bluuebunny/crossref_metadata_2025_split huggingface dataset:
An improved method for detection of methylated circulating tumor DNA in colorectal cancer.
Authors: Boulter Nicky , Tevz Gregor , Yu Betty , Chan Michelle , Murray David , Symonds Erin L. , Young Graeme P. , Pedersen Susanne Kartin 
Published: May 2019

e15120 Background: Assays detecting methylated circulating tumor DNA (ctDNA) hold promise for colorectal cancer (CRC) screening, but there is a need to develop more accurate assays for early stages. In this study, we examined modifications to COLVERA (an IKZF1 and BCAT1 methylation marker qPCR assay) that added a third biomarker (IRF4) as well as introducing double stranded detection. Methods: Bisulfite converted DNA extracted from plasma collected from subjects undergoing diagnosis for CRC was assayed using either a double-stranded (ds) specific multiplexed qPCR for BCAT1 and IKZF1 detection (Assay 1) and/or a single-stranded (ss) specific BCAT1/IRF4, ds-specific IKZF1 multiplexed qPCR (Assay 2). The unmodified COLVERA test (Clinical Genomics) was used for comparison. Detection of any marker was considered positive. Results: Assay 1 performance evaluated against COLVERA on bisulfite converted DNA from 1453 samples showed an improved sensitivity for CRC detection (93/134 (69.4%) vs 79/134 (59.0%) COLVERA, p = 0.02), but specificity was suboptimal (no neoplasia: 861/1023 (84.2%) vs 946/1023 (92.5%) COLVERA, p < 0.0001). The decrease in specificity resulted primarily from modifications in the BCAT1 assay component (1023 no neoplasia: 60 positive with ss- BCAT1 vs 146 positive with ds- BCAT1, p < 0.0001). Thus, a novel configuration, Assay 2 (ss- BCAT1, ss- IRF4 and ds- IKZF1) was compared to Assay 1 using 189 previously untested specimens. Assay 2 showed a notable improvement in specificity (99/104 (95.2%) vs 93/104 (89.4%) Assay 1; p = 0.0351). Both assays exhibited comparable sensitivities for CRC (41/49 (83.7%) vs 39/49 (79.6%), Assay 1, p = 0.3633). Assay 2 was positive in: adenomas, 9/36 (25.0%); Stage I, 3/7 (42.9%); Stage II, 17/19 (89.5%); Stage III, 6/6 (100%); Stage IV, 7/7 (100%) and 8/10 (80%) unstaged CRCs. Prior COLVERA sensitivity estimates were 9% adenoma, 41% Stage I and 76% Stage II. Conclusions: Targeting both of the non-complementary bisulfite converted strands of selective regions of interest markedly improve ctDNA assay sensitivity for cancer including early lesions while achieving good specificity. Prospective evaluation in a true CRC screening population is now underway. Clinical trial information: 12611000318987.
Mutation profiling of BRAF gene in Chinese patients with early or advanced colorectal cancer using comprehensive NGS panel.
Authors: Lin Canfeng , Jia Wanqiu , Sheng Wang , Zhang Lijiao , Zhang Feiran , Gu Yanhong , Zhu Lingjun , Chen Rongrong , Xia Xuefeng 
Published: May 2019

e15124 Background: It has been reported that BRAF gene mutation occurs in approximately 10% of metastatic colorectal cancer (mCRC), and is associated with resistance to EGFR inhibitors. Moreover, patients with non-V600E BRAF mutations with a better prognosis than patients with V600E BRAF mutations in advanced colorectal cancer. However, little is known about mutation profiling of BRAF in early stage colorectal cancer. Methods: We reviewed mutation profiling of 1429 colorectal cancer samples in our institute from 2016 to 2018. Tissue biopsy and/or ctDNA samples were analyzed using hybridization capture-based NGS ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and somatic copy-number alterations at least 59 genes (range 59-1021 genes). Results: A total of 1429 samples from 1120 patients with CRC, included 86 early stage (Ⅰ-Ⅱ ), 966 advanced stage (Ⅲ -Ⅳ), and 377 samples with unknown stage. We identified 109 samples from 94 patients with BRAF gene mutation in the cohort (109/1429=7.63%), of which V600E and non-V600E were 62(4.34%) and 47 (3.29%), respectively. Among the 109 samples, there were 15 of early stage, 84 of advanced stage and 10 of unknown stages. BRAF mutation were more common in early CRC samples (15/86=17.44%) than in advanced CRC samples (84/966=8.7%, p = 0.007). Furthermore, 10 of the 15 early CRC samples yet 32 of the 84 mCRC samples had non-V600E were detected (66.67% vs 38.1%, p=0.039). In contrast to V600E mutation, some of the non-V600E variants were variants of unknown clinical significance (VUS) in this study (see Table). Conclusions: BRAF mutation is more common in early stage CRC, the higher prevalence of non-V600E BRAF mutations in early CRC may account for the better prognosis of early stage CRC. non-V600E BRAF mutation subtype. [Table: see text]
Radiomic profiles via machine learning to predict response, overall survival, and KRAS status in metastatic colorectal tumors treated with FOLFOX/bevacizumab/hydroxychloroquine.
Authors: Rathore Saima , O'Hara Mark H. , Karasic Thomas Benjamin , Redlinger Maryann , Rosen Mark Alan , Davatzikos Christos , O'Dwyer Peter 
Published: May 2019

e15125 Background: Autophagy is a resistance mechanism to chemotherapy that is inhibited by hydroxychloroquine (HCQ). We have reported a phase II trial of FOLFOX/bevacizumab/HCQ in 28 evaluable patients with untreated metastatic colorectal cancer (mCRC). Overall response rate was 68%, with 11% complete response (CR) and 57% partial response (PR), while stable disease (SD) was seen in 30%. We hypothesize that analysis of CT imaging features via machine learning (ML) will enhance subtle yet important radiographic characteristics, and reveal imaging signatures determinant of outcome and mutational status. Methods: Baseline CT images were collected and 1265 quantitative imaging (QI) features extracted across all the metastatic sites – liver, lung, and lymph nodes – including descriptors of size, morphology, texture, and intensity. Cross-validated sequential feature selection coupled with support vector machine (SVM) was used to determine the most discriminative QI features for our integrative predictor of response and mutational status, and support vector regression (SVR) was used to derive imaging predictors of overall survival. The model predictions were compared with actual clinical results, including response, survival, and genomic aberrations. Results: Various QI features, primarily descriptive of texture and tumor volume, were determined as most important by the ML predictor. Using this signature, our predictor classified “Responder (PR+CR) vs Non-responder (SD)” with an accuracy of 85% [sensitivity(se) = 0.84, specificity(sp) = 0.71, AUC = 0.85]. The QI features were also able to detect KRAS and TP53 mutational status with an accuracy of 88% [se = 0.92, sp = 0.85, AUC = 0.87] and 86% [se = 0.80, sp = 0.90, AUC = 0.84], respectively. The SVM model predicted overall survival greater than the median (32 mo) with an accuracy of 86% [se = 0.93, sp = 0.79, AUC = 0.87]. The Pearson correlation coefficient between the SVR score and overall survival was estimated to be 0.73 (p < 0.0001). Conclusions: Radiomic analysis of baseline CT imaging features analyzed by ML yielded an imaging signature predictive of response, survival, and KRAS and TP53 mutational status. If validated in a larger clinical data set, machine learning may offer a predictive biomarker to aid clinical decision making for mCRC patients.
Colorectal cancer molecular subtypes by immunohistochemistry in a patient cohort from Nigeria.
Authors: Abdulkareem F Biade , Khramtsova Galina , Adedokun Babatunde , Rotimi Olorunda , Abudu Kunle , Badmos Kabir , Ibraheem Abiola Falilat , Khramtsov Andrey , Sveen Lise , Hurley Ian , Masaya Hattori , Huo Dezheng , Olopade Olufunmilayo I. 
Published: May 2019

e15145 Background: Colorectal cancer (CRC) classificationusesclinico-pathological characteristics. However, patients with similar histologic features and tumor stages have different clinical outcomes and drug responses. Studies of CRCmolecular heterogeneity have used genome-wide gene-expression data to classifypatients into four consensus molecular subtypes (CMS), but the complexity of analysis has limited its use in practice. Methods: With IRB approval, tissue microarray (TMA) blocks were constructed, IHC was performed and semi-quantitative scores completed. For the MMR proteins, MLH1 (Pierce), MSH2 (LifeTechnologies), MSH6 (Novex), PMS2 (Pierce) antibodies were used. Three markers were selected from transcriptomic analysis for IHC: CDX2 (LifeTechnologies), HTR2B (LifeTechnologies), and ZEB1 (eBioscience). Ki-67 (DAKO) proliferation rate was used as anequivalent marker for β-catenin activation.The CMS1 subtype was first separated using MSI/MSS status. A panel of CDX2, HTR2B, and ZEB1was then used to distinguish between CMS4 and CMS2/CMS3 subtypes, while Ki-67 was used to separate CMS2 from CMS3 subtype. Results: Of the total evaluable 75 CRC cases(mean age 44.8 years (SD = 16.1), 38% were <40 years old, and 60% were males. Of tumors with data on tumor grade (n=66), 62% were well differentiated. 59 patients (79%) had MSS, and the remaining16(21%) had MSI (i.e. CMS1). 22 (29%) patients with increased ZEB1 and lower CDX2 expression were classified as CMS4. 37 (49%) displayed increased CDX2 and lower ZEB1 expression and were classified as CMS2 (n=24) or CMS3 (n=13). HTR2B was universally expressed, but a higher median HTR2B score of 3 was observed in CMS4 cases compared to 1 for other subtypes (p=0.0001). The CMS4 subtype was significantly more likely to occur among young patients (p<0.001): in patients < 40 years, 70% of patients were CMS4 subtype, while in patients > 40, 7% were CMS4 subtype. Of the left-sided cancers, only 5% were CMS1 subtype, while CMS1 composed 75% of right-sided cancers (p<0.001). Conclusions: Using TMAs and a panel of antibodies, we show an association of a poorer prognostic subtype (CMS4) with younger age at diagnosis. IHC-based classification and screening could be a cost effective prognostic and predictive tool for Nigerian reference laboratories.
Machine learning for CT texture analysis in chemosensitivity of colorectal liver metastases: Initial results.
Authors: Miyamoto Yuji , Nakaura Takeshi , Hiyoshi Yukiharu , Baba Hideo 
Published: May 2019

e15148 Background: Despite advances in cancer treatment over the last decades, more efficacious biomarkers are needed in patients with metastatic colorectal cancer. Several studies have reported that CT texture analysis is a useful prognostic biomarker for patients with colorectal cancer liver metastases (CRLM), however, little study has been done to explore those efficacies using machine learning methods. The present study aimed to evaluate the clinical efficacy of CT texture analysis using machine learning methods as a predictive marker of systemic chemotherapy in patients with CRLM. Methods: Sixty-four patients with CRLM who received first-line chemotherapy were included. Texture analysis was performed on 92 features (First Order Statistics, Gray Level Cooccurrence Matrix, Gray Level Run Length Matrix, Gray Level Size Zone Matrix, Neighbouring Gray Tone Difference Matrix and Gray Level Dependence Matrix) using CT within 1 month before treatment. We evaluated the association between those features and chemotherapeutic response by RECIST (CR+PR vs. SD+PD+NE). We performed eXtreme gradient boost (XGBoost) as a machine learning method to predict the chemotherapeutic response and used the receiver operating characteristic curves to evaluate this prediction model. Results: Main characteristics were the following: male/female = 36/28; median age = 63.5. Patients were treated with oxaliplatin-based chemotherapy (80% of patients), bevacizumab (77%) and anti-EGFR antibody (23%). Thirty-nine patients had confirmed responders, for an overall response rate of 61%, whereas 25 patients (39%) were classified as non-responders (CR: PR: SD: PD: NE = 0: 39: 20: 4: 1). The area under curve of this prediction model was 0.771. Conclusions: We confirmed that CT texture analysis using machine learning for CRLM was feasible. Further analyses are ongoing.
Prognostic impact of mutation profiling in Chinese patients with colorectal liver metastases.
Authors: Wang Kun , Yang Yadong , Zhang Xiaoyu , Li Juan , Bao Quan , Wang Hongwei , Jin Kemin , Liu Ming , Liu Wei , Yan Xiaoluan , Wang Lijun , Da Xu , Xing Baocai 
Published: May 2019

e15157 Background: To investigate mutation profiling in Chinese patients with colorectal liver metastases and explore new prognostic biomarkers. Methods: We investigated 197 patients who underwent surgery for colorectal liver metastases at Beijing Cancer Hospital between January 2015 and February 2017. Tumor DNA was isolated from FFPE tissues from liver metastatic lesions. Mutation spectrum was obtained by targeted deep sequencing of 620 selected genes. Tumor mutational burden (TMB) was defined as the number of non-synonymous mutations per 1Mbp and divided into quartiles. MSI status was tested with next-generation sequencing. Studies of impacts of mutation status on disease-free survival (DFS) and overall survival (OS) were performed with Kaplan-Meier analysis. Results: Mutation significance analysis confirmed enrichment in colorectal cancer driver gene mutations of TP53, APC, KRAS, SMAD4, SOX9, FBXW7 and PIK3CA in 72%, 61%, 29%, 14%, 10%, 10% and 9% of liver metastases, with no BRAF mutation found in any of these patients. Additionally, we observed frequent gene-level copy number variations, including amplifications of MYC, BRCA2, ERBB2, CCND2 and deletion of APC. Among 197 patients, only three showed MSI-high, who also exhibited high TMBs. Moreover, KRAS, MXRA5, and SETD2 mutations were significantly associated with shorter DFS ( KRAS mt vs wt: 8 months vs 11 months, p = 0.0086; MXRA5 mt vs wt: 6 months vs 11 months, p = 0.0178; SETD2 mt vs wt: 8 months vs 11 months, p = 0.0381), but KMT2A mutation associated with longer DFS (mt vs wt: 31.5 months vs 10 months, p = 0.0409). SPEN, GNAS, CTNNB1, SETD2 and FANCM mutations were significantly associated with poor OS ( SPEN mt vs wt: 23 months vs 30 months, p = 0.0047; GNAS mt vs wt: 24.5 months vs 30 months, p = 0.0386; CTNNB1 mt vs wt: 20 months vs 30 months, p = 0.0001; SETD2 mt vs wt: 20 months vs 30 months, p = 0.0026; FANCM mt vs wt: 13 months vs 30 months, p = 0.0007). Conclusions: Our study has found a novel panel of prognostic biomarkers in colorectal liver metastases. The clinical significance of mutations of MXRA5, SETD2, KMT2A, SPEN, GNAS, CTNNB1, FANCM needs to be confirmed on a larger scale.
Prognostic nutritional index and colorectal cancer deaths: A retrospective cohort study in Chinese patients with locally advanced colorectal cancer.
Authors: Wang Wenling 
Published: May 2019

e15160 Background: The nutrition and immune status-based scoring system PNI was originally used to assess the nutritional status and surgical risk of surgical patients before surgery. Subsequent studies have shown that PNI is an important prognostic indicator for some malignant tumors, including hepatocellular carcinoma, pancreatic cancer, laryngeal cancer, renal cell carcinoma and gastric cancer. We speculated that since PNI is associated with the prognosis of other malignancies, is it also relevant in colorectal cancer? In view of the obvious increase in the incidence of colorectal cancer in China, and the clinical progress of colorectal cancer in the entire colorectal cancer accounted for up to 70% and current studies on PNI and local advanced colorectal cancer prognosis association study in Chinese is limited. In the present study, our primary objective was to explore whether PNI evaluated at baseline was independently associated with colorectal cancer deaths after controlling other potential confounders. Methods: Through a retrospective cohort study, we analyzed the clinical data of 400 patients with pathologically confirmed colorectal cancer and radical resection of colorectal cancer from January 2013 to April 2018.The exposure variable was PNI at baseline, the outcome variable was death, and other covariates of this study include: Continuous variables: age, platelet count, tumor markers (CEA, CA199, CA724, CA242).Categorical variables: gender, survival status, tumor location, histological type, degree of differentiation, TNM staging, and postoperative treatment. Results: Fully-adjusted model demonstrated that PNI was not associated with deaths of local advanced colorectal cancer and radical resection of colorectal cancer (HR = 0.88; 95% CI, 0.78-1.00). By applying the cubic spline function to the model, we found that the relationship between PNI and death is nonlinear.Two-piecewise cox model suggested that On the left side of the inflection point (41.35), PNI per 1 change is associated with the 68% decrease of risk of deaths (HR = 0.32; 95% CI, 0.13-0.79), to the right of the inflection point, PNI and death The association is not detected. Conclusions: PNI and deaths are nonlinearity, and within a certain range (PNI = 26-41), PNI is an independent protective factor for death risk.
Validation of neoadjuvant rectal cancer(NAR) score as a surrogate endpoint for disease free survival in Chinese FOWARC study.
Authors: Deng Yanhong , Cai Yue , Zhang Jianwei , Hu Huabin , Ling Jiayu , Wu Zehua , Wang Jianping 
Published: May 2019

e15162 Background: NAR score is considered as a surrogate endpoint for survival in patients with locally advanced rectal cancer who received neoadjuvant treatment. Here we validate it in Chinese FOWARC study, especially in the chemotherapy alone arm. Methods: NAR score is calculated based on cT, ypT, ypN as reported for patients who received surgery in FOWARC study. NAR score is correlated to DFS with COX regression and Kaplan-Meier analysis. Results: 451 patients had surgery, 147 in FU-RT group, 152 in FOLFOX-RT arm and 152 in FOLFOX arm. NAR score is a significant prognostic factor in COX regression (P=0.000, HR 1.034, 95% CI 1.024-1.045) and in FOLFOX alone group (p=0.001, HR 1.030, 95% CI 1.013-1.047). When NAR score is quartile to <5, 5-10, 10-15,>15, the survival of patients is listed below, and similar to pathological staging. Conclusions: NAR score can be used as a surrogate endpoint for disease free survival Chinese patients. But it is not superior to pathological stage, especially in patients who received chemotherapy alone. [Table: see text]
Nomogram incorporated the number of adjuvant chemotherapy cycles for predicting the prognosis in stage II-III rectal cancer patients without neoadjuvant therapy.
Authors: Chen Weiwei , Wang Wenling 
Published: May 2019

e15163 Background: Current recommendations for adjuvant chemotherapy in rectal cancer are based on the studies in colon cancer. However, it is now known that rectal cancer differs from colon cancer significantly regarding clinical course and biology. No RCTs in the TME era have evaluated the value of postoperative chemotherapy and are unlikely to be performed as neoadjuvant treatment has become a “gold standard” approach. However, we found that not all patients with locally advanced rectal cancer underwent neoadjuvant chemoradiotherapy before TME in real-world clinical practice in China. Whether the number of adjuvant chemotherapy cycles is significantly related to the prognosis of these patients deserves further study. Methods: A total of 246 patients with stage II-III rectal cancer from January 2013 to April 2018 were enrolled. All patients underwent surgery and had not received neoadjuvant therapy. The survival curve was drawn by the Kaplan-Meier method, and the log-rank method was used for statistical analysis. The Cox proportional hazard model was used for multivariate analysis to determine the independent prognostic factors. Then, MFP(Multiple Fractional Polynominal) and stepwiseAIC were used for variable selection. The R software was used to establish the nomogram. The bootstrap method was employed to internal verification. Concordance index(C-index) was applied to evaluate the predictive power of nomogram. Calibration curves were drawn to compare the 3-year overall survival rate predicted by nomogram and that of actual observation. Results: 87.8% of patients received adjuvant chemotherapy including oxaliplatin combined with fluorouracil or capecitabine. Univariate and multivariate analysis showed that the number of adjuvant chemotherapy cycles was independent prognostic factors. Patients who received more than 5 cycles of chemotherapy (HR = 0.09, 95%CI(0.01,0.80)) had a significantly better overall survival than patients with less than 5 cycles (HR = 0.33,95%CI(0.12,0.89)) or no chemotherapy (p < 0.05).Through MFP and the stepwiseAIC screening, a nomogram was established based on CEA, PLR, N, and the number of chemotherapy cycles, and the C-index of the model was 0.86. Conclusions: The number of adjuvant chemotherapy cycles is an independent prognostic factor in stage II-III rectal cancer patients without neoadjuvant therapy. Moreover, nomogram incorporated the number of chemotherapy cycles was accurate and visible.
Factors of local immunity in patients with rectal cancer after prolonged radiotherapy.
Authors: Kit Oleg Ivanovich , Snezhko Aleksandr V. , Zlatnik Elena Yu. , Novikova Inna A. , Al-haj Nabil , Bondarenko Elena S. , Vladimirova Liubov Yu 
Published: May 2019

e15164 Background: Immunological study of the blood and tumor tissues was performed in patients with rectal cancer receiving neoadjuvant chemoradiotherapy. Methods: 30 patients with rectal cancer (13 women and 17 men aged 37-68 years with stage II-III adenocarcinomas G1-G3) were divided into groups according to results of DNA cytometry and their response to neoadjuvant treatment. When tumor proliferative activity was stable for 4 weeks of treatment, patients received surgery on time (group 1), while patients with verified inhibition of tumor proliferation (the index decrease by 1.5 times and more) continued treatment for 6-8 weeks and then were operated on (group 2). The immune status of patients (T, B, NK, DN, Tregs) was assessed during treatment. Homogenates of tumor tissue samples obtained during surgery were studied for the levels of lymphocytes (flow cytometry) and cytokines TNF-α, IL-1ß, IL-1RA, IL-6, IL-8, IFN-α, IFN-γ (ELISA); tumor proliferation index was assessed by DNA cytometry. Results were analyzed by Statistica 10.0 program. Results: The dynamics of parameters of the cellular immunity was different in patients of two groups. In group 1, percentage of T lymphocytes in blood decreased (from 66.7±3.3 to 50.4±1.6%), as well as their main subsets (CD4+ and CD8+ cells: from 33.6±2.7 to 27.0±1.7% and from 26.7±2.4 to 20.7±1.7% respectively). Patients of group 2 developed an increase in levels of NK cells from 10.1±1.2 to 15.3±2.2%, and levels of CD3+, CD4+ and CD8+ cells were significantly higher than in group 1: 35.0±1.8% for CD4+ and 28.3±2.9% for CD8+ (p < 0.05). The groups also differed in indices of local immunity: DN cells levels in group 2 were lower than in group 1 (5.8±1.0 vs. 18.4±5.4%) and CD4+ were higher (36.6±3.3 vs. 26.2±3.1%; p < 0.05). Patients of group 2 showed lower levels of IL-1ß, IL-6, IL-10, while IFNγ was elevated by 5.4 times, indicating a more favorable local cytokine status of the patients, compared to group 1. Conclusions: In rectal cancer patients with effect confirmed by DNA cytometry, prolongation of chemoradiotherapy to 6-8 weeks provides the formation of a more favorable immunological microenvironment of the tumor, and in such cases it is considered appropriate.