bluuebunny/crossref_metadata_2025_split huggingface dataset:
Left- versus right-side metastatic colorectal cancer: Teasing out clinicopathologic drivers of disparity in survival.
Authors: Mendis Shehara Ramyalini , Lee Belinda , Lee Margaret , Wong Rachel , Kosmider Suzanne , Shapiro Jeremy David , Yip Desmond , Steel Simone Anne , Nott Louise M. , Jennens Ross , Lipton Lara Rachel , Burge Matthew E. , Field Kathryn Maree , Ananda Sumitra , Beck Sophie , Wong Hui-Li , Gibbs Peter 
Published: January 2019

623 Background: Patients with metastatic colorectal cancer (mCRC) arising from a right sided colorectal cancer (RC) have an inferior survival versus patients with a left sided colorectal cancer (LC). Previous analyses have suggested that multiple factors contribute. Methods: The Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) Registry has prospectively captured comprehensive data on consecutive mCRC patients since 2009. For this analysis LC were defined as primary tumors at or distal to the splenic flexure and included rectal cancers. We analysed patient, tumor, treatment and outcome data. Results: Of 2306 patients enrolled from July 2009–March 2018, median age 67 years (range 18–100), 1559 (67.6%) had a LC. Patients with a RC were older (median 71 vs 65 years, p < 0.001), more likely to be female (50.2% vs 36.9%, p < 0.001) and to have a Charlson score ≥ 3 (67.5% vs 54.6%, p < 0.001). More common in RC, where tested, were BRAF mutations (22.3% vs 7.2%, p < 0.001) and deficient mismatch repair (6.4% vs 1.5%, p < 0.001), but not RAS mutations. Peritoneal metastases were more frequent in RC (29.7% vs 14.9%, p < 0.001). RC patients were more likely to have their primary tumor resected (77.9% vs 70.6%, p < 0.001) and to receive less first-line chemotherapy (72.2% vs 78.7%, p = 0.001). Progression-free survival on first-line systemic therapy was inferior for RC patients (8.1 vs 10.8 months, HR 1.38, p < 0.001). Median overall survival (OS) for all RC patients was inferior (19.6 vs 27.5 months, HR 1.44, p < 0.001). Primary side remained a significant factor for OS in multivariate analysis. Conclusions: Our data confirms the poor prognosis associated with RC, contributed to by multiple factors. However, primary side remains significant even when adjusting for these, indicating the existence of further as yet undefined differences. [Table: see text]
Withholding anti-EGFR, the impact on outcome in RAS wild-type metastatic colorectal tumors (WAIT or ACT trial).
Authors: Palmieri Lola-Jade , Mineur Laurent , Tougeron David , Rousseau Benoit , Granger Victoire , Gornet Jean-Marc , Smith Denis Michel , Lièvre Astrid , Galais Marie-Pierre , Doat Solene , Pernot Simon , Bignon Anne Laure , Metges Jean-Philippe , Baba-Hamed Nabil , Sefrioui David , Obled Stephane , Vitellius Carole , Bouche Olivier , Henriques Julie , Coriat Romain ,   Association des Gastro-Entérologues Oncologues (AGEO)
Published: January 2019

626 Background: First line of RAS wild-type (WT) unresectable metastatic colorectal cancer (mCRC) can be doublet chemotherapy with an anti-VEGF (Vascular Endothelial Growth Factor), or an anti-EGFR (Epidermal Growth Factor Receptor). Waiting for RAS status, many oncologists initiate chemotherapy and add the anti-EGFR secondly. The objective was to compare the delayed introduction of the anti-EGFR to the immediate introduction of the anti-VEGF in first-line treatment of RAS WT mCRC. Methods: This was a retrospective cohort analysis from 2013 to 2016, multicentric with 28 health care centers. We included patients with RAS WT unresectable mCRC treated between 2013 and 2016 by a doublet chemotherapy with the anti-VEGF introduced immediately or with the anti-EGFR introduced at C2 or C3. Progression free survival (PFS), overall survival (OS) and response rate (RR) for the two cohorts were compared. Hazard ratios (HR) with 95% confidence interval (95%CI) were estimated with cox regression models weighted on propensity score to deal with potential confounders. Results: A total of 262 patients were included, 129 in the immediate anti-VEGF group and 133 in the delayed anti-EGFR group. Median follow-up was 37.9 months. Ninety-two patients had the anti-EGFR introduced at C2, 40 at C3. The median delay of RAS analysis was 19 days (q1-q3: 13-26). Patients treated with anti-VEGFs were more likely men (68% versus 56%), with more metastatic sites ( > 2 sites: 15% versus 9%). A propensity score including the number of metastatic sites and a possible previous treatment was built. Delayed anti-EGFRs were associated with longer PFS compared to immediate anti-VEGFs: 13.8 versus 11.0 months, p = 0.0244. After weighting, delayed anti-EGFRs were still associated with better PFS: HR 0.74, 95%CI [0.61 – 0.90], p = 0.0024. OS was not different between the two arms (30.5 for anti-VEGF versus 29.9 months, p = 0.3934), even after weighting (HR 0.86, 95%CI [0.69 – 1.08], p = 0.2024). There was a better RR with delayed anti-EGFRs: 66.7% versus 45.6%, p = 0.0007. Conclusions: Our findings suggest that, while waiting for RAS status, the delayed introduction of the anti-EGFR is a valid option, compared to the immediate introduction of the anti-VEGF.
Obesity and its impact on outcomes in stage III colon cancer (CC) patients receiving adjuvant chemotherapy (AC).
Authors: Ding Qirui , McKinnon Geoff , Xu Yuan , Cheung Winson Y. 
Published: January 2019

627 Background: Obesity may complicate CC surgery, which can result in potential AC delays. We aimed to determine the effect of body mass index (BMI) and body surface area (BSA) on CC outcomes, accounting for variations in the time interval between surgery and AC. Methods: We analyzed a population-based cohort of patients from Alberta, Canada who were diagnosed with stage III CC from 2011 to 2016 and underwent AC. Patients were grouped based on their baseline BSA (underweight, < 20 kg/m2; normal, 20-24; overweight, 25-29; obese ≥ 30) and BMI (< 2 m2 vs ≥ 2 m2). Logistic regression models were constructed to examine the effect of BMI/BSA on delays between surgery and AC. The Kaplan-Meier method was used to estimate overall (OS) and cancer-specific survival (CSS) and Cox proportional hazards models were developed to evaluate the impact of BMI/BSA on these outcomes, adjusting for confounders. Results: We examined 915 patients: median age was 64 years, 510 (56%) were men and 155 (17%) had a Charlson comorbidity index (CCI) ≥ 2. In this cohort, 126 (14%), 623 (68%) and 166 (18%) were stage IIIA, IIIB and IIIC, respectively. In total, 132 (14%) were underweight, 452 (49%) normal weight, 233 (26%) overweight and 98 (11%) obese. Based on the Mosteller formula, 527 (58%) patients had normal BSA and 368 (42%) had high BSA. Obese patients were more likely to be men (67% vs 56%, p < 0.001) and had worse CCI (28% vs 17% with CCI ≥ 2, p = 0.03) when compared to non-obese patients. Neither BMI (p = 0.14) nor BSA (p = 0.44) correlated with AC delays after surgery. Similar OS and CSS were observed regardless of BMI and BSA (p = 0.76 and 0.80 for OS and p = 0.60 and 0.89 for CSS, respectively). In multivariate Cox models, only worse nodal stage was associated with inferior OS and CSS (HR 4.74, 95%CI 1.96-11.47, p < 0.001 for OS; HR 4.92, 95%CI 1.42-17.00, p = 0.006 for CSS, comparing IIIC vs IIIA), but BMI and BSA were not (see Table). Conclusions: Obesity as measured by BMI and BSA did not correlate with AC delays or worse outcomes in stage III CC patients. [Table: see text]
Health-related quality of life in the early-access phase IIIb study of trifluridine/tipiracil in pretreated metastatic colorectal cancer (mCRC): Results from PRECONNECT study.
Authors: Taieb Julien , Price Timothy Jay , Ciardiello Fortunato , Peeters Marc , Wyrwicz Lucjan , Bachet Jean-Baptiste , Borg Christophe , De La Fouchardiere Christelle , Becquart Martin , Mounedji Nadjat , Vidot Loïck , Sabater Javier , Falcone Alfredo 
Published: January 2019

638 Background: Pivotal RECOURSE trial assessed efficacy and safety of trifluridine/tipiracil (FTD/TPI) in mCRC patients (pts) without collecting QoL data. Here we describe a preliminary analysis of QoL in mCRC pts treated with FTD/TPI in the ongoing phase 3b PRECONNECT study (NCT03306394). Methods: Eligible pts had histologically mCRC previously treated with available therapies and an ECOG-PS of 0/1. Pts received FTD/TPI (35 mg/m2 twice daily) orally on days 1–5 and 8–12 of each 28-day cycle. ECOG-PS and QoL were assessed at baseline, every 4 weeks on FTD/TPI and at discontinuation. QoL was measured with EORTC QLQ-C30, EQ-5D index and VAS questionnaires. Utility score was based on EQ-5D index and values from Germany, UK and Spain. For QLQ-C30, clinical relevance was assessed using a 10 point threshold. Changes in utility score and VAS were deemed clinically relevant if ≥ 9 and ≥ 7, respectively. Only results where ≥ 10% of the initial cohort completed the questionnaires were assessed, corresponding to 7 cycles of treatment. Results: 464 pts were included at cutoff (1 November 2017). Median FTD/TPI treatment duration was 2.96 months (range 0.4–14.7). Median time to ECOG-PS ≥ 2 was 8.7 months with 74.3% of pts remaining at ECOG-PS 0/1 at discontinuation. At baseline mean QLQ-C30 global health status was 62.75 (SD = 20.50; median 66.67) with values for all scales in line with EuroQoL reference for mCRC (variation < 10 points on function and < 5 on symptom scales). Baseline EQ-5D VAS was 65.55 (SD = 20.11; median 70.00) and utility score 73.11 (SD = 20.71; median 75.27). There was no clinically relevant difference in mean change from baseline at any time point on global health status score nor any of functional or symptom scales. Similar results were obtained for utility score and VAS. QoL was maintained on FTD/TPI in all subgroups based on age and ECOG-PS for all scales except for appetite loss increase at cycle 5 in pts ≥ 65 and in ECOG-PS 0 in whom the score increased by 12.2 and 10.4, respectively. Conclusions: The first prospective data on QoL suggest that mCRC pts can maintain their QoL while on FTD/TPI treatment. Clinical trial information: NCT03306394.
A phase I/II study of pexa-vec oncolytic virus in combination with immune checkpoint inhibition in refractory colorectal cancer: Safety report.
Authors: Morelli Maria Pia , Xie Changqing , Brar Gagan , Floudas Charalampos S. , Fioravanti Suzanne , Walker Melissa , Mabry-Hrones Donna , Greten Tim F. 
Published: January 2019

646 Background: The efficacy of immune checkpoint inhibitor has been limited to small portion of colorectal cancer (CRC) patients whose tumors with mismatch repair (MMR) gene abnormalities. There is an urgent need for patients with MMR proficient (pMMR) tumors. Oncolytic immunotherapy represents a novel therapeutic platform for the treatment of cancer with unique activity compared to conventional chemotherapy. The trial is to evaluate if the combination of Pexa-Vec oncolytic virus (PV) with immune checkpoint inhibition enhance antitumor immunity. Methods: Patients with microsatellite-stable and MSI-H mCRC refractory to PD-1 monotherapy were enrolled. Patients received either Arm A treated with PV + Durvalumab or Arm B with PV + Durvalumab and Tremelimumab. Each arm had two dose levels (DL) of PV, 3 x 108 pfu in DL1 and at 109 pfu in DL2, every 2 weeks for total 4 doses. The first dose of PV was administered on Day -12, followed by three more dose administration on Days 2, 16 and 30 in combination with the immune checkpoint inhibition. The primary endpoint is response rate, safety, tolerability and feasibility of these combination therapy in refractory metastatic CRC. Results: Here we report the safety data of Arm A.A total of 9 patients was enrolled so far. The longest follow-up time is 8 months. Four patients received DL1 PV and subsequent five patients received DL2 PV. No DLT was observed at the time of this abstract. No grade 4-5 adverse event (AE) were observed. All patients experienced lymphopenia. All patients with DL2 developed fever, hypotension and papulopastular rashes and were successfully managed with antipyretics, fluid support and skin protection, respectively. The most frequent treatment-related AEs were lymphopenia (8 [100%], fever (7 [87.5%]), chills (6 [75.0%]), hypotension (5 [62.5%]), papulopastular rashes (5 [62.5%], flu-like symptoms (2 [12.5%]), Nausea/vomiting (2 [12.5%]). Conclusions: Pexa-Vec in combination with Durvalumab showed a favorable safety profile. Clinical trial information: NCT03206073.
Clinical implications of microsatellite instability in mucinous colorectal cancer.
Authors: Keane Fergus , Martin Darrell , Leonard Gregory D. , Hynes Sean , Sheehan Margaret 
Published: January 2019

657 Background: Colorectal Cancer(CRC) is becoming increasingly recognised as a heterogeneous tumor type. Mucinous histological subtype is identified in 10-15% of CRCs, most commonly those with microsatellite instability (MSI), and has traditionally been associated with unfavorable outcomes and poor response to chemotherapy. In contrast, MSI is associated with relatively favourable pathological features and better outcomes, compared with CRCs with microsatellite stability (MSS), such that under the 2010 WHO classification, MSI mucinous CRC is considered low grade, while MSS mucinous CRC is classified as high grade. The aim of this study is to establish the significance of microsatellite stability status in non-metastatic mucinous colorectal cancer. Methods: Between 2010 and 2017, 69 patients with stage II or stage III mucinous colorectal cancer were identified. Microsatellite status was tested in all patients (MSS or MSI), and histological and clinical data, as well as recurrence rates, were assessed in both groups. MSI status was established using polymerase chain reaction(PCR) technique. Results: Sixty-nine patients with mucinous CRC were identified. The median age for the entire group was 73 years (range 32-87), no difference in gender was identified. 63%(n=43) and 37%(n=26) were stage II and stage III respectively at diagnosis. The majority of mucinous CRCs were right-sided (72%). 33% (n=23) were identified as microsatellite unstable (MSI). MSI status was associated with right sided tumours (78% right-sided vs 22% left-sided, p<0.05), older age at diagnosis (mean 76 years vs 68 years, p=0.01), and lower TNM staging at diagnosis (83% vs 52% diagnosed stage 2, p=0.007) compared with the MSS group. A lower disease recurrence rate was identified in the MSI group (4.3% vs 13% in MSS group) at median follow-up time of 33 months (range 8-93 months). Conclusions: In patients with mucinous colorectal cancer, MSI status is a useful marker of favourable histological and clinical features, and is associated with better outcomes. Our study supports the current 2010 WHO classification, and highlights the clinical and prognostic significance of MSI status in this patient cohort.
Genomic alterations in appendiceal carcinoma using circulating DNA.
Authors: Shaib Walid Labib , Roberts Ali , Akce Mehmet , Wu Christina , Alese Olatunji B. , El-Rayes Bassel F. 
Published: January 2019

658 Background: Appendiceal cancers (AC) comprise around 0.5% of all gastrointestinal neoplasia. The genomic landscape of AC has not been well studied. The yield of circulating tumor DNA (ctDNA) from the plasma of patients with AC has not been reported. The aim of this study is to confirm the feasibility of NGS using ctDNA and characterize common alternations in the genomic profile of AC. Methods: The molecular alterations in 372 plasma samples from 303 patients with AC using clinical-grade NGS of ctDNA (Guardant 360) across multiple institutions, was evaluated. The test detects single nucleotide variants in 54 -73 genes, copy number amplifications, fusions, and indels in selected genes. Results: A total of 303 AC patients were evaluated; 169 female (56%). Median age was 56.8 (range: 25-83). ctDNA NGS testing was done on 372 plasma samples; 48 patients had testing performed twice, 9 three times, and 1 was tested four times. Genomic alterations were defined in 207 (55.6%) samples with a total of 288 alterations identified after excluding variants of uncertain significance (VUSs) and synonymous mutations. TP53 associated genes were most commonly altered (n = 96, 33.3%), followed by KRAS (n = 41, 14.2%), APC (n = 19, 6.6%), EGFR (n = 15, 5.2%), BRAF (n = 13, 4.5%), NF1 (n = 13, 4.5%), MYC (n = 9, 3.1%), GNAS (n = 8, 2.7%), PI3CA (n = 7, 2.4%), MET (n = 6, 2.08%), ATM in 6 (1.6%). Other genomic alterations of low frequency, but clinically relevant: AR (n = 4, 1.39%), TERT (n = 4, 1.39%), ERBB2 (n = 4, 1.39%), SMAD4 (n = 3, 1.04%), CDK4 (n = 2, 0.69%), NRAS (n = 2, 0.69%), FGFR1 (n = 2, 0.69%), FGFR2 (n = 2, 0.69%), PTEN (n = 2, 0.69%), RB1 (n = 2, 0.69%), and CDK6, CDKN2A, BRCA1, BRCA2, JAK2, IDH2, MAPK, NTRK1, CDH1, ARID1A, and PDGFRA were all reported once. Conclusions: Evaluation of ctDNA was feasible among individuals with AC. The frequency of genomic alterations in ctDNA testing is similar to those previously reported in tissue NGS. Liquid biopsies are non-invasive methods that can provide personalized options for targeted therapies in patients with AC.
MSI-GC-01: Individual patient data (IPD) meta-analysis of microsatellite instability (MSI) and gastric cancer (GC) from four randomized clinical trials (RCTs).
Authors: Pietrantonio Filippo , Raimondi Alessandra , Choi Yoon Young , Kang WonKi , Langley Ruth E. , Kim Young Woo , Kim Kyoung-Mee , Nankivell Matthew Guy , Perrone Federica , Kook Myeong-Cherl , An Ji Yeong , Grabsch Heike I. , Morano Federica , Cheong Jae-Ho , Noh Sung Hoon , Lee Jeeyun , Cunningham David , Di Bartolomeo Maria , Fucà Giovanni , Smyth Elizabeth Catherine 
Published: January 2019

66 Background: In CLASSIC and MAGIC, MSI was a good prognostic factor, and adjuvant/perioperative chemotherapy had null/detrimental effect. Given the low prevalence of MSI in GCs and its association with other good prognostic variables, larger datasets are needed to draw more robust evidences on its specific prognostic/predictive impact. Methods: This was a multinational IPD meta-analysis of resectable GC pts enrolled in MAGIC, CLASSIC, ARTIST, ITACA-S. Data on pts’ demographics (age, sex, and race), primary site (stomach versus junctional), histotype (intestinal vs. other), T/N stage (7th TNM), treatment received (multimodal therapy vs. surgery alone) and MSI were pooled. Univariable and multivariable associations with disease-free survival (DFS)/overall survival (OS) were assessed. The predictive role of MSI according to treatment received was assessed overall and in the 2 RCTs with a surgery alone arm (MAGIC+CLASSIC). Results: We pooled 1,552 pts with available MSI status: 121 (7,8%) were MSI, 572 Caucasian/980 Asian. In MSI versus MSS subgroups, 5-y DFS was 71.8% (95% CI: 63.8-80.7%) versus 52.3% (49.6-55.0%) (HR = 0.50, 95% CI 0.35-0.72; p < 0.001); 5-y OS 77.4% (69.9-85.8%) versus 59.2% (56.6-62.0%) (HR = 0.50, 95% CI 0.34-0-74; p < 0.001). In multivariable analyses, MSI was independently associated with DFS (HR = 0.48 [0.33-0.70]; p < 0.001) and OS (HR = 0.48 [0.29-0.81]; p = 0.005), as T/N/race/treatment. Conclusions: In resectable primary GC, MSI is an independent good prognostic marker that should be adopted as stratification factor in future RCTs. Chemotherapy omission and/or immune checkpoint blockade should be prospectively investigated in MSI-high GCs according to the clinically-defined risk of relapse. [Table: see text]
Identifying the importance of integrating routine pharmacogenomic testing for UGT1A1 and DPYD/tyms genetic variants in patients receiving irinotecan and/or 5-fluorouracil chemotherapy.
Authors: Baldeo Candice , Hughes Caren , Shahjehan Faisal , Kamatham Saivaishnavi , Kasi Pashtoon Murtaza 
Published: January 2019

660 Background: Adverse toxicities to chemotherapy remain a limiting factor for patients receiving treatment for malignancies. In gastrointestinal cancers, particularly metastatic colorectal cancer, the majority of front line treatment remains chemotherapy containing 5-fluorouracil and/or irinotecan. One particular cause that can predispose a patient to increased toxicity from 5-fluorouracil is genetic variation in the DPYD gene, as well as TYMS gene. Similarly, genetic variation in the UGT1A1 gene can increase the risk of irinotecan toxicity. These gene variations may have major implications when deciding on treatment regimens for these types of patients; however, they are not routinely checked. Methods: In Mayo Clinic Florida, patients with metastatic colorectal cancer receiving 5-fluorouracil and/or irinotecan chemotherapy during the period of July 2017-July 2018 were tested for genetic variants in DPYD/TYMS and UGT1A1. This testing was done during routine clinic visit either by buccal swab or blood test. The DPYD/TYMS and UGT1A1 variant results were evaluated together with a pharmacist for recommendations regarding dose reductions on 5-fluorouracil and irinotecan respectively. Results: A total of 292 patients were tested. Total number of patients who had a variation in the DPYD/ TYMS and/or UGT1A1 gene was 169 (57.9%). The UGT1A1 variation was the most prevalent with 154 (52.7%) patients having a variant (115 heterozygous variant, 34 homozygous variant and 5 double heterozygous variant). Specifically there were 3 patients with both UGT1A1 and DPYD variants and 3 patients with both UGT1A1 and TYMS variants. One patient had both DPYD and TYMS variations. Conclusions: Routine pharmacogenomic testing for UGT1A1 and DPYD/TYMS genetic variants should be done in all patients receiving irinotecan and 5-fluorouracil chemotherapy respectively. Avoiding or preemptively dose reducing these agents in patients with gene variations may help prevent toxic adverse events and make treatment more tolerable.