bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human papillomavirus, radiation dose and survival of patients with anal cancer.
Authors: Kabarriti Rafi , Brodin Patrik , Ohri Nitin , Narang Rahul , Huang Renee , Chuy Jennifer W. , Rajdev Lakshmi , Kalnicki Shalom , Guha Chandan , Garg Madhur 
Published: May 2019

e15071 Background: To determine if anal cancer patients with HPV positive disease have different overall survival (OS) compared to those with HPV negative disease, and to elucidate differences in the association between radiation dose and OS. Methods: We utilized the National Cancer Database (NCDB) registry to identify a cohort of non-metastatic anal cancer patients treated with curative intent between 2008 – 2015. Propensity score matching was used to account for potential selection bias between patients with HPV positive and negative disease. Multivariable Cox regression was used to determine the association between HPV status and OS. Kaplan-Meier methods were used to compare actuarial survival estimates. Results: We identified 5,927 patients with tumor HPV status for this analysis, 3,523 (59.4%) had HPV positive disease and 2,404 (40.6%) had HPV negative disease. Propensity-matched analysis demonstrated that patients with HPV positive locally advanced (T3-4 or node positive) anal cancer had better OS (HR=0.81 (95%CI: 0.68-0.96), p=0.018). For patients with early stage disease (T1-2 and node negative) there was no difference in OS (HR=1.11 (95%CI:0.86-1.43), p=0.43). In the unmatched cohort, there was an increase in 3-year OS for patients with HPV positive tumors or early stage disease up to 45-49.9 Gy (p<0.001), whereas for patients with HPV negative and locally advanced disease there was an increase in survival from 46% at 30-44.9 Gy, to 64% at 45-49.9 Gy (p=0.093) and further to 71% at 50-54.9 Gy (p=0.005). Conclusions: We found HPV to be a significant prognostic marker in anal tumors, especially for locally advanced disease. We further found that higher radiation dose up to 50-55 Gy was associated with better OS, mainly for locally advanced disease in HPV negative patients. Multivariable Cox proportional hazards regression for OS. [Table: see text]
Analytical and clinical validation of a novel amplicon-based NGS assay for evaluation of circulating tumor DNA in metastatic colorectal cancer patients.
Authors: Wang Beili , Wu Shengchao , Huang Fei , Shen Minna , Jiang Huiqin , Yu Yiyi , Yu Qian , Yang Yihui , Zhao Ying , Zhou Yiwen , Pan Baishen , Liu Tianshu , Guo Wei 
Published: May 2019

e15084 Background: Evaluating the tumor RAS/BRAF status is important for treatment selection and prognosis assessment in metastatic colorectal cancer (mCRC) patients. Correction of artifacts from library preparation and sequencing is essential for accurately analyzing circulating tumor DNA (ctDNA) mutations. Here, we assessed the analytical and clinical performance of a novel amplicon-based next-generation sequencing (NGS) assay, Firefly, which employs a concatemer-based error correction strategy. Methods: Firefly assay targeting KRAS/NRAS/BRAF/PIK3CA was evaluated using cfDNA reference standards and cfDNA samples from 184 mCRC patients. Plasma results were compared to the mutation status determined by ARMS-based PCR from matched tissue. For samples with mutation abundance below the limit of detection (LOD), were retested again by droplet digital polymerase chain reaction (ddPCR) or NGS. Results: Firefly assay demonstrated superior sensitivity and specificity with 98.89% detection rate at allele frequency of 0.2% for 20ng cfDNA. Generally, 40.76% and 48.37% of the patients were reported to be positive by NGS of plasma cfDNA and ARMS of FFPE tissue, respectively. The concordance rate between the two platforms was 80.11%. In pre-treatment cohort, the concordance rate between plasma and tissue was 93.33%, based on the 17 common exons that Firefly and ARMS genotyped, positive percent agreement (PPA), and negative percent agreement (NPA) for KRAS/NRAS/BRAF/PIK3CA was 100% and 99.60%, respectively. Conclusions: Total plasma cfDNA detected by Firefly offers a viable complement for mutation profiling in CRC patients, given highly agreement with matched tumor samples. Together, these data demonstrate that Firefly could be routinely applied for clinical applications in mCRC patients.
Real-world study of cetuximab used every other week versus weekly in US patients with metastatic colorectal cancer (mCRC).
Authors: Lamy Francois-Xavier , Batech Michael , Salim Shaista , Boutmy Emmanuelle , Pescott Chris , Ronga Philippe 
Published: May 2019

e15087 Background: After an initial dose of 400 mg/m², cetuximab (CET) at a dose of 250 mg/m² in combination with chemotherapy (CT) is approved for once-weekly (q1w) use in the treatment of RAS wild-type metastatic colorectal cancer (mCRC). However, off-label use of CET 500 mg/m2 administered every other week (q2w) has been observed in clinical practice. This study aimed to test the noninferiority of q2w vs q1w administration on overall survival (OS) using US claims data. Methods: Using IBM MarketScan, a large US insurance claims database, a cohort of patients with mCRC treated with CET + CT between 2010 and 2016 was identified and classified as q1w or q2w based on observed infusion patterns. The initial CET prescription was defined as the index date, and patient death was determined using a previously published algorithm. Confounding was accounted for using high-dimensional propensity scoring (hdPS) methodology with inverse probability of treatment weighting (IPTW). OS for both groups was compared using Cox proportional hazards regression. Confounders that remained imbalanced after hdPS with IPTW were added to the Cox model. The noninferiority of the q2w regimen was tested with a margin hazard ratio (HR) of 1.25 for q2w vs q1w. Results: 2,869 patients with mCRC exposed to CET were identified of which 1,865 (65.0%) and 1,004 (35.0%) were classified in the q1w and q2w groups, respectively. The mean age of patients was 60.1±11.7 years for q1w and 58.1±11.1 years for q2w. Most patients were male: 57.5% and 60.8% in q1w and q2w, respectively. Approximately 70% of patients in both groups had received prior treatment for mCRC. The most frequently used CT with CET was irinotecan based (64.5% in q1w and 76.5% in q2w). There were 1,628 deaths observed during follow-up (56.7%). After hdPS with IPTW adjustment, differences remained in associated CT (standardized difference <0.25). Crude HR for OS was 1.05 (95% CI, 0.94-1.18), and adjusted HR for OS was 1.04 (95% CI, 0.93-1.17). The inferiority hypothesis was rejected at p<0.001. Conclusions: In this large US claims database, when assessing OS, the q2w administration schedule was found to be noninferior to the q1w schedule in patients with mCRC.
The study of the significance and prognosis of the differential expressed miRNAs and their target genes associated with biological in colorectal cancer.
Authors: Wang Mingyun , Yang Mi 
Published: May 2019

e15088 Background: MicroRNAs (miRNAs) have been related to prognostic indicators (such as stage and survival) in colorectal cancer. This study aimed to identify differentially expressed miRNAs and their target genes associated with biological significance and prognosis in colorectal cancer. Methods: The colorectal cancer, colorectal adenoma, and normal samples were obtained from the gene expression profile of GSE71187. A union of differentially expressed genes (DEGs) in the three groups was identified. The significantly different modules with highly interconnected DEGs were identified using weighted correlation network analysis (WGCNA) and were enriched to the KEGG pathway and GO function. Subsequently, the protein-protein interaction (PPI) network for DEGs in the module and the integrated regulatory network of miRNA-DEGs were constructed. In addition, the relationship of target DEGs and prognostic information was analyzed. Results: Three significantly different modules were identified, such as the brown, turquoise, and grey modules. The turquoise module including LTC4S, KLRK1, UNC5C, etc., which was mainly enriched to cell adhesion, cytokine−cytokine receptor interaction, and chemokine signaling pathway, inhibited the development of colorectal cancer. Subsequently, PPI network was constructed with the 678 DEGs in the three modules. Moreover, the miRNA-DEGs network was constructed with the 17 target DEGs (CXCR1, LTC4S, BTK, IGF1, etc.) and 14 miRNA (hsa-miR-335-5p, etc.). Finally, the overexpressed LTC4S was a good prognostic biomarker for colorectal cancer. Conclusions: The hsa-miR-335-5p might have potential prognosis value by targeting LTC4S and CXCR1 in colorectal cancer.
Racial disparities in clinico-pathological features and survival rates of early-onset colorectal cancer.
Authors: Acuna Villaorduna Ana , Kaumaya Meghan , Goel Sanjay 
Published: May 2019

e15089 Background: Early-onset colorectal cancer (EO-CRC) incidence is increasing disproportionately among minorities compared to Non-Hispanic Whites (NHW). EO-CRC have aggressive features such as higher grade and advanced stages. The appropriate age to start screening colonoscopy (SC) in NHW and minorities remains controversial; varying between 45 and 50 years old. We aim to compare EO-CRC clinico-pathological characteristics and survival rates by race groups. Methods: Patients with colorectal adenocarcinoma (CRC) with available race and stage as per AJCC 6th edition were identified using the SEER registry (1973-2010). EO-CRC was defined as CRC before age 50 years. Clinico-pathological features, overall survival (OS) by Kaplan Meier curves and mortality predictors by multivariate analysis were evaluated by race groups. Results: 180 605 patients with CRC were identified; 10.2% had EO-CRC. Mean age of diagnosis was 42.7 years and EO-CRC frequency was higher in minorities (Hispanics (H):16.7%, Non-Hispanic Black (NHB):12.7% and Asian (A): 12.8%) compared to NHW (8.7%). EO-CRC in NHB was predominantly seen in females. The rectum was the most common location for all races. Two-thirds of tumors were located between the sigmoid and anal regions in all races except NHB that had higher frequencies of right-sided tumors. Compared to other races, NHB had worse OS at all stages and tumor locations. NHB was associated with 72% increased risk of death by multivariate analysis. Conclusions: Our data suggest that EO-CRC frequency, pathological features and OS differ by race group; hence SC guidelines should be tailored accordingly. SC would be considered early; especially in minorities. Complete colonoscopy should be considered for NHB given higher rates of right-sided tumors and worse OS; while sigmoidoscopy may be adequate for others up to age 50, given higher rates of tumors located in the sigmoid to anal region. [Table: see text]
Toxicity of chemotherapy in patients with colorectal cancer: The role of age in the Latin American setting.
Authors: Namuche Fernando , Montenegro Paola Catherine , Leon Jorge , Flores Claudio J. 
Published: May 2019

e15095 Background: The incidence of colorectal cancer (CRC) in Peru has increased in the last decades. In our country, the toxicities of systemic treatment have not been analyzed in a large population in the different disease settings. Numerous clinical studies have shown an association between toxicities and age, type of chemotherapy, number of courses, and others. Our objective was to explore the toxicities presented in our population and find if any variables could help us predict these toxicities. Methods: We retrospectively reviewed the electronic medical records of 371 patients with CRC from one specialized Peruvian cancer center between 2006 and 2016. Descriptive results for numeric variables were presented as means with standard deviation (SD) or medians with interquartile range (IQR), depending on their distributions; otherwise, we expressed the qualitative variables as numbers with percentages. The primary outcome measure was if the patient developed toxicity ≥3 assessed with multiple variables: age, sex, tumor location, NLR, PLR, pathological stage group (PSG), type of chemotherapy (CT), liver metastases, metastasectomy performed, albumin level, CEA, nodal involvement, time to CT, number of CT courses. Multivariable analysis in logistic regression model was adjusted for the factors statistically significant in the univariable analysis. Results: A total of 371 patients were included, of which 95 (25.6%) developed a ≥3 grade toxicity. The more frequent toxicity was neuropathy (30.5%). Univariate logistic regression analysis showed that age, albumin level, PSG, time to CT, number of CT courses, type of chemotherapy (CT), tumor location and liver metastases were associated with a ≥3 grade toxicity. Furthermore, multivariate regression analysis demonstrated that stage IV [OR, 0.012; 95% CI, 0.002-0.078; p < 0.001], age ≥70 [OR, 3.475; 95% CI,1.818-6.643; p < 0.001], number of courses [OR, 0.839; 95% CI, 0.763-0.922; p < 0.001] and albumin levels [OR, 0.391; 95% CI,0.257-0.596; p < 0.001]were independently risk factors for ≥3 grade toxicity. Conclusions: Stage IV, age ≥70, a greater number of CT courses and lower albumin levels were independently associated with a ≥3 grade toxicity.
Spatial heterogeneity of KRAS mutations in colorectal cancers: A population-based study in northern France.
Authors: Ploquin Anne , Genin Michael , Hebbar Mohamed , Occelli Florent , Lanier Caroline , Decarpentries Clotilde , Pannier Diane , Turpin Anthony 
Published: May 2019

e15101 Background: Somatic mutations in the KRAS gene are present in about 40% of tumors from colorectal cancer (CRC) patients and are associated with a resistance to anti-EGFR therapies. However, no clinical features have been linked to KRAS mutations in CRC. In this study, we attempted to identify the potential geographical population clusters of KRAS mutations in CRC patients in northern France. Methods: All patients with CRC who were identified to have KRAS mutations performed by pyrosequencing between 2008 and 2014 at the Regional Molecular Biology Platform at Lille University Hospital were included. We retrospectively collected demographic and geographic data from these patients. The proportions of KRAS mutation were smoothed to take into account the variability related to low frequencies and spatial autocorrelation. Geographical clusters were searched using spatial scan statistical models. Then, we made an ecological study. Results: 2,486 patients underwent a KRAS status available. A mutation of KRAS codon 12 or 13 performed by pyrosequencing was found in 1,018 patients (40.9%). We report 5 clusters of over-incidence but only one elongated cluster that was statistically significant ranging from the city of Tourcoing to the city of Marquion (Cluster 1; smoothed proportion of KRAS mutation: 0.4570; RR = 1.29; p = 0.0314). The ecological study did not highlight a significant association between KRAS mutations and the distance to the Closest Waste Incineration Plant , and between KRAS mutations and The French Ecological Deprivation Index. There was a greater frequency of KRAS mutations in some areas close to major highways and big cities in northern France. Conclusions: There is a spatial heterogeneity of KRAS codon 12 or 13 mutations in CRC in northern France. These data demand deeper epidemiological investigations to identify environmental factors such as air pollution as key factors in the occurrence of KRAS mutations.
Exosomes derived miR-454-3P to promote the progression of colorectal cancer via MIER1-mediated Notch signaling activation.
Authors: Li Dawei , Zhao Senglin , Xu Ye , Li Xinxiang , Cai Sanjun 
Published: May 2019

e15108 Background: Mesoderm induction early response 1 (MIER1) was downregulated and predicted poor prognosis in CRC patients. However, the mechanisms of the down regulation of MIER1 in CRC remained unclear. Increasing evidence indicates that dysregulation of microRNAs promotes the progression of cancer through the repression of tumour suppressors.Here, we identified exosomes derived miR-454-3p as a novel regulator of MIER1 in CRC. Methods: The effect of miR-454-3p expression on cancer proliferation and metastasis was assessed in cells by altering the expression of miR-454-3p in vitro and in vivo. Mechanistic investigation was carried out by using cell and molecular biology approaches. Results: Functionally, ectopic expression or silencing of exosomes derived miR-454-3P, respectively, promoted or inhibited CRC cell proliferation, colony formation and cell cycle transition, as well as enhanced or prevented the invasion, metastasis of CRC cells and epithelial to mesenchymal transition of CRC cells in vitro and in vivo. Molecularly, exosomes derived miR-454-3P functioned as an onco-miRNA by activating the MIER1-regulated NOTCH pathway. Overexpression or silencing of MIER1 could partially reverse the effects of the overexpression or repression of exosomes derived miR-454-3P on CRC progress caused by activation of the NOTCH pathway in vitro and in vivo. Clinically, high miR-454-3P expression predicted poor survival in CRC patients, especially combined with low MIER1 expression. Conclusions: Collectively, we identified exosomes derived miR- 454-3p as an onco-miRNA, which acts by directly repressing MIER1 in CRC.
Completion of adjuvant chemotherapy with Cape/CAPOX in colon cancer: A retrospective database study.
Authors: Chu Edward , Wang Xue , Frohlich Maxfield , Tran Melody , Lee Won Chan 
Published: May 2019

e15116 Background: Fluorouracil-based adjuvant chemotherapy has been shown to improve survival of patients with early-stage colon cancer. Suboptimal adherence to oral chemotherapy, such as capecitabine, remains a serious issue and reduces treatment efficacy. Patient barriers to adherence include adverse effects and high medical costs. This study assesses the completion rates and associated factors in patients on capecitabine monotherapy (Cape) and capecitabine with oxaliplatin (CAPOX) for adjuvant treatment of early-stage colon cancer. Methods: Patients with a primary/secondary diagnosis of early-stage colon cancer between April 2013-March 2017, and 1+ claim of Cape or CAPOX within 60 days of colectomy were identified from the MarketScan Commercial/Medicare Database. Therapy completion rates (treatment ≥7 cycles) were calculated. Multivariate logistic regressions analyses were used to assess the factors (patients’ age, gender, payer type, geography, comorbidities, healthcare costs, etc.) associated with treatment completion. Results: A total of 679 patients met the eligibility criteria (mean age ± SD: 57.3 ± 11.5 years, 54% male), of which 382 (56%) were on Cape (mean age ± SD: 60.2±12.4) and 297 (44%) on CAPOX (mean age ± SD: 53.6±9.0). Completion rates were 43% in Cape and 42% in CAPOX. The baseline overall mean monthly healthcare cost was significantly higher in non-completers vs. completers (Cape: $9,870 vs $7,169, P=0.003; CAPOX: $10,009 vs $8,068, P=0.01). Multivariate logistic regression showed that patients <65 years of age on CAPOX were more likely to complete treatment than patients ≥65 years on CAPOX (Odds Ratio=5.1, P=0.03). Conclusions: Cape and CAPOX completion rates are suboptimal in patients with early-stage colon cancer. Non-completion of therapy is associated with significantly higher baseline healthcare costs for both Cape and CAPOX, as is older age for CAPOX. The low completion rates highlight the unmet need for more effective strategies to optimize oral chemotherapy for the adjuvant treatment of early-stage colon cancer. [Table: see text]
Exosomal markers (CD63 and CD9) expression using immunohistochemistry (IHC) in patients with right-sided and left-sided colon cancer.
Authors: Prodduturvar Pranitha , McCormick Ben , Mneimneh Wadad , Dal Zotto Valeria , Grimm Leander , Rider Paul , Hunter John , Iliff Greire , Smith Clayton , Patel Girijesh K. , Pannell Lewis , Singh Seema , Singh Ajay , Perry Josiah , Khushman Moh'd M. 
Published: May 2019

e15119 Background: Embryologically, the right colon (cecum, ascending colon, hepatic flexure and proximal two-thirds of the transverse colon) is derived from the midgut, whereas the left colon (sigmoid colon, descending colon, splenic flexure and distal third of the transverse colon) is derived from the hindgut. There are clinical, pathological and molecular differences between patients with right-sided colon cancer (RSCC) and left-sided colon cancer (LSCC). Exosomes mediate intercellular communications and interactions and have pivotal roles in cancer behavior. CD63 and CD9 are widely accepted exosomal markers. Here we explored CD63 and CD9 expression using immunohistochemistry (IHC) in patients with RSCC and LSCC. Methods: Between 2015 and 2018, 63 patients underwent colon surgical resection for whom we had available tissues for CD63 and CD9 IHC staining. Two pathologists independently scored CD63 and CD9 expression in the tumor and adjacent normal mucosa (ANM). Staining intensity was graded from 1-3. Staining percentage was estimated in 10% increments. Mean quick-score (Q-score) was calculated (intensity x percentage). Unpaired t test was used for statistical analysis. Results: Median age was 64 (range 33-78). Females represented 60% of our cohort. Caucasians, African Americans and other Ethnicities represented 55%, 40% and 5% respectively. The sidedness was designated as RSCC in 52% and as LSCC in 48%. The ANM and Tumor CD63 Q scores were 225 vs 191 (p = 0.009) in RSCC and 224 vs 154 (p = 0.0001) in LSCC respectively. The ANM and Tumor CD9 Q scores are 134 vs 152 (p = 0.142) in RSCC and 135 vs 154 (p = 0.137) in LSCC respectively. In patients with RSCC and LSCC, the mean Tumor CD63 Q score is 191 vs 154 (p = 0.024), while the mean ANM CD63 Q score is 225 vs 224 (p = 0.920). The mean Tumor CD9 Q score is 152 and 154 (p = 0.883) and the mean ANM CD9 Q score is 134 vs 135 (p = 0.926). Conclusions: In our cohort of patients with RSCC and LSCC, the exosomal marker CD63 expression is lower in the tumor compared to the ANM. While ANM CD63 expression was similar between RSCC and LSCC, tumor CD63 expression was higher in RSCC compared to LSCC. The exosomal marker CD9 was not found to have significant differential expression between ANM and tumor and between RSCC and LSCC. To our knowledge, this is the first study to explore exosomal markers expression using IHC in patients with RSCC and LSCC.