaga Kiran , Gamblin T. Clark 
Published: February 2017

339 Background: Margin status is an important prognostic factor of survival following hepatectomy for intrahepatic cholangiocarcinoma (ICC). R0 resection for ICC correlates with improved recurrence-free survival and overall survival (OS). The present study hypothesized that surgical resection margins and survival rates vary between centers. Methods: Patients with ICC undergoing hepatectomy were identified from the National Cancer Database (1998-2011). Treating centers were categorized as Academic Cancer Centers (ACC), and Community Cancer Centers (CCC). Rates of R0 vs. R1/2 resection were examined. OS was analyzed by Kaplan-Meier method, and Cox multivariate modeling identified independent predictors of survival. Results: A total of 2,774 patients were identified. Hepatectomy was most often performed at ACC compared to CCC: 1,928 (69.5%) vs. 846 (30.5%). Hepatectomy at ACC was associated with higher rates of R0 resections compared to CCC (72.5% vs. 68.1%, p= 0.018). Higher 30-day readmission rates were seen following hepatectomy at ACC (9.9% vs. 5.7%, p= 0.002). Improved median OS was seen in ACC across all stages (25.8 months vs. 20.1 months; p< 0.001). After adjusting for age, sex, ethnicity, cirrhosis, alpha-feto protein level, comorbidity, disease stage, and margin status, hepatectomy at ACC was independently associated with improved OS (Hazards ratio: 0.79 [95%CI 0.62-0.99, p= 0.046]). Conclusions: ACC have higher rates of negative resection margins for ICC, but higher readmission rates following surgery. Survival is higher at ACC compared to CCC, suggesting that site of care plays a role in patient outcomes.
Gemcitabine (G) + nab-paclitaxel (nab-P) versus G in patients (pts) with advanced pancreatic cancer (PDAC) after FOLFIRINOX: A single center, retrospective review.
Authors: Chan Edmond Mankee , Hong Theodore S. , Clark Jeffrey William , Blaszkowsky Lawrence Scott , Allen Jill N , Zhu Andrew , Goyal Lipika , Murphy Janet E , Kwak Eunice L , Wo Jennifer Y , Ryan David P. , Faris Jason Edward 
Published: February 2017

348 Background: The MPACT study showed that G + nab-P improved OS and PFS over G as first line therapy for metastatic PDAC. However, there is limited data studying this combination after FOLFIRINOX. Here, we compared G + nab-P to G in pts with advanced PDAC previously treated with FOLFIRINOX. Methods: From 3/2010 to 5/2014, we identified all pts treated with FOLFIRINOX for PDAC who later received G +/- nab-P at the MGH. PFS and OS were calculated from the start of G +/- nab-P and analyzed using Kaplan-Meier and Cox-regression analyses. Results: 40 pts received G + nab-P and 36 pts received G. 29 of 36 pts in the G arm started G prior to the FDA approval of nab-P. Baseline characteristics were similar except 7 pts in the G + nab-P arm had locally advanced PDAC at start of G + nab-P while all other pts in both arms had metastatic PDAC. The median OS was 4.8 months (m) for G + nab-P vs 4.2m with G (HR 0.69, 95% CI 0.42 – 1.13). The median PFS was 2.4m for G + nab-P vs 1.8m for G (HR 0.70, 95% CI 0.44-1.12). The median OS did not change when the analysis was restricted to pts with metastatic PDAC – 4.8m vs 4.2m (HR 0.68, 95% CI 0.41-1.14). The median PFS for pts with metastatic PDAC was also similar – 2.7m for G + nab-P vs 1.8m with G (HR 0.69, 95% CI 0.42-1.12). Pts treated with G + nab-P received a median of 4m of treatment vs 2m for pts with G alone. The median relative dose of G was 50% of the maximum anticipated dose over the first 8 weeks for G + nab-P vs 66% with G. The median relative dose for nab-P was 50% of the maximum anticipated dose over the first 8 weeks. The most common reasons for discontinuing therapy were progression (62.5% vs 69%), patient decision (5% vs 11%), and infection (12.5% vs 0%). Conclusions: Although retrospective and limited by a small sample size, our data suggests that G + nab-P could be considered over G for advanced PDAC after FOLFIRINOX. However, G + nab-P affords marginal improvement in median OS and PFS, thus calling for the need to explore other agents in the second-line setting. Moreover, our experience suggests that the addition of nab-P led to a reduction in the achievable dose of G – raising the question of tolerability in combining further agents to G + nab-P in this setting.