bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modifiable and non-modifiable risk factors associated with early-onset colorectal cancer: Analysis of the National Health Interview Survey.
Authors: Kang Hyeun Ah , Zhang Yahan 
Published: June 2022

e15528 Background: The incidence of early-onset colorectal cancer (EO-CRC), colorectal cancer (CRC) diagnosed in individuals younger than 50 years, is rapidly increasing in the United States. However, risk factors for EO-CRC are poorly understood. Identifying potential risk factors using population-based health data is critical to identify at-risk populations and develop cost-effective screening guidelines and other prevention strategies. This study aimed to identify potential modifiable and non-modifiable risk factors associated with EO-CRC. Methods: This cross-sectional study used data from 2004-2018 National Health Interview Survey (NHIS), a nationally representative health information of US population collected through personal household interviews. Individuals who were at an age of 18-49 years and had a history of CRC diagnosis at the time of the interview were identified as patients with EO-CRC, and their demographic, clinical, and behavioral characteristics were compared with those of non-cancer young adult (18-49 years) population. In addition, their non-age-related characteristics (gender, race/ethnicity, region, and body mass index [BMI]) were compared with those of individuals who were diagnosed with CRC at age 50 or older (late-onset CRC; LO-CRC). For both comparisons, bivariate and multivariable logistic regression (proc surveylogistic) analyses were performed. Results: We identified 156 patients with EO-CRC (weighted: 105,300; 46.4% female; mean age = 41.8 [SE = 0.69]), 204,846 with non-cancer (weighted: 126,257,662; 50.7% female; mean age = 33.6 [SE = 0.05]), and 1,972 with LO-CRC (weighted: 920,231; 48.6% female; mean age = 72.6 [SE = 0.28]). Results from the comparison between patients with EO-CRC and non-cancer population showed that higher odds of having EO-CRC were associated with older age (Odds Ratio [OR] = 1.11; 95% CI = 1.08–1.14), living in Midwest (vs. South; OR = 1.64, 95% CI = 1.06 – 2.55), and history of alcohol consumption (vs. lifetime abstainer; OR = 2.09, 95% CI = 1.01 – 4.36). Lower odds of having EO-CRC were associated with being Hispanic or Asian (vs. non-Hispanic White; OR = 0.43, 95% CI = 0.22 – 0.84 and OR = 0.38, 95% CI = 0.16 – 0.92, respectively) and doing vigorous physical activity (vs. no activity; OR = 0.34; 95% CI = 0.21 – 0.55). Gender, BMI, diabetes, and smoking were not significantly different between the two groups. Compared with patients with LO-CRC, those with EO-CRC were more likely to be Hispanic (vs. non-Hispanic White; OR = 2.21, 95% CI = 1.14 – 4.31) and live in Midwest (vs. South; OR = 1.62, 95% CI = 1.02 – 2.58). Gender and BMI were not significantly different between the two groups. Conclusions: In this cross-sectional population-based study, we identified potential modifiable (alcohol consumption and physical activity) and non-modifiable (age, race/ethnicity, and region) risk factors associated with EO-CRC.
Identifying potential glycoproteomic biomarkers for diagnosis of colorectal cancer (CRC).
Authors: Lindpaintner Klaus , Desai Khushbu , Xu Gege , Rice Rachel , Castellanos Alyn , Serie Danie , Mitchell Alan 
Published: June 2022

e15529 Background: Excluding skin cancers, colorectal cancer is the third most common cancer diagnosed in both men and women in the United States. Colorectal cancer (CRC) affects men and women of all racial and ethnic groups and is most often found in people who are 50 years old or older. To aid diagnosis and improve screening for CRC, this study focuses on identifying glycoprotein biomarkers using blood serum. Methods: Novel methods including liquid-chromatography/mass-spectrometry (LC-MS) with in-house peak integration software PB-Net were used to identify glycoprotein biomarkers by analyzing blood serum. Samples were sourced from different biorepositories including 245 CRC, 38 adenoma and 196 healthy controls. The data were split into 75% training and 25% hold-out test set for multivariable predictions. Statistical analysis was performed on normalized data to identify potential biomarkers differentiating adenoma and different stages of CRC samples from the healthy controls. Results: There were 419 significantly differentially expressed glycopeptides/peptides from comparisons between CRC and adenoma samples against the healthy control samples with an FDR < 0.05. A subset of these biomarkers were assessed, generating a 21-biomarker multivariable classifier model. We observed a test set AUC of 0.926, and the sensitivity for all stages of CRC was 90% (87% early stage, 92% late stage). Notably, sensitivity for adenomas was 79%, a large improvement upon the state of the art in adenoma diagnosis. Conclusions: Identification of these key glycopeptides/peptides in blood serum could prove to be a promising non-invasive diagnostic tool that can help improve screening and aid in early detection of advanced adenomas and CRC.
Deep neural networks and association with inpatient survival for patients admitted to the hospital with colon cancer undergoing open colectomy.
Authors: Baig Aqsa , Khawaja Uzzam Ahmed , Khan Ayesha Liaquat , Khalil Mohammad Hamza , Ali Syed Musadiq , Qaudri Syed Abdul-Qader , Tariq Tooba , Irfan Furqan Bin , Ahmed Fahad Shabbir 
Published: June 2022

e15537 Background: During hospitalization for colectomy patients with colon cancer may be at risk for mortality due to several reasons including underlying cancer, other comorbidities or age. Our aim was to develop a machine learning algorithm to predict end of admission mortality in patients undergoing colectomy for their cancer. We hypothesized that machine learning could be applied to patients undergoing open colectomy as part of their colon cancer treatment. Methods: All adult patients (> 18 years) for the National in-patient Services (NIS) database 2014 was used to develop our algorithm. We extracted all patients with a diagnosis of cancer using the ICD-9 codes and all patients that underwent colectomy. We conducted a multivariate analysis to look at the risk factors that dictate mortality in these patients. We also developed a linear regression model and a deep learning algorithm to predict mortality in these patients. Results: We identified a total of 4120 patients that underwent open colectomy with colon cancer in the NIS 2014. We observed that several clinical and lab-based parameters were statistically significant for multivariate analyses while others were not. With most significant being all patients refined diagnosis related groups (APRDRG) risk mortality (HR = 6.20, 95%CI = 4.10-9.36), APRDRG severity (HR = 4.78, 95%CI = 3.27-7.00), chronic anemia (HR = 0.61, 95%CI = 0.40-0.94), coagulation disorders (HR = 2.32, 95%CI = 1.31-4.10), chronic electrolytes disorders (HR = 2.12, 95%CI = 1.39-3.24), neurological disorders (HR = 1.92, 95%CI = 1.11-3.32), underweight (low BMI) (HR = 2.40, 95%CI = 1.05-5.48), Hyperkalemia (HR = 2.40, 95%CI = 1.28-4.50), Acidosis (HR = 4.04, 95%CI = 2.64-6.19). In the machine learning analysis, we found out that our proposed DNN outperformed the RF with test set accuracy of 91.1%, sensitivity of 88.5%, specificity 91.2%, PPV of 24.7, NPV of 99.5% and AUROC of 0.968 [95%CI = 0.08-.014]. Conclusions: Our novel DNN model outperformed RF classifier models. The model is easy to implement, user friendly and with good accuracy. However, further external validation of the model is required.
Natural distribution of genomic alterations correlated with the resistance to KRASG12C inhibitor in Chinese colorectal cancer.
Authors: He Ke , Chen Yuerong , Liu Fei , Li Liheng , Wu Chaosheng , Lv Xiu , Liu Xinyi 
Published: June 2022

e15550 Background: KRAS inhibitors exhibited promising efficacy as systemic therapy in KRAS G12C-mutant colorectal cancers (CRC) lately. Recent studies have revealed a number of genomic alterations related to acquired resistance to this type of drugs. The discovered resistant gene mutations include: 1. Novel acquired secondary KRAS mutations within the adagrasib-binding pocket such as Y96C, H95D/Q/R, R68S, 2. Activating mutations in genes ( KRAS, BRAF, MAP2K1) MAPK signaling pathway, 3. Oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3, 4. Gene amplifications in KRAS, MET, MYC. Although found as acquired resistance mechanism to KRAS inhibitors, these genomic alterations might be primary or secondary in the setting of other type of therapies. Characterizing the natural distribution of these genomic alterations in cancer patients would contribute to clarifying the application potential of KRAS inhibitors. We herein performed a large-sample size analysis in Chinese colorectal cancer. Methods: A total of 9385 early-stage, late-stage, treated or treatment-naive CRC were included in this analysis. Calling of single nucleotide variants (SNV), copy number variants (CNV), insertion/deletions (indels), fusions and evaluation of tumor mutational burden (TMB) were performed using a wide panel next-generation sequencing (NGS) testing. Results: 43.4% (4069/9385) cases were KRAS-mutant in this cohort. KRAS G12C account for 5.8% (236/4069) in all KRAS-mutant CRC, and 15.7% (37/236) were harbored the above resistance genomic alterations. Fifteen KRAS G12C-mutant CRC were detected to have activating MAPK mutations, including G12D/V (n = 6), G13D (n = 3), Q61H (n = 6), NRAS Q61K (n = 3), MAP2K1 K57T (n = 3), and BRAF V600E (n = 4). Ten KRAS G12C-mutant CRC were detected to have oncogenic fusions, including TGFBR2- CACNA1D (n = 3), TPM4- ALK (n = 1), FGFR3- TACC3 (n = 1), ETV6- SNRPC (n = 1), KAZN- PAX7 (n = 1), NRG1- TTC12 (n = 1), TCF7L2- EWSR1 (n = 1) and ERBB2 arrangement (n = 2). It is noteworthy that a single case was with 5 gene arrangement events in 17q ( ERBB2- ZPBP2, IKZF3- ERBB2, PGAP3- ERBB2, RARA- ERBB2, RARA- GRB7). Thirteen KRAS G12C-mutant CRC were detected to have amplifications in KRAS (n = 5), MYC (n = 5) and MET (n = 4) genes. TP53 (81%), APC (65%) and PIK3CA (32%) were the utmost frequent somatic mutational genes in this subgroup of CRC. In addition, all cases were microsatellite stable (MSS). Tumors harboring fusion variants showed relatively high TMB level in this cohort. Conclusions: Our analysis results indicate about 15% KRAS G12C-mutant Chinese CRC were probable resistant to KRASG12C inhibitor. One-third of these patients had co-existed oncogenic fusions and higher TMB levels, suggesting possibilities for other therapeutic choices.
Mutational profiles of sporadic synchronous colorectal cancer.
Authors: Yang Lu-Ping , Jiang Teng-Jia , He Ming-ming , Zhao Qi , Ling Yihong , Wang Zi-xian , Wu Hao-Xiang , Jin Ying , Zhang Zhen , Xu Rui-hua , Wang Feng 
Published: June 2022

e15555 Background: Synchronous colorectal cancer (SCRC) refers to a special group of CRC with at least two primary tumors detected simultaneously in one patient, with 90% being sporadic. Although the systemic treatments of late-stage SCRC are mainly based on the molecular testing of one primary lesion, this might not be representable of the other tumors and metastatic lesions. This study aimed to investigate the molecular features and genetic heterogeneity of sporadic SCRC in order to guide clinical practice. Methods: We retrospectively collected all the primary tumor samples of 51 patients with sporadic SCRC, profiled 103 samples with whole-exome sequencing, and analyzed their molecular landscape and genomic profiles. We conducted comparative analyses between tumor pairs in one patient, and as well as between SCRC and solitary CRC. The evolutionary dynamics of SCRC tumors was also analyzed. Results: Most gene mutations and copy number variations were inconsistent in paired tumors except for early driving genes APC, TP53 and KRAS. No pathogenic germline variants of familial CRC-related genes were observed . Clonal composition analysis showed that tumors in 94.2% (48/51) of patients with SCRC were genetically heterogeneous. Only 7.8% (4/51) of patients harbored origin-shared tumors. Inconsistent MSI and TMB status were observed in 11.8% (6/51) of patients. For actionable RAS/ BRAF gene loci, 43.1% (22/51) of patients harbored tumor pairs sharing the same wild or mutant status. When compared with solitary CRC, SCRC had higher prevalence of MSI-H (29.4% vs. 12.0-17.0%) or TMB-H (33.3% vs. 10.0-16.0%) and lower mutational frequencies in the RTK/RAS (51.5% vs. 76.1%), PI3K (26.2% vs. 43.4%) and cell-cycle (2.9% vs. 10.2%) oncogenic signaling pathways. Moreover, neutral evolution analysis showed that 84.3% (43/51) of patients had at least one neutral tumor and 45.1% (23/51) of patients had tumors evolving differently. Conclusions: Sporadic SCRC was a special subclass of CRC, featured by prominent TMB-H, dMMR-related signatures, and intertumoral genetic heterogeneity. The tumors from the same SCRC patient tended to have different origins and evolved differently. Thus, clinical treatment strategies for sporadic SCRC should be re-evaluated accordingly.
Landscape of DNA damage response gene mutations in microsatellite-stable colorectal carcinoma.
Authors: Zhong Zhaoyang , Jiang Nan , Zhou Jinming , Shen Lu , Chen Rongrong 
Published: June 2022

e15558 Background: Colorectal carcinoma (CRC) is one of the most frequent and lethal cancers in the world. Important therapeutic progress of immune checkpoint inhibitors (ICIs) is limited to molecular niche of CRC with microsatellite-stable(MSS). The identification of genomic alterations in the DNA damage response (DDR) pathway have been recognized as pathogenic factors in hereditary cancer predisposition. Few studies showed the effects of ICIs on DDR pathway in patients with MSS CRC. Some reports suggested that DDR could reshape tumor immune microenvironment by regulating tissue repair and local immune response. Here we evaluated the molecular roles of DDR pathway and the immune microenvironment in efficacy of immunotherapy in MSS CRC. Methods: A total of 67 patients with MSS CRC were enrolled into the study. All samples were collected and detected by using NGS with a 1021 gene panel which containing 56 DDR genes (Supplementary table 1). Furthermore, comprehensive bioinformatics analysis were performed by the TCGA and MSK data. We defined pathway alteration as at least one gene in DDR pathway mutated. Results: In our results, three DDR pathway alteration showed poor prognosis (P = 0.0167) compared with DDR wild type in TCGA data (Figure 1A). The MSK data demonstrated that three DDR pathway alteration were associated with a better prognosis in MSS CRC patients through ICIs therapy (P = 0.0416, P = 0.00627, respectively, Figure 1B). The clinical data suggested the patient with DDR pathway alteration had longer OS (354.7 ± 134.0 days, PR) than the others with DDR wild type (247.1± 258.4 days, PD/SD) after PD-1-targeted therapies (P = 1.587e-08). Moreover, the patient with DDR pathway alteration showed significant longer PFS (312.3 ± 179.2 days, PR) compared with DDR wild type (163.3 ± 157.7 days, PD/SD) through immune therapies (P = 4.249e-10). Moreover, significant results of immune infiltrate deconvolution revealed resting memory CD4+ T cells were the most prevalent population between DDR pathway alteration and DDR wild type using CIBERSORT analysis (P = 0.0295, Figure 1C). The activated memory CD4+ T cells in DDR pathway alteration were lower than DDR wild type (P = 0.00858, Figure 1C-D) in patients with MSS CRC. The effects of DDR pathway alteration on immune microenvironment was also necessary for effective PD-1-targeted therapy in future study. Our results suggest that two or more DDR pathways and CD4 + T cells may serve as immunotherapy markers for advanced MSS colorectal cancer. Conclusions: Mutations in DDR pathway may serve as a biomarker for PD-1-targeted therapy through memory CD4+ T cells for MSS CRC patients, which warrants further studies.
EPHB1 mutation predicts survival from treatment with immune checkpoint inhibitors and correlated with higher TMB and immune infiltrates in mCRC.
Authors: Cai Jinlin , Fan Dandan , Chen Yaoxu , Huang Mengli 
Published: June 2022

e15559 Background: Colorectal cancer has become a common gastrointestinal tumor. Immune checkpoint inhibitors (ICIs) including pembrolizumab, nivolumab, ipilimumab have shown durable responses and have been approved by FDA. However, ICIs demonstrate antitumor effects only in a fraction of patients, the research exploring the association between gene mutation and clinical benefit is limited. Studies have shown that EPHB1 mutation in the NK cell-related pathway involved in the anti-cancer immune response and associated with survival of NSCLC patients, suggested that EPHB1 may be related to immune microenvironment and tumor immunity. However, the association between EPHB1 mutation and TMB or survival in metastatic Colorectal Cancer (mCRC) is unknown. Methods: Genomic and survival data of mCRC patients administrated with ICIs was retrieved from publicly accessible data(Pancancer.Samstein2018.NGS.1661),the association between EPHB1 mutation and overall survival(OS) was analyzed using Kaplan-Meier curves and log-rank tests. At the same time，the association between EPHB1 mutation and TMB was also analyzed in this public immunotherapy-treated cohort, Wilcoxon test was used for the comparison of TMB. In addition, genome and immune cell infiltration data of 149 patients with Colon Adenocarcinoma (COAD) was obtained from The Cancer Genome Atlas (TCGA). The correlation analysis between immune cell infiltration and EPHB1 mutation status was further analyzed by CIBERSORT-ABS. Statistical significance was set at p = 0.05. Results: 7.3%(8/109) patients in the clinical cohort harbored EPHB1 mutation. Survival analysis in the public cohort demonstrated that EPHB1 mutation resulted in significantly longer OS (14 vs 8 months; HR, 0; p = 0.03) in mCRC patients treated with ICIs. Moreover, EPHB1 mutation was associated with higher TMB in public cohort (p = 0.0004). Furthermore, the correlation analysis between immune infiltration and EPHB1 mutation status in mCRC showed that CD8+T cells, activated memorial CD4+T Cell, M1 macrophages increased significantly in EPHB1 mutation patients(p = 0.023, p = 0.0079, p = 0.034). Conclusions: EPHB1 mutation may serve as a potential positive biomarker of ICIs in mCRC since it relatively correlated with higher TMB. In addition, the up regulation of CD8+T cells, activated Memorial CD4+T Cell as well as the M1 macrophages may be a potential mechanism for the better efficacy of ICIs in patients with EPHB1 mutation.
A phase I clinical trial of trametinib in combination with TAS-102 in patients with chemotherapy-resistant RAS-mutated (PIK3CA/PTEN-wild type) metastatic colorectal cancer.
Authors: Chuang Jeremy , Gong Jun , Li Sierra , Wang Chongkai , Fakih Marwan 
Published: June 2022

e15579 Background: TAS-102 was approved in 2015 after the phase III RECOURSE clinical trial demonstrated a modest improvement in overall survival in refractory metastatic colorectal cancer (mCRC). Preclinical models have shown synergistic activity between MEK inhibitors and TAS-102 in RAS-mutant (MT) and PIK3CA/PTEN wild-type (WT) models . We conducted a phase I study of trametinib plus TAS-102 in this molecularly selected refractory metastatic colorectal cancer patient population to explore the safety and efficacy of this combination. Methods: A 3+3 dose de-escalation single arm phase I clinical trial was performed in patients with mCRC who progressed on prior standard therapies but with no prior TAS-102 exposure. Patients received fixed dosing of trametinib 2mg oral daily along with de-escalating doses of TAS-102 beginning at 35 mg/m2 twice daily on days 1-5 and days 8-12 every 28 days. The primary endpoint of this study was to evaluate the maximum tolerated dose (MTD). Secondary objectives included an assessment of safety and toxicity of the combination regimen by CTCAE version 4.0 and any evidence of clinical activity including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) with this combination per RECIST guideline 1.1. Results: Between March 21, 2018, to March 19, 2020, 25 eligible patients were enrolled in this study. MTD was determined to be TAS-102 35 mg/m2 orally twice daily on days 1-5 and days 8-12 every 28 days with continuous trametinib dosing at 2mg orally daily. No patients achieved a partial or complete response. 5 of 21 evaluable patients (23.81%) achieved a stable disease response. Median PFS was 2 months (95% confidence interval (CI) 1.70-4.82) while median OS was 7 months (95% CI 6.36-11.48). Treatments were well tolerated with most common grade ≥ 3 adverse events being anemia (20%), neutropenia (12%), leukopenia (8%), diarrhea (8%), rash (4%), and fatigue (4%). Conclusions: Trametinib in combination with TAS-102 demonstrated a manageable safety profile however did not achieve meaningful clinical benefit in patients with RAS-MT and PIK3CA / PTEN-WT refractory mCRC. Research sponsor: Novartis. Clinical trial information: NCT03317119.
The professional seniority affects the clinical application of total neoadjuvant therapy for locally advanced rectal cancer.
Authors: Şenocak Taşçi Elif , Aytac Erman , Ajredini Mırac , Mutlu Arda Ulaş , Yildiz Ibrahim , Ozer Leyla 
Published: June 2022

e15590 Background: Total neoadjuvant therapy (TNT) integrates whole planned systemic chemotherapy within standard neoadjuvant protocols either before or after radiotherapy for locally advanced rectal cancer (LARC). Preference of neoadjuvant treatment type may vary among the medical oncologists. This study aimed to evaluate impact of professional seniority on TNT approach for LARC. Methods: A 20-item questionnaire was presented to medical oncologists as a cross-sectional survey during a national oncology congress via tablets. The evaluation was stratified by position; early-career oncologists (ECOs) and seniors. 2 questions were about experience regarding rectal cancer treatment. 5 questions were about physicians’ choice of screening and treatment in LARC and the factors affecting their treatment choices. 13 questions were about TNT approach (the sequencing of treatment, denominators of sequencing, chemotherapy choice, treatment response evaluation, operation preferences, adjuvant treatment and its denominators). Results: 189 medical oncologists were included (62.4% (n = 118) ECOs). An endorectal ultrasound was significantly preferred by the seniors (p = 0.039) in addition to conventional staging tools. 65.6% (n = 124) of the participants preferred long-course chemoradiation as their favorite neoadjuvant treatment approach. External sphincter invasion, threatened circumferential resection margin (CRM) and clinical stage were the most common denominators of TNT regardless of experience. ECOs favored short-course RT (p = 0.009) while the seniors chose long-course chemoradiotherapy (p = 0.041) as the index step of TNT. 57% (n = 108) of the physicians preferred to monitor treatment response for TNT at 8-weeks periods. Almost half of the participants (47.1%) reported pathological complete response (pCR) rates between 25-50% with TNT in their clinical practice. The physicians who prefer to give adjuvant treatment after completion of TNT make individualized decisions when surgical pathology reveals non-pCR, CRM and lymph node involvement. There was a significant difference between the ECOs and seniors (63.6 vs 45.1%, p = 0.013) in terms of choosing the adjuvant chemotherapy based on CRM positivity. Majority of the senior medical oncologists (88%) and ECOs (76.3%) agree that TNT should be the standardized neoadjuvant treatment approach for LARC. The preferred adjuvant chemotherapy after TNT was capecitabine-oxaliplatin (51.1%) or capecitabine alone (46%). Conclusions: TNT for LARC is well accepted among the medical oncologists and the professional seniority seems to affect its clinical application.