bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frequency and prognostic utility of MSI and TILs in advanced noncolorectal GI malignancies.
Authors: Khan Uqba , Hamza Ameer , Khurram Muhammad S , Abraham Renny , Mazzara Paul , Hadid Tarik H. , Kafri Zyad 
Published: January 2019

313 Background: Mismatch repair gene mutation status not only has a role in pathogenesis but also has significant clinical implications with respect to treatment with checkpoint inhibitors. Additionally tumor infiltrating lymphocytes (TILs) are also emerging prognostic biomarker and are utilized in adoptive T-cell therapy as well. Methods: This is a retrospective cohort study of patients who were diagnosed with advanced unresectable non-colorectal GI (NCGI) cancers. Biopsy specimens of patients diagnosed between 2009 and 2015 at St. John Hospital and Medical Center were analyzed. Immunohistochemistry panels were performed on a representative tissue sections for microsatellite instability (MSI) testing. TILs were assessed on the hematoxylin and Eosin stained slide of the same tissue section. MSI was interpreted as stable or high and TILs were categorized as ≤5 and > 5 per high power field. Descriptive statistics were generated using frequency distributions, medians and means. Kaplan-Meier analysis was performed to determine the impact of TILs and MSI on survival; differences by factor were assessed with the Log_Rank test. Results: We analyzed 114 patients; the mean age at diagnosis was 66.8 ± 10.7 years, 61.4% were male. All samples were MSI stable. The percentage of patients with TILs ≤ 5 was 46.5. When stratified by tumor stage, overall median survival by TILs level did not differ significantly. When stratified by type of tumor, overall median survival by TILs level was significantly different only for hepatocellular cancers (HCC) (≤ 5 TILs, 86 days vs. > 5 TILs 312 days, p = 0.031) only, (see table). Conclusions: Our study shows that MSI-H tumors are very rare in advanced NCGI malignancies. TILs are definitely present in tumor microenvironment of NCGI malignancies. Though the number of patients of our study was small, there was a statistically significant difference in median overall survival of patients with HCC when stratified by TILs status.[Table: see text]
Complement levels as predictors of survival in pancreatic adenocarcinoma.
Authors: Sohal Davendra , Lin Feng , Kundu Suman , McCrae Keith , Khorana Alok A. 
Published: January 2019

315 Background: Novel biomarkers to predict outcomes in pancreatic adenocarcinoma (PDA) are urgently needed. Complement activation, an important mediator of inflammatory processes, has been reported in some solid tumors but its role in PDA is unknown. We evaluated the prognostic role of complement in a prospective cohort of PDA patients. Methods: Blood samples were collected from consenting PDA patients at study entry (prior toany new regimen) in a prospective biorepository protocol at Cleveland Clinic from 2013-2016. Samples were processed for C3a, C4a, and C5a levels using ELISA on serum samples (BD Biosciences). Data on clinical variables, treatment, and survival were collected from medical records. Resectability was defined using Intergroup criteria. Statistically significant univariable associations and a priori prognostic variables were tested in multivariable models; adjusted hazard ratios (HR) are presented. Results: The study population comprised 48 consecutive patients. Median age was 65 years (range, 41-84); 60% (n=29) were female; 33 (69%) had potentially curable (resectable or borderline resectable) disease. Overall, 43 (93%) received chemotherapy; 22 (46%) received radiation; 29 (60%) underwent surgery. Median follow-up was 17 months. Median OS was 10.9 (1.6-54.5) months. Baseline levels, and associations with stage and OS are shown in Table. Increasing levels of C3a, C4a and C5a were associated with worsened survival (HR 1.00-1.03 per each unit increase in baseline level) despite not being significantly associated with stage. Conclusions: Levels of C3a, C4a, and C5a are detected in nearly all patients with PDA. Increased levels correlate with OS. Complement activation has not been reported previously in PDA and may be a potential therapeutic target. Our findings suggest that complement levels may serve as novel biomarkers. [Table: see text]
Plasma KRAS as a biomarker for pancreatic ductal adenocarcinoma (PDAC).
Authors: Krantz Benjamin A. , Tsui Dana , Lowery Maeve Aine , Capanu Marinela , Yu Kenneth H. , Kelsen David Paul , Gedvilaite Erika , Zhang Liguo , Selcuklu S Duygu , You Daoqi , Golia Pernicka Jennifer S , Do Richard K. G. , Iacobuzio-Donahue Christine A , O'Reilly Eileen Mary 
Published: January 2019

316 Background: PDAC needs validated diagnostic biomarkers for early detection and predictive markers for outcome. As 95% of PDACs harbor KRAS mutations (mKRAS), circulating tumor DNA (ctDNA) has potential utility in PDAC. We assessed the ability to detect and correlate mKRAS in a metastatic PDAC cohort from Memorial Sloan Kettering Cancer Center. Methods: 10 mL of whole blood was collected. cfDNA was extracted with QIAmp or QIAsymphony DNA extraction kits (Qiagen, Valencia, CA). Directed (KRAS G12D, G12R, G12V, Q61H) or multiplex (G12A, G12C, G12D, G12R, G12S, G12V, G13D) digital droplet PCR (ddPCR) was performed with Raindrop Plus (Raindance Technologies, Billerica, MA) or QX200 (BioRad, Hercules, CA) ddPCR systems. Number and size of liver, lung and lymph node metastases, peritoneal disease (mild, moderate, severe), ascites (trace, small, large) and bone mets (Y/N) were assessed by CT scan. Results: See table. 21 (55%) had detectable ctDNA (ctDNA(+)) with mean mutant allele fraction of 4.5% (0.015-36.8). ctDNA (+) vs (-) PFS and OS from collection were 6.9 and 8.4 months vs. 9.9 and 10.5 (p=0.89 for both). CA19-9, PFS and OS did not correlate with ctDNA tertile (p=0.15, 0.54 & 0.50). On treatment and disease activity were not associated with ctDNA status (p= 0.20 & 0.60). Number and size of liver mets were associated with ctDNA (+) (p=0.006 & 0.007). Conclusions: ctDNA KRAS detection was measurable in metastatic disease with rates consistent with other PDAC reports. Median PFS, OS were lower in ctDNA (+) group but not statistically significant in this diverse cohort. Number and size of liver metastases were significantly higher in ctDNA (+). Future study should focus on practice changing applications with standardized collection, intra-patient comparisons and role of liver disease burden. We have initiated studies to evaluate plasma KRAS prior to and during treatment to address its value as a predictive assay and explore factors affecting ctDNA detection. [Table: see text]
Circulating tumor cells as a surrogate for treatment response in patients with metastatic pancreatic adenocarcinoma.
Authors: Parekh Hiral D. , Starr Jason Scott , Varillas Jose I. , Ivey Alison Marguerite , Barnes Isis , McEwan Margaret A. , Trevino Jose Gilberto , Cioffi Jessica , Hughes Steven J. , Grajo Joseph , Fan Z. Hugh , Allegra Carmen Joseph , George Thomas J. 
Published: January 2019

318 Background: The collection and enumeration of circulating tumor cells (CTCs) are feasible in metastatic breast, prostate and colorectal cancers. CTCs have diagnostic, prognostic and treatment monitoring implications, but have been challenging to detect in pancreatic cancer (PCa). We have proven feasibility of CTCs in PCa. This study is a pilot to assess use of CTCs as a surrogate for imaging response. Methods: Blood samples (7-10mL) from newly diagnosed metastatic PCa were collected within 1 month of treatment initiation (T0) and at repeat scan after 2mo of treatment (T1). Specimens were processed within 6 hours of collection. A UF developed microfluidic device was used to capture and identify EpCam+ CTCs. Isolated cells were verified as CTCs consistent with FDA-approved definitions (cytokeratin+, DAPI+, CD45-). CTC enumeration and changes were correlated with scan RECIST results at T0 and T1. The study was approved by the UF IRB. Results: A total of 16 patients had matched pair CTCs collected and analyzed (Table 1). For the entire cohort, the median CTC count at T0 was 7/mL of blood (range 2-11.5/mL) and decreased to 4.5/mL (range 2-8.5/mL) at T1 (36% reduction). CTCs were reduced to some degree in all patients with therapy. Disease control at T1 was confirmed in 13/16 (81%) with stable disease (n=11), partial (n=1) or complete (n=1) response. Progressive disease was noted in 3 patients. CTCs were reduced by 35% in radiographic stable or responders vs 24% in those with clear progressive disease. Conclusions: This study demonstrated the feasibility of microfluidic technology to reliably and consistently identify CTCs in advanced PCa. While all patients had reduced CTCs with therapy, a trend towards higher reductions were in those with radiographic stable or improved disease. Continued assessment of CTCs in PCa for treatment monitoring are warranted and are ongoing. [Table: see text]
Signet ring cell gastric carcinoma: A descriptive analysis of a unique county population.
Authors: Patel Mital , Patel Neha , Tabibian James H. , Ostrzega Nora 
Published: January 2019

32 Background: Signet ring cell type gastric carcinoma (SRCC) is an uncommon epithelial malignancy of the stomach, with data from the United States (US) being particularly scarce. Compared to other gastric carcinoma types, it has a female predominance, younger age at diagnosis, and late presentation, making treatment particularly challenging. Recent reports suggest this disease may be increasing among even younger patients, for reasons which remain unclear. We aimed to examine the occurrence, features, and outcomes of SRCC in a predominantly minority Los Angeles County patient population. Methods: We identified all patients diagnosed with SRCC at Olive View-UCLA Medical Center (OVMC) from 2004-2017. Clinico-demographic, imaging, and pathologic data were reviewed and analyzed and compared descriptively to available Surveillance, Epidemiology, and End Results (SEER) data. Results: Sixty-six cases of SRCC were identified, of which 77% were Latino, 9% White, 6% Armenian, and the remaining 8% other. Mean age at SRCC diagnosis was 52 years, and 37 (56%) of patients were female. H. pylori infection was present in 35% (43% diagnosed by serum antibody, 35% by pathology, 9% by stool antigen, and 13% by combination). Follow-up was available for 91% of patients. Median survival was 1 year, and 5-year survival was 7%, markedly lower than the 31% reported in SEER. Seventy-two percent of patients were deceased or on hospice within 2 years of diagnosis. Conclusions: In this first US study to assess the clinical epidemiology of SRCC in a predominantly minority population: 1) the mean age of diagnosis was younger than reported in previous studies (55-61 years), 2) the proportion of males was high compared to SEER data, and 3) survival was considerably lower than previously reported. Insofar as the patient population in this study serves as a microcosm of surrounding underserved communities, it is likely that SRCC may be more common than expected in this vulnerable patient population, and that significant clinical differences may exist in presentation and outcomes of SRCC. In light of these differences, further research is needed to examine potential environmental and/or genetic risk factors or disparities which may be operational.
Role of C terminal binding proteins (CtBP) in pancreatic adenocarcinoma (PDAC).
Authors: Joshi Prashant J. , Chawla Ayesha , Memari Patrick , Stansfield John , Idowu Michael , Sima Adam , Grossman Steven R. 
Published: January 2019

320 Background: Overexpression of the oncogenic transcription factors CtBP1 and 2 is common and associated with poor prognosis in ovarian, breast and prostate cancer. CtBP2 drives tumor progression through promotion of epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) activity. Frequent early metastasis observed in PDAC may depend on EMT and CSC activity, prompting us to investigate the prognostic significance of CtBP1/2 in PDAC. In parallel, we determined the oncogenic contribution of CtBP2 to PDAC utilizing a transgenic KRAS mutant mouse PDAC model (CKP) that incorporated heterozygous loss of the Ctbp2 gene (CKP2). Methods: Immunohistochemistry (IHC) using CtBP1/2 antibodies was performed on 69 cases of resected PDAC from VCU Health for the period 2005-16. Clinical data included stage (84% stage 1/2; 16% stage 3/4), initial CA19-9 level, and overall survival. IHC stains were assigned an Allred score (sum of intensity and proportion) by two independent pathologists with a scale from 0-8. Cox Proportional Hazard survival models were fit for CtBP1/2 staining vs. survival. CtBP1/2 correlation with stage and CA19-9 level was tested by ANOVA. CKP mice were bred to Ctbp2 +/- mice, and survival of cohorts (n = 10 each) of CKP vs. CKP2 mice was analyzed by log-rank analysis of Kaplan-Meier survival curves. Results: CtBP1 and 2 expression was uniformly high (7-8) across all cases, including stage 1/2. Thus, no statistically significant survival difference could be derived based on CtBP1/2 expression [CtBP1 HR 1.03 (0.67-1.41) p 0.92, CtBP2 HR 0.75 (0.39-1.43) p 0.31], and no significant association of CtBP1/2 was seen with stage or CA19-9. Suggesting a possible contribution of CtBP2 in human PDAC, Ctbp2 knockout in CKP2 mice improved median survival (9.5 vs. 8.1 weeks, p < 0.05), decreased mean tumor weight (750 mg vs. 400 mg, p < 0.05), and also abrogated peritoneal metastases and ascites normally seen in 100% of CKP mice. Conclusions: While uniformly high CtBP expression in PDAC subverts prognostic use, CtBP may play a pathogenic role, as CKP2 mice exhibited improved survival, lower tumor burden and no peritoneal spread. Our data supports further study of CtBP inhibition as a potential therapeutic strategy in PDAC.
Novel therapeutic strategy to inhibit growth of pancreatic cancer organoids using a rational combination of drugs to induce mitotic arrest and apoptosis.
Authors: Duan Zhijian , Tu Mei-Juan , Zhang Qianyu , Cho May Thet , Huynh Jasmine , Yu Aiming , Kim Edward Jae-hoon 
Published: January 2019

322 Background: The ability of cancer cells to suppress apoptosis is critical for carcinogenesis. The Bcl-2-family of regulator proteins, including the anti-apoptotic members Bcl-2, Bcl-xL and Mcl-1, contributes to a complex network in control of apoptosis. BH3-mimetics (e.g. ABT-263) can inhibit anti-apoptotic Bcl-2 proteins and therefore have been developed as potential cancer therapeutics. Aurora Kinase A (AKA) is over-expressed in pancreatic cancer (PC) and is expressed to regulate G2-M transition during mitosis, making it an attractive target for PC. In this study we hypothesized that a combination of mitotic arrest using an AKA inhibitor (e.g. MLN8237) would sensitize PC to induction of apoptosis by a BH3-mimetic. Methods: Pancreatic cell lines (AsPC-1, PANC-1, MIA PaCa-2, HPAF-II) and patient-derived pancreatic cancer organoids (PDO) were treated with a BH3-mimetic (ABT-263) alone, an AKA inhibitor (MLN8237) alone, or the combination in comparison to untreated controls. Cell viability was measured using the CellTiter-Fluor (Promega) assay. Apoptosis was evaluated by Western blot (WB) for cleaved PARP, caspase 3 or caspase 7, and flow cytometry. Nude mice were implanted with pancreatic cancer cells to generate PC xenografts which were then treated with the same 4 treatment groups as in the in vitro studies. Results: ABT-263 combined with MLN8237 showed greater potency than either single drug alone, demonstrating synergy in inhibiting the growth of PC cells and PDOs. Combined treatment with MLN8237 and ABT-263 in PDOs suppressed organoid formation and proliferation by inducing apoptosis. Mechanistically, MLN8237 enhanced the activity of ABT-263 through reduction of Bcl-xL and Mcl-1 in pancreatic cancer cell lines and PDOs. The combination therapy also showed greater suppression of the growth of xenograft tumors, as compared with control treatments with single drug alone or vehicle. Conclusions: The combination of ABT-263 and MLN8237 appears to synergistically induce apoptosis via reduction of Bcl-2 family proteins in PC and should be further explored.
Downregulation of Raf-1 kinase inhibitory protein as a sorafenib resistance mechanism in hepatocellular carcinoma cell lines.
Authors: Choi Gwang Hyeon , Kim Jin-Sun , Jung Yusun , Kim Kang Mo , Jang Se Jin , Yu Eun Sil , Lee Han Chu 
Published: January 2019

325 Background: Despite enhancing overall survival, sorafenib resistance usually occurs and is a significant limiting factor of improved prognosis in hepatocellular carcinoma (HCC) patients. Therefore, it is important to identify the mechanism of sorafenib resistance. This study is designed to identify that causative factor for sorafenib resistance and to suggest way for overcoming sorafenib resistance. Methods: The sensitivity of sorafenib was compared in human HCC lines and patient-derived HCC primary cells. Based on its cytotoxicity, analysis was performed to examine the altered signaling pathway by sorafenib and its causative factor. It was further investigated that how sorafenib modify the sorafenib resistant inducer through gene or protein expression or stability. We also design the treatment option to overcome sorafenib resistance. Results: Sorafenib activates the Raf/MEK/ERK pathway, causing sorafenib resistance in HCC cell lines and patient-derived HCC primary cells. Reactivation of the MAPK pathway by sorafenib occurs via down-regulation of RKIP at a post-translational level. Knockdown of RKIP increased phosphorylated ERK and consequently suppressed sorafenib-mediated cell death. We also found that sorafenib-reactivated ERK maybe an attractive target for second-line therapy in patients with sorafenib resistance. Sequential combination of sorafenib and PD98059 significantly reduced cell viability and proliferation, while increasing apoptosis efficacy in sorafenib-resistant cells. Conclusions: Our findings suggest that reactivation of the Raf/MEK/ERK pathway through aberrant expression of RKIP is one of the mechanisms for sorafenib resistance in HCC. Sequential combination treatment of sorafenib and PD98059 could provide a new strategy to overcome sorafenib resistance in future clinical studies.
Clinical implementation of a comprehensive targeted amplicon sequencing system for the patients with gastrointestinal cancer as a real world evidence in Japan.
Authors: Hayashi Hideyuki , Tanishima Shigeki , Mori Ryo , Okamura Yasunobu , Yanagita Emmy , Matsuoka Ryosuke , Amano Toraji , Kinoshita Ichiro , Komatsu Yoshito , Akita Hirotoshi , Nishihara Hiroshi 
Published: January 2019

329 Background: Clinical implementation of genome sequencing is recently prevailing in the treatment for cancer. We have launched an in-house clinical sequencing system to perform exhaustive targeted exome sequencing for patients with all types of cancer, as an outpatient service. We have analyzed the clinical utility of this system for patients with gastrointestinal cancer to elucidate real world evidence. Methods: Genomic DNA was extracted from tumor tissues and peripheral blood sera of 86 patients with different types of gastrointestinal cancer, from April 2016 to April 2017. The top five types of primary cancer were colorectal (34%), pancreas (28%), stomach (13%), biliary tract (12%), and esophagus (8%). We performed a targeted amplicon exome sequencing for 160 cancer-related genes. The sequencing data was analyzed using an original bioinformatics pipeline within three days, and we identified cancer-specific somatic gene alterations such as SNV (Single Nucleotide Variation), Ins (Insertion)/Del (Deletion), and CNV (Copy Number Variation). The primary endpoints were the detection rates of potential actionable and druggable genes. The secondary endpoints were the detection rates of incidental germline variants and the period from initial visit to elucidation of the results to the patients. Results: Actionable and druggable gene alterations were detected in 97% (83/86) and 65% (56/86) of the subjects, respectively. Actionable gene alterations were frequently detected in TP53 (64/86), KRAS (38/86), APC (25/86), ARID1A (11/86), and FBXW7 (10/86). Druggable gene alterations were detected in ARID1A (11/86), and FBXW7 (10/86), BRAF (7/86), BRCA1/2 (6/86), and EGFR (4/86). Incidental germline variants were detected only in 6% (5/86) of all the patients. The median period of examination was 30 days (10-78 days). Seven out of the 86 patients (8%) were treated with therapeutic agents, based on the results of our clinical sequencing. Conclusions: Our clinical sequencing system provided a large number of cancer patients with clinically valuable genomic information available in selecting anticancer drugs within about a month.
Does signet-ring cell carcinoma of the stomach (SRCC) need stimulation of neoangiogenesis?
Authors: Surikova Ekaterina Igorevna , Frantsiyants Elena , Goroshinskaya Irina A. , Pogorelova Yulia A. , Bandovkina Valeria A. , Neskubina Irina Valerevna , Maslov Andrey A. , Medvedeva Dar'ja E. , Kaminskiy Gennadiy V. , Tishchenko Irina , Malinin Sergey A. , Chilhahyan Lusegen , Kit Oleg Ivanovich 
Published: January 2019

33 Background: Tumor neoangiogenesis is a complex coordinated process involving various regulatory molecules. Vascular endothelial growth factors, in particular VEGF-A, are important effectors. A multipotent TGF-β1 cytokine can modulate stromal angiogenesis reactions promoting the tumor growth. Our purpose was to study the function of the system of pro-angiogenic cytokines in tissues of stomach tumors of various histological types - adenocarcinoma (AC) and signet-ring cell carcinoma (SRCC). Methods: The concentrations of VEGF-A, VEGF-R1 and TGF-β1 were studied by ELISA in tumors, peritumoral zone and resection line tissues of gastric cancer patients without preoperative therapy: 15 patients with AC (T2-4N0-2M0, G2-G3, 50-84 years) and 10 patients with SRCC, comparable by sex, age and prevalence of cancer process. Results: Levels of VEGF-A, VEGF-R1 and TGF-β1 in the resection line tissues of AC and SRCC did not differ significantly. VEGF-A in AC tumor tissues exceeded significantly the levels in the resection line (by 2.3 times) and in the peritumoral zone (by 1.8 times). VEGF-A in SRCC tumor tissue did not differ significantly from the levels in the corresponding tissues of the resection line and peritumoral zone, but it was 2.6 times lower than in AC tumor tissues. VEGF-R1 levels in AC and SRCC were similar. TGF-β1 in AC tumor tissues was 3.2 and 2.6 times higher than in the resection line and peritumoral zone, respectively. TGF-β1 in SRCC tumor tissues did not differ from the levels in the peritumoral zone and in healthy tissues; TGF-β1 in tumor tissues was 3.2 times lower in SRCC than in AC. Conclusions: SRCC tumor tissues have significantly lower levels of pro-angiogenic VEGF-А and TGF-β1 cytokines, compared to AC tissues, which can indicate that SRCC has no need to form its own vasculature. It is probably associated with the biological characteristic of this histotype of gastric cancer - diffuse growth pattern, in contrast to the solid structure of AC.