bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deviation from the precisely timed phenomic ageotypes can assist in early CRC screening and reveal underlying pathophysiology.
Authors: Thyparambil Sheeno P. , You Jin , Liu Kang , Sun Hui , Peng Junjie , Cai Sanjun , Li Yaqi , Fu Chen , Bao Pingping , Li Qing , Hao Shiying , Zhang Yani , Li Zhen , Yang Jingzhi , Yin Ziyu , Yao Xiaoming , Zhu Xiurui , Schilling James , Sylvester Karl G. , Ling Xuefeng B. 
Published: May 2020

e16098 Background: Human serum proteome and metabolome profiles have been analyzed to explore the molecular changes that occur with aging. We hypothesized that deep phenomic profiling of longitudinal sera would allow the identification of distinct phenomic chronologic patterns as a normal biological clock baseline to study personal aging. We further hypothesized that molecular assessment of this chronologic deviation, due to advance adenoma and early CRC, from the normal reference ageotypes would be instrumental as potential early diagnostics and reveal underlying pathophysiology. Methods: A cohort of 7673 normal, 746 advanced adenoma, 1177 stage I, 103 stage II and 119 stage III blood samples were assembled. Innovative multi-omics approaches, with global and targeted LCMS data production (metabolomics, lipidomics, and 2D proteomics), were applied to deep profile these subjects. Identification of the age-associated molecular patterns in normal subjects, modeled with an elastic net algorithm, established the reference baseline to mirror a biological clock. CRC associated deviation from this chronologically paced multi-omics clock was quantified to screen for early CRCs and explore the underlying pathophysiology. Results: Multiple mProbe aging indices of proteins and metabolites were identified, strongly predicting chronologic age ( P < 0.001, R > 0.90). Significant disruptions from normal molecular patterns were observed in advanced adenoma and early CRCs patients (R < 0.7). Pathway analysis of the proteins/metabolites with deviating patterns revealed both known and new pathways underlying CRC. Unsupervised cluster analysis identified unique aging subgroups among advanced adenoma and different stage CRC patients, indicating unique underlying biology relating to aging with different severities of cancer burdens. Conclusions: Deviations from the meticulously timed phenomic aging patterns may provide utility to allow future early CRC screening. Close examination of the underlying pathophysiology associated with early CRC, relating to ageotypes, not only may improve the sensitivity and specificity of prognostic and diagnostic tests of early CRCs, but also shed new insights into CRC therapeutics.
Copy number variation and expression of CT-genes in patients with colorectal cancer.
Authors: Gevorkyan Yuriy A. , Kutilin Denis S. , Kit Oleg I. , Soldatkina Natalya V. , Kharagezov Dmitry A. , Dashkov Andrey V. , Kaymakchi Dmitry O. , Poluektov Sergey I. , Kolesnikov Vladimir E. , Dontsov Vladimir A. , Tolmakh Roman E. , Ilchenko Sergei A. , Stateshny Oleg N. , Petrov Dmitry S. , Grechkin Fedor N. , Oganyan Nairi B. , Mirzoyan Ellada , Fomenko Yuriy A. 
Published: May 2020

e16104 Background: Cancer-testis antigens (CTAs) can be used for immunotherapeutic approaches and early detection of malignant tumors. Despite numerous studies of CTA expression in various tumors, including colon tumors, the mechanisms of transcriptional activity regulation in colorectal cancer (CRC) remain poorly studied. One of the possible mechanisms of regulation of gene expression is a change in their copy number (CNV). The aim of the study was to analyze the changes in the copy number and expression of CT-genes in patients with CRC. Methods: Tumor and normal colon tissues of 81 patients were used in the study. DNA was isolated by phenol-chloroform extraction. RNA was isolated by the Chomczynski&Sacchi method (2006). The REVERTA-L reagent kit was used for the cDNA synthesis. Determination of expression and copy number of 16 CT genes ( MAGE-A1, -A2, -A3, -A4, MAGE-B1, -B2, GAGE-1, -3, -4, MAGEC1, BAGE, XAGE3, NYESO1, SSX2, SCP1, PRAME1) was performed using the Real-Time qPCR method (reference genes - GAPDH and GUSB). Differences were evaluated using the Mann-Whitney test, correlation analysis - using Spearman's rank correlation coefficient (r). Results: An analysis of CT-gene expression and CNV in tumor and normal colon tissues (n = 81) revealed a statistically significant (p < 0.05) difference between these parameters in tumor tissue relative to normal one: for MAGEB1 an increase of 2.0 and 2.7 times, GAGE3 an increase of 2.0 and 2.5 times, GAGE4 decreased by 5.0 and 6.8 times, BAGE decreased by 2.4 and 1.7 times, SSX2 increased by 1.8 and 2.1 times, SCP1 increased copy number by 4.4 times and PRAME1 increased expression and copy number by 2.9 and 2.3 times, respectively. When comparing CNV and expression of 16 CT genes, a positive correlation was observed (r = 0.875). Conclusions: Thus, the aberrant expression of MAGEB1, GAGE3, GAGE4, BAGE, SSX2 and PRAME1 found in the tumor tissue of CRC patients depends on the copy number of these CT-genes.
Treatment modalities and outcomes in patients with rectal cancer (RC) in a referral center in Mexico.
Authors: Camargo Vanessa Rosas , Buerba Hector , Martinez Cruz Perla Lizeth , Anaya Sánchez Luis Guillermo , Cedro-Tanda Alberto , Caballero Rosa , Nieto Garcia Zuleyma , Meneses Medina Mónica Isabel , Flores Balcázar Christian Haydeé , Gamboa Dominguez Armando , Salgado Nesme Noel , Huitzil Melendez Fidel David 
Published: May 2020

e16105 Background: Regarding cancer care, health system in Mexico is characterized by heterogeneous medical and technical infrastructure among institutions. Limited access to specialized surgeons, radiation therapy and medications may differ and affect survival. Our institution has surgeons, medical oncologists and radiation therapy for the treatment of uninsured low-income patients with RC. The institution does not provide chemotherapy or biologic therapy. Our aim was to describe treatment modalities and outcomes in patients (pts) with RC treated in a referral center in Mexico. Methods: A retrospective database of all consecutive pts with histological diagnosis of rectal adenocarcinoma evaluated at our institution from January 2010 to December 2016 was created. Clinical and pathological variables at diagnosis and treatment modalities were recorded. Overall survival (OS) was estimated using Kaplan-Meier method and compared by log rank test. Results: 99 pts were included, 61.6% male gender. Median age was 61 y/o (range 19 – 97). EGOG PS 0 – 1: 86%. 69% were moderately differentiated. Tumor location: lower (25%), middle (57%), and upper third (18%). Clinical stage (CS) was localized (T1-2, N0 M0) 5%, locally advanced (T3-4, or N+) 71% and advanced (M1) 24%. Treatment modalities (TM) by stage are presented in the Table. For those with advanced disease, 58% had metastasis in one site. RAS and BRAF mutation determination was performed in 21%. 5-year survival rate: 56%. Median OS (months): 25.3 for localized, 103.1 for locally advanced and 18.6 for advanced disease (P = 0.001). Conclusions: In our center, pts with local and regional RC had treatment according to international guidelines and survival was not compromised. On the contrary, limited access to systemic therapy affected patients with advanced disease and decreased survival was documented. To improve survival in patients with advanced disease, health policy adjustments to incorporate systemic treatment coverage are required. [Table: see text]
A novel xenonucleic acid mediated molecular clamping technology for early colorectal cancer diagnostics.
Authors: Sun Qing , Pastor Larry , Du Jinwei , Powell Michael Joseph , Zhang Aiguo , Bodmer Walter , Sha Michael Y. 
Published: May 2020

e16106 Background: Colorectal cancer (CRC) is one of the leading causes of cancer-related death. Early detection is critical to reduce CRC morbidity and mortality. In order to meet this need, we developed a molecular clamping assay called ColoScape for early colorectal cancer diagnostics. Methods: Nineteen mutations in four genes APC, KRAS, BRAF and CTNNB1 associated with early events in CRC pathogenesis are targeted in the ColoScape assay. Xenonucleic Acid (XNA) mediated qPCR clamping technology was applied to minimize the wild-type background amplification in order to improve assay sensitivity of CRC mutation detection. The assay analytical performance was verified and validated, cfDNA and FFPE CRC patient samples were assessed for clinical performance, and a ROC curve was applied to evaluate its performance. Results: The data showed that the assay analytical sensitivity is 0.5% Variant Allele Frequency, corresponding to ~7-8 copies of mutant DNA with 5ng total DNA input per test. This assay is highly reproducible with intra-assay CV < 3% and inter-assay CV < 5%. We have investigated 380 clinical samples including plasma cfDNA and FFPE samples from patients with different stages of CRC. The preliminary assay clinical specificity and sensitivity for cfDNA were 100% (95% CI, 80.3-97.5%) and 92.2% (95% CI, 94.7-100%) respectively with AUC being about 0.96; and 96% (95% CI, 77.6-99.7%) specificity and 92% (95% CI, 86.1-95.6%) sensitivity with AUC 0.94 for FFPE. Conclusions: XNA mediated molecular clamping assay is a rapid, precise, and sensitive assay for the detection of CRC mutations in cfDNA or FFPE samples.
Circulating tumor DNA to monitor treatment response and investigate resistance mechanism in BRAF inhibitor treated colorectal cancer patients.
Authors: Wang De-Shen , Li Yu-Hong , Bao Hua , Chen Xiaoxi , Hu Ming-Tao , Li Ting , Yang Hui , Ju Huai-Qiang , Wu Xue , Shao Yang , Xu Rui-hua 
Published: May 2020

e16112 Background: BRAF mutations are found in about 10% of colorectal cancer (CRC) patients and is a poor prognosis factor in standard chemotherapy. Combination of BRAF and EGFR inhibition exerts a better therapeutic effective, whereas the resistance develops through undefined mechanisms. Circulating tumor DNA (ctDNA) is a non-invasive approach to assess the genetic evolution of tumors and prognosis in response to therapy, which would help better understanding the treatment response and resistance mechanism in BRAF inhibitor treated colorectal cancer patients. Methods: We performed panel next-generation sequencing of 425 cancer-related genes in 39 serial plasma samples collect from 19 patients who have BRAF V600E mutation CRC to track the resistance during the Vemurafenib treatment in combination with Irinotecan and Cetuximab (VIC) and evaluate the treatment response. Tumor responses were assessed radiologically every two months and are used to determine patients with innate or acquired resistance Results: A total of 19 patients were enrolled into the vemurafenib treatment with irinotecan and cetuximab. By January 20, 2020, treatment had been discontinued in 12 (63.2%) of the patients due to disease progression, while the other 7 cases were still under treatment. Among them, four patients with innate resistance (n = 4, 21.1%) were defined as those with PFS of less than 2 months, while patients (n = 15, 78.9%) with acquired resistance were defined as those with PFS of greater than 2 months. The VIC regimen demonstrated efficacy in patients with BRAF-mutant mCRC, with overall response rates was 63.2% (n = 12). Changes in levels of ctDNA at 4 weeks predicts therapeutic responses. CBLB, TP53 and APC baseline mutations were enriched in baseline samples of innate resistant patients. In contrast, MYC and Cell-cycle pathway alterations were enriched in baseline samples of patients with acquired resistance. Acquired RAS and MAPK mutations, known to confer resistance to BRAF inhibitors, were identified in 60% of acquired resistance patients. Moreover, acquired TGFBR2 and SMAD4 loss-of-function mutations were identified as novel resistant mechanism to the combination of BRAF and EGFR inhibition. Experimental validation is ongoing. Conclusions: Longitudinal analysis of ctDNA in BRAF CRC patients provides insights of molecular difference between innate and acquired resistance and gene alternation during resistance requiring. Serial ctDNA monitoring provides early indication of response to BRAF inhibitor in CRC patients.
Identifying education, knowledge and communication gaps in biomarker testing between YO-CRC patients, caregivers, and their medical team.
Authors: Newcomer Kim Lynn , Peterson Danielle , Yarden Ronit ,   N2Young Advisory Board
Published: May 2020

e16115 Background: The proportion of new young-onset colorectal cancer (YO-CRC) cases diagnosed in young people (20-49) had doubled over the past 3 decades, and it is becoming an alarming public health issue. YO-CRC patients face unique clinical challenges, as many are diagnosed at advanced stages of the disease and subjected to aggressive treatments. With the increase of targeted therapies and precision medicine available, NCCN and ASCO guidelines recommend that all stage IV, metastatic CRC patients be tested for 4 biomarkers in addition to MSI-H. However, not all eligible patients benefit from biomarker testing and biomarker-driven therapies. Methods: We conducted an online survey to assess patients, survivors and caregivers’ knowledge and understanding of biomarker testing and whether they feel empowered to discuss with their doctor different treatment options based on their unique tumor characteristics and their preferences. Results: The cross-sectional study was completed by patients and survivors (N = 885) and unrelated caregivers of YO-CRC patients (N = 203). The median age of patients and survivors was 42, and the median age of caregivers was also 42. The majority of the participants were college graduates. Although 82% of stage IV, YO-CRC patients felt informed before treatment began, only 70% indicated their tumor was tested for biomarkers, and 54% of them received biomarker testing before treatment initiation. Only 33% of patients reported they became aware of biomarkers by their medical team while others indicated resources such as internet searches, family and friends, or patient navigators. Many of the caregivers who reported that they served as a liaison between patients and medical information retrieval felt that they did not fully understand the critical aspects of the patients' medical treatment plan. Conclusions: Multiple studies have shown that patient-centered care improves patients’ outcomes. Our organization encourages patients and their families to use medical information to navigate their journey. Our patient-reported study suggests that there are gaps in patients’ and caregiver’s understanding of biomarker testing that may hinder patient's empowerment for reaching evidence-based shared-decision treatment plan together with their physicians.
Genomic biomarkers to determine survival in Multicenter Study of RAS mutations (MURAS) in patients with colorectal liver metastases receiving Y90 radioembolization treatment.
Authors: Dendy Case Meaghan , Ghodadra Anish , Novelli Paula M. , Wu Vincent , Ganguli Suvranu , Wildgruber Moritz , Kohler Michael , Robinson Charles , Kim Charles , Wang David S. , Sze Daniel Y. , Kolbeck Kenneth , Russell Lori , Ludwig Johannes M. , Uhlig Johannes , Kim Kevin 
Published: May 2020

e16119 Background: Assessment of the clinical outcomes and prognostic value of genomic mutations in colorectal liver metastases treated with Y90 radioembolization. Methods: Multi-institution retrospective study of patients who underwent Y-90 radioembolization treatment after tumor genotyping was completed for CRLM. Patients treated between 2008 and 2019 were included from 7 institutions within the United States and Europe. Patient demographics, tumor characteristics, pre- and post- treatment regimens, serum laboratory evaluation and overall survival were analyzed between patients with differing histopathologic and genomic status. Tumor genotyping was obtained for KRAS, BRAF, PIK3CA, AKT, MEK, NRAS and MMR genes. Kaplan-Meier survival estimation and multivariate Cox regression were analyzed. Results: 434 patients treated with Y90 radioembolization fulfilled the inclusion criteria. Of the total cohort, 399 patients were available who had sufficient documented tumor profiling data. Average age at diagnosis was found to be 58.8 years for all patients (60.1% male, 39.9% female). Decreased survival post Y-90 treatment was shown in those patients with increased number of documented tumor mutations (n = 0,1 or ≥2 mutations: median OS 9.63 mos vs. 6.2 mos vs. 5.3 mos; p < 0.0001). Additionally, the median survival in patients with mutated BRAF was 5.0 months, as compared to 9.4 months in those patients with wild-type BRAF (p = 0.0009). Primary colon cancer sidedness was also shown to demonstrate significant difference in survival post-Y90 treatment with left sided primaries showing improved median overall survival (left = 7.5 mos vs. right = 6.3 mos; p = 0.04.) Patient demographics including gender, age and race were not shown to be significant in overall survival post-Y90 treatment (p-values > 0.05). Number of tumor mutations (p < 0.0001, HR = 1.69 CI: 1.39-2.05), BRAF status (p = 0.02, HR = 2.6 CI:1.20-4.9), primary sidedness (p = 0.01, HR = 0.65 CI:0.47-0.90), pre-treatment neutrophil-lymphocyte ratio (p = 0.04, HR = 1.42 CI: 1.02-1.98) and KRAS mutation status (p < 0.0001, HR = 1.81 CI: 1.45-2.26) all persisted as significant predictors of survival on multivariate analysis. Conclusions: Number of tumor mutations, BRAF mutation status, primary tumor sidedness, neutrophil-lymphocyte ratio and KRAS mutation status are all shown to be significant prognostic factors in patients with colorectal liver metastases receiving Y90 radioembolization.
The prognosis valve of tumor regression grade in the same ypStage patients after neoadjuvant treatment in locally advanced rectal cancer: Post-hoc analysis of a prospective trial.
Authors: Zhang Jianwei , Cai Yue , Hu Huabin , Wu Zehua , Xie Xiaoyu , Ling Jiayu , Deng Yanhong 
Published: May 2020

e16129 Background: The ypStage after neoadjuvant treatment was an important prognosis factor in locally advanced rectal cancer (LARC). pCR or ypStage 0 showed best prognosis, while ypStage II-III showed poor prognosis and further adjuvant chemotherapy with FOLFOX was recommended. Tumor regression grade (TRG) was another factor to evaluate the response to neoadjuvant treatment. Even in the same ypStage, the TRG could be different. Here, we tried to analyze the prognosis valve of TRG in the same ypStage after neoadjuvant treatment in LARC from a prospective trial (FOWARC study). Methods: Patients with stage II/III rectal cancer were randomly assigned (1:1:1) to five cycles of infusional fluorouracil plus radiotherapy followed by surgery and seven cycles of infusional fluorouracil as adjuvant treatment, the same treatment plus intravenous oxaliplatin 85 mg/m2 on day 1 of each cycle (mFOLFOX6), or four to six cycles of mFOLFOX6 followed by surgery and six to eight cycles of mFOLFOX6. The primary end point was 3-year disease-free survival (DFS). Survival analysis was performed on different ypStage and TRG (WHO classification) group. Results: In total, 495 patients were randomly assigned to different neoadjuvant treatment. 444 patients received surgery with a median follow-up of 45.2 months. The 3-year disease free survival (DFS) in ypStage 0, ypStage I, ypStage II and ypStage III was 95.8%, 89.2%, 71.7% and 55.1%, respectively (P < 0.0001). In TRG 0, 1, 2 and 3, the 3-year DFS was 93.3%, 83.2%, 68.4% and 63.6%, respectively (P < 0.0001). In ypStage I subgroup, TRG was not an independent prognosis factor, the 3-year DFS for TRG 1, 2 and 3 was 90.0%, 90.7% and 76.2%, respectively (P = 0.277). In ypStage II population, the 3-year DFS for TRG 1, 2 and 3 was 78.6%, 70.3% and 64.7%, respectively (P = 0.184). The ypStage III group showed great heterogeneity, the 3-year DFS for TRG 0-3 was 60.0%, 70.0%, 41.8% and 59.5%, respectively (P = 0.067). Conclusions: Both ypStage and TRG was strong prognosis factor for rectal cancer after neoadjuvant treatment. However, TRG was not an independent prognosis factor in the same ypStage after neoadjuvant treatment. Clinical trial information: NCT01211210 .
Clinical study on the tunnel approach in laparoscopic radical right hemicolectomy.
Authors: Zhang Xijie , Zhang Junli , Zhao Yuzhou 
Published: May 2020

e16135 Background: The medial to lateral approach Laparoscopic right hemicolectomy complies with the “no-touch” principle, but need a demanding procedure with a steep learning curve. This study was designed to assess the superiority of the tunnel approach compared to traditional medial-to-lateral approach in laparoscopic right hemicolectomy for patients with right-sided colon cancer. Methods: The new method was called Tunnel Approach: The tunnel was formed with Toldt's gap was dissociated upward from the attachment of ileocecal part and retroperitoneum, then the right mesocolon was lifted to expose and divide the superior mesenteric blood vessel. We analyzed retrospectively the patients with resectable right-sided colon cancer confirmed by colonoscope and imaging who received the laparoscopic radical right hemicolectomy. The patients were divided into the tunnel approach (group A) and the traditional medial-to-lateral approach (group B) according to the surgical maneuver performed. Results: A total of 84 patients who received laparoscopic radical right hemicolectomy were assigned to group A (n = 42) or group B (n = 42) between January 2016 to June 2017. There was no difference in baseline characteristics including demographics, body mass index (BMI), tumor stage, tumor location and differentiation. The operation time and intraoperative blood loss in group A were significantly better than group B (137.74±22.7 vs. 153.1±28.8min, p < 0.05; 49.0±40.7 vs. 142.9±87.4ml, p < 0.05, respectively).There was no difference in tumor size(5.7±2.1 vs. 5.7±2.1cm, p>0.05), conversion to laparotomy rate(0 vs. 3, p>0.05), lymph node yield(30.5±14.4 vs. 27.9±12.7, p>0.05), time to first flatus(3.4±1.3 vs. 4.0±1.3d, p>0.05), postoperative hospital stays(10.0±2.2 vs. 12.3±3.0d, p>0.05) and complications(2 vs. 3, p>0.05) between two groups. There was no treatment-related death in both groups. Conclusions: The characteristic of “tunnel” approach is to convert the anatomy from a two-dimensional to a three-dimensional view, it showed the benefits of both speed and safety with low intraoperative conversion to laparotomy rate and mortality. This new tunnel approach right hemicolectomy is worth recommended.