bluuebunny/crossref_metadata_2025_split huggingface dataset:
RAINFALL: A randomized, double-blind, placebo-controlled phase III study of cisplatin (Cis) plus capecitabine (Cape) or 5FU with or without ramucirumab (RAM) as first-line therapy in patients with metastatic gastric or gastroesophageal junction (G-GEJ) adenocarcinoma.
Authors: Fuchs Charles S. , Shitara Kohei , Di Bartolomeo Maria , Lonardi Sara , Al-Batran Salah-Eddin , Van Cutsem Eric , Ilson David H. , Tabernero Josep , Chau Ian , Ducreux Michel , Mendez Guillermo Ariel , Molina Alavez Alejandro , Takahari Daisuke , Mansoor Wasat , Lacy Jill , Gorbunova Vera , Ferry David , Lin Ji , Das Mayukh , Shah Manish A. ,   For the RAINFALL Study Group
Published: January 2019

5 Background: Ramucirumab, a VEGFR-2 IgG1 human monoclonal antibody, is the only biologic with proven efficacy as both a single-agent and in combination with paclitaxel in the second-line treatment of G-GEJ adenocarcinoma. RAINFALL (NCT02314117) is a global, double-blind, placebo-controlled randomized clinical trial addressing the hypothesis that adding ramucirumab to first-line Cis plus Cape or 5-fluorouracil (5FU) produces significant clinical benefit. Methods: Metastatic G-GEJ cancer patients eligible for first-line chemotherapy with ECOG performance status 0-1 were randomized 1:1 to receive either RAM (8 mg/kg iv D1, D8) or placebo (PL), every 21d. All patients received Cape (or 5FU)+Cis. Cis was given for up to 6 cycles. Cape+RAM/placebo was continued until progressive disease, toxicity or other discontinuation criteria. The primary endpoint was progression-free survival (PFS) for the first 508 patients; overall survival (OS) for ITT population was a powered secondary endpoint. Results: 645 patients were randomized to receive RAM+Cape/Cis (n=326) or PL+Cape/Cis (n=319). PFS was significantly prolonged in patients treated with RAM+Cape/Cis versus PL+Cape/Cis (HR, 0.75; 95% CI 0.61–0.94; p=0.011; median, 5.7 vs 5.4 mos), meeting the primary endpoint. There was no survival benefit for patients treated with RAM+Cape/Cis versus PL+Cape/Cis (HR, 0.96; 95% CI 0.80–1.16; p=0.68; median, 11.2 vs 10.7 mos). ORR in the ITT population was 41.1% in the RAM arm (95% CI 35.8–46.4) and 36.4% (95% CI 31.1–41.6) in the PL arm. Grade ≥3 adverse events in ≥10% of patients in the RAM arm were: neutropenia (26.3% RAM; 27.0% PL), anemia (12.1% RAM; 14.0% PL), and hypertension (9.9% RAM; 1.6% PL). No new safety signals were observed. Conclusions: In treatment-naïve patients with metastatic G-GEJ adenocarcinoma, the addition of ramucirumab to first-line chemotherapy conferred a significant 25% reduction in the risk of disease progression or death in the primary endpoint of PFS; however, ramucirumab was not associated with an improved OS. Clinical trial information: NCT02314117.
An analysis of the efficacy and safety of direct oral anticoagulants (DOACs) in gastrointestinal cancer-associated venous thromboembolism (GI-CAVTE).
Authors: Recio Boiles Alejandro , Babiker Hani M. , Scott Aaron James , Malangone Steve , McBride Ali , Elquza Emad 
Published: January 2019

505 Background: Two major trials and meta-analysis of patients (pts) with active cancer and VTE suggests that apixaban (A) and rivaroxaban (R) showed similar efficacy to enoxaparin and warfarin while having less associated major bleeding. GICA is associated with a higher incidence of VTE compared to other tumors. Moreover, bleeding complications of DOACs are not well defined in GICA pts. We compared the efficacy and safety of DOACs in pts with active GICA and VTE at the University of Arizona Cancer Center (UACC). Methods: A retrospective chart review of pts receiving DOACs with GICA and VTE treated at UACC was performed (11/2013-02/2017). GICA subgroup extracted from clinical trial delineations followed: active cancer, defined as cancer diagnosed at any stage +/- 6 months of VTE diagnosis. Efficacy outcomes were recurrent DVT, nonfatal pulmonary embolism (PE), or fatal PE. Safety outcomes for major bleeding were Hg drop of ≥2 g/dL, transfusion of ≥2 units of PRBC, bleeding in a critical site, or bleeding contributing to death. Fisher exact test is used for testing the difference in categorical variables for p-value < 0.05. Results: Our review included pts on A (n = 28) and R (n = 34). Pts had similar baseline characteristics compared to AMPLIFY (n = 81) and pooled-EINSTEIN (n = 71). Recurrent VTE at 6 months were 7.1% and 2.9% for pts on A and R, respectively. VTE historical comparison to AMPLIFY (3.7%) and EINSTEIN (2.8%) showed no significant difference. Major bleeding at 6 months were 7.1% and 14.7% for A and R, respectively, compared to 2.3% AMPLIFY / 2.8% EINSTEIN. R had the one recurrent non-fatal PE event and a significantly worse safety profile with 2 fatal bleeds (hemopericardium and upper GI bleed) and 2 critical bleeding sites (subarachnoid hemorrhage and retroperitoneal) [p = 0.0348], whereas A had non-significant of the before stated. Conclusions: To our knowledge, this is the first retrospective analysis to present long-term outcome data of DOACs in pts with GICA and VTE, which showed a similar risk of recurrent VTE and worse safety profile with R versus A. This data warrants further prospective clinical analysis of the efficacy and safety of DOACs in pts with GICA and VTE.
Postoperative proton therapy for pancreatic cancer patients enrolled on the Proton Collaborative Group (PCG) registry.
Authors: Nichols Romaine Charles , Morris Christopher G. , Prabhu Kiran , Hartsell William F. , Cahlon Oren , Apisarnthanarax Smith , McGee Lisa , Vargas Carlos E. 
Published: January 2019

513 Background: The PCG registry is a multicenter registry for patients receiving proton therapy for various malignancies. The current abstract reviews the outcomes for patients receiving postoperative proton therapy for resected pancreatic cancer. Methods: From March, 2013 to August,2016 18 patients with resected pancreatic adenocarcinoma received postoperative proton therapy. The current study reviews the pretreatment characteristics and outcomes of these patients. Results: Median age -70 years (range 52 to 79); Males 12, Females 6; pT Stage -T2–4, T3–13, T4–1; N Stage -N1–12, N0–6; Margin Status -Close-8, Positive-4, Negative-6; Surgical approach -open-16, laparoscopic 2; Operations performed: standard pancreaticoduodenectomy-11, pylorus sparing pancreaticoduodenectomy-4, total pancreatectomy-1; Pancreaticoduodenectomy with portal vein reconstruction –1; Pancreaticoduodenectomy with irreversible electroporation. Median lymph nodes taken-16.50 (range 3 to 72); Median lymph nodes positive-1.5 (range 0 to 7); PNI positive-9, PNI negative-2, PNI unknown-4; LVI positive-7, LVI negative-6, LVI unknown-5; Median tumor size –3.1cm (range 2.2 to 6.2); Median dose delivered –50.51Gy(RBE) (range 27.88 to 54.00); Median treatment duration –38 calendar days (range 25 to 48); One patient died during treatment. One additional patient demonstrated grade 3 toxicity (anorexia, nausea, diarrhea). Only one patient’s treatment was protracted by more than 5 days. Median available follow up is 1.1 years (range 0.07 to 3.4 years); 2 year survival 37%. Conclusions: Postoperative proton therapy after pancreatectomy was well tolerated without treatment interruption or severe toxicity.
Natural history of small nonfunctioning pancreatic neuroendocrine tumors.
Authors: Choi Jin Ho , Lee Sang Hyub , Choi Young Hoon , Kang Jinwoo , Paik Woo Hyun , Ryu Ji Kon , Kim Yong-Tae 
Published: January 2019

515 Background: Asymptomatic sporadic nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs) are rare disease but are diagnosed more frequently than before. The aim of this study was to evaluate the natural course of small NF-PNETs. Methods: We performed retrospective study of patients with suspected NF-PNETs from 1999 to 2015. Patients older than 18 years with NF-PNETs diagnosed either by pathology or other clinical evidences were included. Patients with clinical symptoms of hormonal hypersecretion, more than 20 mm in size, local invasion, nodal or distant metastasis, less than two follow-up imaging studies , and follow-up period of less than 6 months were excluded. Results: Small NF-PNETs in patients initially recommended surveillance (n = 69; mean age, 58.9 ± 11.1 yrs) were mainly located in the pancreatic head (n = 32, 46.4%) with mean mass size of 10.9 ± 3.1 mm. The average follow-up period was 52.2 ± 38.7 months. Tumor size changes during the follow-up period were as follows: increased (n = 9, 13.0%), sustained (n = 58, 84.1%), decreased (n = 2, 2.9%). The mean growth rate of increasing tumor was 0.9 ± 2.9 mm/year. Non-hypervascular tumors showed a tendency to increase in size compared to hypervascular tumor. (P = 0.04) Thirteen patients (18.8%) underwent surgery during the follow-up at average 32.9 ± 42.6 months later. According to the WHO 2010 grade classification, grade 1 was found in 18 patients, grade 2 in 1 patient, and grade 3 in 0 patient. The pathologic AJCC TNM stages of surgically resected tumors were Ia in 7 patients, Ib in 1 patient, IIa in 2 patient, IIb in 1 patients. Two patients (10.0%) received reoperation for recurred tumors at 34 and 50 months after surgery. Two patients (2.9%) showed distant metastasis after surgery but no disease-related death occurred. Conclusions: Most of small NF-PNETs do not increase in the size and seldom show metastasis during follow-up. Wait-and-see strategy can be applied for NF-PNETs less than 2cm in size.
The clinicopathologic features and optimal surgical treatment of duodenal gastrointestinal tumor.
Authors: Lee Seungjae , Song Ki Byung 
Published: January 2019

519 Background: Because of unclear clinicopathologic features, the optimal surgical procedure for duodenal gastrointestinal stromal tumor (GIST) remains poorly defined. We analyze clinicopathological features and recommend optimal surgical treatment of duodenal GIST. Methods: From July, 2000 to April 2017, 118 patients who had localized duodenal GIST were treated by curative surgical resection at a single institution. We retrospectively reviewed the clinicopathological characteristics and survival outcomes. Results: In survival analysis of all patients, 5-year overall survival (OS) and disease-free survival (DFS) rate were 94.9 and 79.2%, respectively. 19 patients developed recurrent disease at a median of 26.1 months from surgery and most common recurrence site was liver (63.2%). In multivariate analysis, mitotic count was the statistically significant prognostic factors of DFS. Our 20 cases of duodenal GIST in 1st or 4th portion were completely resected by limited resection(LR), regardless of tumor size. 98 patients with GISTs in 2nd or 3rd portion of duodenum underwent LR (n = 53) or pancreaticoduodenectomy (PD) (n = 45). Patients in the LR group had a smaller median tumor size (4.0 vs 5.3 cm, p = 0.026), more antimesenteric-sided location (41 vs 7cases, p < 0.001), less late complications (1 vs 7 cases, p = 0.014) and no postoperative newly developed diabetes mellitus (0 vs 4 cases, p = 0.027) than those in the PD group. When 53 patients in LR group further divided into minimal invasive LR (MILR) (n = 12) and open-LR (n = 41), MILR group had shorter operation time (155.0 vs 218.8 minutes, p = 0.013) and postoperative hospital stay (12.0 vs 19.4 days, p = 0.036). Conclusions: Patients with duodenal GIST who underwent complete surgical resection have favorable survival outcomes. Predictor of disease recurrence at multivariate analysis was mitotic count. LR is feasible and effective surgical treatment for the patients with small-sized, and anti-mesenteric sided duodenal GIST in terms of long-term oncologic outcomes and quality of life. MILR has better perioperative outcomes than open LR. Therefore, we should consider MILR as optimal surgical treatment for the selected patients with duodenal GIST.
Health-related quality-of-life (HRQoL) results from the FAST study: A phase II trial of epirubicin, oxaliplatin, and capecitabine with or without IMAB362 in patients with advanced CLDN18.2+ gastric and gastroesophageal junction adenocarcinoma.
Authors: Morlock Robert , Turnbull James , Blahut Steven , Krukas-Hampel Michelle R , Hawryluk Emily , Tureci Özlem 
Published: January 2019

54 Background: In the FAST study, IMAB362 (loading dose 800 mg/m2 then 600 mg/m2 d1 qd21) plus EOX (epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 d1, and capecitabine 625 mg/m2 bid) was compared with EOX alone in patients with advanced/metastatic gastric (GA), gastroesophageal (GE), and gastroesophageal junction (GEJ) adenocarcinoma. The FAST study exhibited a clinically relevant benefit in PFS and OS with a manageable safety profile in patients treated with IMAB362. Here we present the HRQoL results from the FAST study. Methods: CLDN18.2-positive patients (intermediate/strong membrane staining in ≥40% of cells) with advanced/metastatic GA/GE/GEJ adenocarcinoma were randomized 1:1 to first-line EOX for a maximum of 8 cycles with or without 600 mg/m2 q3w IMAB362, which after 8 cycles could be continued as monotherapy until disease progression (DP). The EORTC QLQC30 and a gastric cancer specific measure EORTC STO22 were collected at baseline (BL), Cycle 5, end of EOX therapy (EOT) and post-EOT every 12 weeks until DP. Change from BL in EORTC scores over 8 cycles of EOX treatment were analyzed using mixed model repeated measures. Time to deterioration in HRQoL was defined as time from randomization to first minimally clinically important difference (MCID) decline in each HRQoL domain. Results: The HRQoL analysis included 74 EOX and 68 IMAB362 + EOX per protocol patients. There were no significant differences in mean changes from BL in EORTC QLQC30 Global Health Status/QoL Score and STO22 Total Score across the 8 cycles of treatment with EOX. The QLQC30 Nausea and Vomiting domain showed a statistical difference (p = 0.0108) in favor of EOX-only. The median time to first HRQoL MCID deterioration for the QLQC30 Global Health Status was 8.6 mo for EOX + IMAB362 and 6.0 mo for EOX alone (p = 0.008). For patients who remained on IMAB362 post EOT, HRQoL improved from BL. Conclusions: HRQoL was maintained for a longer duration in pts with advanced/metastatic GA/GE/GEJ adenocarcinoma who received EOX + IMAB362 therapy vs EOX alone. HRQoL post EOT was improved for EOX + IMAB362 therapy vs EOX alone. Clinical trial information: NCT01630083.
Nivolumab + ipilimumab combination in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): First report of the full cohort from CheckMate-142.
Authors: Andre Thierry , Lonardi Sara , Wong Mark , Lenz Heinz-Josef , Gelsomino Fabio , Aglietta Massimo , Morse Michael , Van Cutsem Eric , McDermott Raymond S. , Hill Andrew G , Sawyer Michael B. , Hendlisz Alain , Neyns Bart , Svrcek Magali , Moss Rebecca Anne , Ledeine Jean-Marie , Cao Z. Alexander , Kamble Shital , Kopetz Scott , Overman Michael J. 
Published: January 2019

553 Background: Nivolumab (NIVO) provided durable responses (investigator-assessed [INV] ORR, 31%) and disease control (DCR, 69%) in pretreated pts with dMMR/MSI-H mCRC in CheckMate-142 (NCT02060188; Overman et al Lancet Oncol 2017). An interim analysis of the NIVO + ipilimumab (IPI) combination cohort of CheckMate-142 reported a preliminary ORR of 55% and manageable safety profile in a subset of pts (n = 84) with dMMR/MSI-H mCRC and ≥ 6 mo of follow-up (André et al ASCO 2017). Here we report for the first time efficacy and safety from the complete population (N = 119) of the NIVO + IPI cohort of CheckMate-142, which is the largest single-study report of an immunotherapy regimen in pts with dMMR/MSI-H mCRC. Methods: Pts with dMMR/MSI-H mCRC received NIVO 3 mg/kg + IPI 1 mg/kg Q3W for 4 doses followed by NIVO 3 mg/kg Q2W. Primary endpoint was ORR (INV; RECIST 1.1). Other endpoints were DOR, PFS, OS, and safety/tolerability. Results: Of 119 treated pts, 76% had ≥ 2 prior lines of therapy. Median follow-up was 13.4 mo. The ORR was 55% and DCR was 80% (Table). Notably, ORR in pts with a BRAF mutation was 55%. Among all responders, median DOR was not reached (NR), with 94% of responses ongoing at data cutoff. Tumor burden was reduced from baseline in 77% of pts. The 9-mo PFS and OS rates were 76% and 87%, respectively. Gr 3–4 TRAEs occurred in 32% of pts; 13% (any gr) and 10% (gr 3–4) of pts had TRAEs that led to discontinuation. No treatment-related deaths were reported. Results including a similar follow-up of the NIVO arm will also be presented. Conclusions: In the largest cohort of dMMR/MSI-H pts treated with an immunotherapy regimen, NIVO + IPI built on the efficacy reported with NIVO monotherapy, demonstrating enhanced clinical benefit and manageable safety, and may represent a new standard of care in pts with dMMR/MSI-H mCRC. Clinical trial information: NCT02060188. [Table: see text]
Cost-effectiveness of immune checkpoint inhibition in metastatic gastric and esophageal tumors.
Authors: Ostvar Sassan , Choi Jin G. , Chu Jacqueline N. , Dougan Michael Lawrence , Gainor Justin F. , Reynolds Kerry Lynn , Nipp Ryan David , Kong Chung Yin , Hur Chin 
Published: January 2019

56 Background: Immune checkpoint inhibition has shown early promising results in patients with chemotherapy-refractory metastatic or advanced tumors of the esophagus, gastroesophageal junction, and stomach. We explore the cost-effectiveness of checkpoint inhibitors as second-line treatment agents for this group of patients using a decision analytic approach. Methods: A Markov model was developed to simulate the course of a virtual cohort of patients treated by (i) nivolumab 3 mg/kg, (ii) combination of ipilimumab 3 mg/kg and nivolumab 1 mg/kg, and (iii) best supportive care (BSC). Patients in the hypothetical cohort were 55-year-olds in an advanced/metastatic stage who had received at least one prior line of chemotherapy. Patients who remained stable in treatment were monitored for adverse events until death. Rates of cancer-specific mortality, disease progression, and drug-related adverse events were estimated using results from the CheckMate 032 clinical trial. The primary endpoints were survival, measured in life-years (LY), quality adjusted life years (QALY), and incremental cost-effectiveness ratios (ICER). Cost-effectiveness of each strategy was evaluated from a US-payer perspective considering costs of drugs, treatment, and management of immune-related adverse events. Cost-effectiveness was defined with a willingness to pay threshold of $100,000/QALY. Results: Combination therapy with nivolumab and ipilimumab yielded the highest effectiveness (QALYs = 0.47, LYs = 1.09) in our base case modeling results, compared with nivolumab (QALYs = 0.43, LYs = 1.03), and BSC (QALYs = 0.19, LYs = 0.42). Nivolumab had an incremental cost of $84,555/QALY compared with BSC, while nivolumab with ipilimumab resulted in an incremental cost of $1.1M/QALY compared with nivolumab alone. The cost gap between the two was associated with the higher price of ipilimumab, and costs of managing increased toxicity. Conclusions: Our modeling analysis finds that combination therapy of ipilimumab and nivolumab is the most effective, but from a cost-effectiveness perspective, it is expensive, making nivolumab monotherapy the cost-effective option. Additional clinical data are needed to confirm our modeling results.
The prognostic role of microsatellite status, tumor mutational burden, and protein expression in CRC.
Authors: Schwartz Sarit , Tian Yuan , Cecchi Fabiola , Nguyen Andrew , Kim Yeoun Jin , Goh Brian , Chew Min Hoe , Tang Choon Leong , Toh Ee-Lin , Skanderup Anders , Koo Si-Lin , Chua Clarinda Wei Ling , Leow Wei Qiang , Tan Iain Beehuat , Vaske Charles Joseph , Sanborn Zack , Benz Stephen Charles , Lim Kiat Hon Tony , Hembrough Todd A. 
Published: January 2019

572 Background: Comprehensive molecular profiling of CRC can inform treatment decisions by identifying patient subgroups at varying risks of death. Microsatellite instability (MSI) is prognostic in CRC and is used to select patients for immunotherapy. High tumor mutational burden (TMB) is associated with genomic instability and is prognostic in melanoma. Expression of p16 protein is prognostic in many tumor types. We used proteomic and genomic profiling to measure MSI, TMB and p16 in CRC tumors and to assess associations with patient survival. Methods: In archived clinical samples of CRC, 76 proteins were quantitated with mass spectrometry-based proteomics. MSI was measured by WGS and RNA-seq; unstable loci were quantified in tumor and normal samples. Cutoffs were derived via ROC analysis: high TMB was defined as > 4.5 somatic mutations per megabase; p16 as > 108 amol/ug. Patients were grouped by microsatellite status (MSI vs. microsatellite stable [MSS]), TMB (high vs. low), and p16 protein expression level. Survival curves were compared with the Mantel-Cox log-rank test. Results: Of 145 samples, 39 (27%) had high TMB and 29 (20%) had MSI. Patients with MSI tumors had longer OS than patients with MSS tumors (HR: 0.096; p = 0.003). Similarly, patients with high TMB had longer OS than those with low TMB (HR: 0.076; p < 0.001). High p16 expression was prognostic of poor survival (HR: 2.874; p = 0.019). Among patients with MSS tumors or low TMB, those with low p16 levels had longer OS than patients with high p16 (HR: 0.257; p = 0.002 and HR: 0.249; p = 0.002, for MSS and low TMB, respectively). A combination of MSS, low TMB, and low p16 also differentiated between long and short survivors (HR: 0.249; p = 0.002). These associations remained after adjustment for tumor sidedness. Further analyses of clinical correlates will be presented. Conclusions: A combination of MSS, low TMB and low p16 expression characterized a subset of patients with longer survival. This is important because patients with MSS tumors have limited treatment options but may respond to CDK4/6 inhibitors due to low p16 expression. Molecular profiling of CRC may identify patient subgroups with a relatively poor prognosis who could benefit from personalized therapy.
Single nucleotide polymorphisms of mir-608, LCS-6, and overall survival in the MAGIC trial.
Authors: Smyth Elizabeth Catherine , Kouvelakis Kyriakos , Cunningham David , Peckitt Clare , Nankivell Matthew Guy , Allum William H. , Wotherspoon Andrew , Hahne Jens , Lampis Andrea , Langley Ruth E. , Valeri Nicola 
Published: January 2019

58 Background: Single nucleotide polymorphisms (SNPs) in mir-608 (rs4919510) are prognostic in colorectal cancer (CRC) and hepatocellular cancer. SNPs of the let-7 complementary site 6 (LCS-6) 3'-untranslated region of KRAS (rs61764370) are associated with prognosis in CRC and platinum sensitivity in head and neck cancer. We investigated the prognostic effects of these SNPs in patients treated with surgery and with perioperative epirubicin, cisplatin and 5-fluorouracil chemotherapy plus surgery in the MRC MAGIC trial. Methods: DNA was extracted from tumour tissue using the QIAamp DNA FFPE Tissue Kit (Qiagen, Hilden, Germany). Samples were genotyped using the Taqman assay (Life Technologies, Carlsbad, CA) for rs4919510 in mir-608 and rs61764370 in LCS-6. SNP status was assessed for association with patient characteristics and survival. Results: 305 patients (of 456 operated) had mir-608 and/or LCS-6 results available. SNPs mir-608 and LCS-6 were in Hardy-Weinberg equilibrium. Pathological tumour regression grading was not different for any SNP genotype. No genotype was statistically significantly associated with overall survival in either surgery arm or chemotherapy plus surgery arm of the trial (Table). Conclusions: Germline polymorphisms in mir-608 and LCS-6 showed no evidence of a prognostic effect in patients with gastric and gastroesophageal cancer treated with surgery or chemotherapy plus surgery in the MAGIC trial. However, the small number of patients with selected genotypes means that these analyses may be underpowered to detect survival differences. [Table: see text]