bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation of peripheral blood markers of DNA damage and immune response with chemoradiation response in patients with locally advanced rectal cancer.
Authors: Arora Sanjeevani , Demidova Elena , Avkshtol Vladimir , Lesh Randy , Browne Amanda J , Handorf Elizabeth A. , Golemis Erica , Meyer Joshua E. 
Published: May 2019

e15109 Background: Approximately 60% of newly diagnosed rectal cancers are locally advanced. The standard of care for these malignancies is neoadjuvant chemoradiation therapy (nCRT) followed by surgery. Unfortunately, only approximately 20% of patients experience a complete response, but all are at risk for toxicity. There are no biomarkers to predict who will derive the greatest benefit from CRT. We hypothesized that inherent DNA damage recognition and repair (DNA-DRR) capacity contributes to CRT response in rectal cancer. Methods: We used primary peripheral blood lymphocytes (pPBLs) from rectal cancer patients to study differences in DNA-DRR capacity. The blood samples used were either drawn prior to nCRT or post a standard course of ~5.5 weeks of nCRT. We used immunofluorescence and Luminex-based multianalyte approaches to study DNA-DRR capacity in pPBLs. To determine if the tested biomarkers correlated with CRT response, we segregated patients by neoadjuvant rectal (NAR) score, a validated surrogate endpoint in rectal cancer. Results: Using pPBLs, we found that a subset of patients had elevated phosphorylated histone H2AX (γ-H2AX) foci, a well-described marker of DNA double strand breaks. We found that poor responders (PoR; NAR score > 14; n = 21) had lower γ-H2AX foci then complete responders (CR; NAR score < 1; n = 21) (P < 0.0001, Kruskal-Wallis test). We also did not observe any significant differences in γ-H2AX foci from pPBLs drawn prior to CRT versus post nCRT (p = 0.519, n = 11, Wilcoxon rank sum test). Next, by multianalyte testing, we found that a combined score derived from six DNA-DRR markers (ATR, MDM2, phosphorylated forms of H2AX (γ), p53, Chk1, Chk2) strongly correlated with CR (p < 0.001). Finally, by multianalyte testing, we also detected a serum signature of inflammatory markers that significantly correlated with CRT response (p < 0.05). Conclusions: Our data suggest that rectal cancer patients who differ in their response to CRT differ in global, inherent DNA-DRR capacity, suggesting that DNA-DRR capacity in pre-treatment pPBLs can form the basis of a predictive biomarker. This predictive capacity may reflect underlying epigenetic or genetic differences, or inflammatory state. Validation and further development of this novel assay is warranted, as it has the capacity to substantially improve patient selection in an era with growing treatment options for these patients.
Sensitive detection of microsatellite instability in tumors and liquid biopsies using nuclease-based enrichment.
Authors: Ladas Ioannis , Mamon Harvey J. , Ng Kimmie , Yu Fangyan , Leong Ka Wai , Kulke Matthew H. , Makgrigiorgos G. Mike 
Published: May 2019

e15117 Background: The role of MSI in colorectal cancer (CRC) is well characterized, and tumors are classified as MSI-High or MSI-Stable by screening specific microsatellites. MSI-H reflects mismatch repair deficiency, is predictive for CRC therapy outcome in chemotherapy and immunotherapy and has a higher 5-year survival. While tumor testing is the gold standard, a convenient approach to screen for MSI before and during cancer treatment is screening circulating DNA (liquid biopsy) using a blood draw. However, using electrophoresis or next generation sequencing for MSI detection presents challenges at low levels of MSI due to polymerase slippage (‘stutter’) that generate high false positive rates at positions of homo-polymers. We present a new approach for enrichment of altered micro-satellites prior to DNA-amplification thereby reducing stutter from wild-type alleles and facilitating detection of MSI. The method employs a double-strand-DNA-specific nuclease and overlapping oligonucleotide-probes interrogating multiple micro-satellite targets (‘NaMe-PrO’, nuclease-assisted minor-allele enrichment with probe-overlap). Following DNA denaturation, the probes form double-stranded regions with their targets, thereby guiding nuclease digestion to selected sites. Microsatellite indels create ‘bulges’ that inhibit digestion, thus subsequent amplification yields DNA with microsatellite alterations enhanced at multiple targets. Methods: We first validated the method by evaluating 5 MSI targets simultaneously, NR27, NR21, NR24, BAT25 and BAT26 using DNA from tumor biopsies and circulating-DNA from colorectal cancer patients. The technique detected microsatellite alterations down to 0.01% altered allele frequency, thus improving detection sensitivity by > 100-fold relative to current approaches. Next, a clinical study was performed. We screened microsatellites in circulating DNA from groups of early stage colon cancer patients with known MSI status in the tumor. Results: Combination of NAME-PRO with capillary electrophoresis demonstrated 100% sensitivity (10/10) and 90% specificity (9/10) in detecting MSI status in the blood, thereby opening the possibility of early cancer detection for MSI positive tumors, or for application in minimal residual disease detection. Conclusions: We anticipate application of this highly- multiplex-able method either with standard 5-plex reactions or with NGS-based detection of MSI on thousands of targets to enable sensitive detection in tumors and liquid biopsies.
Incidence of venous thromboembolic disease (VTE) in a cohort of patients with colorectal cancer (CRC) according to KRAS, NRAS and BRAF status.
Authors: Garcia-Alfonso Pilar , Ortega Morán Laura , Gallego Gallego Iria , García González Gonzalo , Torres Pérez-Solero Gabriela , Aguilar Caballero Iker , de Toro Carmena María , Morón García Blanca , Tirado Anula Victoria , Gutiérrez Alonso Natalia , Bringas Beranek Marianela , Soto Alsar Javier , Sandoval García Carmen , Aguado Orihuela Gema , Martínez Delfrade Íñigo , Blanco-Codesido Montserrat , Calvo Ferrándiz Aitana , Martin Miguel , Muñoz Martín Andres J. 
Published: May 2019

e15136 Background: A recent study has suggested that KRAS mutation could increase the risk of VTE in patients with CRC. The role of others biomarkers, such as BRAF, in this setting is unknown. The aim of this study is to analyze the incidence of cancer-associated thrombosis in a cohort of patients with CRC based on KRAS, NRAS and BRAF status. Methods: We performed a retrospective review of patients with metastatic CRC and KRAS/NRAS/BRAF status known, attended in the Medical Oncology Department of the Hospital General Universitario Gregorio Marañón (Madrid, Spain) between January 2010 and January 2018. Results: 194 patients were identified and included in the analysis. The median age was 64 years (18-86). Most were metastatic at diagnosis (58.1%). Khorana’s predictive model: low-risk 67.7%, intermediate-risk 31.0%, high-risk 2.3%. The median follow-up was 35 months (2-240). 41 patients (21.1%) experienced VTE (11 pulmonary embolism, 15 lower extremity deep-vein thrombosis, 12 visceral vein thrombosis, 2 catheter-related thrombosis, 1 unknown). Most had metastatic disease at the moment of VTE (90.2%). 40% of the events occurred at the time of diagnosis or within the first 6 months. 65% were incidental events. Khorana’s predictive model in VTE patients: low-risk 63.4%, intermediate-risk 24.5%, high-risk 7.3%. According to biomarkers, the incidence was 19.1% (13/68) in KRAS/NRAS mutated patients, 28.6% (6/21) in BRAF mutated patients and 21% (22/105) in triple-wild-type patients. 6/38 patients (15.8%) developed recurrent thrombosis. In the univariate analysis, the presence of chronic kidney disease (p = 0.022), ECOG ≥ 2 (p = 0.038) and high-risk Khorana score (p = 0.011) were significantly associated with increased risk of VTE. Metastatic disease showed a trend towards the statistical significance (p = 0.053). In the multivariate model, including this variables, age, sex and biomarkers, only ECOG ≥ 2 remained independent predictor of VTE (OR 8.73; CI 95% 1.32-57.82; p = 0.025). Conclusions: The biomarkers have not been associated with the risk of VTE. We have observed a high incidence of VTE in BRAF mutated patients that should be investigated in further studies.
RAS analysis of circulating tumor cells from advanced colorectal cancer using BEAMing technology.
Authors: Cabezas-Camarero Santiago , García-Barberán Vanesa , De la Orden-García Virginia , Mediero-Valeros Beatriz , Paz Cabezas Mateo , López-Alfonso Ana , Sánchez Ruiz Antonio Carlos , Ruiz-Casado Ana , Díaz-Millán Isabel , Sastre Javier , Sotelo Lezama Miguel , Diaz-Rubio Eduardo 
Published: May 2019

e15151 Background: RAS mutations predict a lack of response to anti-EGFR therapies in metastatic colorectal cancer (mCRC). BEAMing technology is useful for detecting hot-spot mutations in ctDNA in mCRC. Analysis of these mutations in DNA from Circulating Tumor Cells (CTC) may increase the predictive value in mCRC patients (pts). Our aim was to explore the feasibility of studying RAS status using BEAMing in DNA from CTC. Methods: First, spiking experiments (SE) using wild-type (WT) and KRAS-mutated (MUT) cell lines were performed to establish the limit of detection (LOD) for RAS analysis with BEAMing. Second, SE were performed with CTC collected by CellCelector (removes non-CTC background achieving 100% purity of CTC). Finally, BEAMing was used for RAS analysis in ctDNA and in DNA from CTC isolated either with IsoFlux or with CellCelector in 9 mCRC pts with confirmed RAS mutation in primary tumor. Total DNA from CTC was preamplified using RepliG. Results: In SE, 10 and 5 KRAS MUT-cells using different backgrounds of WT-cells (10-0.2% MUT-cells) were detected using BEAMing. However, 3 and 1 MUT-cells (0.009-0%) were not detected. In SE of CTCs collected with CellCelector, BEAMing detected KRAS mutations with 50, 20, 10, 6, 4, 2 and 1 cell (MAF: 23.8%±3.8). A mutation (codon 13) was detected in CTC from one patient positive in tissue and ctDNA (CellCelector; 15 CTCs; MAF: 11.4%). Discordant results were found in 8 patients when CTCs were isolated using Isoflux (min: 0, max: 9 CTCs). CTC from another patient were possibly mutated but WT in ctDNA. Conclusions: This pilot study indicates that RAS mutations can be detected in CTCs using BEAMing. Reducing the non-CTC cellular background may be needed in cases with low CTC number. Molecular information provided by CTC and ctDNA may prove complementary and useful for taking therapeutic decisions in mCRC. These results merit confirmation in larger, prospective studies.
Association between primary tumor site, perioperative CEA ratio, smoking status, and overall survival in patients with colorectal cancer.
Authors: Odeny Thomas A , Farha Nicole , Hildebrand Hannah , Allen Jessica , Vazquez Wilfred , Martinez Maximillian , Saeed Anwaar , Kasi Anup 
Published: May 2019

e15156 Background: There are differences in the incidence, clinical presentation, molecular pathogenesis and outcome of colorectal cancer (CRC) based on tumor location. Emerging research suggests that perioperative carcinoembryonic antigen (CEA) ratio (post-op/pre-op CEA) is a prognostic factor for CRC patients. We aimed to determine the association between tumor location, CEA ratio, smoking status and overall survival (OS) among patients with CRC. Methods: We analysed 323 patients who underwent resection for CRC at KUMC. After excluding those without pre- or post-operative CEA data, 162 patients were classified as either high ( > = 0.5) or low ( < 0.5) ratio. Primary outcomes were: 1) OS stratified by tumor location; 2) OS stratified by CEA ratio; and 3) whether the association between CEA ratio and OS differed by tumor location, after adjusting for stage and smoking status. Kaplan-Meier method was used to estimate survival rates, and Cox proportional hazards models for multivariate analysis. Results: The median age was 63 years (inter-quartile range 53-72), 61% male, 43% smokers, 73% left-sided tumors, median pre-operative CEA was 3.0 (IQR 1.5-7), and 64% had CEA ratio > = 0.5. The OS rates were 85.7% and 91.9% in patients with left-sided vs right-sided tumors respectively (log-rank p-value = 0.9). The OS rates were 83.5% and 91.5% in patients with high vs low CEA ratios respectively (log-rank p-value = 0.3). The effect of CEA ratio on OS was significantly different when stratified by tumor location (p-value for interaction < 0.001). However, in the stratified analysis, the n was too small to permit further inferential analysis. In multivariate analysis, both tumor location (HR 0.6; p = 0.5) and CEA ratio (HR 1.5; p = 0.5) were not significantly associated with OS after adjusting for smoking status and tumor stage. Smoking was significantly associated with higher rates of death (HR 3.9; p = 0.04) when adjusted for tumor location, CEA ratio, and tumor stage. Conclusions: There was no difference in OS between left versus right-sided tumors. The association between CEA ratio and OS was significantly modified by tumor location. However, to attribute this modification to left vs right warrants validation in a larger cohort as our sample size was limited. Smoking increases mortality irrespective of right vs left sided CRC.
The prognostic significance of magnetic resonance imaging (MRI) following neoadjuvant concurrent chemoradiation (NCCR) in patients with locally advanced rectal adenocarcinoma (LARA).
Authors: Fahmawi Yazan , Smith Clayton , Grimm Leander , Khullar Shikha , Rider Paul , Hunter John , Iliff Greire , Mneimneh Wadad , Roveda Kelly , Wang Bin , Prodduturvar Pranitha , Campos Yesica , Mehta Ansh , McCormick Ben , Khushman Moh'd M. 
Published: May 2019

e15166 Background: In patients with locally advanced rectal adenocarcinoma (LARA), the response to neoadjuvant concurrent chemoradiation (NCCR) correlates with long-term outcomes. Neoadjuvant rectal (NAR) score ([5 ypN - 3 (cT - ypT) + 12]2/9.61) is a novel short-term surrogate endpoint for disease free survival (DFS) and Overall survival (OS). The prognostic significance of magnetic resonance imaging (MRI) findings following NCCR is yet to be explored. Here, we evaluated the agreement between post NCCR MRI yT and yN and pathological ypT and ypN. In addition, we calculated the post NCCR MRI NAR (mNAR) score using the MRI yT and yN ([5 yN - 3 (cT - yT) + 12]2/9.61) and explored its prognostic significance. Methods: Between 2014 and 2018, all patients with LARA were identified. Among those, 43 patients received NCCR, had post NCCR MRI and underwent surgical resection. Weighted Kappa was used to measure the agreement between post NCCR MRI yT and yN and pathological ypT and ypN. Paired t-test was used to compare the means between NAR and mNAR scores. NAR and mNAR scores were classified as low ( < 8), intermediate (8-16) and high ( > 16). DFS and OS were analyzed using Kaplan-Meier curves. Results: In our cohort, the agreement was slight between post NCCR MRI yT and Pathological ypT (p = 0.111), and fair between post NCCR MRI yN and pathological ypN (0.278). The mean NAR score was 16 and the mean mNAR score was 20 (p = 0.0079). Low-intermediate and high NAR scores were seen in 31 (72%) and 12 (28%) patients respectively. However, low-intermediate and high mNAR scores were seen in 20 (47%) and 23 (53%) patients respectively. The median DFS in patients with low-intermediate and high NAR scores was not reached and 30 months (p = 0.00063) respectively. The median OS in patients with low-intermediate and high NAR scores was not reached and 40 months (p = 0.00056) respectively. The median DFS in patients with low-intermediate and high mNAR scores was not reached in both groups (p = 0.058). The median OS in patients with low-intermediate and high mNAR scores was not reached in both groups (p = 0.15). Conclusions: Post NCCR MRI yT and yN had slight and fair agreements with ypT and ypN respectively. In our cohort, there was a difference between NAR and mNAR. NAR demonstrated prognostic significance for DFS and OS, while mNAR did not at the time of analysis.
Stage of disease and initial surgical intervention in colon cancer patients: An exploratory analysis of the SEER database.
Authors: Denneny Rachel Gray , Delgado David J. , Nguyen Victoria , George Brandon , Mitchell Edith P. , Subramoney Jay 
Published: May 2019

e15170 Background: Colorectal cancer (CRC) is the third-leading cause of cancer-related deaths in the United States. CRC’s decreasing mortality rate has been attributed to increased screening and early detection. This study explored the association between stage at diagnosis with initial surgical intervention for patients (pts) with colon cancer (CC), using data extracted from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) data. Methods: Retrospective cohort study using the SEER database from 1998-2015. Included were pts with CC, aged 18 or older, and with disease in either the proximal or distal colon. Pts with rectal cancer were excluded. Stage was defined as local, regional versus distant, and initial treatment was defined as none versus any surgery. Multivariable logistic regression was used to describe the association between stage and initial surgical intervention, controlling for pts and tumor characteristics. Results: 354,640 CC pts were included in this analysis: 46%(localized), 36%(regional), 18%(distant), and 92.45%(received surgery). Multivariable analysis indicated that pts with regional disease were more likely to receive initial surgical intervention compared to those with localized disease (OR = 4.49,95% CI = 4.24,4.77). Pts with distant stage of disease were less likely to receive surgery compared to those with localized disease (OR = 0.11,CI = 0.11,0.12). Other factors significantly associated with an increased likelihood of initial surgical intervention included mucinous adenocarcinoma histology, papillary adenocarcinoma histology, having a partner relationship, adenomatous polyps on histology, white race, female sex, and lesion location in the proximal colon. Additionally, African American pts were significantly less likely than white pts to receive surgery as an initial intervention for colon cancer (OR = 0.76,CI = 0.73,0.79). Conclusions: We conclude that distant stage at diagnosis was associated with reduced odds of initial surgical intervention. This highlights the importance of screening and early detection to identify pts with operable disease and as a method of decreasing mortality.
Risk factors predicting colorectal cancer recurrence in a Latin American population.
Authors: Leon Jorge , Namuche Fernando , Montenegro Paola Catherine , Flores Claudio J. 
Published: May 2019

e15180 Background: The incidence of colorectal cancer (CRC) in Peru has increased in the last decades. In our population more than 80% of patients are stage I-III. Recurrence is one of the most important factors to consider in the survival of CRC patients. The aim of this study was to identify which factors influence in the recurrence of CRC in our population. Methods: We retrospectively reviewed the electronic medical records of 506 patients with stage I-III CRC from one specialized Peruvian cancer center between 2006 and 2016. Survival analysis (with recurrence as the event to evaluate) was performed with Kaplan Meier curves and Long-rank test. We use a preliminary univariate analysis to do the multivariate analysis with Cox regression. We performed a ROC curve analysis to determine an appropriate cut-off value for the tumor size (≥4.2). Results: In the univariate analysis we found that sidedness, tumor size (cut-off ≥4.2), CEA, lymph node involvement, stage, histological grade, LVI, PNI, and chemotherapy were statistically significant. In the multivariate model, tumor size [HR, 1.462; 95% CI, 1.065-2.217; p<0.05], lymph node involvement [HR, 0.136; 95% CI,0.41-0.447; p<0.001], and stage III [HR, 0.003; 95% CI, 0.263-0.758; p<0.05] retained a significant association and were independent factors with relapse disease. Conclusions: In stage I-III CRC pts it is important to evaluate tumor size, lymph node involvement and clinical stage as they are possible prognostic factors that will help our diagnosis and treatment along with other standard features.
Regorafenib-associated adverse event management in colorectal and gastrointestinal stromal cancer patients: A systematic review and meta-analysis.
Authors: Xie Ganfeng , Gong Yuzhu , Wu Shuang , Li Chong , Yu Songtao , Wang Zhe , Chen Jianfang , Zhao Quanfeng , Li Jianjun , Liang Houjie 
Published: May 2019

e15181 Background: Adverse events (AEs) observed in regorafenib treated metastatic colorectal cancer (mCRC) and gastrointestinal stromal tumors (GIST) often require treatment modification. However, due to dearth of literature reporting AE management, we performed a systematic review and meta-analysis to assess the success of different methods of managing regorafenib-associated AEs and also determined risk factors of the AEs. Methods: A comprehensive search was conducted in PubMed, Embase and Cochrane Library, to retrieve RCTs and observational studies published from inception to May 2018, discussing the management methods of AEs with rate of improvement and risk factors of the AEs. The success rate for each method was evaluated as percentage and compared using chi2-test. Risk factors were presented using Pearson correlation. Results: We identified 28 studies for this analysis (N = 3120 patients; 305 GIST and 2,815 mCRC). Methods used for management included intermittent dose withdrawal (66.7%), delayed treatment schedules (54%), dose reductions (41%), complete drug withdrawal (19%) and preventive measures like dexamethasone and lactose administration or surgery (63.7%). Reduction or improvement in AEs was observed in 57%, 17% and 100% patients after lowering the initial dose, intermittent withdrawal of regorafenib and using other preventive measures, respectively. Patients aged < 65 years had significantly higher occurrence of AEs compared with patients aged ≥65 years (27.6% vs. 71.3%, p = 0.001). A significant positive correlation was observed between the occurrence of all and grade 3AEs with 160mg dose (r = 0.967 and 0.746 respectively; p = 0.001 for both) with no significant correlation observed for 120-mg and 80-mg doses and any gender. Conclusions: Initiating dose of 160mg is a major risk factor for regorafenib associated AEs in mCRC and GIST patients; with intermittent dose reduction, withdrawal, and delayed treatment being the commonly used management strategies. To allay the risk of AEs and maintain the efficacy, 120mg initial dose is recommended for mCRC and GIST patients. However, further studies are required to confirm the results.