bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multicenter phase ib-IIR trial assessing activity of regorafenib in combination with modified gemcitabine-oxaliplatin (mGEMOX) in patients with advanced biliary tract cancer (aBTC).
Authors: Assenat Eric , Portales Fabienne , Ychou Marc 
Published: January 2019

427 Background: News therapeutic options are needed in aBTC systemic treatment. Regorafenib (a multi target tyrosine kinase inhibitor) showed efficacy in several digestive tumors and could be associated with conventional chemotherapy in BTC. The Phase Ib primary objective was to determine the recommended Regorafenib dose combined with mGEMOX. The randomized phase II will assess efficacy of the combination compared to mGEMOX alone. We present here the results of the analysis planned at the end of phase Ib. Methods: Three dose levels (80, 120 and 160mg) of Regorafenib combined with mGEMOX, 3 to 6 patients each, were planned, and up to 12 patients to confirm the recommended dose-level. Patients received Regorafenib from day 1 to 14, and mGEMOX on days 1 and 8 (IV Gemcitabine 900mg/m2 followed with Oxaliplatin 80mg/m2 IV). Results: From 10.2014 to 11.2016, 22 patients were included in two French centers: 6, 3 and 13 patients in levels 1, 2 and 3, respectively. 2 patients (level 3) were not evaluable for recommended dose identification or tolerance and excluded from analysis. Patients were 70% men, of median age 62.5 years (20-74), ECOG PS 0 (60%) or 1 (40%). Primary tumor was localized within (60%) or outside (30%) the liver, or in the gall-bladder (10%). Eight (30%) patients underwent surgery. The Regorafenib relative dose-intensity was 101.8 [89.3-107.1], 100 [96.4-100] and 100% [51.8-103.6] for dose levels 1, 2 and 3, respectively. Regorafenib dose modifications during treatment occurred for 0 (level 1), 0 (level 2), and 3 patients (27%) (level 3). Toxicities were (level 1, 2, 3): grade 3 diarrhea (1, 0, 0), grade 3 asthenia (0, 0, 1), grade 2 hand-foot syndrome (1, 0, 0), grade 3 hypertension (2, 1, 2), grade 3/4 neutropenia (1/0, 1/0, 0/2), grade 3 thrombopenia (1, 0, 1), grade 3 anemia (0, 0, 1). Four DLTs were reported: 1 in level 1 (grade 3 diarrhea) and 3 in level 3 (2 grade 4 neutropenia, 1 grade 3 anemia). Conclusions: Regorafenib shows acceptable toxicity combined with mGEMOX; the DLTs reported were mainly related to conventional chemotherapy. Dose level 3, 160mg/day Regorafenib will be used in ongoing phase IIR assessing efficacy of this combination. Clinical trial information: NCT02386397.
Gemcitabine, nab-paclitaxel, cisplatin, and anakinra (AGAP) treatment in patients with localized pancreatic ductal adenocarcinoma (PDAC).
Authors: Becerra Carlos , Paulson Andrew Scott , Cavaness Keith M , Celinski Scott A. 
Published: January 2019

449 Background: Treatment options for localized PDAC include surgery, chemo- and radio-therapy. Inflammatory stimuli cause IL-1 release and mediate inflammatory and immunological responses. PDAC cells can induce secretion of IL-1β which facilitates tumor development and progression. We showed that anakinra, a recombinant, non-glycosylated form of the human interleukin-1 receptor antagonist, when given with FOLFIRINOX, was safe for use in metastatic PDAC. Herein we report the preliminary results of AGAP in patients with non-metastatic PDAC. Methods: 16 patients with non-metastatic PDAC were treated with AGAP on Day 1 and 8 of a 21 day cycle for up to 6 cycles. Patients self-administered anakinra a day after their first dose of chemotherapy (100 mg every other day; SC). Restaging scans evaluation was performed after every 2 cycles. Patients filled a QOL questionnaire once a month and serum was collected at baseline and at defined time points for biomarker analysis. Results: Grade 3/4 toxicities: neutropenia (50%), alopecia (13%), anemia (25%), thrombocytopenia (19%), diarrhea (19%), hypomagnesemia (13%), vomiting (13%), and 6% of patients, respectively had febrile neutropenia, nausea, hypocalcemia, and erythema at the injection sites. Twelve patients had surgery and all had negative margins in the pathology specimen. Ten patients had normal CA19-9 prior to resection and 3 had disease recurrence. Two patients had elevated CA19-9 prior to surgery and 1 patient had disease recurrence. Four patients did not have surgery; 3 received XRT and had disease progression and 1 patient declined further therapy and expired on hospice. No patients had systemic progression while on AGAP chemotherapy. Eight patients are alive without recurrence at a median follow up of 13 months. Conclusions: AGAP was tolerable with expected toxicities from the combination regimen. Biomarker analysis, disease recurrence and survival will be updated at the meeting. The study has been expanded to include additional patients. Clinical trial information: NCT02550327.
Circulating tumor DNA (ctDNA) landscape and prognostic implications in advanced gastroesophageal adenocarcinoma (GEC).
Authors: Maron Steven Brad , Joshi Smita Suhas , Lomnicki S , Oliwa Tomasz , Landron Stacie , Johnson Julie , Kiedrowski Lesli Ann , Nagy Rebecca J , Lanman Richard B. , Janjigian Yelena Yuriy , Kelly Kaitlyn J. , Kim Seung Tae , Lee Jeeyun , Catenacci Daniel V.T. 
Published: January 2019

45 Background: Esophagogastric junction (EGJ) and gastric (GC) cancer, together GEA, have a poor prognosis, high molecular heterogeneity, and few targeted therapeutic options. Guardant360 is a clinical gene panel test for next generation sequencing (NGS) of plasma circulating tumor (ct) DNA. Methods: We evaluated a large cohort of ctDNA-derived genomic results (Guardant Health, Inc.), including a subset of pts from the University of Chicago (UC) with clinical data. GEA pts in these 2 cohorts were assessed for genomic alteration (GA) distribution: mutations (mt), indels, amplifications (amp) and fusions. UC survival analyses were performed using log-rank test and select gene-by-gene alteration frequency by pt with chi-square comparisons. Results: The overall ctDNA cohort comprised 1128 pts with median age 64 yrs (range 19-98) and 73% males. At least 1 detectable GA (median 4, range 0-102) was observed in 870 pts (77%). The UC subset of pts (n=171), median age 63 yrs (range 19-87), included 2/10/27/61% stage I/II/III/IV, 77/13/5/5% Caucasian/African American/Asian/Hispanic, 74% male and 63% EGJ. At least 1 detectable GA (median 4, range 1-102) was observed in 157 pts; median GAs per test by stage I vs II/III vs IV was 1.5/3.5/4.5. GA distributions were similar to the larger cohort (Table 1). Stage IV pts tested within 6 weeks of diagnosis/recurrence (n=34) had a median survival of 8.7 months. In these pts, BRAF/ FGFR2 amps and ARAF mts were each prognostic for worse survival ( p<0.05), and MET and KRAS amps trended towards significance. Mt allele frequency (MAF) ctDNA burden inversely correlated with survival ( p=0.01) . In 138 pts with ≥2 serial tests, non-synonymous GAs in MET, PIK3CA, and FGFR1 were more commonly late events (all p<0.05 ). Conclusions: GAs in plasma ctDNA were detected in 77% of GEA pts including numerous actionable targets. ctDNA analysis merits further evaluation as a prognostic biomarker assessing specific genes, overall ctDNA burden, and molecular heterogeneity at baseline and serially. [Table: see text]
Efficacy and tolerability of tremelimumab in patients with metastatic pancreatic ductal adenocarcinoma.
Authors: Sharma Padmanee , Dirix Luc , De Vos Filip Yves Francine Leon , Allison James Patrick , Decoster Lore , Zaucha Renata , Park Joon Oh , Vanderwalde Ari M. , Kataria Ritesh S. , Ferro Salvatore , Patel Gargi , Ben Yong (Ben) , Oh Do-Youn 
Published: January 2019

470 Background: Clinical activity and tolerability of the anti-CTLA-4 antibody, tremelimumab, has yet to be established in metastatic pancreatic ductal adenocarcinoma (mPDAC). In a Phase 2, multicenter, open label study (NCT02527434), tremelimumab was evaluated in pts with advanced solid tumors. We report a planned analysis of the safety and efficacy of tremelimumab monotherapy in a cohort of pts with mPDAC. Methods: Eligible pts were adults with histologically or cytologically confirmed mPDAC with tumor progression following prior standard first-line 5-FU- or gemcitabine-containing chemotherapy. Pts received tremelimumab 750 mg IV Q4W for 7 doses, followed by 750 mg Q12W for 2 doses, for up to a total of 12 mo (total 9 doses in 12 mo) or until disease progression or unacceptable toxicity. Pts were radiographically assessed Q6 wks relative to first dose. The primary endpoints were safety (evaluated by CTCAE v4.0) and objective response rate (ORR) by investigator assessments (evaluated by RECIST v1.1). Results: As of April 5, 2017, 20 mPDAC pts had received treatment and were evaluable for efficacy analysis. Median treatment duration was 1.8 mo. There were no observed objective responses (ORR 0%; 95% CI, 0.0, 16.8%). Of 20 pts, 2 were not evaluable and 18 had progressive disease (PD). Based on the full analysis set (N = 20), progression occurred in target lesions in 14 (70%), non-target lesions in 7 (35%), and new lesions in 13 (65%) pts (not mutually exclusive categories). At the time of progression, 11 (61%) pts were on treatment and 7 (39%) had discontinued treatment. Median overall survival was 4 mo (95% CI 2.83 - 5.42). Two (10%) pts were still in follow up at 12 mo after treatment initiation. Treatment-related AEs (trAEs) occurred in 14 pts (70%); grade ≥3 trAEs occurred in 6 pts (30%). Three pts (15%) discontinued therapy due to trAEs. There were no treatment-related deaths. Conclusions: Tremelimumab monotherapy did not appear to be active in mPDAC pts who had tumor progression following prior standard first-line 5-FU- or gemcitabine-containing chemotherapy. Clinical trial information: NCT02527434.
Retrospective study of postoperative chemoradiation of cholangiocarcinoma in South Korea: Efficacy, side effect, and prognostic factors.
Authors: Lee Guk Jin , Lee Jong Hoon , Kim Sung Hwan , Shim Byoung Yong 
Published: January 2019

486 Background: There is no estabilished consensus about chemoradiation therapy for resected cholangiocarcinoma, and many studies are ongoing. We tried to cofirm the effectiveness and side effects of chemoradiation after operation of cholangiocarcinoma and find the prognostic factors. Methods: We found the patients with cholangiocarcinoma who receieved chemoradiation after surgery between 2002 and 2015 from two hospitals in South Korea. We checked the baseline chareacteristics, efficacy and toxicities. And we tried to identify the prognostic factors for recurrence by statistical anaylsis. Results: We retrospectivally studied 51 cholangiocarcinoma patients. Median age was 64 (range 48-83), and Men was 30 patients (58.8%) of them. By location, there were 10 (19,6%) intrahepatic cholangiocarcinomas, 13 (25.5%) hilar cholangiocarcinoma, and 28 (54.9%) extrahepatic cholangiocarcinomas. All patient received 5-FU chemoradiation after surgery. R0 resections were 31 (60.8%), R1 resections were 20 (39.2%) There was recurrence with 35 (68.6%) patients. Median relapse free survival was 292 (range 86-1769) days. Locoregional recurrence were 16 (31.4%), and distant recurrences were 26 (51.0%). For hematological toxicity, the patients showed grade 3 toxicities, as leukopenia 5 (9.8%), anemia 1 (2.0%) , thrombocytopenia 1 (2.0%). For non-hematological toxicities, there were G3 toxicities as Infection 2 (4.0%), nausea/vomiting 1 (2.0%), Adhesive ileus 1 (2.0%), bleeding 1 (2.0%). For multivariate analysis, Tumor site (HR 1.88 (95% CI 1.09-3.23). P = 0.022) and modality of radiation therapy (HR 13.27 (95% CI, 3.56-49.50)), P < 0.001) were statistically meaningful factors. Conclusions: Although this is a retrospective study, we found that the result of chemoradiation therapy for some patients showed good efficacy and tolerable toxicity. We could consider chemoradiation for adjuvant therapy in cholangiocarcinoma, especially for extrahepatic cholangiocarcinoma. And intensity-modulated radiation therapy should be performed than three-dimensional radiation therapy in cholangiocarcinoma.
Efficacy of oral chemotherapy with capecitabine and temozolomide (CapTem) in metastatic neuroendocrine tumors (NETs): A single-institution experience.
Authors: Smiroldo Valeria , Carnaghi Carlo , Rimassa Lorenza , Personeni Nicola , Pressiani Tiziana , Bozzarelli Silvia 
Published: January 2019

487 Background: CapTem chemotherapy regimen represents one of the standard of treatment for NETs, an interesting option of care due to its feasibility and efficacy although not enough prospective data support this evidence. Methods: This retrospective analysis included all patients (pts) with metastatic NETs treated with CapTem regimen at our institution from April 2013 to April 2017. This oral chemotherapy included capecitabine 600 mg/m2/BID (capped at 1,000 mg BID total dose) on days 1–14 and temozolomide 75 mg/m2/BID on days 10–14 every 28 days according to the schedule published by Fine RL et al. (Cancer Chemother Pharmacol, 2013). Overall survival (OS), progression free survival (PFS), overall response rate (ORR) and toxicities were retrospectively evaluated. Results: Twenty-seven pts (15 males) were included. Median age was 61 yrs (range 46-85). Primary tumor included pancreas in 8 pts (29.6%), midgut 8 pts (29.6%), lung 8 pts (29.6%), other NETs 3 pts (11.1%). Most of pts had well-differentiated tumors (88.8%) and Ki67 was less than <20% in 59% of pts. Median number of cycles was 6 (range 2-25). Ten pts (37.0%) received CapTem as 1st line treatment, 7 pts (25.9%) as 2nd line and 10 (37.0%) pts as > 3rd line. ORR was 33.3%; 31.2% for Ki67 < 20% group and 40.0% in Ki67 >20%. DCR (partial response + stable disease) for the entire cohort was 59.2%. Median PFS was 4 mos, without any differences between pancreatic, midgut and lung groups, but mPFS was 8.0 mos for pts who received CapTem as 1st line treatment. At present mOS was not reached. In term of toxicity CapTem regimen was very well tolerated and only 1 pt reported a G3 reversible toxicity (neutropenia). No G3/4 toxicity were observed. Conclusions: Our experience confirms that CapTem regimen is effective and well tolerated. Efficacy does not seem to be related to the primary tumor or Ki67. DCR and ORR are superior to the response produced by tyrosine kinase inhibitors, suggesting a strategy when tumour shrinkage and symptom control are needed.
Specificity of methylated BCAT1 and IKZF1 for colorectal cancer.
Authors: Symonds Erin L. , Yao Beibei , Pedersen Susanne Kartin , Murray David , Young Graeme P 
Published: January 2019

580 Background: Methylated BCAT1 and IKZF1 are useful circulating tumor DNA (ctDNA) biomarkers for detection and following the course of colorectal cancer (CRC). This study aimed to determine the specificity of methylated BCAT1/ IKZF1 for CRC detection by assaying specimens from patients with other adenocarcinomas. Methods: Blood was collected from patients with invasive adenocarcinoma of the prostate (n = 32), breast (16), oesophagus (15) or colon/rectum (212), prior to any treatment or resection, and from 245 clinically assessed controls with no known prior or current adenocarcinoma. Biopsies were collected from cancer tissue and adjacent non-neoplastic tissue either prior to treatment or at surgery from 9 prostate, 26 breast, 6 oesophagus, 15 CRC cases. All specimens were assayed for methylated BCAT1 and IKZF1 DNA. Calculation of positivity rates: tissue, the proportion of tissue cases with ≥ 5% methylation; blood, the proportion of cases with any detectable signal of either marker. Results: ctDNA positivity rates were significantly higher in CRC (126/212, 59.4%, 95% CI: 52.5 - 66.1) and oesophageal cancer (6/16, 33.3%, 11.0 - 58.7) cases only compared to controls (16/245, 6.5%, 3.8 - 10.4; p < 0.01). ctDNA was more likely to be positive in late stage cancers, although only significant for CRC, Table. Cancer tissue positivity rates were: CRC, 15/15, 100% (96.4 - 100); oesophageal, 5/6, 83.3% (35.9 - 99.6); prostate, 4/9, 44.4% (13.7 - 78.8); breast, 5/26, 19.2% (6.6 - 39.4). All cancer tissues had significantly higher methylation levels than the adjacent tissue (Chi2 test, p >0.05). Conclusions: Only colorectal and oesophageal cancer patients had significantly higher ctDNA positivity rates (using methylated BCAT1/IKZF1) compared to controls. This was also reflected in a higher proportion of cases showing methylation in the cancer tissue. The methylated BCAT1/IKZF1 blood test should be investigated further as a screening and surveillance tool for oesophageal cancer. [Table: see text]
Molecular subtype assay to reveal anti-EGFR response sub-clones in colorectal cancer (CRC).
Authors: Fontana Elisa , Nyamundanda Gift , Cunningham David , Ragulan Chanthirika , Sclafani Francesco , Eason Katherine , Bali Maria Antonietta , Vendrell Ines , Patil Yatish , Hulkki Wilson Sanna , Moorcraft Jenkev Samantha Sing Yu , Begum Ruwaida , Chau Ian , Starling Naureen , Sadanandam Anguraj 
Published: January 2019

658 Background: We previously stratified CRC into five intrinsic gene expression subtypes (CRCAssigner) and four consensus molecular subtypes (CMS1-4) using expensive and time-consuming microarray/RNAseq platforms. Recently, we developed a low-cost (NanoCRC) assay using nCounter platform (NanoString Technology) and robust gene signatures to classify individual samples into both CRCAssigner and CMS subtypes. Here, we tested the assays using formalin-fixed paraffin-embedded (FFPE) patient samples from Royal Marsden Hospital. Given increased sensitivity to cetuximab in one of our CRCAssigner subtypes transit-amplifying (TA) that represents partly CMS2 subtype, we associated anti-EGFR response to the presence of TA sub-clones. Methods: FFPE from resected and biopsy CRC samples were profiled for our NanoCRC assay. Along with our single-sample subtyping method, we developed a tool to identify sub-clones of TA within individual samples. RAS/BRAF wild-type patients treated with single agent anti-EGFR therapy were statistically associated with sub-clonal molecular profiles, sidedness and single gene expression. Results: NanoCRC assay was highly reproducible with > 0.9 correlation coefficient. Among 76 samples (from 64 patients), all the five CRCAssigner, four CMS subtypes (including the mixed samples) and their associations with RAS/BRAF mutations were successfully identified. Subtype-mutational associations were similar to our previous publications. Among 15 KRAS/BRAF wild-type (wt) patients with single agent anti-EGFR therapy response data, TA sub-clone was identified in 7/9 with clinical benefit and 1/6 with no benefit (p < 0.05). The other sub-clones, sidedness and individual genes within the panels were not significantly associated. This TA sub-clone association was further confirmed using a publicly available cetuximab response data (39 KRAS wt; Khambata-Ford data; p=0.02). Conclusions: Overall, we developed a robust NanoCRC assay to classify CRC FFPE samples in to molecular subtypes. With caveat of small numbers, the presence of TA sub-clones is significantly associated with cetuximab response. Extensive validation is warranted.
Prevalence of RAS and BRAF mutations in metastatic colorectal cancer (mCRC) patients by tumor location.
Authors: Bylsma Lauren C , Gillezeau Christina , Garawin Tamer , Kelsh Michael Anthony , Fryzek Jon , Sangaré Laura , Lowe Kimberly 
Published: January 2019

681 Background: There is evidence to suggest that tumor biology and pathology differ for right- and left-sided colon tumors which may affect treatment efficacy and clinical outcomes. Therefore, we conducted a systematic review and meta-analysis of the available scientific literature to summarize the prevalence of RAS and BRAF mutations by primary tumor location and to identify potential sources of heterogeneity in mutation prevalence. Methods: This study was conducted in accordance with PRISMA guidelines. Using comprehensive search strings, several medical research databases were queried and relevant variables abstracted including tumor mutation prevalence, study country, metastasis site, tissue source, study design, study dates, median age of the cohort, mutation assessment method, and length of follow-up. Results: Final abstraction was performed on 40 articles, 36 observational studies and 4 randomized trials. Most studies were from Europe (n = 16), followed by Asia (n = 11), USA, (n = 7), Australia (n = 3), and the remaining 3 were conducted in multiple countries. The proportion of males in each study ranged from 37% to 72%, and the mean age ranged from 55 to 76 years. The prevalence of all RAS mutations was significantly higher among right-sided colon tumors than left-sided colon tumors (44%, 95% Confidence Interval [CI]: 38 – 50% vs 34%, 95% CI: 29 – 38%; p = 0.009). BRAF mutation prevalence was also higher in right-sided tumors (16.1%, 95% CI: 13.1 – 19.6% vs 4.4%, 95% CI: 3.4 – 5.8%; p < 0.0001). Conclusions: This systematic review and meta-analysis found that mutation prevalence varied by primary tumor right- or left-sided location among mCRC patients. Some of this variation may be explained by study characteristics such as mutation assessment method, country and length of follow-up. Further research will help to better understand treatment and outcome implications of tumor sidedness and mutation prevalence.
Prognostic and predictive factors in metastasic colorectal cancer.
Authors: Garcia Alfonso Pilar , Garcia Gonzalo , Gallego Iria , Peligros Isabel , Corcuera Ana , Puente Beatriz , Lobo De Mena Miriam , Ruperez Ana , Aguado Gema , Sandoval Carmen , Blanco-Codesido Montserrat , Calvo Aitana , Muñoz Martín Andres J. , Martin Miguel 
Published: January 2019

690 Background: In recent years, prognostic and predictive factors in mCRC are becoming more important, outstanding the tumor and metastasic location, the primary tumor and/or metastasis resections as well as molecular biomarkers (KRAS, NRAS, BRAF and PIK3CA). Methods: We conducted a retrospective study of 334 patients with mCRC diagnosticated between January 2010 and June 2015 in the Oncology Service from HGUGM. The objective of our study was to evaluate the overall survival (OS) relating to each of these settings. We also evaluated OS considering the biological treatment received in first line. Multivariant analysis was performed with independence of tumor and metastasic location, metastasectomies, no primary tumor resection, biological treatment used in first line, age, sex and moleculars biomarkers. Results: Median OS was 24,34m. The advantageous prognostic factors which statistically significant impact on the median OS have been triple (RAS and BRAF) (n = 86) and quadruple (RAS, BRAF and PIK3CA) (n = 76) wild-type (wt 36,6m vs mut 23m, p = 0,02; wt 37,6m vs mut 23,38m, p = 0.02, respectively), left tumor location with rectum (left 25,55m vs right 19,44m, p = 0,001) and isolated hepatic and pulmonary metastasic location (30,32 vs 23 m, p = 0,03; 45,32m vs 23,38 m, p = 0,004, respectively). The main disadvantageous prognostic factor has been the no primary tumor resection (13,75m vs 31,61m, p = 0,00001) with independence of synchronous presentation of the disease as well as biomarkers mutational status. Median OS in first line was 30.13 m with bevacizumab (n = 54) vs 16,18m with antiEGFR (n = 28) (p = 0.02) in extended RAS wild-type patients (n = 101). Considering the multivariate analysis, the independent prognostic factors have been the isolated pulmonary metastasis (HR = 0,46; CI 95% 0,30-0,73;p = 0,001), quadruple wild-type (HR = 0,69;CI 95% 0,49-0,97; p = 0,031), metastasectomies (HR = 0,29; CI 95% 0,21-0,4; p = 0,000), right location (HR = 1,43; CI 95% 1,08-1,9;p = 0,014) and no primary tumor resection (HR = 2,06; CI 95% 1,49-2,86; p = 0,000). Conclusions: Isolated pulmonary metastasis, quadruple wild-type, metastasectomies, left location and primary tumor resection have independent positive prognostic value, according to our retrospective study.