bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of Dworak grading system as a prognostic indicator after neoadjuvant chemoradiotherapy in rectal cancer patients.
Authors: Buecker Rebecca , Torsten Hansen , Hartmann Frank , Schafer Ulrich 
Published: May 2019

e15053 Background: The objective of this study was to assess the prognostic role of Tumor Regression Grading (TRG) according to the Dworak system on progression free survival (PFS) after chemoradiotherapy (CRT) in locally advanced rectal cancer. Methods: In total, 159 patients with locally advanced rectal cancer who underwent neoadjuvant CRT from January 2007 and December 2016 were enrolled. PFS (any relapse after surgery) was tested against TRG (Dworak grade 1+2 versus Dworak grade 3+4) and other potential risk factors (age, gender, pre- and postoperative T-stage, pre- and postoperative N-stage, grading, lymph invasion, vessel invasion, chemotherapy regime, resection margin, treatment delay). Risk factors with a highly significant influence (p < 0.01) in the univariate Kaplan-Meier (KM) estimation were tested for independence using the multivariate cox regression model. Results: With a mean follow-up of 42.5 months, 5 years and 10 years estimated PFS for all patients was 60.1% and 49.1% respectively. Estimation of 5 years and 10 years PFS was 49.7% and 45.5% for TRG Dworak grade 1+2 (n = 109) and 83.8% and 67% respectively for TRG Dworak grade 3+4 (n = 50). This difference was highly significant (p < 0.001). Other highly significant risk factors were postoperative N-stage (negative versus positive), lymph invasion (L0 versus L1), and resection margin (R0 versus R1/2). In the multivariate analysis, only TRG and post-op N-stage were identified as independent risk factors for PFS. Conclusions: In this analysis, Dworak Tumor Regression Grading appears to be a prognostic marker for oncologic outcomes in locally advanced rectal carcinoma patients treated with neoadjuvant CRT.
Effect of acid-reducing agents on the efficacy of capecitabine in metastatic gastrointestinal cancers.
Authors: Bah Tonjeh Mary Stella , Comeau Jill , Clarke Andrea , Robinson Arelis , Storer Amanda , Shi Runhua , Kavanaugh Mindie Michelle 
Published: May 2019

e15058 Background: Recent retrospective and subgroup analyses have evaluated the effects of capecitabine with acid-reducing agents both in the adjuvant setting for colon cancer and in the palliative setting for stage IV gastroesophageal malignancies. Efficacy outcomes in these studies are contradictory. Acid-reducing agents are thought to reduce the absorption of capecitabine by increasing gastric pH leading to a concern of decreased efficacy. Studies thus far have not included stage IV colorectal cancers, a common population who receives capecitabine-based regimens. Methods: We conducted a retrospective chart review of patients diagnosed with stage IV Gastro Intestinal (GI) cancers treated with capecitabine-based therapies between 2012 and 2018. Electronic health records were used for data collection. Descriptive statistics and COX regression model were utilized for data analysis. Results: Of the 249 charts that were screened for inclusion, 58 were included in this review. Thirty-eight (65.5%) had a diagnosis of colon cancer, 11 (19%) had rectal cancer, and 9 (15.5%) had other GI malignancies. The most common capecitabine-based regimens included XELOX alone (29%) or with bevacizumab (36%). During capecitabine treatment, 20 (34.5%) patients received concomitant acid-reducing therapy. This included 19 patients taking a PPI and 1 patient taking a H2 Inhibitor. Patients who did not receive acid-reducing therapy had a 1-year PFS of 23.7% compared to 25% in patients who did not, (HR 0.55, p = 0.46). The 1-year OS was 68.4% in the non-acid-reducing agent group and 60% in the patients who did receive acid-reducing agents during capecitabine treatment, respectively (HR 0.17, p = 0.68). Conclusions: Receiving acid-reducing agents concomitantly with capecitabine-based regimens appears to not have an effect on 1-year PFS or OS in patients with Stage IV GI cancers. These outcomes may have been affected by the sample size, incomplete home medication lists, and compliance issues with capecitabine. Larger population studies are needed to validate these findings and identify the significance of utilization of acid-reducing agents in patients with Stage IV GI cancers receiving capecitabine.
Comprehensive immune transcriptomic subtypes of colorectal cancer for development of precision immunotherapy.
Authors: Jing Zhou , Guo Xueguang , Zhao Jing , Zhao Xiaochen , Zhang Yuzi , Huang Mengli , Cai Shangli , Zhu Haitao 
Published: May 2019

e15078 Background: Immune checkpoint blockades (ICBs) have been approved for colorectal cancer (CRC) with microsatellite instability high (MSI-H). However, 50% to 60% MSI-H and almost 100% microsatellite stability (MSS) CRC patients can’t benefit from ICBs treatment. How to warm these “cold tumor” for boosting response to ICBs is still a problem. We aimed to integrate the expression signatures of T cell activation, exclusion and dysfunction to generate immune microenvironment subtypes which may guide precision immunotherapy. Methods: RNA-Seq of 596 CRC patients from The Cancer Genome Atlas were analyzed. T cell activation, dysfunction and exclusion signatures were calculated from TIDE model algorithm. Unsupervised clustering was used to classify CRC into various immune subtypes. Mann Whitney U test and Kruskal test were used to compare the difference among two or more than two groups. COX regression multivariate analysis was applied to analyze the association of subtypes with overall survival (OS). Results: Compared with 543 patients with MSS, 83 patients had significantly higher expression of T cell activation related genes (including CD8A, CXCL9, CXCL10, GZMB, IFNG et al) and immune checkpoint genes (including PD-L1, PD-1, LAG3 et al.), but lower signatures scores of M2-like tumor-associated macrophage (TAM) and T cell exclusion ( all P value<0.001). Based on expression signatures of myeloid-derived suppressor cell (MDSC), cancer-associated fibroblast (CAF), M2-like TAM, cytotoxic T-lymphocytes (CTL) and PD-L1, all the patients were clustered into four subtypes. Cluster 4 was enriched by MSI-H and characterized with high T cell activation and moderate T cell dysfunction and exclusion. Comparatively, another MSI-H enriched Cluster 1 had both high CTL and T cell dysfunction which indicated that activated T cell might be escaped by tumor cell. Cluster 2 and Cluster 3 were enriched by MSS and characterized with moderate T cell activation and high T cell exclusion. In survival analysis, Cluster 4 had prolonged OS (HR [95% CI]=0.46 [0.27-0.80]) compared with Cluster 1, 2 and 3, after adjusted for age, pathological stage, tumor residue, MSI status, BRAF and PIK3CA mutations. In MSS, Cluster 4 also had better prognosis than the other three clusters (HR [95% CI]=0.38 [0.20-0.73]). Conclusions: Our findings provide evidence to guide further patient stratification in ICBs treatment. The distinct immune subtypes of CRC also paved the way of combination immunotherapy based on immune microenviroment to turn “cold tumor” into “hot tumor”.
Detection of KRAS mutations in colon adenocarcinoma by droplet digital PCR.
Authors: Enin Yaroslav S. , Kit Oleg I. , Gevorkyan Yuriy A. , Soldatkina Natalya V. , Kharagezov Dmitry A. , Milakin Anton G. , Sustretov Vyacheslav A. , Dashkov Andrey , Vladimirova Liubov Yu 
Published: May 2019

e15080 Background: The screening of mutations in the KRAS gene is a traditional marker of the effectiveness of targeted therapy for colorectal cancer. Mutations in the 12 codon of the second exon of the KRAS gene are present in 40% of colorectal tumors, and monitoring of the mutational status together with the level of mutant DNA is of particular clinical interest. However, the sensitivity level of the traditionally used real-time polymerase chain reaction (RT-PCR) method is insufficient in some cases. Recently, Droplet Digital PCR (DD-PCR) has been considered as an alternative method, which is more sensitive. The purpose of this study was to compare the methods of detection of somatic mutations in the second exon of the KRAS gene using DD-PCR versus RT-PCR. Methods: This study included 134 patients with colon adenocarcinoma. The presence or absence of activating mutations in the second exon of the KRAS gene in samples of FFPE blocks was detected by RT-PCR using the “Real-time-PCR-KRAS-7M reagent kit” (Biolink, Russia) and Digital Droplet PCR using the “KRAS Screening Multiplex kit” (Bio-Rad, USA). Results: For all 134 samples, selected for the study, the WT status of the KRAS gene was identified by the RT-PCR method. According to the results of DD-PCR for 131 samples (96.2%), a positive amplification response of mutant DNA with more than 200 events was obtained. The number of amplicons varied from 312 to 117917 per sample, the median was 2940 copies. According to recent trials, a clinically significant level of mutational events must exceed 5% of the total number of amplicons in a sample. In our study, 12.9% of cases (17 patients) met this criterion. Conclusions: The DD-PCR method demonstrated a much higher analytical sensitivity for the detection of SNP mutations in comparison with RT-PCR that may be of critical importance in the therapeutic decision.
Frequency of somatic mutations in the KRAS gene in patients of the South Russia diagnosed with colorectal cancer.
Authors: Gvaldin Dmitry Yu. , Kit Oleg I. , Omelchuk Ekaterina P. , Kaymakchi Dmitry O. , Poluektov Sergey I. , Petrov Dmitry Sergeevich , Kolesnikov Vladimir E. , Vladimirova Liubov Yu 
Published: May 2019

e15081 Background: Colorectal cancer (CRC) is a common pathology in the world; the annual incidence rate reaches 1 million cases, and the annual mortality rate exceeds 500,000. The target therapy of EGFR with monoclonal drugs improves the survival of patients with this pathology. However, the effectiveness of therapy depends on the presence of mutations in genes involved in the EGFR signaling cascade, in particular KRAS. The purpose of this study was to determine the frequency of somatic mutations in the KRAS gene in tumor samples of patients from the South Russia diagnosed with colorectal cancer, as well as to analyze the effect of point mutations G12A, G12C, G12D, G12R, G12S, G12V and G13D on tumor metastasis. Methods: 744 patients diagnosed with colorectal adenocarcinoma were examined for mutations in 12th and 13th codons of KRAS. Somatic mutations in the KRAS gene were detected with reagent kit Biolink (Russia) using FFPE DNA samples of tumor tissues. Statistical analysis was performed using the method of binary logistic multiple regression and χ2-test. Results: Mutations in the KRAS gene were found in 32% of patients in the pooled sample; the most common mutation was the replacement of G12D in the KRAS gene (36%). Less common detectable mutations in the KRAS gene were G13D (18%), G12V (16%), G12A (10%), G12C (8%), G12S (10%), G12R (2%). Metastatic CRC was found in 86% of carriers of the wild-type allele and in 88% of carriers of the mutant allele. The presence of a G12V substitution almost 6 times increased the risk of metastasis in patients with CRC (OR = 5.89; 95% CI: 0.8-43.45; p = 0.049). Conclusions: Mutations in the KRAS gene were found in 32% of patients with CRC in the South of Russia. A significant association of G12V replacement with a high risk of metastasis was established. Further study of somatic mutations in the KRAS gene will allow to choose the most effective therapeutic strategies in the presence of one or another of the studied mutations.
Clonal hematopoiesis mutations in plasma cfDNA RAS/BRAF genotyping of metastatic colorectal cancer.
Authors: Wang Beili , Huang Fei , Shen Minna , Wu Shengchao , Yu Qian , Jiang Huiqin , Yu Yiyi , Yang Yihui , Zhao Ying , Zhou Yiwen , Pan Baishen , Liu Tianshu , Guo Wei 
Published: May 2019

e15083 Background: Clonal hematopoiesis (CH) leads to blood-derived somatic mutations in KRAS, NRAS and BRAF. Our aim is to identify the prevalence of CH-derived mutations in these three genes in metastatic colorectal cancer (mCRC) patients and reveal the practical clinical implication of these mutations on plasma genotyping. Methods: We analyzed KRAS, NRAS and BRAF genotypes in plasma and matched tumor tissues of 236 mCRC patients through next-generation sequencing (NGS) and polymerase chain reaction. Suspected CH mutations were defined as those only detected in plasma with variant allelic frequencies (AFs) of <5% and were confirmed by paired peripheral blood cells (PBCs) using droplet digital PCR (ddPCR). The hemopoietic lineage harboring a CH-derived mutation was analyzed through flow cytometry. Results: We identified suspected CH mutations in twenty patients (8.4%, 20/236). Three of these patients (1.27%, 3/236) had a CH-derived KRAS mutation, which was confirmed present in paired PBCs. Two of them had a KRAS G12X and the third had a KRAS Q61H. We did not detect CH-derived NRAS or BRAF mutations in our cohort. All three patients harboring a CH-derived mutation previously received chemotherapy treatment. In a selected CH-derived KRAS G12X case, the mutation was enriched in lymphocytes and persisted in plasma cell-free DNA (cfDNA) over the course of 4 months of therapy. Conclusions: In summary, we confirmed the existence of CH-derived KRAS mutations in a small proportion of mCRC patients. This should be noted to prevent misclassification as tumor somatic mutations when performing cfDNA sequencing in the absence of genotyping matched PBCs.
Chemotherapy-induced neuronal dysfunction in the absence of axon degeneration.
Authors: Housley Stephen Nick , Flores Ann Marie , Wang Allison B. , Perreault Eric J. , Nardelli Paul , Carrasco Dario , Matyunina Lilya , McDonald John F. , Cope Timothy C. 
Published: May 2019

e15091 Background: Colorectal cancer is one of the three most prevalent cancers. Mortality rates have largely decreased due, in part, to advanced treatments such as platinum-based chemotherapy (e.g. oxaliplatin – OX). Unfortunately, OX induces severe off-target, neurotoxic side-effects in the sensory nervous system that can limit or end treatment and diminish patient quality of life for years. Patient symptoms are often attributed to dying-back degeneration of primary sensory axons despite the absence of conclusive evidence. We tested the hypothesis that proprioceptive disorders persisting after chemotherapy result solely from axon degeneration of muscle proprioceptors. Methods: We used a rat model to test our hypothesis. In a rodent model of OX clinical cancer treatment, one that exhibits sensorimotor deficits in a test of proprioceptive behavior, we performed single-neuron in vivo electrophysiological and immunohistological experiments. We then profiled transcriptomes of sensory neurons to gain unbiased insight into molecular evidence of degeneration. We compared the OX group of rats (n = 18) to healthy, control rats (n = 6) using hierarchical Bayesian analysis. Results: We found no evidence for sensory axon degeneration in electrophysiologic measures of axon conduction or in immunohistochemical analysis of the axon terminals of sensory neurons, OX and control rats were indistinguishable by these measures. Unbiased transcriptional profiling gave little evidence of neuronal degeneration, although genes related to axon transport showed signs of dysregulation. Structural degeneration was also ruled out by finding that all sensory neurons fired in response to stretch. Nonetheless, anomalous firing patterns were observed, e.g. decreased spike activity in response to mechanosensory stimulation, consistent with changes in ion channel physiology. Conclusions: Our findings reject the hypothesis that nerve degeneration is required to explain OX-related sensorimotor disorders. Our research suggests biological mechanisms that are alternative to axon degeneration in explaining sensorimotor changes due to OX.
The metabolic clinical risk score (mCRS) as a new prognostic model for surgical decision in patients with colorectal liver metastases.
Authors: Duran Derijckere Ivan , Levillain Hugo , Bohlok Ali , Mathey Celine , Nezri Jonathan , Muteganya Raoul , Lucidi Valerio , Bouazza Fikri , Van Simaeys Gaetan , Goldman Serge , Hendlisz Alain , Flamen Patrick , Donckier Vincent 
Published: May 2019

e15094 Background: Selection for surgery in patients with colorectal liver metastases (CRLM) remains poorly accurate. We evaluated if baseline metabolic characteristics of CRLM, as assessed by [18]-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18FDG-PET/CT), may predict the postoperative outcome in patients operated for CRLM. Methods: In a series of 450 patients operated for CRLM, we retrospectively identified 2 groups: The long-term survival (LTS), as defined by postoperative recurrence-free survival (RFS)≥5 years, and the early relapse groups (ER), as defined by RFS < 1 year. Clinicopathologic characteristics, Clinical Risk Score (CRS) and baseline 18FDG-PET/CT metabolic parameters were analyzed. Baseline 18FDG-PET/CT was performed at the time of diagnosis of CRLM, before any preoperative treatment. Low and high-risk CRS were defined by scores of 0 to 2 and 3 to 5, respectively. Metabolic CRS (mCRS) was implemented, using 1 additional point to the standard CRS when the highest tumor standardized uptake value (SUVmax) and normal liver mean SUV (SUVmean(liver)) ratio was > 4.3. Low and high-risk mCRS were defined by scores of 0 to 2 and 3 to 6, respectively. Results: We analyzed 53 patients. No difference was observed between LTS (n = 23) and ER (n = 30) groups for clinicopathologic parameters related to the primary tumor and CRLM, CRS and rates of low/high risk CRS. All metabolic parameters analyzed, including SUVmax and SUVpeak, at the exception of metabolic tumor volume, were significantly increased in ER group. Median SUVmax/SUVmean(liver) ratio was significantly increased in the ER vs LTS, respectively of 4.2 and 2.8 (p = 0.008). mCRS was significantly higher in ER as compared to LTS patients (p = 0.024), while 61% of the LTS patients had a low-risk mCRS and 73% of the ER patients had a high-risk mCRS (p = 0.023). Conclusions: Baseline 18FDG-PET/CT characteristics demonstrate an increased tumor glucose uptake in patients who rapidly recur after curative-intent surgery for CRLM. The introduction of these data into clinical risk model may represent a new tool to improve selection for surgery in patients with CRLM.
The mutational landscape of circulating cell-free DNA to identify neoadjuvant chemotherapy response in colorectal cancer patients.
Authors: Liu Yanlong , Wei Xiaoli , Shi Xinying , Yang Ying , Fu Lili , Mao Beibei , Zhang Henghui , Cui Binbin 
Published: May 2019

e15096 Background: The neoadjuvant chemotherapy plays an important role in the current treatment of colorectal cancer (CRC), even though parts of patients could not be benefit from it. This study was aimed to explore the specific mutational profile of plasma cell free DNA (cfDNA) in CRC patients with or without response to neoadjuvant chemotherapy. Methods: 16 eligible CRC patients were enrolled in this study from Harbin Medical University Cancer Hospital. These patients were divided into two groups: with response ( R, n = 8) and without response (NR, n = 8) to neoadjuvant chemotherapy. All patients received neoadjuvant chemotherapy and their baseline blood samples were collected. The cfDNA fragments were extracted for enrichment of a panel covering exon regions of 1,086 genes. Gene alterations were analyzed to investigate the relationship between genetic characterizations of cfDNA and response to neoadjuvant chemotherapy. Results: Principal component (PCA) analysis for copy number variation(CNV) of cfDNA differed significantly in two groups. In the R group, there were higher frequency CNV loss in ABL-1, ERBB3, SMO, IGF1R, AURKA, PDGFRA, IDH1, BRAF, PIK3CB, NRAS, NF1, MITF, PTCH1 genes, and CNV gain in MTRR, HSP90AA1, VHL, CREBBP, CHEK2, DDR2, MUTYH, NCOA1, XPC, FANCA genes. Regarding to the area under the ROC curve, CNV of these genes had a high value of 0.967, which implied that CNV of the candidate genes have predictive value for identifying response to neoadjuvant chemotherapy in CRC patients. Furthermore, the Copy Number Instability (CNI) value of R group was significantly higher than NR group(p = 0.0014). Conclusions: The candidate genes’ copy number variation and CNI value of baseline plasma cfDNA can identify the colorectal cancer patients with response or without response to neoadjuvant chemotherapy in this small cohort. The molecular profile of cfDNA in plasma may be a potential biomarker for predicting the response to neoadjuvant chemotherapy in colorectal cancer patients. These findings warrant further expanded prospective cohorts to validate.
Single center experience: Management of metastatic appendiceal cancer with peritoneal carcinomatosis.
Authors: Malapati Sindhu Janarthanam , Khan Uqba , Mouabbi Jason Aboudi , Kafri Zyad , Hadid Tarik H. , Berri Richard N. , Sakhi Ramen , Mazzara Paul , Szpunar Susan 
Published: May 2019

e15103 Background: Appendiceal tumors constitute only 1% of intestinal malignancies with no established standard of care due to their relative rarity. Timing, preferred regimen and utility of chemotherapy in this malignancy are among the many questions that still remain unanswered. Methods: Retrospective chart review of patients treated for appendiceal carcinoma at our institution who had slides available for pathology review (96 patients met this criteria). Results: Mean age at diagnosis was 55.8 years. 84% were Caucasian and 13.8% were African American, 19.8% had a family history of colon cancer. Mucinous adenocarcinoma was the most frequent subtype (70.8%) followed by colonic (8.3%), signet ring, goblet cell and mixed. 63 had cytoreductive surgery, 63 had HIPEC, 23 had neo-adjuvant and 41 patients had adjuvant chemotherapy. 30 patients received bevacizumab with first line. 6 of 43 patient with CCR0, 0 of 10 patients with CCR1 and 1 of 10 patients with CCR2 died during follow-up. Eventually, 17 patients had second surgery (debulking in 6, debulking+HIPEC in 11). 52 patients had progression and this was most frequently diagnosed on surveillance imaging (73.1%.) Mean time to progression (TTP) was 39.3 months (8-432 months) and second progression was 62.4 months (21.5-177.6 months.) Median time from surgery to progression was 31.6 months (9.6-417.5 months). TTP and OS are not associated with age and although mean survival was numerically greater in women (303.9 months) than men (220.5 months), this was not statistically significant (p=0.903). Pathologic grade 1 had a longer time to progression compared to grade 2 and 3 (176.9 months versus 55.5 and 59.1 months, p= 0.001). There was a significant difference in TTP based on tumor differentiation (p=0.019) with 191.5 months, 45.3 months and 67.2 months in well, moderate and poorly differentiated respectively. Survival by pathologic grade approached significance (p=0.067), 336.3 months, 171.9 months, 129.1 months in grade 1, 2 and 3 respectively. Conclusions: 80% patients have peritoneal carcinomatosis at diagnosis and for every 1 increase in PCI, the risk of progression increases by 4.8% but this does not affect survival. FOLFOX/ Xelox in first line was associated with longer time to progression. [Table: see text]