bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overlooking MMR deficiency in carriers of certain pathogenic variants by routine MSI and/or IHC testing in Lynch syndrome: Implications for a wider MMR deficiency testing.
Authors: Staninova Stojovska Marija , Kubelka Sabit Katerina , Jasar Dzengis , Jovanovic Rubens , Matevska Nadica , Angelovska Biljana , Mitrevski Nenad , Panovski Milco , Dimovski Aleksandar J 
Published: May 2020

e16107 Background: DNA mismatch repair (MMR) deficiency occurs in both inherited/sporadic colorectal cancer (CRC) and endometrial cancer, but it may also be found in some other types of cancer. At present, MMR status testing in clinical practice is recommended for all CRC patients in order to identify those who should be offered genetic testing for the Lynch syndrome (LS), inform disease prognosis, and guide therapeutic management.There are two commonly accepted methods for MMR deficiency analysis, one based on the detection of microsatellite instability (MSI) by PCR and the other based on the detection of protein expression of the MMR genes using immunohistochemistry (IHC). The objective of this study was to evaluate the concordance between IHC and MSI in tumors from 18 LS patients with known pathogenic germline variants in MMR genes (MLH1, MSH2, PMS2 and MSH6). Methods: The MSI testing was performed using the five gene Bethesda panel (BAT25, BAT26, D2S123, D5S346, D17S250) while the IHC testing was done with the use of a standard 4 antibody panel (MLH1, MSH2, PMS2 and MSH6). Results: High concordance of the two methods was observed in 13/18 (72.2%) patients, mainly with disruptive mutations in the МLH1, MSH2 and PMS2 genes. Inconsistent results were obtained in 5/18 (28.8%) patients, of whom two had a positive result only with the use of the PCR method [carriers of MLH1 c.62C > T (p.Ala21Val) and c.244A > G (p.Thr82Ala) missense variants], other two had a positive result only with IHC [carriers of MSH6 c.3514dupA (p.Arg1172LysfsTer5) and c.2384T > C (p.Ile795Thr)] and one patient had normal results using both methods (carrier of MSH6 c.457+1G > T splice site mutation that results in exon 3 skipping). A positive predictive value of either MSI or IHC used as a single methods for screening was 83.3%, which indicates that a substantial number of cases with MMR tumors can be misdiagnosed by using only either one or the other of these two methods. Conclusions: These results have a potential implication not only for LS screening in CRC patients, but also for the detection of the MMR deficiency in patients with various tumors that might benefit from the checkpoint inhibitor immunotherapy. The use of extended MSI NGS panels might provide a higher sensitivity for the detection of MMR deficiency compared to the standard MSI or ICH testing.
Expression profile of micro-RNA of lymphovascular invasive colon cancer.
Authors: Chen Zhongning , Fugere Tyler , Pandey Yadav 
Published: May 2020

e16109 Background: Lymphovascular invasion (LVI) is an independent predictor of disease progression in patients with colorectal cancer, and is often associated with high tumor grade and advanced tumor stage. In concordance, micro-RNA(miRNA), which are small non-coding RNA that regulate post-transcriptional gene expression, have also recently been shown to be promising biomarkers to predict disease prognosis. The purpose of this study is to investigate [1] potential mechanism of tumor invasion by identifying miRNA that are differentially expressed with respect to LVI status, and [2] create a model to predict likelihood of SVI. Methods: Data was obtained from the TCGA database. Patients were selected based on biopsy proven diagnosis of adenocarcinoma of the colon. Patients were divided into based on the status of lymphovascular invasion (209 patients LVI negative, and 145 patients positive). A total of 130 miRNA were analyzed after filtering out miRNA expression counts < 10. The differential expression profile of the miRNA between the two groups were analyzed using a quasi-likelihood F test implemented by bioconductor package, edgeR. This package is well documented for analyzing RNA-seq data due to adjustment for biological variations and measuring error using a negative binomial distribution. After adjusting for gender, the expression of miRNA |Log2FC| > .3 and P value < 0.05 were obtained. A model was created using support vector machine (SVM) using miRNA that are differentially expressed. Results: Compared to negative LVI group, the positive LVI group has a miRNA profile with the down regulation of hsa-let-7f-1, hsa-let-7f-2, hsa-mir-200c, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-378a, hsa-mir-374a, hsa-mir-361, hsa-mir-128-1, and hsa-mir-200b, and up regulation of hsa-mir-142, hsa-mir-199b, hsa-mir-199a-1, and hsa-mir-199a-2. A support vector machine classifier with a predict power of 70% was created using the miRNA described as above. Conclusions: This miRNA expression profile unifies known pathways for LVI, such as over expression of myosin heavy chain 9 gene, or dysregulation of zinc finger E-box binding homeobox 1. They also act as biomarkers to predict the likelihood of LVI.
PD-L1 expression on tumor cells and tumor infiltrating immune cells in Chinese colorectal cancer patients.
Authors: Yang Jianjun , Xu Guanghui , Zheng Jiyang , Du Kunli , Zhou Wei , Wei Jiangpeng , Wang Haoyu , Yao Anliang , Zhao Fuyan , Cong Yuwei , Zhao Xiaochen , Bai Yuezong 
Published: May 2020

e16111 Background: Nowadays, immune checkpoint inhibitors (ICIs) targeting programmed death-1/ligand-1 (PD-1/PD-L1) have been an alternative in cancer treatments. Previous biomarker analysis found that response to anti-PD1/PD-L1 was associated with PD-L1 expression on tumor cells and/or tumor infiltrating immune cells in some cancer types. Explorations of IMblaze370 study demonstrated better survival outcome in colorectal cancer (CRC) patients with positive PD-L1 expression compared with those with negative PD-L1 expression in the atezolizumab group. Our study investigated PD-L1 expression profile in Chinese CRC population. Methods: PD-L1 expression on tumor cells or tumor infiltrating immune cells in 816 CRC tumors between January 01, 2017 and December 02, 2019 in 3D Medicines database was assessed by immunohistochemistry assay (SP263 or 22C3). We defined percentage of PD-L1 expression on tumor cells as tumor proportion score (TPS) strong positive ≥50%, moderate positive ≥5% and < 50%, weak positive ≥1% and < 5%, and negative < 1%. Similarly, we defined percentage of PD-L1 expression on infiltrating immune cells as immune proportion score (IPS) strong positive ≥10%, moderate positive ≥5% and < 10%, weakly positive ≥1% and < 5%, and negative < 1%. In addition, MSI status was evaluated with targeted next-generation sequencing covering 100 MSI loci. Results: 12 (1.5%) individuals had TPS as strong positive, 63 (7.7%) as moderate positive, 95 (11.6%) as weak positive and 646 (79.2%) as negative. Meanwhile, TPS of patients were 55 (6.7%) for strong positive, 49 (6.0%) for moderate positive, 34 (4.2%) for weak positive and 678 (83.0%) for negative, respectively. 16.9% in Chinese CRC patients here were defined as positive PD-L1 expression (IPS ≥1%), which is lower than the positive proportion of CRC in IMblaze370 study (39.9% for IPS ≥1%, P < 0.0001). The PD-L1 expression on tumor cells and on tumor infiltrating immune cells showed minimal overlap. In detail, only 29 (3.6%) patients exhibited simultaneously TPS positive (≥1%) and IPS positive (≥1%). Furthermore, IPS was not associated with MSI status (P = 0.9153), while TPS showed an association with MSI-H (P < 0.0001). In detail, 45.5% of MSI-H CRC patients were TPS positive. Conclusions: Chinese CRC patients express PD-L1 with 20.8% TPS positive and 17.0% IPS positive, and TPS positive were related to MSI-H. When studying the connection between the efficacy of PD1/PD-L1 inhibitors and PD-L1 expression, TPS and IPS detection would be both considered to engage.
Effect of neoadjuvant chemotherapy and early chemotherapeutic response evaluation for low/intermediated-risk mid-low stage II/III rectal cancer: A prospective, open-label, single-arm, phase II trial.
Authors: Deng Xiangbing , Bi Liang , Wu Qingbin , He Du , Gou Hongfeng , Wu Bing , Yu Yongyang , Meng Wenjian , Meng Qiu , Wang Ziqiang 
Published: May 2020

e16133 Background: Neoadjuvant chemoradiotherapy (NCRT) is the standard of care for stage II/III rectal cancer (RC) for its local-control effect. As advancement in surgery, local relapse was no longer the primary cause of failures, especially in low/intermediated-risk stage II/III RCs, in which benefit of radiotherapy in local control wasn’t shown in our previous trial. Distant relapse has become the major form of recurrences, and occurs at an increased rate when chemotherapy was delayed. This trial explores the effect of neoadjuvant chemotherapy (NCT), and the possibility of early assessment of chemotherapeutic response in low/intermediated-risk stage II/III RCs. Methods: This prospective, single arm, phase II trial planned to enroll 60 low/intermediate-risk stage II/III mid-low RCs (low: cT3a-bN0-1M0 MRF(-); mid: cT3a-c or T4aN0-1M0). 4 cycles of CAPOX NCT were scheduled. Rectal MRI, transanal US, endoscopy, CT were examined prior to treatment and after every two cycles. The primary outcome was the clinicopathological response, defined as pathological TRG0-1, TRG2 without tumor length increase, or TRG3 with tumor length regression over 30%. This study was approved by the Ethics Committees of West China Hospital and registered at ClinicalTrials.gov (NCT03666442). Results: From Dec. 2017 to Oct. 2019, 61 eligible patients were enrolled. Two patients received 3 cycles and 2 had only 2 cycles of chemotherapy due to intolerable adverse effects; 57 cases finished 4 cycles. In pathological evaluation, 13 patients (21.3%) were complete response (pTRG0) with one positive node in one patient; 5 cases were pTRG1; 26 were pTRG2; 17 had no response (pTRG3). 48 cases (78.7%) were responders. In the ROC curve predicting the responder via the 2-cycle regression in tumor length, the AUC was 0.864 (95%CI (0.764,0.963), p < 0.001), and the best cutoff regression rate after 2 cycles NCT was 27%. With this cutoff, the sensitivity was 83.3%; specificity was 84.6%; accuracy was 83.6%; positive likelihood ratio was 5.42; negative likelihood ratio was 0.20. Conclusions: NCT achieve more favorable pCR and tumor response rate in low/intermediated-risk stage II/III RCs, comparing to previous studies. The tumor regression after 2 cycles NCT had good accuracy in diagnosing the chemotherapeutic response. This early assessed chemosensitivity may become another feature for tailored use of neoadjuvant treatments, further cohort study will be conducted. Clinical trial information: NCT03666442 .
In-hospital outcomes of splanchnic vein thrombosis including Budd Chiari syndrome associated with GI malignancies.
Authors: Handa Shivani , Gupta Kamesh , Khan Ahmad , Mehta Kathan , Kasi Anup 
Published: May 2020

e16503 Background: Patients with gastrointestinal (GI) malignancies are at increased risk of developing splanchnic vein thrombosis (SVT). However, there is a dearth of information about the epidemiology of splanchnic vein thrombosis associated with specific GI malignancies. We sought to compare the differences in hospitalizations and mortality related to SVT among various GI malignancies. Methods: We included the top three discharge diagnoses to identify cases of splanchnic vein thrombosis (portal/mesenteric/hepatic and splenic vein thrombosis) along with a secondary diagnosis of a GI malignancy, namely esophagus, gastric, hepatic, colorectal, pancreatic and cholangiocarcinoma within the 2010-2014 Nationwide Inpatient Sample (NIS). Outcomes including mortality, hospitalization charges and length of stay were compared for different types of GI malignancies for SVT hospitalizations using the chi-square test. Complications related to SVT were also identified. Data was analyzed using STATA 15. Results: There were 320,804 total weighted admissions for SVT, of which 33,556 or 11.6% occurred in patients with GI malignancies. Hepatic cancer was the most common GI malignancy associated with SVT, responsible for 5.1% of all cases, followed by pancreatic cancer (2.76% cases). Hepatic vein thrombosis was the commonest type of SVT occurring in patients with GI malignancy. Hospitalizations for SVT in GI malignancies increased from 5743 in 2010 to 8415 in 2014, representing an increase of 46% over 5 years. On univariate analysis, patients with esophageal cancer and SVT had higher rates of cardiac arrest (3.5% vs 0.7% average for other cancers, p = 0.03), but there were no significant differences in rates of other complications studied including intracranial hemorrhage, requirement for blood transfusion, mechanical ventilation or variceal bleeding. Inpatient mortality rate for admission with SVT was the highest for esophageal cancer (21.1%), followed by gastric cancer (17%) against an average of 9.3% for all GI malignancies (p < 0.05).The median cost of an admission for a patient with SVT were highest for esophageal cancer $102,452, followed by colorectal cancer ($97,491) and the least for hepatic cancer ($67,007). Conclusions: We found that hospitalizations for splanchnic vein thrombosis in patients with GI related malignancies has been steadily increasing and represent a significant burden. Hospitalizations for SVT in esophageal, gastric and colorectal cancer patients bear poorer outcomes as compared to hepatic cancer.
Safety and preliminary antitumor activity of the transforming growth factor beta (TGF-β) receptor I kinase inhibitor, vactosertib, in combination with paclitaxel in patients with metastatic gastric adenocarcinoma.
Authors: Jung Minkyu , Lee Choong-Kun , Kim Hyo Song , Ock Chan-Young , Bum Bae Jin , Lee Jin , Kang Dong Woo , Hwang Sunjin , Kim Seong-Jin , Chung Hyun Cheol , Rha Sun Young 
Published: May 2020

e16505 Background: Recent studies demonstrated that TGF-β signaling attenuation in combination with paclitaxel inhibits epithelial-to-mesenchymal transition and cancer stem-like cells features, especially in diffuse type. We are reporting dose finding part in phase 1b study evaluating the combination of vactosertib, a highly selective and potent TGF-β inhibitor, with paclitaxel as a second line treatment in patients with metastatic gastric adenocarcinoma (GA). Methods: Eligible patients (pts) are ≥19 years old, have ECOG status ≤1, and have progressed on the first line treatment of metastatic GA treated with the combination therapy of fluoropyrimidine and platinum, or trastuzumab containing combination therapy in HER2-positive GA. The primary objective is to assess the safety and recommended phase 2 dose (RP2D) of vactosertib given 5 days on/2 days off in combination with weekly paclitaxel 80 mg/m2. Three dose levels of vactosertib (100, 200, and 300 mg BID) were tested. Results: As of Jan. 25, 2020, 12 pts were enrolled to the study (6, 3, and 3 pts in 100, 200, and 300 mg BID, respectively) and finished the safety evaluation. Median age was 50 (range, 39-65), 50% were male, and 75% had gastrectomy (4 pts with subtotal gastrectomy; 5 pts with total gastrectomy). At all cohorts, no dose limiting toxicity was observed. The most frequently reported treatment related adverse events (AEs) were anemia (50.0%), anorexia (41.6%), fatigue (33.3%), and urticaria (33.3%). AEs were mostly grade 1 or 2 and manageable. One case of grade 3 anorexia was reported as a treatment-related severe adverse event. Among 6 evaluable patients in 200/300 mg BID cohorts, the best responses to treatment were partial response in 1 patient; 57% decrease from baseline, 16.7% of overall response rate, and 83.3% of disease control rate at 12 weeks. Median progression free survival of the RP2D cohort has not been reached yet. Updated safety, PK, efficacy and biomarker data will be presented at the meeting. Conclusions: The combination of vactosertib plus paclitaxel has been well tolerated. The anti-tumor activity of this combination in patients with metastatic GA is now under exploration in the phase 2a part of the study. Clinical trial information: NCT03698825 .
Radiotherapy in localized gastric cancer management: To be or not to be?
Authors: Hussein Amany , Al Saleh Khaled , El-Sherify Mustafa , Nazmy Nashwa , Shete Jitendra 
Published: May 2020

e16511 Background: Gastric adenocarcinoma still have dismal outcome in spite of the progress made in systemic treatment in last 2 decades. In localized disease, treatment outcome still suboptimal, with up to 88% suffer from recurrence/metastasis. Hence, improvement in radical initial treatment is mandatory. Recent trials showed survival benefit of adding radiotherapy (preoperative or adjuvant) with favorable toxicity profile when using current advances radiation techniques. Methods: We retrospectively analyzed impact of radiotherapy in management of localized gastric cancer in Kuwait. 87 adult patients with newly diagnosed gastric cancers were treated and followed up at Kuwait Cancer Control Center (KCCC) between 2009-2015, 12 were excluded due to inoperability. 13 patients were excluded as they had early disease and underwent only surgery. Finally, 62 patients were submitted in study 48 patient received radiotherapy (RT group) as part of treatment (44 postoperative, 3 postoperative after induction Chemotherapy, 1 preoperative). 14 patients did not receive radiotherapy (NRT group); five received perioperative chemotherapy, nine received postoperative chemotherapy). Survival analysis was done using Kaplan-Meier, and comparison was done according to clinicopathological features. Results: The median age at diagnosis was 55 (range 25-70). Men represented 65.5%. Asian were 17 patients and Caucasian were 70 patients. 68.9% were nonsmoker while 31% were smoker. Median follow up was 45 months (1-89). 2 year Overall survival in the NRT group was 50% while in RT group was 79.1%. 3 year OAS was 42.8% and 64.5% in NRT group and RT group respectively. Median overall survival for NRT group was 82 months. While for the RT group median survival was not reached at time of analysis with p value (0.025). 2 year DFS in NRT group was 50% while in RT group was 66.6%. 3 year DFS was 42.8% and 54.1% in NRT group and RT group respectively. Median DFS not reached in both groups p value (0.04). On correlation of prognostic clinicopathological features with benefits of adding radiotherapy it was noticed that high grade, positive margins statistically benefit more from local radiotherapy and had better local control. Distal tumours behave badly whether received radiotherapy or not. Interestingly benefit of adding radiotherapy was not significantly affected by nodal status. Conclusions: Radiotherapy should be part of management in postoperative locally advanced gastric cancer especially with high grade tumours and positive margins. However still ongoing trials to clear the role of radiotherapy in preoperative setting.
Precise early detection of gastric cancer and blood cell circuit.
Authors: Kshivets Oleg 
Published: May 2020

e16512 Background: Significance of blood cell circuit in terms of early detection of gastric cancer (GC) was investigated. Methods: In trial (1975-2020) consecutive cases after surgery, monitored 136 GC patients (GCP) (m = 90, f = 46; distal gastrectomies = 95, proximal gastrectomies = 34, total gastrectomies = 7) with pathologic stage IA (tumor size = 1.81±0.70 cm; adenocarcinoma = 136; T1N0M0 = 136; G1 = 67, G2 = 26, G3 = 43, 5-year survival = 100%) and 120 healthy donors (HD) (m = 69, f = 51) were reviewed. Variables selected for study were input levels of blood cell circuit, sex, age, TNMG. Differences between groups were evaluated using discriminant analysis, clustering, nonlinear estimation, structural equation modeling, Monte Carlo, bootstrap simulation and neural networks computing. Results: It was revealed that early detection of GC from HD (n = 256) significantly depended on: leucocytes (abs, total), segmented neutrophils (%, abs, total), lymphocytes (%), monocytes (%, abs, total), stick neutrophils (%, abs, total), eosinophils (%, abs, total) (P = 0.007-0.000). Neural networks computing, genetic algorithm selection and bootstrap simulation revealed relationships of early detection of GC and lymphocytes (rank = 1), segmented neutrophils (rank = 2), monocytes (3), stick neutrophils (4), leucocytes (5), eosinophils (6). Correct detection of early GCP was 100% by neural networks computing (error = 0.000; area under ROC curve = 1.0). Conclusions: Early detection of GC from HD significantly depended on blood cell circuit.
Limonoid compounds from Xylocarpus granatum and their anti-cancer activity against esophageal cancer cells.
Authors: Jing Li , Feng Li , Zhou Zhiguo , Shi Shuai , Deng Ruoying , Wang Zhicong , Liu Yibing 
Published: May 2020

e16516 Background: We aimed to study the anti-cancer effects of limonoid compounds that were isolated and purified from Xylocarpus granatum fruits on human esophageal cancer cells. A structure-activity relationship experiment was designed to identify the functional moiety of limonoid compounds identified as being critical for its anti-cancer activity. Methods: Esophageal cancer Eca109 cells were treated with limonoid compounds. Cell proliferation was determined by the MTT assay in vitro and cellular apoptosis by flow cytometry and Western Immunolotting. Results: Four linonoid compounds strongly inhibited the cellular proliferation of Eca109 cells. Xylogranatin C was the strongest inhibitor, whose inhibitory effect was comparable to that of the well-known chemotherapeutic agent, cisplatin. Furthermore, xylogranatin C might induce Eca109 cell apoptosis through joint effects on multiple pathways, including the death receptor and endoplasmic reticulum pathways. Additionally, xylogranatin C suppressed tumor cell proliferation by up-regulating miR-203a expression in Eca109 cells. Conclusions: Inhibitory effects of xylogranatin C were more potent than cisplatin. Xylogranatin C induced Eca109 cellular apoptosis and exerted anti-tumor activity. Xylogranatin C might have induced Eca109 cellular apoptosis via joint effects on multiple pathways, including the death receptor and mitochondria-dependent signaling pathways. Additionally, xylogranatin C suppressed tumor cell proliferation by up-regulating miR-203a expression in Eca109 cells.