bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival impact of metastasis surgical resections and sidedness of primary (1º) tumor location in metastatic colorectal cancer (mCRC) without monoclonal antibodies: Retrospective review from 2003 through 2019.
Authors: Portella Marcos André Marques , Gonçalves Mariana Paula Cunha , Murad Junior Munir , dos Santos Borges Robson , Preisser Ana Livia Alves , Azevedo Junia Brunelli Cassétte , Fernandes Amandio S. , Fonseca Roberto Porto
Published: May 2020

e16022

Background: Recent data demonstrated a median overall survival (OS) about 35 months for patients with mCRC based on the use of monoclonal antibodies (MA), anti-VEGFR and / or anti EGFR, with sidedness of primary tumor as an independent prognostic marker. However the influence of surgical resections of metastases has not yet been quantified especially after 2003 when were attributed to the inclusion of MA (Kopetz et al 2009). We hypothesized the impact of metastatectomy rate (MR) in the OS of a population without MA and their influence on primary tumor location. Methods: Data from 291 consecutive patients diagnosed with mCRC treated in a clinical center in Brazil, from 2003 to 2019, without MA. 1° location was determined by chart review: R-sided = cecum to hepatic flexure; L-sided = splenic flexure to rectum. Pts with transverse tumors were excluded. Survival from diagnosis was calculated via kaplan-Meier and compare between the right and the left side has estimated via Cox Regression. Results: 50.85%(148) of patients had a primary tumor in the left colon. Oxaliplatin was used in 1° line in 85 % and irinotecan in 75% in 2° line, most of the metastasis was metachronous, only to a single-organ (50,9% liver, 18% lung) and 40 % underwent resection at the diagnosis. The overall survival for the entire cohort was 34.1 months (95% CI, 28.9 to 45.4 months) with 39 % MR. Sidedness (R vs L) had interaction with resected and non-resected metastasis p < 0.001). See OS Table results by sidedness below. Conclusions: It was possible to infer that the metastasectomy rate still have a significant and isolated benefit in the OS of this cohort without the use of MA, regardless of the mutational status of the tumors, being influenced by the sidedness of the primary tumor in the analyzed outcomes. [Table: see text]
Cohort study on patients with metastatic colorectal cancer with integrated Chinese and western medicine.
Authors: Zhang Tong , He Wenting , Tang Mo , Yang Yufei
Published: May 2020

e16030

Background: To investigate the efficacy of integrated Chinese and Western medicine in the treatment of mCRC in a cohort study (Registry No. ChiCTR-IOR-17010497). Methods: The survival outcome of patients receiving integrated Chinese and Western medicine was compared with that of patients receiving Western medicine alone. The study design was adopted with "continuous administration of traditional Chinese medicine for ≥ 3 months" as the exposure factor. Patients who met this exposure factor were assigned to the integrated Chinese and Western medicine cohort. Patients who did not meet this exposure factor were assigned to the Western medicine cohort. The overall survival, 5-year survival rate in the two cohorts were compared. Results: 335 subjects were assigned into two groups (Group A 129 patients, Group B 206 patients). The median overall survival (OS) in Group A and B were 19.2 months (95% CI 16.2–23.2) and 15.2 months (95% CI 13.3–17.2), P= 0.019. Group A demonstrated significantly longer OS and PFS than Group B in the following subgroups: female patients, right-side colon, first-line treatment, RAS mutation. Conclusions: Integrated traditional Chinese and Western medicine can prolong the survival of patients with mCRC. Clinical trial information: ChiCTR-IOR-17010497 .
Combination of anlotinib and irinotecan in the second-line treatment of patients with advanced colorectal cancer: An open-label, multicenter phase I/II study.
Authors: Zhang Bo , Wang Xi , Zhu Lingjun , Li Qun , Liu Yun , Qi Ling , Shu Yongqian , Huang Jing
Published: May 2020

e16036

Background: Efficacious therapeutic options for advanced colorectal cancer (CRC) are limited, and treatment outcomes remain to be improved in the second-line setting. Anlotinib is a multi-target antiangiogenic small molecule that primarily inhibits VEGFR1/2/3. We conducted this open-label, multi-center phase 1/2 study to evaluate the safety and efficacy of anlotinib plus irinotecan in patients with previously treated advanced CRC. Methods: We enrolled patients with advanced CRC whose disease had progressed after first-line systemic therapy and had not previously received irinotecan. In the 3+3 dose escalation (phase 1) part of the trial, patients received anlotinib (8mg, 10mg and 12mg, po, 2 weeks on/1 week off) in combination with fixed-dose irinotecan (180mg/m2, iv, q2w) to define the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). In the dose-expansion (phase 2) part, patients were treated with the RP2D of anlotinib and irinotecan. The primary endpoints were MTD and objective response rate (ORR). Secondary endpoints included progression-free survival (PFS) and disease control rate (DCR). Results: A total of 31 patients were enrolled from 2 centers between May 2018 and Jan 2020. The median follow-up duration was 12.48m (95% CI 7.43-15.24). Anlotinib was well tolerated in combination with irinotecan with no MTD identified in the phase 1 part, and the RP2D was therefore 12mg. Twenty-eight patients were evaluable for efficacy analysis. Eight patients achieved partial response (PR), in which 6 had confirmed PR and 2 were unconfirmed. The ORR was 21.4% (95%CI 8.3%-41.0%) and the DCR was 100% (95%CI 87.7%-100%). The median PFS and OS were 6.97m (95%CI 3.71-11.20) and 13.87m (95%CI 11.47-NR), respectively. All patients were included in the safety analysis. The most common grade 3 treatment-related adverse events (AEs) (≥5%) were diarrhea (16.1%), neutropenia (12.9%), fatigue (6.5%) and hypertension (6.5%). Grade 4 AEs included neutropenia (6.5%) and thrombocytopenia (3.2%). There were no treatment-related deaths. Conclusions: The combination of anlotinib and irinotecan had promising anti-tumor activity in the second-line treatment of advanced CRC with a manageable safety profile. Clinical trial information: NCT03545711 . [Table: see text]
Differential genetic variations and prognostic predicting factors in colorectal cancer patients with or without liver metastasis.
Authors: Peng Honghua , Liu Guifeng , Song Lele , Bao Ying , Zhang Xi , Zhou Lehong , Cao Sudan , Dang Shiying , Chen Shifu , Xu Mingyan , Cao Peiguo
Published: May 2020

e16049

Background: Although liver metastasis is the most common metastasis for colorectal cancer (CRC), the molecular mechanism determining the metastasis has not been clarified. Our study aims to investigate the potential molecular mechanisms of liver metastasis by comparing the genetic variations between patients with or without liver metastasis, and to explore the prognostic factors for the two groups of patients. Methods: 57 stage I-IV CRC patients (49 with stage III/IV) were enrolled. 26 patients had no liver metastasis while 31 patients had liver metastasis when they were recruited. Whole-exome sequencing was performed on the primary cancer tissues of all patients. All patients were followed up for up to 50 months. Results: We found that the tumor mutation burden (TMB) of primary cancer tissue from patients with liver metastasis was significantly higher than those without metastasis (P < 0.05). When the mutation frequency was compared at whole-exome level, the mutation frequency of TCF7L2 and TRIM77 genes of primary cancer tissues was found to be significantly higher in patients with liver metastasis (TCF7L2: 35.48% vs. 3.85% (P = 0.0037) for patients with or without metastasis; TRIM77: 16.13% vs. 0% (P = 0.050) for patients with or without metastasis). Further study revealed that in patients with liver metastasis, patients with TRIM77 mutations showed worse overall survival (OS) than those without TRIM77 mutations (P < 0.0001). Similarly, patients with 7_12p.13.33 amplification, 10_14q32.33 amplification, and 4_10q23.31 deletion showed worse OS than those without the mutations (P < 0.05). In contrast, in patients without liver metastasis, patients with 6_20q13.33 amplification showed worse OS than those without the amplification. Conclusions: The TMB of CRC patients with liver metastasis was significantly higher than those without liver metastasis. TCF7L2 and TRIM77 gene mutations may be predictive for liver metastasis. TRIM77 mutation, 7_12 p.13.33 amplification, 10_14q32.33 amplification, and 4_10q23.31 deletion were related to poor OS in patients with liver metastasis, while 6_20q13.33 amplification was related to poor OS in patients without liver metastasis.
FGFR expression, fusion and mutation as detected by NGS sequencing of DNA and RNA.
Authors: De Dios Ivan , Ma Wanlong , Antzoulatos Spiraggelos , Estella Jeffrey , Albitar Maher
Published: May 2020

e16061

Background: Fibroblast Growth Factor Receptors (FGFR1-4) abnormalities (fusion, amplification and mutations) are common in urothelial, breast and endometrial cancers. However, FGFR1-4 have been shown to play a major role in cell proliferation, differentiation, and apoptosis in other types of cancers including colorectal (CRC) and lung cancers. We explored the value of using DNA and RNA next generation sequencing (NGS) in determining the presence of abnormalities in FGFR1-4 in various types of cancer. Methods: Using targeted panel and next generation sequencing (NGS), we analyzed DNA sequencing data (434 genes) in 438 Solid tumors and RNA data (1408 genes) in 160 lung cancers and 53 colorectal cancers (CRC). The expression levels of the CRC and lung cancer were also compared with expression levels of 32 cases of endometrial, urothelial and breast cancers as a group of cancers known to have high incidence. Results: The DNA data showed mutations in 85 samples and CNV in 12 samples. The detected mutations were 18% in FGFR1, 25% in FGFR2, 45% in FGFR3, and 12% in FGFR4. Only 20% of the detected mutations by NGS testing can be detected if the PCR-based FDA-approved kit was used. Analysis of the expression levels of FGFR1-4 mRNA in CRC and lung cancer showed highest expression in FGFR2, followed by FGFR1 then FGFR3. Expression of FGFR4 was the lowest (P < 0.0001). There was no difference between CRC and lung cancer in FGFR1 and FGFR2 mRNA, but FGFR3 was slightly higher in lung cancer as compared with CRC (P = 0.01). FGFR4 was significantly higher in CRC as compared with lung cancer (P < 0.0001). No fusion involving FGFR1-4 was detected in any of the tested CRC or lung cancers. Upon comparing overall expression between CRC/lung cancer with the group of cancers that are known to have high incidence of FGFR1-4 abnormalities (urothelial, breast, and endometrial), FGFR1 and FGFR2 mRNA were significantly lower in CRC/lung cancers (P < 0.0001 and P = 0.0002, respectively), but there was no significant difference in FGFR3. However, significant overlap is noted. In contrast, FGFR4 was significantly higher in CRC (P < 0.0001). Conclusions: This data suggests that while FGFR1-3 genes are overall expressed in CRC and lung, some cases may have significantly high expression of FGFR1-3 and perhaps these cases should be singled out for treatment with FGFR inhibitors. Furthermore, NGS testing for mutations significantly more efficient and can detect significant number of mutations that can be missed if PCR-based testing is used. NGS testing of DNA and RNA is the most appropriate testing for abnormalities in FGFR1-4.
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.
The effect of hapten on the clinical efficacy and survival of patients with liver cancer treated by UMIPIC.
Authors: Gao Feng , Jing Peng , Liu Jian , Han Wei , Xu Xingyou , Shang Wei , Feng Jianbin , Zhang Peicheng , Zhang Xiaomin , He Guangyong , Wu Yanfei , Yu Baofa
Published: May 2020

e16130

Background: To observe the effect of adjuvant on the clinical efficacy and survival period of patients with liver cancer treated by UMIPIC (Ultra-minimum Incision personalized intratumoral chemoimmunotherapy). Methods: 156 liver cancer patients who were treated with UMIPIC with hapten or without hapten from January 2011 to December 2015 were selected for the study objects, including 124 cases with hapten as studying group and 32 cases without hapten as comparing group. All patients signed the treatment consent, treated according to the treatment guidelines of UMIPIC, followed up for the efficacy and the survival period of all patients more than 3 months, and observed whether there was effect on the clinical efficacy, adverse reactions, survival period and survival rate of patients with liver cancer patients treated with UMIPIC. Results: The common side effects of hapten group were fever 45.16%, pain 27.42%, hemoglobin reduction 14.78%, leucopenia 11.97%, thrombocytopenia 10.26%, liver function damage 5.26%, nausea 4.03%, renal dysfunction 2.61%. No rash, neurotoxicity and hair loss were found; The common adverse reactions in the non hapten group were fever 40.63%, pain 25.00%, hemoglobin reduction 17.24%, leucopenia 13.79%, thrombocytopenia 10.34%, nausea 6.25%. No other adverse reactions were found; there was no difference between the two groups (P > 0.05). The benefit rate of hapten group was 89.06% lower than that of non hapten group (94.74%) (P > 0.05). According to the follow-up results, the mean and median survival time of hapten group was 26.421 and 9.930 months, significantly higher than that of non hapten (16.473 and 7.230 months) (P < 0.05).The 1-year, 2-year, 3-year and 5-year survival rates of adjuvant group respectively were 45.69%, 33.33%, 25.68% and 20.83%,The 1-year, 2-year, 3-year and 5-year survival rates in the adjuvant free group respectively were 27.50%, 20.59%, 14.81% and 14.29%, The 1-year survival rate of hapten group was significantly higher than that of non hapten group (P < 0.05). Conclusions: There is no significant difference in the adverse reactions and clinical efficacy of UMIPIC in the treatment of liver cancer patients with and without hapten. Adding hapten can significantly prolong the survival time and improve the survival rate of patients with liver cancer patients treated with UMIPIC.
Acceptance of preventive colonoscopy in rural areas in Germany.
Authors: Fahlke Joerg , Friedrichs Kai-Stephan , Fahlke Sophie , Habermann Peter , Barroso da Fonseca Lorenz , Lippert Hans , Ridwelski Karsten
Published: May 2020

e16143

Background: Colorectal cancer is one of the most common types of cancer in Germany. Colonoscopy is certainly one of the most efficient diagnostic methods in preventing and early detection of colorectal cancer. Nevertheless, acceptance of colonoscopy as a useful screening method among the population in Germany is moderate, with around 22% of those entitled to claim. Methods: In order to better assess the reasons for the low level of acceptance, patients who presented themselves from March 2016 to June 2017 in the General Surgery Clinic of the Johanniter Hospital Stendal were randomly selected and interviewed using a questionnaire. These randomized patients did not suffer from colorectal cancer. The questionnaire asked whether the patients had participated in Colon Cancer Screening and if not for what reasons. Respondents were asked to choose among 8 preselected reasons or give their own. The options for not having participated in colorectal cancer screening were: lack of knowledge about the offer of colorectal cancer screening, fear of the examination, fear of cancer as an outcome, lack of time for the examination, didn't get an appointment for the exam, place of examination is too far away, excessive travel costs, examination makes no sense, and other (free text entry). Results: A total of 238 questionnaires were completed, 235 of which could be evaluated with regard to gender and age. The proportion between women and men was balanced (m 123, w 112). Surprisingly, contrary to expectations, significantly more respondents participated in colorectal cancer screening than not. There were no differences between females and males. The participation rate in colorectal cancer screening was 71%, which was significantly higher than expected. A significantly lower rate was found in respondents ages between 55 to 60 years old, with 41% of men and 67% of women having participated in a colorectal screening. Asked specifically about the reasons why they did not take advantage of the preventive medical check-up, the men of the affected age group (55-60 years) gave: fear of the examination, fear of cancer as an outcome, and examination makes no sense. Conclusions: The results underline the importance of determining why the acceptance of colorectal cancer screening has not yet reached the desired level. Considering and discussing these three main reasons show that there are opportunities to continuously increase awareness of the importance of participation rates in colonoscopy as a screening method for colorectal cancer through target public education.
Referral-to-treatment attrition and its impact on outcomes of patients with advanced gastroesophageal cancers.
Authors: Peng Jenny , Batra Atul , Cheung Winson Y.
Published: May 2020

e16504

Background: Advanced gastroesophageal cancers (AGCs) are aggressive tumors. Prior research has demonstrated that patients with poor prognostic cancers are inconsistently or infrequently referred to oncology specialists because of misperceptions that oncologic treatments are futile and do not alter overall outcomes. The aim of this real-world study was to characterize the attrition of patients with AGCs as they proceed through the diagnostic-therapeutic pathway and to assess its impact on survival. Methods: A retrospective population-based analysis was performed using data from the cancer registry and electronic medical records in a large province (Alberta, Canada). Patients diagnosed with AGCs from 2010 to 2017 were included. Details on demographics, setting of referral (outpatient or inpatient), time from referral to consultation to treatment, and modality of treatment (best supportive care, systemic therapy, and/or radiation) were collected. Logistic regression was used to determine factors associated with referral. Cox regression models were constructed to determine factors associated with overall survival (OS). Results: We identified 1,244 patients, of whom 633 (51%) had gastric and 611 (49%) had esophageal cancer. Median age was 67 years (IQR 58-78 years) and 72% were men. In this cohort, 87% were referred to a cancer center, 80% were seen by an oncologist, and only 44% received first-line treatment. Median time from referral to consultation was 13 days and consultation to treatment was 12 days. In logistic regression, advanced age (OR 0.274; 95% CI 0.183-0.412, p<0.0001) and those with a gastric primary (OR 0.437; 95% CI 0.303-0.628, p<0.0001) were less likely to be referred. In Cox regression, receipt of chemotherapy (HR 0.79; 95% CI 0.76-0.83, p<0.0001) and shorter time from consultation to treatment (HR 0.994; 95% CI 0.991-0.997, p<0.0001) were predictive of better OS. The setting of referral (inpatient vs. outpatient) was not significantly associated with OS (HR 1.11; 95% CI 0.85-1.45, p=0.414). Conclusions: Attrition was most significant as patients proceeded from consultation to treatment. Streamlining processes to narrow the consultation to treatment window may increase the number of patients with AGCs who may be eligible for potentially effective therapies or new clinical trials, which can improve their overall outcomes.
Cancer genomics-based screening of new therapeutic targets and biomarkers for esophageal cancer.
Authors: Daigo Yataro , Takano Atsushi , Nakamura Yusuke
Published: May 2020

e16514

Background: Since the number of esophageal cancer patients who show objective response to standard therapies is still small, development of new anti-cancer agents with minimum risk of adverse events and highly precise molecular biomarkers is eagerly awaited. Methods: We have been screening novel therapeutic targets and their companion diagnostics for esophageal cancers as follows; i) To identify up-regulated genes in esophageal cancers by the gene expression profile analysis, ii) To verify the candidate genes for their low expression in normal tissues, iii) To validate the clinicopathological significance of their protein expression by tissue microarray covering 265 esophageal cancers, and iv) To verify their function for the growth of the esophageal cancer cells by siRNAs and gene transfection assays. Results: We identified dozens of candidate oncoproteins and selected a metyltransferase ESOC1 (esophageal cancer-associated oncoprotein 1). Immunohistochemical analysis revealed that ESOC1 positivity was observed in 68.5% of esophageal cancers and associated with tumor size. Moreover ESOC1 expression was an independent prognostic factor for esophageal cancer patients. Suppression of ESOC1 expression by its siRNAs inhibited growth of esophageal cancer cell lines. Introduction of ESOC1 increased the growth activity of mammalian cells, suggesting that ESOC1 is likely to be a prognostic biomarker and therapeutic target for esophageal cancers. Conclusions: Cancer genomics-based approach could be useful for the development of new cancer biomarkers as well as therapeutic targets for small molecules, antibodies, nucleic acid drugs, and immunotherapies.
Is the peritoneal lavage cytology coincided with peritoneal metastasis for gastric cancer?
Authors: Wang Wei , Xiong Wenjun , Peng Yaohui , Li Jin , Huang Haipeng , Zheng Yansheng , Luo Lijie , Wan Jin
Published: May 2020

e16533

Background: Gastric cancer (GC) with peritoneal metastasis (PM) is associated with a poor prognosis. The free cancer cells are the prerequisite of peritoneal metastasis. Peritoneal lavage cytology (PLC) is the main measure to identify the free cancer cells, but its positive rate is relatively low. This study aims to investigate the association between the result PLC and peritoneal metastasis for GC. Methods: From November 2017 to December 2019, 33 patients with GC were confirmed with PM through computerized tomography or diagnostic laparoscopy. The inflow and outflow catheters were inserted laparoscopically in all patients for postoperative hyperthermic intraperitoneal chemotherapy. PLC was performed with at least 200 ml of fluid and examined by measures of cytology and immunocytopathology. Ascites was aspirated if detected or 500 milliliter of normal saline infused the Douglas cavity, para-colic gutters and the right and left sub-phrenic cavity and then aspirated. Results: There were 15 males and 18 females and the median age was 56 (24-84) years old. All patients had a cT4a/cT4b and an N-positive tumor. The overall positive PLC (PLC+) rate was 63.6% (21/33). The distribution of Lauren classification was respectively 5 (15.2%) intestinal, 26 (78.8%) diffused and 2 (6.1%) mixed tumor. The diffused cases had a higher rate of PLC+ ( P = 0.004). All 5 intestinal GC had a negative PLC (PLC-). 71.4% (20/28) of patients with a grade G3/G4 had a PLC+, compared, no PLC+ was recorded in 5 grade G1/G2 patients (P = 0.003). The median peritoneal carcinomatosis index (PCI) was 14 (1-39). The PLC+ rate was 94.7% (18/19) in PCI > = 10 group and 21.4% (3/14) in PCI < 10 group ( P < 0.001). The median ascites was 200 (0-7000) ml. The PLC+ rate was 88.2% 15/17) in ascites > = 200 ml group and 37.5% (6/16) in ascites < 10 ml ( P = 0.002). The median follow-up was 13(1-27) months and the overall survival was 75.8%, but no significance was detected between PLC+ group and PLC- group. Conclusions: The present study suggested that the result of PLC was not completely coincided with PM for GC by measures of cytology and immunocytopathology, especially for intestinal and grade G1/G2 tumor.