bluuebunny/crossref_metadata_2025_split huggingface dataset:
Leveraging the integrated EHR for trial matching across a nationwide network.
Authors: Yeatman Timothy Joseph , Watson Mark , Chasse Adam 
Published: February 2020

165 Background: The Guardian Research Network (GRN) is a nationwide consortium of integrated health systems, who share their electronic health records (EHR) to democratize clinical trial access through improvements in “process”. The GRN is a unique-in-class, free-to join, non-exclusive consortium leveraging the digital EHR---including labs, medications, demographics and non-discrete data (all text) data--- mining nightly for clinical trial candidates. Using a suite of NLP and AI tools, the GRN dramatically improves the efficiency of the clinical research staff, by electronically searching all records for the I/E criteria for trials. The GRN uses a central IRB, one contract and legal review, promising to revolutionize the trial accrual process and speed drug development. Methods: With a database of > 1.0M patients, the GRN reviews all active cancer records nightly from > 110 member hospitals to produce lists of trial candidates. Comprehensive electronic screens were filtered by manual reviews to rapidly find best candidates. Results: Our data collected over 10 mo suggest comprehensive electronic queries examining hundreds of thousands of records daily eliminate > 90% of ineligible patients in minutes. Manual review further refines eligible list. This is vastly different from current opportunistic screening approaches that examine only a tiny fraction of potential trial candidates (last week's new patients). Conclusions: The GRN has executed an all-inclusive approach to trial accrual, embedding a scalable database search technology within an integrated trial network. The novel approach seeks to exponentially expand operational capabilities of CTOs with limited staff, review all eligible patients, and solve for a large unmet need for democratizing trial access in the community. [Table: see text]
RAS status in circulating-tumor DNA (ctDNA) and outcomes during rechallenge treatments with anti-EGFR antibodies in metastatic colorectal cancer (mCRC).
Authors: Sunakawa Yu , Nakamura Masato , Ishizaki Masahiro , Kataoka Masato , Satake Hironaga , Kitazono Masaki , Yanagisawa Hideyuki , Kawamoto Yasuyuki , Kuramochi Hidekazu , Ohori Hisatsugu , Nakamura Michio , Maeda Fumiyo , Komeno Chihiro , Takeuchi Masahiro , Fujii Masashi , Yoshino Takayuki , Ichikawa Wataru , Tsuji Akihito 
Published: February 2020

166 Background: We have evaluated rechallenge treatment with irinotecan plus cetuximab (JACCRO CC-08, n = 36) or panitumumab (JACCRO CC-09, n = 25) in patients (pts) with KRAS wild-type mCRC [Tsuji A, WCGC 2018], and the primary endpoint of PFS rate at 3 months was met in both trials. RAS status in ctDNA may potentially predict responders of the rechallenge treatment in mCRC resistant to anti-EGFR antibody [Cremolini C, JAMA Oncol 2018]. Methods: A post-hoc biomarker study was performed to investigate an association between RAS status in ctDNA and clinical outcomes in the JACCRO phase II trials comprised mCRC pts who achieved a clinical benefit from 1st-line anti-EGFR antibody-based therapy, then had a disease progression at 2nd-line treatment. RAS status in ctDNA was analyzed at the time points of baseline, 8 weeks, and progression using OncoBEAM RAS CRC Kit for specific KRAS/ NRAS mutations, using cut-off value defined as the number of beads with amplified-mutant molecules specifically set per each codon. Results: Sixteen pts (median 67.5-y old, 50% of PS0, 25% of right-sided primary, cet/pani: 4/12) were enrolled in this study, with response rate of 0% and disease control rate (DCR) of 62.5%. RAS mutations (mt) were found at the baseline in 6 out of 16 pts (all left-sided pts with KRAS codon 12, codon 61 and/or NRAS codon 61 mt simultaneously). Pts without RAS mt at baseline experienced longer PFS in 1st-line treatment (11.5 vs. 9.0 m). The DCR was 33% in pts with RAS mt in ctDNA, while it was 80% in pts without RAS mt at baseline. Pts with RAS mt at baseline had significantly shorter PFS and OS than pts without RAS mt [median PFS 2.3 vs 4.7 m, HR 6.2 (95%CI 1.6-30.5), p = 0.013; median OS 3.8 vs. 16.0 m, HR 12.4 (95%CI 2.7-87.7), p = 0.0028]. Six of 10 pts without RAS mt at baseline acquired RAS mt ( KRAS/ NRAS codon 12 or 61) in ctDNA at progression, however there was no difference in survival between pts with/without RAS mt at progression. Conclusions: Our study demonstrated that RAS status in ctDNA using OncoBEAM RAS CRC Kit predicts survival of rechallenge treatment with anti-EGFR antibody in mCRC pts. These data can support the application of RAS monitoring into clinical practice. Clinical trial information: UMIN000015914/UMIN000015916.
CD3+ tumor-infiltrating lymphocytes (TILs) as prognostic in patients (pts) with stage II colon cancer (CC) not treated with adjuvant chemotherapy (ADJ).
Authors: Francini Edoardo , Ou Fang-Shu , Lazzi Stefano , Petrioli Roberto , Multari Andrea Giovanni , Pesola Guido , Messuti Luciana , Colombo Elena , Livellara Virginia , Bazzurri Serena , Cherri Sara , Salvatora Miano , Wolfe Eric , Alberts Steven R , Hubbard Joleen Marie , Yoon Harry H. , Francini Guido 
Published: February 2020

167 Background: Previous studies have reported high TILs are a favorable prognostic factor in stage II CC. However, whether the impact of TILs on overall survival (OS) differs among pts who did or did not receive ADJ is still to be determined. We assessed the prognostic value of CD3+ TILs in pts with stage II CC according to whether they received ADJ or not (no-ADJ). Methods: Pts treated with curative surgery for stage II CC (2002-2013) were identified through the Santa Maria alle Scotte Hospital database. CD3+ TILs at the invasive front, center of tumor, and stroma, were determined by immunohistochemistry and manually quantified as the rate of TILs/total tissue areas. High TILs (H-TILs) was defined as > 20%. Pts were classified as high or low TILs (L-TILs) and ADJ or no-ADJ. Cox models were used to assess OS with hazard ratio estimates (95% CI). Results: Of the 678 pts included (356 deaths), 137 (20%) received ADJ while 541 (80%) did not. ADJ comprised fluoropyrimidine +/- oxaliplatin. Median follow-up was 8.5 years. The distributions of the 4 groups were: 16% (L-TIL/ADJ), 64% (L-TIL/no-ADJ), 5% (H-TIL/ADJ), 15% (H-TIL/no-ADJ). Compared to H-TILs/no-ADJ, ADJ pts had a significantly longer OS (P < .0001) regardless of the TILS rate while L-TILs/no ADJ had significantly shorter OS and higher risk of death (HR = 1.41; 95% CI, 1.06-1.88; P < .0001) [See table]. On multivariable analysis, adjusting for perforation, obstruction, T-stage, grade, < 12 lymph nodes resected, lymphovascular and perineural invasion, the adverse prognostic impact of L-TILs (vs H-TILs) in no-ADJ pts was confirmed (HR = 1.36; 95% CI 1.02, 1.82; P = .0373). Conclusions: Low CD3+ TILs rate was independently associated with shorter OS in stage II CC pts who did not receive ADJ, but was not prognostic among pts who had ADJ. These data suggest a potentially different impact of TILs in chemo-treated vs -untreated stage II CC which could affect clinical decision making. [Table: see text]
Analysis of consensus molecular subtypes (CMS) classification in the TRICOLORE trial: A randomized phase III trial of S-1 and irinotecan (IRI) plus bevacizumab (Bmab) versus mFOLFOX6 or CapeOX plus Bmab as first-line treatment for metastatic colorectal cancer (mCRC).
Authors: Yuki Satoshi , Gamoh Makio , Denda Tadamichi , Takashima Atsuo , Takahashi Shin , Nakamura Masato , Ohori Hisatsugu , Yamaguchi Tatsuro , Kobayashi Yoshimitsu , Baba Hideo , Kotake Masanori , Amagai Kenji , Kondo Hitoshi , Shimada Ken , Sato Atsushi , Ishioka Chikashi , Komine Keigo , Ouchi Kota , Morita Satoshi , Komatsu Yoshito 
Published: February 2020

169 Background: The TRICOLORE trial previously demonstrated that S-1+IRI+Bmab (Arm B) was non-inferior to mFOLFOX6/CapeOX+Bmab (Arm A) in terms of progression-free survival (PFS) as first-line treatment for mCRC, irrespective of RAS status. CMS was reported to be a prognostic factor for mCRC. Previously, it was reported that the CMS could be a predictive factor for the efficacy of oxaliplatin (OX) and IRI (Okita A, et al. Oncotarget. 2018). In this exploratory study of TRICOLORE trial, we examined if the CMS could be a predictive factor of OX and IRI regimen. Methods: We collected formalin-fixed paraffin-embedded (FFPE) primary tumor tissues and performed gene expression analysis by microarray. The subtype of CMS was determined by the CMS classifier (Guinney et al. Nature Med. 2015). PFS and overall survival (OS) were compared between arm A and B in each subtypes of CMS. Results: Total of 308 FFPE samples from 487 cases who were enrolled in the TRICOLORE study were collected. Number of patients classified into CMS1 to CMS4 were 47, 72, 99 and 90, respectively. Similar to the previous reports, the proportion of RAS mutant cases was highest in CMS3 and the most of BRAF mutant cases were classified into CMS1. The median PFS (mPFS) of arm A and B were almost same in CMS2 (16.1m vs. 17.6m, HR = 1.10, p = 0.79) and CMS3 (10.6 vs. 11.4, HR = 0.95, p = 0.81). In CMS1, mPFS of arm A was worse than that of arm B, although not statistically significant (7.4m vs. 13.2m, HR = 0.73, p = 0.35). In CMS4, mPFS of arm B was better than that of arm A, although not statistically significant again (9.7m vs. 14.1m, HR = 0.72, p = 0.15). The median OS (mOS) of both arm in CMS2-CMS4 and arm B in CMS1 were good and were 29.0m or more. On the other hand, mOS of arm A in CMS1 (18.1m) was worse than the others. Conclusions: From these results, it was not concluded that CMS was a predictor of mFOLFOX6/CapeOX+Bmab and S-1+IRI+Bmab. However, mPFS and mOS of mFOLFOX6/CapeOX+Bmab in CMS1 were poor unlike other CMS subtypes, and these were consistent with a previous report. Whereas S-1+IRI+Bmab was effective in all subtypes of CMS. Clinical trial information: UMIN000007834.
Preclinical drug testing for clinical trial planning of novel combinative therapy with PI3K and MAPK inhibitors in colorectal cancer(CRC).
Authors: Lee Cha Len , Toomey Sinead , Cremona Mattia , Workman Julie A. , Hennessy Bryan 
Published: February 2020

179 Background: Combinative inhibitors with multiple actions to target downstream effectors are good strategy to reduce resistance occurrence. This is a preclinical study to evaluate efficacy of Palbociclib (P; CDK4/6 inhibitor) in combination with either Gedatolisib (G; P13K/mTOR dual inhibitors) or PD0325901 (PD; MEK 1/2 inhibitor) in CRC cell models. Methods: Five CRC cell lines with hot-spots mutations in PI3K and MAPK pathways genes are used. Cell growth assay is used to evaluate antiproliferative response to P, G and PD alone and in combination. RPPA is used to clarify the role actions of combinative drugs on resistance development and new druggable proteins. Paired t-test is used. Results: All cell lines except LS1034 (IC50=7.2µM) were sensitive to G. LS411N and SNUC4 were sensitive to P whereas Caco2, DLD1 and LS1034 were resistant (IC50>15µM). All cells lines were sensitive to PD. When tested in combination, P+G has synergistic response in all cells lines, except for LS411N (CI=0.9; p=0.02). P+G is highly synergistic in LS1034 with KRAS mutation (CI=0.1; p=0.11). P+G is also synergistic in DLD1 with co-occurring PIK3CA and KRAS mutations (CI=0.6; p=0.04). P+PD is synergistic in all cells lines except for LS411N. In SNUC4 with PIK3CA mutation, both drug combinations have equal synergism (CI=0.5; p<0.05). RPPA analysis is in progress and will be included in final abstract. Conclusions: This offers good rationale for further clinical development of P+G as beneficial therapy in treatment-resistant CRC patients. P+G offers better alternative to P+PD since MEK inhibitor resistance had been associated with tumours harbouring KRAS with(out) PIK3CA mutations. BRAFV600E and ERBB2 mutations are useful negative predictors in this cohort. [Table: see text]
Prognostic impact of SOX9 in stage II colon cancer: Results from a large nationwide cohort.
Authors: Hansen Torben , Trabjerg Natacha D. , Kjaer-Frifeldt Sanne , Eriksen Ann Christina , Lindebjerg Jan , Jensen Lars Henrik , Jakobsen Anders Kristian Moeller , Sørensen Flemming Brandt 
Published: February 2020

183 Background: Up-regulation of the transcription factor SOX9 has been described in colon cancer, and it has been argued that differences in the expression levels dictates cell proliferation. The aim of the present study was to analyze the prognostic impact of SOX9 in patients with stage II colon cancer. Methods: Individual patient data and formalin fixed paraffin embedded tumor tissue were collected from a large unbiased, population-based cohort, representing all patients operated for stage II colon cancer in Denmark in 2002 and 2003. The SOX9 expression was evaluated by immunohistochemistry on whole tumor sections. Patients were classified into three groups dependent on the SOX9 expression gradient in the tumor: luminal, peripheral, and uniform for comparison with the clinical data. The endpoint was disease free survival (DFS). Results: A total of 1,153 patients were included. We detected an expression-dependent relationship between SOX9 and prognosis. Patients with tumors exhibiting a luminal expression pattern (N = 267, increasing SOX9 expression towards the luminal compartment of the tumor) were characterized by a significantly better DFS compared to the uniform (N = 846) and peripheral (N = 40) patterns, p = 0.0070. The five-year DFS rates were 74%, 67%, and 56%, respectively. Multiple Cox regression analysis, confirmed an independent prognostic advantage of the luminal SOX9 expression pattern, as compared to the uniform pattern, hazard ratio (HR) 0.7211 (95% confidence interval (CI) 0.5561-0.9351), p = 0.0137, whereas the possible disadvantage of the periphery pattern could not be verified, p = 0.1405. Conclusions: The present results support a prognostic impact of SOX9 in stage II colon cancer. The consequence of an altered SOX9 expression seems to differ between intra-tumoral compartments, and we propose that a gradient-dependent evaluation should be applied to provide the most clinically relevant information about this transcription factor.
Genomic alterations in colitis-associated cancers in comparison to those found in sporadic colorectal cancer and present in precancerous dysplasia.
Authors: Chatila Walid Khaled , Walch Henry S. , Benhamida Jamal , Hechtman Jaclyn Frances , Barriga Francisco M. , Kundra Ritika , Ismalgeci Dorina , Miller Vincent A. , Ganesh Karuna , Faleck David , Schultz Nikolaus , Tang Laura H. , Kelsen David Paul , Yaeger Rona 
Published: February 2020

191 Background: Patients with inflammatory bowel disease (IBD) [Crohn’s disease (CD) and ulcerative colitis (UC)] are at increased risk for small bowel or colorectal cancers (Colitis Associated Cancers, CAC). Currently CAC is treated the same as sporadic colorectal cancer (CRC) with significantly shorter overall survival for advanced CAC compared to matched patients with CRC. In a pilot series, we found that tumors developing in IBD have distinct genomic alterations (GA) with potential implications for early detection and treatment. We now extend this analysis and characterize the relationship of GA in synchronous dysplasia and cancer. Methods: 104 CAC (54 UC-associated and 50 CD-associated) were sequenced with targeted-exome sequencing of > 300 cancer-related genes. GA in CAC were compared to those reported for sporadic CRC. Whole exome sequencing was performed on paired mucosa, dysplasia and carcinoma samples obtained from 15 colectomy specimens; in these cases, expert pathology review confirmed normal appearing mucosa intervening between areas of dysplasia and CAC. Results: TP53 mutations (89%), MYC amplifications (24%), and cell cycle copy number alterations (20%) were significantly enriched in CAC compared to sporadic CRC, while APC alterations (21%) were significantly less common in CAC compared to sporadic CRC. Distinct GA in CAC consisted of IDH1 R132 mutations (7%) and FGFR pathway alterations (7%). While IDH1 R132 mutations and PI3K pathway alterations were more common in CD-associated CAC, MAPK ( BRAF/ MEK1) alterations were more common in UC-associated CAC. GA in CACs did not significantly vary by duration of preceding IBD. GA were often shared in dysplasia and carcinoma, despite normal-appearing intervening mucosa. GA involving TP53, APC, KRAS, and IDH1 mutations were identified in dysplasia and shared between CAC and dysplasia. Conclusions: CAC exhibit distinct GA compared to sporadic CRC with near universal TP53 mutation, increased copy number alterations involving transcription factors and cell cycle genes, and unique drivers. A field effect can be seen for GA between distant dysplasia and carcinoma, but many GA remain private to CAC.
Multimodality management of brain metastasis from colorectal cancer.
Authors: Jin Zhaohui , Breen William , Jin Rui , Brown Paul D. , Hubbard Joleen Marie 
Published: February 2020

204 Background: More than 50% of colorectal cancer (CRC) patients will develop metastatic disease. Brain metastasis (BM) from colorectal cancer is uncommon (0.6-1.36%). This study aims to investigate the patient characteristics, treatment modalities and prognostic factors in this rare population. Methods: 104 patients with brain metastasis disease from CRC were identified from over 30,000 colorectal cancer patients at the Mayo Clinic Rochester between 1/1994 and 6/2019. A retrospective review was conducted by using data from electronic medical records (EMR). Statistical analysis utilized the Kaplan-Meier method, Log-rank test, and Cox proportional hazards models. Results: Among the 104 patients, 62 were male (59.6%) and 42 were female (40.4%). Median age at CRC diagnosis was 58.4 and at BM diagnosis was 61. Thirty-three patients had right-sided colon cancers, 27 patients had left-sided colon cancers and 39 patients had rectal cancer. Median time from CRC diagnosis to BM was 30.7 months. The majority of patients (58.7%) presented with a solitary brain lesion. Eighty-six patients (82.7%) had extracranial metastatic disease at BM diagnosis. Median survival was 7.0 months (95% CI 2.6-16.9) from BM diagnosis. Age <70, solitary BM, surgery, radiation, and chemotherapy were associated with statistically significant improved survival on univariate and multivariate analysis. Multi-modality treatment including surgical brain lesion resection, postoperative stereotactic radiation (SRS) with/without whole brain radiation (WBRT), and chemotherapy significantly improved median overall survival (Table). Conclusions: Although BM from CRC carries poor prognosis, multi-modality treatment (surgery, radiation and systemic chemotherapy) for patients with limited BM improves clinical outcome. [Table: see text]
Exploratory longitudinal analysis of cfDNA to reveal potential biomarkers of CRC progression and treatment response.
Authors: Vallania Francesco , Assayag Karen , Warsinske Hayley , Ulz Peter , St John John , Brachmann Carrie , Patterson Scott D. , Thai Dung , Bhargava Pankaj , Shah Manish A. , Lenz Heinz-Josef , Bendell Johanna C. , Rubio Claudia 
Published: February 2020

207 Background: Blood-based tests can predict drug response and disease progression. Many tests rely on detecting tumor DNA, which represents only a fraction of all cell-free DNA (cfDNA). Here, we used a novel methodology to infer gene activation from cfDNA. This unique platform offers the ability to identify potential non-tumor derived biomarkers that may be associated with clinical outcomes in colorectal cancer (CRC). Methods: Longitudinal plasma samples from metastatic CRC patients enrolled in NCT01803282 (andecaliximab/chemotherapy/bevacizumab; 92 samples from 12 patients) were evaluated. Patients were classified as progressors (SD+PD) or responders (CR+PR) based on best objective response. Gene activation was inferred from cfDNA fragment length and counts around transcription start sites using whole-genome sequencing. Transcription factor activity was estimated by measuring binding site accessibility across the genome. Tumor fraction (TF) was estimated using ichorCNA. Results: Gene activation profiles inferred from cfDNA across the entire genome identified several genes differentially expressed in progressors or responders. Specifically, all patients with elevated KIR2DL1, an inhibitory NK cell receptor, progressed (p = 6.35e-14). Additionally, BMPR1A activation decreased in responders (p = 0.002) while the DNA- binding activity of SMAD1, which functions directly downstream of BMPR1A in the BMP2 pathway, increased in responders post-therapy (p = 0.03). These 3 genes (i.e., KIR2DL1, BMPR1A and SMAD1) are related to NK cell maturation, suggesting an immunological mechanism. Notably, pre-therapy TF did not predict response. Conclusions: In this pilot study, we demonstrated the ability of a unique cfDNA platform to interrogate multiple features to reveal genes associated with drug response and their underlying mechanism. We identified that KIR2DL1 is associated with progression, and BMPR1A and SMAD1 are associated with response. This work highlights the potential of cfDNA to provide biological insights beyond TF and that identification of non-tumor-derived signals may benefit biomarker discovery and drug target identification.
Local immune response in colon cancer: Indicative of good or poor prognosis?
Authors: Alexander Peter G , In Jitwadee AF , Roseweir Antonia K. , Powell Arfon GMT , Edwards Joanne , Roxburgh Campbell SD , Horgan Paul G. , McMillan Donald C. , Park James Hugh 
Published: February 2020

213 Background: The tumour microenvironment is an important determinant of survival in patients with colon cancer. Although the generalised inflammatory infiltrate as assessed by Klintrup-Mäkinen (KM) grade is a stage-independent prognostic marker, immunohistochemical staining for specific immune cell populations, such as T-cells, may have greater prognostic value. The present study examines the clinical utility of combined assessment of KM grade in addition to cytotoxic (CD8) and regulatory (FoxP3) T-cells. Methods: KM, CD8 and FoxP3 were assessed retrospectively in a cohort of 520 patients with stage I-III colon cancers. The relationship between KM grade, T-cell density and cancer-specific survival was examined. Results: KM was high in 33% of patients, of which: 16% had high FoxP3, 12% high CD8 and 56% both FoxP3 and CD8, while the remaining 15% were high KM alone. Conversely, 67% had low KM and of these: 47% had high CD8 alone or with FoxP3; 27% were high for FoxP3 alone and 25% had no inflammatory infiltrate. KM in the presence of other T-cells resulted in good outcome (Table), whereas CD8 with low KM with or without FoxP3 resulted in intermediate outcome. FoxP3 alone with low KM resulted in poor outcome. Similarly, KM alone without T-cells resulted in poor outcome. When no inflammatory cells were present, outcomes were comparable to KM or FoxP3 alone. Conclusions: A co-ordinated immune response results in good outcome and this can be assessed using a combination of a simple H&E based method (KM) in addition to T-cell markers. Where KM is low, despite the presence of cytotoxic T-cells, survival outcome is worse. Conversely, high KM in the absence of T-cells, or FoxP3 alone, are associated with poor outcome, comparable to no inflammatory response. [Table: see text]