bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of capecitabine, carboplatin, and bevacizumab for metastatic or unresectable gastroesophageal junction and gastric adenocarcinoma.
Authors: Kunz Pamela L. , Nandoskar Prachi , Koontz Michael Zach , Ji Hanlee , Ford James M. , Balise Raymond R. , Kamaya Aya , Rubin Daniel , Fisher George A. 
Published: February 2017

115 Background: Gastroesophageal junction (GEJ) and gastric adenocarcinomas constitute a major health problem worldwide. In the United States, the incidence of adenocarcinoma of the esophagus, GEJ and gastric cardia is rising rapidly. Chemotherapy for metastatic disease improves survival and quality of life when compared to best supportive care. The addition of bevacizumab to chemotherapy in a large, randomized, multinational study showed conflicting results. Methods: Patients (pts) with biopsy proven metastatic or unresectable GEJ and gastric adenocarcinomas received bevacizumab 15 mg/kg IV and carboplatin AUC 6 IV on day 1 and capecitabine 850 mg/m2twice daily by mouth on days 1-14 on a 21-day cycle. Pts with stable disease (SD) or partial response (PR) were allowed to continue therapy with bevacizumab with or without capecitabine. Primary endpoints were progression free survival (PFS) and toxicity; secondary endpoints were overall survival (OS) and response rate by RECIST. Results: Between April 2009 and April 2013, a total of 35 pts were enrolled. At present, 29 patients are off treatment and 6 are still actively receiving treatment. 29 pts are available for response assessment, 6 patients came off study prior to their first tumor assessment. Baseline characteristics are: M:F = 25:10; median age = 58 years (range 25-81); primary site = GEJ (17) and gastric (18); degree of differentiation = well (3), moderate (12), poor/signet ring (18), and unknown (2); race = White Non-Hispanic (24), White Hispanic (6), and Asian (5). The 1-year PFS is 21% and median PFS is 8.5 months. Median OS is 14.3 months. Best response by RECIST is as follows: PR in 17 pts (49%), SD in 6 pts (17%), and progressive disease (PD) in 6 pts (17%). The treatment was well-tolerated with toxicities as expected. Conclusions: The combination of capecitabine, carboplatin and bevacizumab in metastatic or unresectable unresectable GEJ and gastric adenocarcinomas is well tolerated and shows promising response rates, though did not meet the primary endpoint of PFS. Clinical trial information: NCT00780494.
Risk factors for surgical complications after D2 gastrectomy following neoadjuvant chemotherapy for gastric cancer.
Authors: Yoshikawa Takaki , Aoyama Toru , Hayashi Tsutomu , Tanabe Kazuaki , Nishikawa Kazuhiro , Ito Yuichi , Cho Haruhiko , Morita Satoshi , Miyashita Yumi , Tsuburaya Akira , Sakamoto Junichi 
Published: February 2017

164 Background: The feasibility and safety of D2 surgery following neoadjuvant chemotherapy (NAC) has not yet been fully evaluated in patients with gastric cancer. Moreover, the risk factors for surgical complications after D2 gastrectomy following NAC are also unknown. The aim of the present study was to identify risk factors for postoperative complications after D2 surgery following NAC. Methods: This study was conducted as an exploratory analysis of a prospective randomized phase II trial of NAC. This randomized phase II trial compared two and four courses of neoadjuvant S-1/cisplatin (SC) and paclitaxel/cisplatin (PC) using a two-by-two factorial design for locally advanced gastric cancer. Sample size was set at 60 to 80 to achieve 10% improvement of 3-year OS by four courses or by PC with approximately 80% probability of the correct selection. The surgical complications were assessed and classified according to the Clavien-Dindo classification. The uni- and multivariate logistic regression analyses were performed to identify risk factors for morbidities. Results: Among the 83 patients who were registered in the phase II trial, 69 patients received NAC and D2 gastrectomy. Postoperative complications were identified in 18 patients, and the overall morbidity rate was 26.1%. The results of the univariate and multivariate analyses of various factors potentially affecting the overall surgical morbidity identified a creatinine clearance (CCr) < 60ml/min (P = 0.016) as the sole significant independent risk factor for overall morbidity. The incidence of pancreatic fistula was significantly higher in the patients with a low CCr than in those with a high CCr. Conclusions: A low CCr was found to be a significant risk factor for surgical complications associated with D2 gastrectomy after NAC. Careful attention is therefore required for these patients. Clinical trial information: UMIN000002595.
Outcome of chemoradiotherapy followed by surgery for locally advanced T4 thoracic esophageal squamous cell carcinoma.
Authors: Akutsu Yasunori , Kono Tsuguaki , Uesato Masaya , Hoshino Isamu , Murakami Kentaro , Matsubara Hisahiro 
Published: February 2017

170 Background: Chemoradiotherapy (CRT) is a standard modality for locally advanced esophageal squamous cell carcinoma (ESCC). The outcome of CRT with/without following surgery for locally advanced ESCC was demonstrated. Methods: 1,235 new ESCC patients from 2001 to 2012 were obtained. From these, locally advanced thoracic ESCC was selected. If the patients showed resectability with down-staging after CRT, a subsequent surgery was performed. For the remaining cases, an additional CRT was prescribed, following by a re-evaluation for surgery. If down-staging and resectability were achieved, the patients underwent surgery. In the surgery group, pathologic effectiveness in the primary tumor and lymph nodes was observed and survivals both in surgery and non-surgery group were calculated. Results: From 1,235 new ESCC patients, 153 patients (12.4%) were of locally advanced thoracic ESCC. Among these, 28 patients (18.3%) showed finally down-staging of the primary tumor and could undergo following surgery. 12 patients (7.8%) could obtain down-staging and underwent surgery (surgery H group). In total, 40 patients (26.1%) could undergo surgery (surgery group). The rate of residual tumor in the primary tumor was detected in 32 cases (80%). The 5-year overall survival was 33.0% in the surgery group and 10.0% in the non-surgery group (P=0.002). The 5-year cause-specific survival was 65.0% in the surgery group and 18.1% in the non-surgery group (P=0.002). Conclusions: CRT for locally advanced thoracic ESCC is the standard modality and following surgery have benefits. However, the outcome is not satisfactory and further improvements of treatments for such cases are requested.
EVOLVE-1: Phase 3 study of everolimus for advanced HCC that progressed during or after sorafenib.
Authors: Zhu Andrew X. , Kudo Masatoshi , Assenat Eric , Cattan Stéphane , Kang Yoon-Koo , Lim Ho Yeong , Poon Ronnie Tung Ping , Blanc Jean-Frédéric , Vogel Arndt , Chen Chao-Long , Dorval Etienne , Peck-Radosavljevic Markus , Santoro Armando , Daniele Bruno , Furuse Junji , Jappe Annette , Perraud Kevin , Anak Ozlem , Sellami Dalila B. , Chen Li-Tzong 
Published: February 2017

172 Background: No effective treatment options exist for advanced HCC following sorafenib failure. Preliminary data suggest everolimus may provide benefit after sorafenib. EVOLVE-1 (NCT01035229) assessed the efficacy and safety of everolimus for advanced HCC after sorafenib failure. Methods: Pts aged ≥18 y with BCLC stage B or C HCC and Child-Pugh A liver function whose disease progressed during or after sorafenib or who were sorafenib intolerant were randomized 2:1 to everolimus 7.5 mg/d or placebo. All pts received best supportive care. Randomization was stratified by region (Asia v rest of world) and macrovascular invasion (yes v no). Study drug was given continuously until disease progression or intolerable toxicity. CT/MRI was performed every 6 wk. Primary endpoint was OS. Secondary endpoints were TTP, disease control rate (DCR; percentage of pts with best overall response of CR, PR, or SD per RECIST 1.0), and safety. Final analysis was performed when 454 deaths occurred. Results: 546 pts from 18 countries enrolled from Apr 2010 to Mar 2012 (everolimus = 362, placebo = 184). Baseline characteristics were balanced between arms; median age was 66.0 y, 84.8% of pts were male, 86.3% had BCLC stage C disease, 16.7% were from Asia, 32.8% had macrovascular invasion, and 74.0% had extrahepatic disease. Prior sorafenib was discontinued for disease progression in 80.8% of pts and intolerance in 19.0%. Median OS was 7.56 mo with everolimus and 7.33 mo with placebo (HR 1.05; 95% CI 0.86-1.27; P = .675). Median TTP was 2.96 mo and 2.60 mo, respectively (HR 0.93; 95% CI 0.75-1.15). DCR was 56.1% and 45.1%, respectively (P = .010). The most common grade 3/4 AEs with everolimus (v placebo) were anemia (7.8% v 3.3%), asthenia (7.8% v 5.5%), decreased appetite (6.1% v 0.5%), and hepatitis B viral load increase or reappearance (6.1% v 4.4%). No pts experienced HCV flare. HBV reactivation was experienced by 39 pts (29 everolimus, 10 placebo); all cases were asymptomatic, but 3 everolimus recipients discontinued therapy. Conclusions: Everolimus did not improve OS in pts with advanced HCC whose disease progressed on or after sorafenib or who were sorafenib intolerant. The safety profile was consistent with that previously observed with everolimus. Clinical trial information: NCT01035229.
Randomized controlled trial of irinotecan drug-eluting beads with simultaneous FOLFOX and bevacizamab for patients with unresectable colorectal liver-limited metastasis.
Authors: Martin Robert C. G. , Scoggins Charles R. , Rilling William S. , Schreeder Marshall T. , Kauh John S. , Strasberg Steven M. , Crocenzi Todd S. , Redman Rebecca , Sharma Vivek R. 
Published: February 2017

174 Background: Reports have demonstrated the activity of combining both Irinotecan and Oxaliplatin into a FOLFOXIRI therapy. An option to gain similar benefits and less toxicity to FOLFOXIRI would be to administer the irinotecan through an hepatic arterial apporach. The aim of this study was to assess the maximal response and adverse event rates of Irinotecan Drug Eluting Beads (DEBIRI) with FOLFOX and Bevacizumab (Bev) as a first line treatment for unresectable colorectal liver metastasis (CLMs). Methods: Metachronous and Synchronous CLMs were randomly assigned to mFOLFOX6/Bev or mFOLFOX6, Bev and DEBIRI (FOLFOXDEBIRI). Primary end point was optimal response rates and adverse events. Secondary endpoints were patients (pts) converted to resection and survival. Results: The intention-to-treat population comprised 70 pts, 40 pts randomly assigned to the FOLFOXDEBIRI arm and 30 pts to FOLFOX/Bev arm. Both were similar with synchronous disease (50% vs. 36%), extent liver involvement (35% vs. 31%), but greater percentage in the FOLFOXDEBIRI arm of ECOG 1/2 (57% vs. 31%), p=0.04) and extra-hepatic disease (51% vs. 36%, p=0.02). Median number of chemotherapy cycles was similar in both arms of 8, with a similar Grade 3/4 adverse event rate of 54% FOLFOXDEBIRI and 46% FOLFOX/Bev arm. The overall response rate was significantly greater in the FOLFOXDEBIRI arm vs. FOLFOX/BEV at 2 mons (78% vs. 54%), 4 mons (95% vs. 70%) and 6 mons (76% vs. 60%, p=0.03). Significantly greater downsizing to resection in the FOLFOXDEBIRI arm vs. FOLFOX/Bev (35% vs. 16%, p=0.05), with an improved median progression free survival (15.3 mons vs. 7.6 mons). Overall improvement in hepatic specific progression free survival was seen in the treatment arm (12.8 mons vs. 10.5 mons). Conclusions: Simultaneous mFOLFOX6 with bevacizumab and hepatic arterial irinotecan drug eluting beads is safe, without causing chemotherapy delivery delays and without increasing chemotherapy toxicity. Simultaneous FOLFOXDEBIRI leads to improved overall response rates, improved hepatic progression free survival, and more durable overall progression free survival in patients downsized to resection. Clinical trial information: NCT00932438.
Pancreatic circulating tumor cells as a diagnostic adjunct in pancreatic cancer.
Authors: Ankeny Jacob S , Hou Shuang , Lin Millicent , OuYang Hank , Song Min , Rochefort Matthew M , Girgis Mark D , Isacoff William H. , Wainberg Zev A. , Tseng Hsian-Rong , Tomlinson James S 
Published: February 2017

175 Background: Current diagnosis of pancreatic ductal adenocarcinoma (PDAC) relies upon image guided tissue sampling, which is expensive, inconvenient, and not without patient risk. Circulating tumor cells (CTCs) may improve our ability to diagnose PDAC, obtain pure molecular information uncontaminated by stromal cells, and potentially improve our ability to accurately stage patients at the time of diagnosis. Therefore, we evaluated CTCs as an adjunctive diagnostic biomarker of PDAC at the time of presentation. Methods: We performed a prospective analysis on 50 consecutive pre-treatment patients with either suspicion for, or recent diagnosis of PDAC who were referred to our UCLA Center for Pancreatic Diseases. 2 mL venous blood was evaluated for the presence and number of CTCs. Capture and enumeration was carried out with a novel microfluidic NanoVelcro technology enhanced by anti-EpCAM enrichment. CTCs were defined by size > 10 um and IHC staining pattern (DAPI+, CK+, and CD45-). Of note, KRAS mutational status was assessed in CTCs from 3 patients to confirm PDAC origin of CTCs. Diagnostic performance was then assessed via analysis of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and receiver operating characteristic (ROC) curves. Results: Of the 50 patients, 32 patients had PDAC and 18 had non-malignant pathology on tissue biopsy. CTCs were detected in 62.5% of PDAC patients, and in 5.5% of patients with non-malignant pathology. Specificity of CTCs for the diagnosis of PDAC was 94.4%, PPV 95.2%, and NPV 58.6%. ROC curve analysis determined optimal ability for CTCs to distinguish between benign and malignant disease with detection of ≥ 1 CTC. Additionally, in patients with a diagnosis of PDAC, CTC number correlated with stage and the presence of ≥ 2 CTCs distinguished local from systemic disease. Conclusions: In this study, CTCs were a useful adjunct for diagnosis of PDAC. Additionally, CTCs were capable of identifying patients with metastases. Addition of outcomes data may allow CTCs to be established as a biomarker for improved staging at the time of diagnosis, with subsequent improvement in delivery of stage-specific treatments.
Updated survival from a randomized phase III trial (MPACT) of nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients (pts) with metastatic adenocarcinoma of the pancreas.
Authors: Goldstein David , El Maraghi Robert Hassan , Hammel Pascal , Heinemann Volker , Kunzmann Volker , Sastre Javier , Scheithauer Werner , Siena Salvatore , Tabernero Josep , Teixeira Luis , Tortora Giampaolo , Van Laethem Jean-Luc , Young Rosemary , Wei Xinyu , Lu Brian , Romano Alfredo , Von Hoff Daniel D. 
Published: February 2017

178^ Background: In the phase III MPACT trial, nab-paclitaxel (nab-P) + gemcitabine (G) was tolerable and demonstrated superiority to G alone for all efficacy endpoints in pts with metastatic pancreatic cancer (MPC). nab-P + G vs G alone met the study’s primary endpoint by demonstrating a significant improvement in overall survival (OS; median 8.5 vs 6.7 months; HR 0.72; 95% CI, 0.617 - 0.835; P < 0.001) and the secondary endpoints of progression-free survival (PFS; median 5.5 vs 3.7 months; HR 0.69; 95% CI, 0.581 - 0.821; P < 0.001) and overall response rate (ORR; 23% vs 7%; P < 0.001). The 1-year survival rates for nab-P + G vs G alone were 35% vs 22%. The OS data reported above were based on a database cutoff of September 17, 2012, at which time 80% of pts had died. Here, we report an updated OS analysis (post hoc) from MPACT. Methods: 861 pts with MPC and a Karnofsky performance status (KPS) ≥ 70 were randomized at 151 community and academic centers 1:1 to receive nab-P 125 mg/m2 + G 1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle or G alone 1000 mg/m2weekly for 7 weeks followed by 1 week of rest (cycle 1) and then days 1, 8, and 15 of a 28-day cycle (cycle ≥ 2). The data for this survival analysis were collected through April 1, 2013. Results: As of the updated data cutoff, 380/431 (88%) pts in the nab-P + G arm and 394/430 (92%) pts in the G alone arm had died. OS was superior for nab-P + G vs G alone in the intent-to-treat population, and the longer follow-up allowed an estimate of the 3-year survival rates (Table). The treatment effect was consistent across all pt subgroups examined. Conclusions: This updated survival analysis revealed a sustained difference in OS over time between the 2 arms. MPACT is the first phase III study in MPC to report 3-year survival rates. These data confirm and extend the previous report of the primary endpoint and support the superior efficacy of nab-P + G over G alone. These results may encourage efforts to build upon this well tolerated backbone to further extend survival. Clinical trial information: NCT00844649. [Table: see text]
Biomarker assessment from EUS-guided biopsy to predict outcomes and treatment in pancreatic cancer.
Authors: Nguyen Nam Q. , Ruszkiewicz Andrew , Chang David , Bambrick Jenna , Biankin Andrew Victor 
Published: February 2017

182 Background: Current methods of pre-operative predicting outcome of pancreatic cancer and related pancreatectomy are limited. While several prognostic biomarkers, including S100A2 and S100A4, are associated with poor outcomes, these currently can only be assessed in operatively resected specimens. The amount of tissue from EUS guided fine needle aspirations is often insufficient for biomarker assessment. Procore needles aim to acquire larger volumes of tissue that may be suitable. We aim to (i) evaluate the feasibility of S100A2 and S100A4 assessment in EUS guided biopsy specimens using the Procore needle, and (ii) evaluate the relationship of these biomarkers with outcome. Methods: Clinico-pathological data from 79 patients (70 ± 2yrs; 44M:35F) with pancreatic ductal adenocarcinoma (PDAC) were prospectively acquired. All subjects had EUS guided biopsy with a 22G Procore needle and cell-block preparation was performed. Sections of cell-block material were assessed for S100A2 and S100A4 protein expression using immunohistochemistry. Results: Pre-operative biomarker assessments from EUS acquired specimens were possible in 90% (72/79) of patients, 14 of which then had pancreatectomy. Thirty-five (49%) of patients expressed S100A2 and S100A4, which were co-expressed in 97% of cases. Patients with S100A2/A4 tumours on EUS had a significantly shorter median survival (10.0 vs. 17.5 months, p=0.03). Among patients with S100A2/A4 expressing tumors, pancreatectomy (n=8) didn't lead to a survival benefit compared with those managed non-surgically (n=27) (12.5 vs. 10.0 months, p=0.70). Of patients who had pancreatectomy, those with S100A2/A4 expressing tumors (n=8) had shorter survival than those with S100A2/A4-negative tumors (n=6) (12.5 vs. 20.5 months; p = 0.04). Conclusions: Biomarker assessment from EUS guided biopsy specimens is feasible and successful in 90% of cases. The presence of S100A2 and S100A4 expression predicts both survival and response to pancreatectomy in patients with pancreatic cancer. These findings demonstrate a “proof-of-concept”, that pre-operative EUS guided biopsy could inform clinical decision-making, particularly with regard to selection for operative resection of PDAC.
Next-generation sequencing in pancreatic cancer: Revealing genomic mutations beyond KRAS.
Authors: Teague Andrea S. , Tan Benjamin R. , Lockhart Albert C. , Picus Joel , Strasberg Steven M. , Hawkins William G. , Fields Ryan C. , Linehan David , Wang-Gillam Andrea 
Published: February 2017

208 Background: Pancreatic adenocarcinoma (PA) continues to have one of the worst prognoses of all malignancies, prompting the search for known oncogenic mutations that might be targets for therapy. Methods: We conducted a retrospective analysis of patients with PA who had next generation sequencing (NGS) performed by the Genomics and Pathology Services laboratory at Washington University School of Medicine. Some of main genes included APC, ATM, BRAF, FLT3, NOTCH1, MET, FGFR4, MAPK1, MAP2K2, IDH1, IDH2, RET, JAK2, KRAS, NRAS, PTEN, EGFR, PIK3CA, PDGFRA, RUNX1, KIT, ALK, and TP53. Fluorescence in-site hybridization (FISH) for EGFR gene amplification, and MLL and ALK gene rearrangement was also performed. Results: Among 46 patients with adequate tissue for sequencing, 36 (78.3%) had KRAS mutations (G12D: 44.4%, G12V: 33.3%, G12R:11.1%, Q61H:5.6%, G12A:2.8% and G12R:2.8%). Out of 10 patients with wild type KRAS, 7 patients had either novel mutations or potential targetable mutations (table). TP53 mutations were seen in 73.9% of patients. Among 33 novel mutations not previously described in the COSMIC database, more than 10% are predicted to have deleterious effect by PROVEAN and SIFT. For example, a G1137R variant identified in ALK is predicted to be deleterious and damaging. Of 29 patients whose tumors underwent FISH, 3 patients had EGFR gene amplification, 1 patient had both EGFR gene amplification and ALK gene rearrangement, and 1 patient was positive for the MLL gene rearrangement. Conclusions: NGS of pancreatic cancer not only confirmed common mutations such as KRAS and TP53, but also revealed genomic alterations that may potentially be responsive to available targeted agents. The discovery of novel mutations in wild type KRAS tumors warrants further investigation. [Table: see text]
Genomic profiling of intrahepatic cholangiocarcinoma: Refining prognostic determinants and identifying therapeutic targets.
Authors: Pawlik Timothy M. , Borger Darrell R. , Kim Yuhree , Cosgrove David , Alexandrescu Sorin , Groeschl Ryan Thomas , Deshpande Vikram , Lindberg James M. , Ferrone Cristina , Sempoux Christine , Popescu Irinel , Bauer Todd W. , Gamblin T. Clark , Gigot Jean Francois , Anders Robert , Zhu Andrew X. 
Published: February 2017

210 Background: The molecular alterations that drive tumorigenesis in intrahepatic cholangiocarcinoma (ICC) remain poorly defined. We sought to define the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection. Methods: 138 patients who underwent resection at 6 centers in the United States and Europe were included in the cohort. Mutational profiling was performed using nucleic acids that were extracted from resected ICC tumor specimens; mutations were identified using a multiplexed mutational profiling platform. The frequency of mutations was ascertained and the impact on outcome determined. Results: Most patients had a solitary tumor (82%) and median tumor size was 6.0cm. Most patients had R0 resection (89%); 19% patients had N1 disease, while 15% had microscopic vascular invasion. A minority received adjuvant therapy (30%). The majority (55%) of patients had no genetic mutation identified. Among the 62 (45%) patients with a genetic mutation, only a small number of gene mutations were identified with a frequency of >5%: IDH1 (17.4%), KRAS (8.7%), BRAF (5.8%), PIK3CA (5.1%). In contrast, other genetic mutations were identified in very low frequency: IDH2 (3.6%), NRAS (3.6%), TP53 (2.2%), MAP2K1 (1.5%), CTNNB1 (0.7%), and PTEN (0.7%). Approximately 7% of IDH1-mutant tumors were associated with a concurrent PIK3CA gene mutation, and to a much lower extent, a mutation in MAP2K1 (2%). No concurrent mutations in IDH1 and KRAS were noted. Compared with ICC tumors that had no identified mutation, IDH1-mutant tumors were more often bilateral (OR 3.46), while KRAS-mutant tumors were more likely to be associated with perineural invasion (OR 5.72)(both P<0.05). While clinicopathological features such as tumor number and nodal status were associated with survival, no specific mutation was associated with prognosis. Conclusions: Most patients with resected ICC had no somatic mutation identified on multiplexed mutational profiling. IDH1 and KRAS were the most common mutations noted. While certain mutations were associated with ICC clinicopathological features, mutational status did not seemingly impact long-term prognosis.