bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defining population response of patient-derived colorectal cancer organoids against prospective clinical outcomes.
Authors: Kratz Jeremy D. , Gillette Amani , Rehman Shujah , Sunil Aishwarya , Johnson Katherine Anne , Pasch Cheri , Lemmon Kayla , Lassen Nicole , Abbott Daniel Erik , Carchman Evie , Foley Eugene F. , Heise Charles , Lawson Elise Hanna , LoConte Noelle K. , Lubner Sam Joseph , Mulkerin Daniel , Matkowskyj Kristina A. , Uboha Nataliya Volodymyrivna , Skala Melissa C. , Deming Dustin A. 
Published: February 2020

177 Background: No current clinical tool can predict the efficacy of cancer therapeutics for patients with colorectal cancer (CRC). We recently demonstrated the feasibility of using patient-derived cancer organoids (PDCOs) to examine therapeutic response and tumor heterogeneity for individual patients with CRC via optical metabolic imaging (OMI). Here we expand these analyses in a cohort of patients with clinical outcomes. Methods: CRC tissue was collected from patients on IRB-approved protocols. PDCOs were matured and treated with chemotherapy regimens concurrent with patient treatment. Previously established effect size response thresholds were used for diameter ( > 1.5) and OMI ( > 0.5) following 48 hours of treatment. OMI measures the intrinsic autofluorescence of NAD(P)H and FAD using 2-photon microscopy without specific reagents or dyes. Clinical outcomes were prospectively collected by manual chart review. Results: 12 CRC PDCOs were established from patients with CRC. PDCOs were collected from initial diagnosis and advanced setting of both primary and metastatic sites by core needle biopsy and surgical resection. Differential growth rates were observed across lines. PDCOs with RAS/RAF alterations had more uniform growth, while PDCOs without these alterations demonstrated more heterogeneous growth and metabolism. Clinical correlation of PDCOs response with recurrence of disease in the adjuvant setting will be presented. Cases with prior 5-FU-based chemotherapy at the time of PDCO collection had intermediate sensitivity. For PDCOs collected pre-treatment, PDCO response predicted clinical response for 5 of 6 cases using predefined sensitivity thresholds. In the case that overall PDCO response did not predict clinical response, a heterogenous response was observed with distinct sensitive and resistant populations. Across PDCOs, greater post-treatment heterogeneity was observed in resistant lines compared to those with treatment sensitivity. Conclusions: Tumor heterogeneity in treatment response can be assessed using PDCOs growth and metabolism. The utility of PDCOs to predict clinical outcomes for patients with CRC deserves further prospective validation.
A 13-gene colorectal cancer liquid biopsy with greater than 90 percent accuracy in diagnosis and assessment of disease status.
Authors: Modlin Irvin Mark , Kidd Mark S. , Drozdov Ignat A. , Kitz Alexander , Malczewska Anna , Kusnierz Katarzyna , Aslanian Harry 
Published: February 2020

18 Background: There are a paucity of blood-based biomarkers with clinical utility for colorectal cancer (CRC) We report the use of a 13-gene colon cancer circulating-free mRNA to diagnose CRC and identify disease burden and status Clinical utility of the assay was assessed in surgical and chemotherapy patients. Methods: Gene identification and validation: Publicly available colon cancer transcriptomes (TTs) (E-MTAB-57); gene expression in 3 CRC cell-lines (LOVO, LS-180 and COLO320DM) and validated in CRC tumors ( n=33). Tumor TT analysis: co-expression network generation and differential expression analysis compared with normal blood-based TT to identify candidate markers. Blood gene expression: CRC set (cancers: n=312, controls n=117) and a CRC artificial intelligence model constructed. Normalized gene expression algorithmically scored (0-100). Matched tumor/ blood samples were available in 33 patients. RECIST criteria Clinical score assessment: Score utility was assessed in surgical and treated cohorts: Surgical: n=37, follow>7 days. Treated chemotherapy: n=75; stable disease (SD): n=20, progressive disease (PD): n=55) The relationship to CEA and CA-19-9 were assessed. Statistics: Non-parametric (Mann-Whitney), Pearson-correlation, Fisher’s and AUROC analyses (Mean±SEM). Results: Transcriptomic analysis identified a13 genes blood signature for CRC. Expression levels were significantly elevated ( p<0.001, 20-100-fold) in cell lines and CRC tumors. The matched tissue/blood correlation r: 0.795 ( p=0.002). In CRC, levels were 54.4±1.5 ( p<0.0001) compared to controls (9.5±1.7); AUROC: 0.91±0.02, accuracy 90.5% (sensitivity 93.1%, specificity 81.2%). Surgical cohort: CRC assay accuracy 100% vs CEA (35%) or CA-19-9 (17%) (both p<0.0001). Resection (R0 – 92%) significantly decreased levels (47±2) at follow-up ( p=0.0055). Treated cohort: Levels were elevated in PD (63±4.1) vs SD (30±3.2, p<0.0001). Conclusions: The diagnostic accuracy of CRC blood-signature was 91%; significantly greater than CEA or CA-19 Surgical resection decreased levels. CRC score was elevated in progressive vs stable disease. A colorectal cancer liquid biopsy has probable clinical utility in management.
Plasma deoxyuridine levels in metastatic colorectal cancer (mCRC) patients and clinical response after 5FU based therapy in combination with arfolitixorin.
Authors: Taflin Helena Anna , Odin Elisabeth , Carlsson Göran Ulf , Tell Roger , Gustavsson Bengt , Wettergren Yvonne 
Published: February 2020

185 Background: 5-Fluorouracil (5FU) is one of the most commonly used cancer drugs. FdUMP is a metabolite from 5FU which inhibits thymidylate synthase (TS). TS inhibition causes a rise in the intracellular pool of the natural TS substrate dUMP leading to increased global levels of deoxyuridine (dUR). In order to increase TS inhibition, 5FU is combined with folates, usually leucovorin (LV). However, LV needs enzymatic conversion to become active. The LV conversion capacity differs between patients, with the consequence that many patients will have a reduced effect of 5FU-based treatment. Arfolitixorin is a biologically active folate, 5,10-methylenetetrahydrofolate, which doesn´t need enzymatic conversion; hence it could potentially be more efficacious. Methods: ISO-CC-005 is a phase I/II safety and tolerability study in mCRC patients receiving 5FU/arfolitixorin alone or in combination with irinotecan or oxaliplatin ± bevacizumab. Efficacy was evaluated as Overall Response Rate (ORR) after 4 cycles of chemotherapy. A LC-MS/MS method was developed for quantification of plasma dUr and 5FU. Blood samples were collected before and 24 h after 5FU administration at the first (C1) and fourth (C4) treatment cycle (n = 33). The C4/C1 ratio for dUr and 5FU, respectively, were calculated.The clinical response, which is an ordered categorical data, was modelled using nominal logistic regression using the ratio C4/C1 and the absolute values C1 and C4 as explanatory variables. Results: A positive correlation between dUr and 5FU levels was seen (r = 0.89, p = 0.0011) at C4. The C4/C1 ratio for dUr and 5FU in plasma correlated positively (r = 0.95, p = 0.0001). A positive correlation was also found between arfolitixorin dose and plasma levels of dUr (r = 0.44, p = 0.016) at C1, but not at C4. In the model test, the C4/C1 dUr ratio, as well as the individual dUr levels at C1 and C4, had a highly significant effect on ORR (p = 0.0075). Conclusions: The results demonstrate that the arfolitixorin dose has an impact on plasma levels of dUr and also on clinical response. dUr could potentially be an early surrogate marker for TS inhibition in mCRC patients treated with 5FU/arfolitixorin. Clinical trial information: NCT02244632.
Prognostic and predictive impact of primary tumor sidedness in first-line trials for advanced colorectal cancer: An analysis of 7,828 patients in the ARCAD database.
Authors: Yin Jun , Cohen Romain , Jin Zhaohui , Liu Heshan , Pederson Levi , Adams Richard , Maughan Tim , Venook Alan P. , Van Cutsem Eric , Cremolini Chiara , Tebbut Niall , Seymour Matt , Bokemeyer Carsten , Diaz-Rubio Eduardo , Wasan Harpreet Singh , Heinemann Volker , De Gramont Aimery , Shi Qian , Lenz Heinz-Josef 
Published: February 2020

188 Background: Unplanned subgroup analyses from several studies have suggested primary tumor sidedness (PTS) as a potential prognostic and predictive parameter in metastatic colorectal cancer (mCRC). We aimed to investigate the prognostic and predictive impact of PTS on outcomes. Methods: PTS data of 7,828 mCRC patients (pts) from 10 first-line randomized trials in the ARCAD database were pooled. PTS was defined as right-sided (RS) or left-sided (LS) if tumor arose from the cecum to the hepatic flexure or from the splenic flexure to the rectum, respectively; transverse colon cancers were not included. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for age, sex, performance status (PS), prior radiation/chemo, and stratified by treatment arm. Predictive value was tested by interaction term between PTS and treatment (anti-EGFR plus chemotherapy vs. chemotherapy alone). Results: Compared to RS pts (2407, 31%), LS pts (5421, 69%) had better OS (median: 21.6 v 16.8 mos; HRadj: 0.73, 95% CI 0.69-0.78, P < .001) and PFS (median 8.4 v 7.2 mos; HRadj: 0.81, 95% CI 0.76-0.86, P < .001). Results were consistent among subgroups defined by age, sex, PS, metastatic sites and chemo backbone (irinotecan- and oxaliplatin-based). Interaction between PTS and KRAS mutation was significant (Pinteraction< .001): LS is associated with better prognosis only among KRAS wild-type (wt) (HRadj: OS 0.62, 95% CI, 0.55-0.70; PFS 0.71, 95% CI 0.63-0.80), but not among KRAS mutated pts. Among KRAS wt pts, survival benefit from anti-EGFR was observed for LS, but not for RS (table). Conclusions: The prognostic value of PTS is restricted to the KRAS wt population. PTS is predictive of anti-EGFR efficacy, with a significant improvement of survival for LS mCRC pts. These results suggest treatment stratification in mCRC studies by both PTS and KRAS status. [Table: see text]
Predicting CD8+ T-cell infiltration in colorectal cancer using versican proteolysis across molecular profiles.
Authors: Johnson Katherine Anne , Emmerich Philip , Matkowskyj Kristina A. , Deming Dustin A. 
Published: February 2020

189 Background: The clinical indications for immunotherapies continue to increase across cancer types. In colorectal cancer (CRC), there has been little progress in the use of these therapies outside of mismatch repair deficient cancers (dMMR). However, even in dMMR cancers only a minority actually respond to the FDA-approved anti-PD1 agents. The tumor microenvironment is increasingly implicated in the resistance of cancers to immune-based therapies. Our group has previously described that accumulation of a matrix proteoglycan, versican, correlates with a reduction in CD8+ T-cell infiltration in CRCs, while proteolysis of versican, releasing the bioactive fragment versikine, correlates with increased infiltration. Here we examine the impact of pathogenic mutations on the utility of MMR status and versican proteolysis to predict CD8+ T-cell infiltration. Methods: Matched normal colon and CRC tissues from 122 patients were stained for versican, versikine, MLH1, MSH2, MSH6, PMS2, CNNB1, and CD8. Each was reviewed by a blinded GI surgical pathologist and CD8 quantified as tumor infiltrating lymphocytes (TILs) per high power field (hpf). 107 of the CRC samples were available for sequencing using the Qiagen Comprehensive Cancer Panel examining 160 genes across cancer relevant hotspots. The molecular profile was correlated with the IHC staining. Results: As previously reported, dMMR tumors had higher CD8+ T-cell infiltration. This trend persisted across dMMR genotypes (dMMR vs proficient (p)MMR p = 0.0016). Versican proteolysis correlated with increased CD8+ T cell infiltration in dMMR and pMMR cancers and was present in cancers with/without APC, TP53, and KRAS mutations. Across common mutations, cancers with the versican proteolysis predominant phenotype had more CD8+ T-cell infiltration than those without (APC mutant (mt): 11.82 vs 1.97 CD8+ TILs/hpf, p < 0.001; KRAS mt: 9.39 vs 3.08, p = 0.15; BRAF mt: 25.00 vs 7.50, p = 0.13; TP53 mt: 8.61 vs 1.63, p < 0.001). Conclusions: Across common mutations, versican proteolysis predicts CD8+ T-cell infiltration in both dMMR and pMMR CRC. Further investigation into whether this increase in infiltration will lead to greater immunotherapy response is warranted.
Effect of previous chemotherapy treatments on circulating tumor-associated cells in colorectal cancer.
Authors: Limaye Sewanti , Crook Timothy , Page Raymond , Patil Darshana , Akolkar Dadasaheb , Datta Vineet , Schuster Stefan , Sims Cynthe , Patil Revati , Patil Sanket , Mhase Vishakha , Apurwa Sachin , Khan Shabista , Srinivasan Ajay , Datar Rajan 
Published: February 2020

194 Background: Resistance to combination regimens of fluorouracil, oxaliplatin and irinotecan are commonly observed in Colorectal cancers (CRC). There are presently no viable approaches for ‘real-time’ monitoring of innate and acquired chemoresistance. We used a novel method for chemo-interrogation (CI) by harvesting from peripheral blood sufficient numbers of Circulating-Tumor Associated Cells (CTACs) which are defined as apoptosis-resistant cells of tumorigenic origin which are positive for Epithelial Cell Adhesion Molecule (EpCAM) and pan-cytokeratins (pan-CK) irrespective of CD45 status. Methods: Peripheral blood was collected from 110 patients with confirmed diagnosis of CRC, among whom 56 were recently diagnosed and therapy naïve while 54 were pre-treated. Peripheral blood mononuclear cells (PBMCs) were harvested by centrifugation and treated with commercially available stabilizing agents by a proprietary protocol to stabilize apoptosis resistant C-TACs. Surviving C-TACs were confirmed by immunostaining for EpCAM and pan-CK. Harvested C-TACs were treated in vitro with 5-fluorouracil, irinotecan and oxaliplatin and the fraction of surviving cells estimated to determine resistance profiles. Results: Among the 56 cases of recently diagnosed therapy naïve CRC, innate chemoresistance was observed in 37.5%, 47.3% and 41.8% of samples (unique patient-drug combinations) towards 5-fluorouracil, irinotecan and oxaliplatin respectively. Among the 54 cases of previously treated CRC, acquired chemoresistance was observed in 92.6%, 92.6% and 95.5% of samples towards 5-fluorouracil, irinotecan and oxaliplatin respectively. Conclusions: We show for the first time that sufficient C-TACs can be harvested for meaningful CI in newly diagnosed treatment naïve CRC as well as refractory CRCs. Post-treatment chemoresistance being an order of magnitude higher than the untreated cohort indicates that C-TACs in CRC are resistance-educated by previous treatments and can guide treatment strategy.
5-hydroxymethylation signatures in plasma circulating cell-free DNA as markers for appendiceal and colorectal peritoneal metastasis.
Authors: Berger Yaniv , Cui Xiao-Long , West Diana , Rivas Marco , Hsu Phillip , Dougherty Urszula , Deng Zifeng , Hindi Enal , Eng Oliver , Bissonnette Marc , Polite Blase N. , Turaga Kiran 
Published: February 2020

195 Background: Noninvasive tests for peritoneal metastasis (PM) detection lack sensitivity. Genome-wide mapping of 5-hydroxymethylcytosine (5hmC) on nanogram quantities of peripheral plasma circulating cell-free DNA (PcfDNA) was previously shown to differentiate non-metastatic colorectal cancer from healthy subjects. We aimed to examine if patients with colorectal cancer (CRC), high grade appendiceal cancer (HGA) or low grade appendiceal cancer (LGA) with PM have distinct signatures of 5hmC in PcfDNA compared to each other and to patients matched for tumors without PM. Methods: We analyzed plasma samples from a prospectively collected tissue bank. To correlate 5hmC signatures with intraoperative findings, only patients who underwent abdominal surgery in proximity to plasma collection were selected. Key steps of PcfDNA processing included extraction from plasma, nano-hmC-Seal chemical labeling and enrichment of 5hmC-modified fragments, next-generation sequencing, and mapping to the reference human genome. DESeq2 R package was finally used to compare relative 5hmC enrichment and detect distinct 5hmC signatures according to disease histology and PM presence. Results: Plasma samples were collected between 11/2016 – 3/2019 from 46 patients with CRC (n = 21), HGA (n = 17) and LGA (n = 8). Of those, 32 (70%) had PM based on intraoperative findings (median peritoneal cancer index score = 15, range 2-39) and 14 did not have PM. Most samples (91%) were collected on the same day as surgery. An average of 24 million paired-end reads were sequenced for each sample. Four samples (8.7%) were excluded from the analysis due to low sequencing coverage or high duplication level. Unique 5hmC enrichment patterns were found to discriminate with p < 0.05 between CRC PM and HGA PM (n = 616 differentially hydroxymethylated genes (DHMGs)), CRC/HGA PM and LGA PM (n = 1074 DHMGs), and CRC/HGA PM and CRC/HGA patients without PM (n = 1576 DHMGs). Conclusions: Distinct signatures of 5hmC in PcfDNA could differentiate patients with CRC/HGA/LGA PM from each other and from patients with similar tumor histologies without PM. Thus 5hmC signatures in PcfDNA might potentially serve as a sensitive marker of occult PM.
Association of KRAS and BRAF mutations with progression-free survival (PFS) with second-line FOLFIRI +/- regorafenib in metastatic colorectal cancer (mCRC).
Authors: Innocenti Federico , Selitsky Sara R. , Parker Joel S. , Auman James Todd , Hammond Kelli , Patil Sushant A. , Sanoff Hanna Kelly , Lee Michael Sangmin 
Published: February 2020

196 Background: LCCC1029 was a 2:1 randomized phase II trial of 2nd-line FOLFIRI plus either regorafenib or placebo in mCRC. The addition of regorafenib improved PFS (median PFS 6.1 vs 5.3 mo, HR 0.73, 95% CI 0.53-1.01). However, the effect of somatic mutations on regorafenib activity has not been tested. Methods: We performed whole exome sequencing on archival primary tumor tissue and paired normal tissue in 85 patients of LCCC1029. We compared PFS and OS using Kaplan-Meier method and log-rank tests, and hazard ratios (HR) were estimated using Cox proportional hazards method. Results: Among the 85 subjects, 54 (64%) had tumors wild-type (WT) for KRAS and BRAF, 26 (31%) had tumors with KRAS mutations in exons 2-4, and 5 (6%) had tumors with BRAF V600E. The addition of regorafenib to FOLFIRI improved PFS in the KRAS/ BRAF WT subgroup (median PFS 8.0 vs 4.9 mo, HR 0.68, 95% CI 0.48-0.97, log-rank p=0.028), but not in the KRAS mutant subgroup (median PFS 6.8 vs 5.5 mo, HR 0.90, 95% CI 0.61-1.35, log-rank p=0.617) or the BRAF mutant subgroup (log-rank p=0.156). In all of these subgroups, the addition of regorafenib was not associated with significant difference in OS. BRAF V600E was prognostic and associated with significantly worse OS (median OS 8.4 vs 18.0 mo, HR 2.59, 95% CI 1.01-6.66, log-rank p=0.04). Conclusions: The addition of regorafenib to FOLFIRI improves PFS among the subgroup of patients with KRAS and BRAF dual WT CRC, but not among the KRAS mutant subgroup. These results indicate that the addition of anti-angiogenic therapy to second-line chemotherapy backbones may be more effective in KRAS/ BRAF WT tumors in particular. More confirmatory studies are needed to corroborate this finding.
Real-world costs of cetuximab + chemotherapy administered every two weeks versus weekly for treatment of metastatic colorectal cancer.
Authors: Pescott Chris , Batech Michael , Boutmy Emmanuelle , Ronga Philippe , Lamy Francois-Xavier 
Published: February 2020

22 Background: Cetuximab (CET) 250 mg/m2 weekly (q1w) after an initial dose of 400 mg/m2 added to chemotherapy (CT) is licensed for treatment of (K)RAS wild-type metastatic colorectal cancer (mCRC). In practice, administration of CET 500 mg/m2 plus CT every 2 weeks (q2w) is common. We compared healthcare costs between q2w and q1w regimens in a US claims database study. Methods: A cohort of 2,943 mCRC patients CET-treated between 2010 and 2016, identified in IBM MarketScan, was analyzed for costs associated with CET+CT q2w vs q1w. All-category costs (ACC), stratified by overall outpatient (OO), inpatient (OI), and pharmacy (OP) claimed costs during the exposure period, were compared between groups. Additionally, subcategories of CRC- and skin toxicity (ST)–related claims were explored, and imputation of capitated claim costs was performed. Patients were weighted by the stabilized inverse probability of treatment (IPTW) based on a high-dimensional propensity score to control for confounding. Generalized linear models (GLMs) with gamma distributions were used to compare regimens. Inflation-adjusted costs (2016 US dollars) are presented per patient per month ($PPPM) with 95% CIs. Results: 1,779 and 951 patients were classified as q1w and q2w, respectively. Median ACC were 14,089 (q2w) vs 14,034 (q1w) $PPPM. Mean ACC and OO, OI, and OP costs are summarized in the table. CIs overlapped in each category, with GLMs showing no statistically significant differences. This finding was similar for CRC and ST subcategories. Conclusions: No cost differences were found between q2w and q1w regimens. In line with published noninferiority of overall survival with the q2w regimen, it represents an effective, cost-neutral option for treating mCRC patients. [Table: see text]
Clinical utility of the systemic inflammatory response (SIR) in identifying high-risk stage II colon cancer.
Authors: Golder Allan Matthew , McMillan Donald C. , Mansouri David , Horgan Paul G. , Roxburgh Campbell SD 
Published: February 2020

220 Background: Surgery for TNM Stage II colon cancer is considered curative however approximately 20% of patients will have recurrence of their disease. A number of high risk pathological features guide the use of adjuvant chemotherapy. More recently the preoperative SIR has been consistently shown to have prognostic value but to date has not been utilised clinically as a high risk feature. The present study compared the influence of the SIR versus established high-risk clinical features on overall/cancer specific survival (OS/CSS). Methods: Patients in the West of Scotland undergoing curative resection for Stage II colon cancer from 2011-2015 were identified with survival updated until December 2018. Additional data was obtained from online records. Through uni/multivariate analysis (UVA/MVA) we compared the effect on survival of the SIR measured using the modified Glasgow Prognostic Score (mGPS), neutrophil-lymphocyte ratio (NLR) and lymphocyte-monocyte ratio (LMR) when entered individually into a multivariate model alongside established high-risk features. Results: 982 patients were identified having had a curative resection of Stage II colon cancer. Median follow up was 61 months and there were 307 deaths during follow up. For OS: emergency presentation, T stage, adjuvant chemotherapy, nodal harvest, margin involvement, mGPS, LMR, NLR (all p≤0.001) and EMVI (p < 0.05) were significant on UVA. On MVA: age (HR 1.51), T stage (HR 1.59), nodal harvest (HR 1.67), margin involvement (HR 1.94), adjuvant chemotherapy (HR 0.47), mGPS (HR 1.38), NLR (HR 1.35) and LMR (HR 1.50) remained significant (all p < 0.05). For CSS: age, emergency presentation, T stage, margin involvement, mGPS, NLR, LMR (all p < 0.001), nodal harvest and adjuvant chemotherapy (both p < 0.05) remained significant on UVA. On MVA emergency presentation (HR 1.88), T stage (HR 2.02), margin involvement (HR 2.98), adjuvant chemotherapy (HR 0.51) and mGPS (HR 1.34) remained significant (all p < 0.05). Conclusions: The present study suggests that the SIR is an independent predictor of worse OS/CSS in Stage II colon cancer and should be considered a high risk feature in future prospective studies.