bluuebunny/crossref_metadata_2025_split huggingface dataset:
A nomogram for predicting cancer specific survival (CSS) in patients with pathological T3N0M0 (pT3N0M0) rectal cancer.
Authors: Liu Shuang , Xi ShaoYan , Wu Xiao-Jun , Cai Peiqiang , Ding Pei-Rong , Chen Gong , Pan Zhi-Zhong , Gao Yuan-Hong , Xiao Weiwei 
Published: January 2022

113 Background: Preoperative chemoradiotherapy followed by total mesorectal excision (TME) surgery has been widely adopted as the standard treatment for stage II-III rectal cancers. However, the role of adjuvant chemotherapy in pathological T3N0M0 (pT3N0M0) patients remains controversial. A reliable prognostic model is needed to discriminate the high-risk patients from the low-risk patients, and optimize adjuvant chemotherapy treatment decisions by predicting the likelihood of adjuvant chemotherapy benefit for the target population. Methods: We gathered and analyzed 276 patients in Sun Yat-Sen University Cancer Center from March 2005 to December 2011. All patients underwent total mesorectal excision, without preoperative therapy, and were pathologically proven pT3N0M0 rectal cancer. LASSO regression model was used for variable selection and risk factor prediction. Multivariable cox regression was used to develop the predicting model. Optimum cut-off values were determined using X-Tile plot analysis. The 10-fold cross validation was adopted to validate the model. The performance of the nomogram was evaluated with its calibration, discrimination and clinical usefulness. Results: A total of 188 patients (68.1%) had adjuvant chemotherapy and no patients had adjuvant radiotherapy. Age, carbohydrate antigen 19-9 [CA199], monocyte percentage [MONO%], lymph node dissection numbers [LNDs] and nerve invasion were identified as significantly associated variables that could be combined for an accurate prediction risk of CSS for pT3N0M0 patients. The model adjusted for CSS showed good discrimination with a C-index of 0.723 (95% CI = 0.652 to 0.794). The calibration curves showed that the nomogram adjusted for CSS was able to predict 3-, 5-, and 10-year CSS accurately. The corresponding predicted probability was used to stratify high and low-risk patients. Adjuvant chemotherapy improved survival rate in the low-risk patients (HR = 0.338, 95% CI: 0.135 to 0.848, P = 0.021), while it did not exhibit a significant benefit in the high-risk patients. Conclusions: The nomogram effectively predicts CSS in patients with pT3N0M0 rectal cancer, which can be conveniently used in clinical practice. Adjuvant chemotherapy may improve overall survival in the low-risk patients. But the benefit of adjuvant chemotherapy was not seen in the high-risk patients.
Radioembolization with chemotherapy for liver-dominant colorectal cancer: Analysis of patient subgroups in the EPOCH trial.
Authors: Harris William Proctor , Mulcahy Mary Frances , Salem Riad ,   On behalf of the EPOCH Trial Investigators
Published: January 2022

115 Background: The EPOCH trial evaluated potential benefit of second-line transarterial radioembolization (TARE) plus chemotherapy compared to chemotherapy alone in patients with liver-dominant metastatic colorectal disease (mCRC). Presented here are additional results from EPOCH of depth and duration of response (DoR), and progression-free survival (PFS) and hepatic progression-free survival (hPFS) subgroup analyses. Methods: EPOCH was a 1:1 randomized, open-label, global, multicenter phase 3 trial of second-line chemotherapy for liver-dominant mCRC comparing outcomes from chemotherapy with or without unilobar or same-day bilobar TARE treatment using glass microspheres. Primary study endpoints were PFS and hPFS. Pre-specified subgroup analyses of PFS and hPFS were performed. PFS, hPFS, DoR for patients with objective response, and depth of response (percent change from baseline to nadir in sum of longest diameters of target lesions) were based on blinded, independent central review using RECIST 1.1. The use of TheraSphere in the trial in the USA was under Investigational Device Exemption from FDA. Results: Both primary endpoints of PFS (HR = 0.69, 95% CI: 0.54, 0.88; 1-sided p=0.0013) and hPFS (HR = 0.59, 95% CI: 0.46, 0.77; 1-sided p<0.0001) were met in the EPOCH study. Median DoR in the 73 responders of the TARE arm was numerically longer, with 7.2 months by Kaplan-Meier analysis; in the 45 responders of the chemotherapy only arm, 6.6 months (HR = 0.79, 95% CI: 0.48, 1.30; 1-sided p = 0.178). Mean depth of response across all patients in the TARE arm with data available (N=196) was -25.6%, compared to -13.0% in the chemotherapy only arm (N=182; mean difference -12.6 percentage points; 95% CI: -18.9, -6.3; 1-sided p = 0.0001). Key subgroups of interest which showed improved PFS and/or hPFS in the TARE arm (ie, 95% CI for the HR entirely below 1) are as follows: Conclusions: These data suggest that liver-dominant mCRC patients in this trial benefitted in second-line treatment from a combination of TARE plus chemotherapy based upon improved PFS and hPFS over the full set of patients and in a number of subgroups. The addition of TARE to chemotherapy improves depth of response compared to chemotherapy alone. Clinical trial information: NCT01483027. [Table: see text]
Maintenance therapy following an anti-EGFR-based induction regimen in metastatic colorectal cancer (mCRC): A network meta-analysis of clinical trials.
Authors: Lopes da Silva Laércio , Nazareth Aguiar Pedro , D'Alpino Renata , Dienstmann Rodrigo 
Published: January 2022

128 Background: A fluoropyrimidine with or without bevacizumab is often used in clinical practice as maintenance therapy after a first-line chemotherapy + bevacizumab induction in mCRC. However, the role of maintenance following an anti-EGFR-based induction and the optimal regimen are not well established. Methods: We searched PubMed and conferences’ proceedings for clinical trials assessing maintenance therapy after first-line treatment for RAS WT mCRC. Two independent reviewers excluded single-arm studies and retrospective reports from trials that were not designed to assess maintenance therapy. We used the method of Guyot et. al. to obtain the individual patient data, followed by a Cox procedure to derive the survival hazard ratios (HR) from studies that did not report that value. Safety analysis included grade 3-4 asthenia, neuropathy, neutropenia, rash, and diarrhea. We performed a random-effects bayesian network metanalysis using the package “GeMTC R Package” to compare all treatment strategies included (anti-EGFR, anti-EGFR + chemotherapy [CT], CT alone, and observation). The risk of bias was assessed according to the Cochrane Handbook for Systematic Reviews of Interventions. Results: The systematic review retrieved 145 studies from which 142 were excluded. Two additional studies were found in the Conferences’ Proceedings review. Consequently, 5 studies were included in this NMA. In terms of Progression-Free Survival (PFS), there was a benefit of anti-EGFR and anti-EGFR+CT versus CT alone (HR 0.63 [95%CrI 0.31-1.30] and 0.72 [95%CrI 0.41-1.30], respectively). The rank probability of anti-EGFR being the best option considering PFS was 61%. In terms of Overall Survival (OS), the benefit of anti-EGFR and anti-EGFR+CT versus CT alone was statistically weak (HR 0.92 [95%CrI 0.54-1.50] and 0.84 [95%CrI 0.57-1.20], respectively). The rank probability of anti-EGFR+CT be the best option in terms of OS was 51%. Comparing anti-EGFR versus anti-EGFR+CT resulted in no statistically significant difference. Anti-EGFR-containing regimens increased the rate of rash and diarrhea compared to CT alone (RR 11.23 and 1.23, respectively). The risk of bias was average low, except for the unclear risk of selection bias linked to unpublished studies. Conclusions: Anti-EGFR±CT maintenance therapy improves PFS and OS compared to CT alone or observation in RAS WT mCRC, with manageable safety profile.
TACH101, a first-in-class pan-inhibitor of KDM4 for treatment of gastrointestinal cancers.
Authors: Perabo Frank , Chandhasin Chandtip , Yoo Sanghee , Dang Van , Del Rosario Joselyn , Chen Young K , Stafford Jeffrey , Quake Stephen , Clarke Michael F. 
Published: January 2022

132 Background: TACH101 is a novel, potent small molecule inhibitor of KDM4, a novel epigenetic target for cancer therapy. KDM4 is a family of histone lysine demethylases that, when overexpressed, drives key processes linked to cancer. Validation of KDM4 as a driver gene was confirmed across gastrointestinal tumor types including esophageal, colon and gastric cancers, and is associated with formation of aggressive tumors. Methods: TACH101 was evaluated in in vitro and in vivo studies including cell inhibition assays, patient-derived xenograft (PDX) and organoid models, and bioinformatics analyses studies. Results: In vitro, TACH101 treatment potently inhibited cell proliferation in cell lines and organoid models representing esophageal, CRC, and gastric cancers. TACH101 induced apoptosis in human CRC (HT-29) and esophageal (KYSE-150) cancer cell lines (EC50s 0.033 - 0.092 µM). Further evaluation using a panel of > 300 cell lines from different tumor types showed potent activity of TACH101 against gastric cancer and CRC. In gastric cancer, 2D cell viability inhibition assays conducted on a panel of 11 gastric cancer cell lines showed 9/11 (82%) were sensitive to TACH101 treatment (IC50 0.004 - 0.072 µM); in PDX models, 4/5 (80%) were sensitive to TACH101 treatment (IC50 0.007 - 0.039 µM). In CRC, bioinformatics analysis indicated increased TACH101 sensitivity in cell lines with MSI-H status (IC50 1-150 nM). Sensitivity of MSI-H CRC to TACH101 was further confirmed in a panel of 14 CRC PDX models and 7 CRC organoid models in culture-based viability inhibition assays. In PDX models, 5/5 (100%) characterized as MSI were sensitive to TACH101 treatment (IC50 0.001 - 0.014 µM), whereas 4/8 (50%) characterized as MSS were sensitive to TACH101 (IC50 0.003 - 0.270 µM). In patient derived CRC organoid models, 3/3 (100%) characterized as MSI were sensitive to TACH101 treatment (IC50 0.022 - 0.149 µM) whereas 0/3 (0%) characterized as MSS were sensitive (IC50 > 10 µM). In vivo, TACH101 triggered effective tumor control (≥70%) in xenograft models of CRC (SU60), esophageal (KYSE-150) and gastric (GXA-3036) cancers. Pharmacologic studies showed TACH101 demonstrated favorable cell permeability, good oral bioavailability, and high metabolic stability. Conclusions: Preclinical work on TACH101 KDM4 inhibitor demonstrates compelling data and applicability as a potential therapy for gastrointestinal cancers. Preparations to advance TACH101 into clinical trials are underway.
Ensemble voting decreases false positives in AI second-observer reads for detecting colorectal cancer.
Authors: Salinel Brandon , Grudza Matthew , Zeien Sarah , Murphy Matthew , Adkins Jake , Jensen Corey , Bay Curt , Kodibagkar Vikram , Koo Phillip , Dragovich Tomislav , Choti Michael A. , Kundranda Madappa N. , Wang Hongzhi , Syeda-Mahmood Tanveer , Chang John ,   2022 GI-ASCO
Published: January 2022

141 Background: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths, and survival can be improved if early, suspect imaging features on CT of the abdomen and pelvis (CTAP) can be routinely identified. At present, up to 40% of these features are undiagnosed on routine CTAP, but this can be improved with a second observer. In this study, we developed a deep ensemble learning method for detecting CRC on CTAP to determine if increasing agreement between ensemble models can decrease the false positives detected by artificial intelligence (AI) second-observer. Methods: 2D U-Net convolutional neural network (CNN) containing 31 million trainable parameters was trained with 58 CRC CT images from Banner MD Anderson (AZ) and MD Anderson Cancer Center (TX) (51 used for training and 7 for validation) and 59 normal CT scans from Banner MD Anderson Cancer Center. 20 of the 25 CRC cases from public domain data (The Cancer Genome Atlas) were used to evaluate the performance of the models. The CRC was segmented using ITK-SNAP open-source software (v. 3.8). To apply the deep ensemble approach, five CNN models were trained independently with random initialization using the same U-Net architect and the same training data. Given a testing CT scan, each of the five trained CNN models was applied to produce tumor segmentation for the testing CT scan. The tumor segmentation results produced by the trained CNN models were then fused using a simple majority voting rule to produce consensus tumor segmentation results. The segmentation was analyzed by the percentage of correct detection, the number of false positives per case, and the Dice similarity coefficient (DSC). If parts of the CRC were flagged by AI, then it was considered correct. A detection was considered false positive if the marked lesion did not overlap with any CRC; contiguous false positives across different slices of CT image were considered a single false positive. DSC measures the quality of the segmentation by measuring the overlap between the ground-truth and AI detected lesion. Results: Our results showed that increasing the agreement between the 5 models dramatically decreases the number of false positives per CT at the expense of slight decrease in accuracy and DSC. This is described in the table. Conclusions: Our results show that AI-based second observer can potentially detect CRC on routine CTAP. Although the initial result yields high false positives per case, ensemble voting is an effective method for decreasing the false positives with a slight decrease in accuracy. This technique can be further improved for eventual clinical application.[Table: see text]
Tumor microbiome variation in young versus average onset colorectal cancer.
Authors: Barot Shimoli V , Sangwan Naseer , Nair Kanika G. , Schmit Stephanie , Xiang Shao , Kamath Suneel Deepak , Liska David , Khorana Alok A. 
Published: January 2022

144 Background: The incidence of young onset colorectal cancer (yoCRC) is rising at alarming rates. The gut microbiome may be a factor accounting for the increase. We analyzed differences in the intratumoral microbiome of yoCRC vs average onset CRC (aoCRC) and its clinical impact. Methods: We identified 314 histologically confirmed cases of stage I-IV CRC that underwent surgical resection at our institution from 2000-2020, diagnosed <50 years of age for yoCRC and >60 years for aoCRC, who consented to a prospective biorepository. 36 cases were excluded due to nonmalignant, non-adenocarcinoma or metastatic site specimens. Fresh frozen tissue from the primary tumor with paired adjacent nonmalignant tissue specimens were analyzed. 16S rDNA was isolated and sequence reads were assigned to genus level amplicon sequence variants in DADA2 and analyzed for alpha and beta diversity using Phyloseq. Statistical tests included analysis of variance (ANOVA), permutational multivariate analysis (PERMANOVA), linear regression, and Wilcoxon test. Differential abundance and correlation analysis were adjusted for sex and ethnicity as confounding factors. Correlation analysis was adjusted with Benjamini Hochberg correction. Clinical differences were analyzed using Fisher's exact test. Results: Of the cohort of 278 patients, 137 had yoCRC (median age 43 years, range 16-49) and 141 had aoCRC (median age 73 years, range 61-95). yoCRC patients were more likely to have stage III or IV disease at presentation (29% vs 14%, p =0.002; 29% vs 18%, p =0.024 respectively), left sided tumors (74% vs 58%, p =0.003) and receive neoadjuvant therapy (29% vs 15%, p =0.004). yoCRC had significantly higher tumor microbial alpha diversity than aoCRC ( p <2.22e−16, Wilcoxon rank-sum test). Beta diversity analysis demonstrated significantly different diversity of genera between the groups (R2=0.12, p =0.001, PERMANOVA). The prevalent taxa identified in both groups were Lactobacillus, Bacillus and Listeria. Differential abundance analysis (ANOVA, p <0.05) revealed a significant variation of intratumoral microbiome (Table). Correlation analysis revealed an association of longer overall survival (OS) with the presence of Akkermansia in yoCRC (R2 =0.36, p <0.001), but not in aoCRC. Conclusions: We found significant differences between the intratumoral microbiome of yoCRC and aoCRC. In particular, Akkermansia, considered a healthy gut microbe, was found in greater relative abundance in yoCRC and correlated with improved OS. Further studies are warranted to understand the nature of association of these microbes with the development of and outcomes in yoCRC. [Table: see text]
Analysis of tumor-associated macrophages' heterogeneity in colorectal cancer patients using single-cell RNA-seq data.
Authors: Nussbaum Yulia Innokenteva , Manjunath Yariswamy , Kaifi Jussuf T. , Warren Wesley , Mitchem Jonathan B. 
Published: January 2022

146 Background: Colorectal cancer (CRC) is one of the deadliest malignancies worldwide. Though immune checkpoint inhibition has proven effective for a number of other tumors, it offers benefits in only a small group of CRC. In general, heterogenous cell groups in the tumor microenvironment (TME) are considered as the major barrier for unveiling the causes of low immune response. Therefore, deconvolution of cellular components in highly heterogeneous microenvironments is crucial for understanding those mechanisms. Single cell sequencing technology revolutionized TME research enabling profiling cells in high resolution. Methods: We have analyzed scRNA-seq data from 23 CRC patients with pre-treatment primary tumors using Seurat V3 pipeline. To investigate intercellular ligand-receptor interactions, we used CellPhoneDB and CellChat methods. The results of two independent analyses showed 4 CRC samples with no SPP1-CD44 interaction. It is known, that OPN which is the protein encoded by SPP1 gene, binds to CD44 and can cause cell survival, proliferation, and angiogenesis. Interestingly, analysis of the cellular composition of all 23 samples did not reveal differences in SPP1+ macrophages’ content for those 4 “no SPP1-CD44” samples. To investigate the mechanisms that could cause differences in SPP1-CD44 expression across the samples, we analyzed developmental trajectories of single cells using Slingshot trajectory inference method. Results: Ligand-receptor interactions analysis revealed 4 CRC samples that lacked SPP1-CD44 interaction that is known to be responsible for tumor progression in CRC. But the proportion of SPP1+ cells was not significantly different in those 4 samples compared to other samples. Trajectory inference analysis showed that the cells from “no SPP1-CD44” samples had high expression of anti-inflammatory macrophage markers in the end of the trajectory. While cells from “high SPP1-CD44” samples had high expression of pro-inflammatory macrophage markers at the same point. Conclusions: Based on our data-driven study, we suggest that SPP1+ macrophages’ heterogeneity may affect SPP1-CD44 interaction. Thus, targeting SPP1+ macrophages that have anti-inflammatory phenotype can potentially interrupt SPP1-CD44 interaction and therefore reduce tumor progression and immune suppression.
Comprehensive landscape of BRAF variant classes, clonalities, and comutations in metastatic colorectal cancer using ctDNA profiling.
Authors: Johnson Benny , Yang Dong , Dada Hiba I. , Drusbosky Leylah , Kopetz Scott 
Published: January 2022

152 Background: Although BRAF V600E accounts for the majority of the BRAF mutations in mCRC, non-V600 BRAF variants have been shown in recent years to represent a distinct molecular subtype of mCRC. This study provides a comprehensive profile of BRAF V600 and non-V600 variants, their clonalities and co-mutations in mCRC using a large genomic database of circulating tumor DNA (ctDNA). Methods: A systematic analysis of Guardant360 results was performed among ctDNA samples of mCRC patients from September 2014 to May 2021. A variant was defined as clonal if the mutant allele frequency (MAF) was greater than 50% of the highest somatic MAF in the sample; otherwise it was defined as subclonal. A previously validated anti-EGFR exposure score was applied to predict prior anti-EGFR therapies. Co-mutation analysis was conducted with BRAF, KRAS, NRAS, NF1, ERBB2, PIK3CA and SMAD4. Results: 1,733 out of 14,742 mCRC patients had at least one BRAF variant, including 6.5% of patients with BRAF V600 variants, 1.1% with class II variants, 1.9% with class III variants, and 3.2% with unclassified variants. 431 unique BRAF variants were identified in a total of 1,905 BRAF variants. 70.7% of BRAF V600 variants were clonal while most (56.0%-78.8%) class II, III and unclassified BRAF variants were subclonal (Table). Patients with non- BRAF V600 variants tend to be younger and male. The prevalence of BRAF class II and III variants were higher (2.1% and 3.7%) in patients with predicted prior anti-EGFR exposure compared with patients predicted to have no prior exposure (0.8% and 1.4%). BRAF variants of all classes are more likely to be subclonal in patients predicted to have anti-EGFR exposure than those predicted nonexposed ( p <0.05 in all classes, Fisher’s exact test). Among patients with non- BRAF V600 variants, a greater fraction of co-occurring KRAS and NRAS mutations were detected in those predicted to have prior anti-EGFR exposure. In the patients without predicted EGFR exposure, BRAF class II and III variants showed a higher rate of co-occurring KRAS mutations (25.6% and 21.5%) and co-occurring NRAS mutations (5.8% and 2.7%) compared with BRAF V600 variants (2.4% for KRAS and 0.1% for NRAS); however, co-occurring KRAS G12C was only noted in one patient with a BRAF class II variant. The analysis of outcome data by variant class will be presented at the meeting. Conclusions: We noted significant differences between BRAF V600 and class II/III variants using a large genomic database. Within BRAF class II and III variants, the enrichment in patients with predicted anti-EGFR exposure and the high fraction of co-mutations in KRAS/ NRAS suggest a unique therapeutic need for these patients.[Table: see text]