bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mismatch repair deficiency testing in colorectal cancer and factors associated with nonadherence to guidelines.
Authors: Ngo Phuong , Kumar Rohit , Rojan Adam 
Published: May 2020

e16069 Background: Mismatch repair (MMR) deficiency is characteristic of Lynch syndrome, which typically affects patients < 50 years old with colorectal cancer (CRC) but can also occur in sporadic CRC. MMR deficiency causes microsatellite instability (MSI) and affects therapy response and prognosis. Guidelines now recommend universal testing of MMR/MSI in all CRC patients, but universal testing has not been achieved. Our study sought to evaluate factors associated with MMR/MSI testing in CRC patients. Methods: The National Cancer Database (NCDB) identified 433,968 patients diagnosed with stages I-IV CRC from 2011-2016. Variables included gender, race, stage, insurance status, education, income, and treatment facility type. Baseline characteristics were compared using Pearson's chi‐square test between patients not tested versus tested for MMR/MSI status. Multivariate logistic regression analysis determined the factors associated with increased probability of MMR/MSI testing. Results: Only 34.7% patients were tested for MMR/MSI and those £ 40 years old were more likely to be tested as were Caucasian patients. Patients with private insurance were more likely to be tested compared to uninsured (OR 1.21; 95% CI 1.1601.27, p < 0.001). Testing also correlated with increasing education, reported as the percentage of adults over 25 years old who did not graduate high school within a zip code. Diagnosis at an academic/research program was also a positive predictor of MMR/MSI testing compared to a community program (OR 1.74; 95% 1.71-1.77, p < 0.001). Testing was dependent on stage with the greatest likelihood of testing in stage II (OR 1.44, 95% CI 1.41-1.46, p < 0.001) and the least in stage IV (OR 0.72; 95% CI 0.71-0.74, p < 0.001) compared to stage I. Still, the trend for testing increased over the years (trend p < 0.001), with that in 2016 being 4 times more likely than in 2011 (OR 4.66; 95% CI 1.53-4.80, p < 0.001). Conclusions: Our study identified established risk factors affecting care such as African American race, treatment at a non-academic facility and being uninsured. It also showed age and stage were factors associated with noncompliance to new guidelines regarding testing for MMR/MSI with testing being less frequent in older patients and those with later stages. An explanation and study limitation is that NCDB only collected diagnoses until 2016 while immunotherapy in MSI-H or dMMR CRC was approved in 2017. With more treatment options available now to these patients, testing rates will hopefully improve with more research needed to capture this.
DNA methylation signatures predicting liver metastasis of colorectal cancer: A proof-of-concept pilot study.
Authors: Ying Jianming , Li Weihua , Liu Kaihua , Xiao Cong , Wu Shuyu , Bao Hua , Wu Xue , Wang Xiaonan , Shao Yang 
Published: May 2020

e16080 Background: Liver metastasis (LIM) is the leading cause of death in colorectal cancer (CRC) patients. Early detection of LIM may improve outcome in CRC patients. The aim of this study was to evaluate the feasibility of predicting LIM of CRC using methylation profiles. Methods: We performed Roche targeted (~5.5 million methylation sites) bisulfite sequencing of matched primary, metastatic and their adjacent normal tissue samples from 5 CRC patients with LIM, 5 patients with lung metastasis (LUM) and 8 patients without metastasis in the training cohort (n = 48 samples). Differential methylation regions (DMR) of LUM were identified and a predictive model was developed. The model was further validated in primary tumor sample from nine patients (6 with LIM). Results: By comparing primary tumor vs adjacent normal tissues and metastatic tumor vs adjacent normal tissues in CRC patients with LIM, we identified 28954 common DMRs which indicating the methylation characteristic of CRC with LIM. Similarly, 16187 DMRs were identified in patients with LUM. 9179 DMRs are shared in both LIM and LUM comparisons which should be the common characteristic of CRC tumor tissue regardless of the location of metastasis. 7008 DMRs are LUM specific and 19775 DMRs are LIM specific. In order to predict LIM in primary, early changes in LIM specific DMRs should be identified. Hence, we further selected 4134 DMRs by chossing significantly differentically methylated regions between LIM primary tissues and LUM primary tissues. To increase the ability of distinguishing LIM from other normal tissues and non-matastasis CRC tumors, 1215 DMRs were finally selected which also showed increasing or decreasing trend of methylation level through the progression of CRC. The final 1215 biomarkers were used to construct a random forest model using methlylation profile of 5 CRC patients with LIM as positive training data and 5 CRC patients with LUM as well as 8 patients without metastasis as negative training data. Through the feature recursive elimination method, one methylation site (chr8.72468901-72469000) was identified with ROC of 0.9 in the training dataset. The predictive model was validated in an independent dataset which is composed of 6 patients with LIM and 3 patients without metastasis, and achieved an AUC of 0.87. Conclusions: Our findings demonstrate the utility of methylation biomarkers for the molecular characterization of metastatic precursors, with implications for prediction and early detection of liver metastasis in CRC.
Prognostic value of piR-39980 in patients with colorectal cancer.
Authors: Peng Wei , Mei Jingfeng , Lu Jianwei , Bao Jun , Zhou Guoren 
Published: May 2020

e16087 Background: Colorectal cancer (CRC) accounts for a common gastrointestinal malignancy all over world. Piwi-interacting RNAs (piRNAs) show a substantial role in the oncogenesis of a variety of tumors. The objective of this work was to uncover the expression profile of piR-39980 and its prognostic value in CRC. Methods: The levels of piR-39980 expression in CRC tissues and paired normal tissues was determined by quantitative real-time polymerase chain reaction (qRT-PCR). Association of piR-39980 with CRC clinical feathers was assessed by Chi-square test. Overall survival curve was built via log-rank test by Kaplan–Meier analysis. The prognostic significance of piR-39980 in CRC was measured by Cox regression model. Results: piR-39980 was upregulated in CRC specimens than the paired normal specimens ( P < 0.001). Importantly, upregulation of piR-39980 was related to tumor size and T stage (all P < 0.05). Survival evaluation suggested that CRC folks with high expression of piR-39980 went through poorer overall survival than folks with low piR-39980 expression (log rank test, P = 0.0429). piR-39980 could be an independent indicator for CRC patients’ prognosis (HR = 3.308, 95% CI = 1.762-6.594, P = 0.043). Conclusions: piR-39980 plays oncogenic roles in CRC tumorigenesis and may be an independent indicator for CRC prognosis.
Contrast-enhanced CT radiomics for predicting calcification in metastatic colorectal cancer: Based on machine learning.
Authors: Zhou Yuwen , Meng Qiu 
Published: May 2020

e16095 Background: In patients with metastatic colorectal cancer (mCRC), calcification is a predictive factor and associated with a better prognosis. This study was aimed to estimate the textural features performance derived from contrast-enhanced CT in prediction of calcification in mCRC. Methods: Four hundred fifty patients from a single center with pathologically diagnosed colorectal adenocarcinoma (training dataset, n = 159; validation dataset, n = 31) were enrolled in our retrospective study. A three-dimensional region of interest (ROI) around the margin of the lesion was manually assessed by two radiologists on the basis of CT scans, and all textural parameters were retrieved from the ROI. The least absolute shrinkage and selection operator (LASSO) method was applied to select the textural feature. The differential diagnostic capabilities of textural features, morphological features, and their combination were analyzed by receiver operating characteristic (ROC). AUC was used as the main indicator. Results: Twenty-one radiomics features extracted from contrast-enhanced CT were screened as a calcification-associated radiomics signature of mCRC. They were able to predict calcification in both the training group (slice thickness of 5 mm, sensitivity 0.84, specificity 0.71, accuracy 0.81, AUC 0.916, 95%CI 0.87-0.97) and the validation group (slice thickness of 5 mm, sensitivity 1.00, specificity 0.88, accuracy 0.77, AUC 0.964, 95%CI 0.904-1.0). Conclusions: In summary, a noninvasive radiomics signature derived from contrast-enhanced CT images was conveniently used for the prediction of calcification in mCRC before therapy, which might be a non-invasive approach in clinical practice to determine whether surgery is needed. However, multi-center studies with larger sample size are needed to confirm these results.
H&E image-based consensus molecular subtype classification of colorectal cancer using weak labeling.
Authors: Kruger Andrew J. , Sha Lingdao , Kannan Madhavi , Joshi Rohan P. , Leibowitz Benjamin D. , Zhang Renyu , Khan Aly A. , Stumpe Martin 
Published: May 2020

e16097 Background: Using gene-expression, consensus molecular subtypes (CMS) divide colorectal cancers (CRC) into four categories with prognostic and therapy-predictive clinical utilities. These subtypes also manifest as different morphological phenotypes in whole-slide images (WSIs). Here, we implemented and trained a novel deep multiple instance learning (MIL) framework that requires only a single label per WSI to identify morphological biomarkers and accelerate CMS classification. Methods: Deep learning models can be trained by MIL frameworks to classify tissue in localized tiles from large ( > 1 Gb) WSIs using only weakly supervised, slide-level classification labels. Here we demonstrate a novel framework that advances on instance-based MIL by using a multi-phase approach to training deep learning models. The framework allows us to train on WSIs that contain multiple CMS classes while further identifying previously undiscovered tissue features that have low or no correlation with any subtype. Identification of these uncorrelated features results in improved insights into the specific tissue features that are most associated with the four CMS classes and a more accurate classification of CMS status. Results: We trained and validated (n = 735 WSIs and 184 withheld WSIs, respectively) a ResNet34 convolutional neural network to classify 224x224 pixel tiles distributed across tumor, lymphocyte, and stroma tissue regions. The slide-level CMS classification probability was calculated by an aggregation of the tiles correlated with each one of the four subtypes. The receiver operating characteristic curves had the following one-vs-all AUCs: CMS1 = 0.854, CMS2 = 0.921, CMS3 = 0.850, and CMS4 = 0.866, resulting in an average AUC of 0.873. Initial tests to generalize to other data sets, such as TCGA, are promising and constitute one of the future directions of this work. Conclusions: The MIL framework robustly identified tissue features correlated with CMS groups, allowing for a more efficient classification of CRC samples. We also demonstrated that the morphological features indicative of different molecular subtypes can be identified from the deep neural network.
Investigation of Leptin and its receptor (LEPR) for single nucleotide polymorphisms in colorectal cancer: A case-control study involving 2,306 subjects.
Authors: Lin Jing , Chen Yu , Lan Bin , Guo Zeng-qing , Tang Wei-feng , Chen Gang , Xia Xuefeng 
Published: May 2020

e16100 Background: Colorectal cancer is a leading cause of cancer deaths, with poor prognosis. Some studies have reported that obesity and overweight are risk factor for the development of CRC. Leptin ( LEP) and its receptor ( LEPR) single nucleotide polymorphisms (SNPs) might regulate energy balance and be implicated in the development of CRC. The aim of this case-control study was to assess the association of LEP rs2167270 G > A, rs7799039 A > G, LEPR rs6588147 G > A, rs1137100 G > A and rs1137101 G > A SNPs with susceptibility to CRC in Eastern Chinese Han population. Methods: 1,003 CRC cases and 1,303 matched controls was compared. Five functional SNPs in LEP and LEPR genes were chosen to evaluate the correlation of these chosen SNPs with CRC susceptibility. We used the SNPscan genotyping assay to genotype LEP and LEPR SNPs. Results: A significantly decreased risk of CRC was found to be associated with the LEPR rs6588147 polymorphism (GA vs. GG: crude P= 0.007 and GA/AA vs. GG: crude P= 0.018). With adjustments for risk factors (e.g. age, gender, drinking, BMI and smoking), these associations were not changed. In subgroup analyses, the association of LEP rs2167270 with a decreased risk of CRC was found in the ≥61 years old subgroup. For LEPR rs1137100, the association of this SNP with an increased susceptibility of CRC was found in the BMI < 24 kg/m2 subgroup. In subgroup analyses for LEPR rs6588147, we identified that this locus also decreased the susceptibility of CRC in the male subgroup, < 61 years old subgroup, never smoking subgroup and never drinking subgroup. For LEPR rs1137101, the relationship of this polymorphism with a decreased susceptibility to CRC was found in the never drinking subgroup. Conclusions: The present study highlights that LEPR rs6588147, rs1137101 and LEP rs2167270 may decrease the risk of CRC. However, LEPR rs1137100 is associated with susceptibility to CRC. Further case-control studies with larger sample sizes should be conducted to validate our findings.
Exploring fingerprint ctDNA as a stratifying factor in colorectal cancer.
Authors: Sun Wending , Zhang Jianwei , Wei Jinwang , Dai Chun , Liu Jun , Deng Yanhong 
Published: May 2020

e16101 Background: Colorectal cancer (CRC) ranks near the top in tumor-related deaths. Its standard-of-care is surgical resection plus adjuvant chemotherapy, which can extend patient’s live and disease-free survival for up to several years. However, choosing an appropriate chemotherapy agent is difficult because CRC is a heterogenous disease. It is believed that molecular stratification can help to improve treatment accuracy and this has been proven by the consensus molecular subtypes (CMS) classification. However, the CMS classification relies on expensive and complex gene-expression profiling, and more cumbersomely, is limited to early stage patients without prior chemotherapy, radiation and metastasis. This situation denies many CRC patients from the benefit of CMS classification. Circulating tumor DNA (ctDNA) is a minimally invasive way to monitor disease progression and treatment response in solid tumors but its clinical utility in CRC remains to be validated. We explore the potential of using patient’s fingerprint ctDNA (defined below) as a stratifying factor in CRC patients to assist clinical decision. Methods: WES is performed on tumor and matched blood samples from 149 CRC patients. Based on the WES result, 20-30 tumor specific genes are selected for each patient and form their ctDNA fingerprints. The patients are grouped according to their level of fingerprint ctDNA (high- vs. low-ctDNA). Results: The two groups of patients show significant difference in treatment responses and mutational profiles. The low-ctDNA group in general respond to treatment well and have good prognosis. The high-ctDNA group, in contrast, often experience relapse or recurrence. Interestingly, the low-ctDNA group is dominated by point and small indel mutations in the top mutated genes while the high-ctDNA group is dominated by gene copy variations (CNV). SMAD4 deficit and DCC amplification are well known CNV in CRC, but they only appear in the high-ctDNA group. Similarly, CNV of AGO2, ACTG1, MYC, and BRD3 are only associated with the high-ctDNA group but not the low-ctDNA group. Conclusions: Our result indicates a strong correlation of fingerprint ctDNA level to both tumor mutational profile and prognosis. This suggests fingerprint ctDNA level may be used as an effective stratifying factor in CRC. At the same time, possibly a common molecular cause is driving persistent ctDNA production in CRC patients, including a large portion of them who have received surgical and adjuvant chemotherapy. Further perspective study, however, is needed to test whether fingerprint ctDNA can be a predictive biomarker.
Age, sex, and specific gene mutations affect the effects of immune checkpoint inhibitors in colorectal cancer.
Authors: Lin Anqi , Zhang Hongman , Luo Peng , Zhang Jian 
Published: May 2020

e16103 Background: The effect of age and sex on the prognosis of colorectal cancer (CRC) patients treated with immune checkpoint inhibitors (ICIs) has been controversial, and the effect of specific gene mutations on the prognosis of patients treated with ICIs remains to be explored. Based on detailed clinical and genetic data, this study analyzed the influence of the above factors on the overall survival (OS) of CRC patients after ICI treatment and explored the influencing mechanism of various prognostic factors. Methods: We performed survival prognostic correlation analysis and bioinformatics analysis on the clinical CRC cohort receiving ICIs published by Samstein et al. and the clinical and genetic data from The Cancer Genome Atlas (TCGA)-CRC dataset, including immunogenicity and immunosignature analysis, DNA damage response and repair (DDR) pathway analysis, and gene set enrichment analysis (GSEA). Results: Both clinical characteristics and specific gene mutations may be prognostic factors for ICI treatment in CRC patients. Mutation count > 11 (tumor mutation burden (TMB)-high), age > 65, male, RNF43, CREBBP, NOTCH3, PTCH1, CIC, DNT1, and SPEN mutant (MT) were associated with longer OS, while APC-mMT and TP53-MT were significantly correlated with shorter OS. The reason why protective prognostic markers provide better survival benefits to CRC patients may be related to factors such as higher immunogenicity, highly infiltrated immunoactive cells and active immunoactive pathways. Conclusions: Our study is the first to elucidate comprehensive prognostic factors for the treatment of ICIs in CRC patients, from clinical characteristics such as age and sex to specific gene mutations, providing new ideas for immunotherapy in CRC.
Utility of neutrophil to lymphocyte ratio in predicting colorectal cancer prognosis at a VA hospital: Do stage and sidedness matter?
Authors: Kim Kee-Hwan Michael , Gemoets Darren , Le Maithao N. 
Published: May 2020

e16110 Background: Pretreatment neutrophil-lymphocyte ratio (pNLR) has been shown to associate with prognosis in patients with colorectal cancer (CRC). We asked if pNLR equally predicted prognosis in CRC regardless of stage and tumor location. We also asked if pNLR changed with time, especially within one year of diagnosis. Methods: Retrospective clinical data including age at diagnosis, pathological stage, location of tumors, treatments, disease free survival, NLR at one week, three months, and one year (if available) pretreatment of 934 veterans treated for CRC at one Veteran Affair Medical Center between July 1995 and December 2011 were collected. Disease-free survival (DFS) were analyzed using Kaplan-Meier analysis and compared using the log-rank test. pNLRs were grouped into three categories: less than or equal to three, greater than three and less than or equal to five, and greater than five. Univariate and multivariate Cox regression analyses were used to identify the prognostic value of pNLR. Boxplot analysis was used to evaluate the changes in pNLR over time. Results: In patients with stage 1 or stage 4 CRC, pNLRs of more than 5 and not between 3 and 5 predicted worse prognosis. In patients with stage 2 or 3 CRC, pNLRs did not correlate with prognosis. Interestingly, for patients with recurrent CRC after curative treatment, NLRs obtained prior to treatment of recurrent disease of more than 3 associated with worse prognosis. In subgroup analysis, we found that in patients with stage 1 or 4 left side colon or rectal cancer (LCRC), pNLRs of more than 5 but not between 3 and 5 predicted worse prognosis. In patients with stage 2 or 3 LCRC, NLRs obtained prior to treatment of recurrent disease did not correlate with prognosis. Similarly, for patients with recurrent LCRC after curative treatment, NLRs obtained prior to treatment of recurrent disease of more than 3 associated with worse prognosis. pNLRs did not correlate with prognosis in patients with right side colon cancer (RCC) regardless of stage. When comparing NLRs obtained at 1 year, 3 months, and 1-week pretreatment, boxplots showed a gradual increase leading up to the time of treatment suggesting that NLR changes according to the time of collection. Conclusions: In our large retrospective study, the role of pNLR in predicting oncologic prognosis differed according to the stage and the sidedness of the CRC. In addition, the value of pNLR varied depending on the time of collection. These findings suggested a complex relationship between immunologic parameters and oncologic survival.
Racial and socioeconomic disparities in overall survival in colorectal cancer (CRC) at West Cancer Center & Research Institute (WCCRI), Memphis, TN.
Authors: Wookey Vanessa , Bufalino Gabriella , Vidal Gregory A. , Somer Bradley G. , Schwartzberg Lee S. , Grothey Axel 
Published: May 2020

e16122 Background: WCCRI, a comprehensive regional community oncology center in Memphis, Tennessee and the Mid-South region, serves a racially, geographically and socioeconomically diverse patient cohort. We sought to evaluate disparity of outcomes in survival by race and socioeconomic status, in addition to patient and tumor characteristics. Methods: All consecutive patients referred to and treated at WCCRI with colorectal adenocarcinoma from 2007-2013 were included. Individual chart review was performed to verify diagnosis, stage, and date and cause of death. Kaplan-Meier Overall Survival curves were generated for the entire cohort and by race, sex, tumor location and income derived from zip code. WCCRI survival data were compared to SEER data. Results: From 2007-2013, 1,176 patients were included in the analysis: 405 blacks, 757 whites, 14 others. Median age at diagnosis: Blacks 58 yrs, whites 61 yrs. Stage distribution at diagnosis: stage 1: 100, stage 2: 275, stage 3: 425, stage 4: 376. All stages combined, blacks trended towards shorter OS vs whites (5-year OS: 52.8% vs 58.3%; median survival 71.0 mos vs 98.6 mos; p= 0.095). Blacks presented at later stages (71.4% at stage 3 or 4 vs 66.3% for whites) but no statistically significant OS differences were seen when compared by stage. Patients at or below the median income of $39,590 for WCC had worse 5-year OS (51.6% vs. 61.1%; p= 0.006), as did patients without private insurance (5-year OS: uninsured: 48.0%, Medicare/Medicaid: 50.0%, private: 62.0%; p< 0.001). Adjusted for stage, 5-year OS was statistically significant for stage 4 (private: 18.0%, Medicare/Medicaid: 9.4%, uninsured: 8.3%; p= 0.020). A higher proportion of blacks were below the median income (69% vs 39%) but no statistically significant OS differences were seen when adjusted by race. Overall, cancer survival outcomes were similar to SEER results. Conclusions: At WCCRI, black patients with CRC presented at a later stage than whites, however, adjusted for stage, no significant racial difference in OS was found. Income and insurance status influenced survival outcomes. Overall, our results reveal racial and socioeconomic disparities in colorectal cancer in a diverse US population and further detailed multivariate data analyses are underway.