bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical significance of high expression of a specific solute carrier transporter in HCC.
Authors: Gifu Patricia , Brun Sonia , Wang Guanxiong , Bassissi Firas , Caron de Fromentel Claude , Merle Philippe , Halfon Philippe
Published: January 2019

303

Background: Hepatocellular carcinoma (HCC) is the third cause of cancer-related death. GNS561 (Genoscience Pharma, France) is a small molecule inducing apoptosis by lysosome inhibition and caspase activation. GNS561 has high hepatotropism and anti-tumorigenic capacity on tumor bulk and cancer stem cells. Its main target is a specific solute carrier transporter (SLCt). We describe here the clinical relevance of the overexpression of SLCt in HCC patients. Methods: The expression of SLCt was investigated by iQRT-PCR in surgically resected HCC tumors (T) and the matched non-tumor (NT) liver tissues (n=180) as well as healthy livers (HL) devoid of chronic or acute disease (n=10). Pearson's chi-squared test was employed for significant correlation tests while univariate and multivariate survival analysis were performed by Cox proportional hazard ratio (HR) method. Results: SLCt was overexpressed in 40.5% of T and 30.3% of NT as compared to HL. High SLCt in T was associated with microvascular emboli (p=0.034) and expression of the cancer stem cell markers Sox2 (p=0.025) and CD133 (p=0.034). High SLCt in NT correlated with cirrhosis (p=0.009) and presence of satellite nodules (p<0.001). Univariate analysis showed association between high SLCt in T and shortened overall survival (OS) (HR=1.08, p=0.020), lower progression-free survival (PFS) (HR=1.76, p=0.006) as well as early recurrence-free survival (ERFS) (within 2 years post-surgery) (HR=1.88, p=0.008). In multivariate analysis, high SLCt tended to be an independent factor for OS, and this was strongly significant for PFS and ERFS. High SLCt in NT, is quite a poor outcome factor on late recurrence-free survival (HR=2.33, p=0.056) together with cirrhosis in univariate analysis, but remained dependent of cirrhosis in multivariate analysis. Late recurrence is linked to the intrinsic tumorigenic status of the liver. Conclusions: Overexpression of the SLCt in HCC tumors is associated to stemness features and appears as a poor outcome factor impacting on early recurrence. Further, SLCt in NT is associated with development of de-novo HCC. Validation cohorts and prospective assessments are needed to define high SLCt as a potential biomarker of HCC stemness and patient outcome.
Characteristics of circulating tumor cells in newly diagnosed metastatic pancreatic adenocarcinoma.
Authors: Starr Jason Scott , Parekh Hiral D. , Varillas Jose I. , Ivey Alison Marguerite , Barnes Isis , McEwan Margaret A. , Allegra Carmen Joseph , Trevino Jose Gilberto , Cioffi Jessica , Hughes Steven J. , Mramba Lazarus , Zhang Jinling , Fan Z. Hugh , George Thomas J.
Published: January 2019

304

Background: Circulating tumor cells (CTCs) represent real time dissemination of solid tumors. Historically, CTC enumeration has been challenging to perform successfully in pancreatic cancer (PCa). Using a previously published microfluidic device designed to increase cell capture, we analyzed CTC characteristics in a cohort of newly diagnosed patients with metastatic PCa. Methods: After provision of informed consent, blood samples (7-10mL) were collected within 1 month of treatment initiation. 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-). Statistical analysis was performed using Scheffe’s method along with analysis of variance to test interactions between the clinical demographics and groups. The study was approved by the UF IRB. Results: A cohort of 27 patients had CTC determination at treatment onset with multi-agent chemotherapy for metastatic PCa. Cohort characteristics included: median age 65 (range 29-76), 63% male, 92% white, 85% with intact primary pancreatic tumor, pancreatic tumor location: head (n = 12), body (n = 5), tail (n = 6), number of sites of metastasis: 1 (n = 18), 2 (n = 7), 3 (n = 2), and median albumin 3.9 g/dl. Median CTC for the entire cohort was 7/mL of blood (range 2-12). CTCs were detected and quantified in all patients analyzed. In those with intact primary tumors, there were no significant differences in CTCs based on age (≥65), sex, albumin (≥3.5 g/dl), or number of metastatic organ sites (1, 2, or 3). However, primary tumor location in the head vs. tail was different (mean 7.7 vs. 4.3/mL; p = 0.02; CI -5.78 – [-] 0.41). Conclusions: This analysis demonstrates the feasibility of measuring CTCs in patients with metastatic PCa. CTC amount does not appear impacted by systemic tumor burden or demographic differences. However, anatomic differences in primary tumor location may be important in CTC studies. Further analysis of a larger and more diverse patient data set is planned.
Prognostic implication of soluble programmed death-ligand 1 (sPDL1) and its dynamic changes during FOLFIRINOX chemotherapy in unresectable pancreatic cancer.
Authors: Park Hyunkyung , Bang Ju-Hee , Nam Ah-Rong , Park Ji Eun , Kim Mei Hua , Bang Yung-Jue , Oh Do-Youn
Published: January 2019

306

Background: Programmed death-ligand 1 (PD-L1) expressed on a tumor or in a tumor microenvironment has an important role in the tumor escaping from the immune system. The soluble form of PD-L1 (sPD-L1) has been suggested to have an immunosuppressive activity. In pancreatic cancer, the acquisition of a sufficient amount of tumor tissue is an obstacle. In this study, we measured the serum levels of sPD-L1 and evaluated its prognostic implications in unresectable pancreatic cancer. Methods: We prospectively enrolled 60 pancreatic cancer patients who were treated with FOLFIRINOX as the first-line palliative chemotherapy. We collected blood samples at the time of diagnosis, first response assessment and disease progression. Serum sPD-L1 was measured using an enzyme-linked immunosorbent assay. Results: The median sPD-L1 was 1.7ng/mL (range, 0.4-5.7ng/mL). The median overall survival (OS) and progression free survival (PFS) were 10.3 months (95% CI: 8.5-12.11) and 6.5 months (95% CI: 4.9-8.1), respectively. Patients with low levels of sPD-L1 at diagnosis ( < 4.6 ng/mL) showed a better OS than the patients with a high sPDL1 (OS: 12.6 vs. 8.0 months HR 2.796, P = 0.015). In the multivariable analysis, sPD-L1 and the neutrophil-to-lymphocyte ratio were independent prognostic factors for OS. During chemotherapy, more patients achieved CR(complete response)/PR (partial response) as the best response when sPD-L1 was decreased at the first response assessment. (CR+PR rate; sPDL1 decreased group vs. sPD-L1 increased group: 14/29 (48.3%) vs. 5/24 (20.8%), P = 0.038). For patients who achieved CR/PR as the best response, sPD-L1 was significantly increased at disease progression compared with the first response assessment (mean 3.5 vs. 1.9 ng/mL, P = 0.025). Conclusions: sPD-L1 at diagnosis confers a prognostic value for OS in pancreatic cancer patients treated with chemotherapy. The dynamics changes of sPD-L1 during chemotherapy correlates with disease progression
Prospective analysis of somatic and germline genetic alterations in patients with ampullary carcinomas.
Authors: Wong Winston , O'Reilly Eileen Mary , Varghese Anna M. , Yu Kenneth H. , Iacobuzio-Donahue Christine A , Shia Jinru , Klimstra David , Allen Peter J. , Lowery Maeve Aine
Published: January 2019

308

Background: Ampullary carcinoma (AC) is a rare gastrointestinal cancer. Germline alterations (GA) in BRCA2 have been identified in patients with AC. Also, potentially targetable somatic alterations (SA) in other genes including ERBB2, and ELF3 have been identified in AC. MSKCC has implemented an opt-in strategy for germline (GT) and somatic genetic testing (ST) for patients with AC. Methods: Patients (pts) with pathologically confirmed AC were consented prospectively for ST using MSK-IMPACT (410 genes). A subset of pts was also consented for GT using MSK-IMPACT (76 genes) under an IRB approved protocol. Clinicopathologic features, treatment history and survival data were collected and analyzed. Results: N = 36 AC pts consented to ST from 9/2016 to 4/2017 of which 19/36 (52.7%) were male. Median age at diagnosis was 63 years, range 35-81. Pathology: 6/36 (16.7%) intestinal subtype, 19/36 (52.7%) pancreaticobiliary subtype, 4/36 (11.1%) mixed type, and 7/36 (19.4%) undifferentiated/other subtypes.29/36 (80.5%) pts had a family history of cancer. SA in KRAS 11/36 (30.5%), MDM2 (AMP) 6/36 (16.7%), ERBB2 3/36 (8.3%), PIK3cA 3/36 (8.3%), and ELF3 2/36 (5%) were seen in the highest frequency. 15/36 (41.6%) pts also consented for GT. Subgroup analysis revealed 4/15 (26.6%) pts with GA. Table 1 summarizes this subgroup. Conclusions: SA/GA in multiple genes including BRCA2, ERBB2/ELF3, and NTRK were observed. Also, novel GA in ATM (13%) and SA in MDM2 (AMP) (16.7%) were identified. Correlations of pathologic subtypes to clinical history, outcomes and mutations will be reported at the meeting. Further investigation of SA/GA in this disease is warranted given potential therapeutic and family screening implications. [Table: see text]
Perioperative inflammatory marker as a predictive factor for prolonged postoperative ileus after gastrectomy for gastric cancer.
Authors: Park Hyojin , Kim Yoon Su
Published: January 2019

31

Background: Inflammatory markers such as the C-reactive protein (CRP), neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) have recently been proposed as prognostic markers for post-operative complications and poor prognosis in solid tumors especially in colon cancer. However, there are few related reports in gastric cancer patients. Therefore, the aim of this study is to assess how perioperative inflammatory markers influence the prolonged postoperative ileus (PPOI) following gastric cancer surgery. Methods: Between 2013 and 2016, 435 patients were diagnosed with gastric cancer and underwent surgery in Gangnam Severance hospital. Patients were divided into prolonged postoperative ileus (PPOI) and control groups. Uncomplicated postoperative ileus (POI) is generally identified as an inevitable process after surgery, which typically resolves within 3 days. Ileus that persists for more than 3 days following surgery is termed PPOI. Results: The total PPOI rate was 33.8%. In univariate analysis, PPOI group was significantly associated with male sex, old age, open operative technique, preoperative gastric outlet obstruction and combined colon resection. PPOI group also was significantly associated with elevated perioperative inflammatory marker (pre- and post-operative CRP, NLR, and PLR). In multivariate analysis, open operative technique and elevated perioperative inflammatory markers (CRP, NLR and PLR) were identified as significant predictors of PPOI. In addition, postoperative length of hospital stay delayed in PPOI group compared with the control group (11.58 ± 9.48 vs.7.98 ± 5.44, respectively; P < 0.001). Conclusions: In this study, PPOI group was significantly associated with elevated perioperative inflammatory marker. Patients with PPOI also are more likely to have an increased postoperative hospital stay. Therefore, the perioperative inflammatory markers may be used as clinically relevant predictive markers for PPOI following gastric cancer surgery
Change in liver function as measured by change of Child Pugh Score to predict survival in patients with advanced hepatocellular carcinoma (HCC) during the treatment course.
Authors: Prins Petra , Sharma Titiksha , Kim Kyung S , Bhardwaj Prarthna V , Collins Noah , Lu Emily , Bowie Anna , Fegler Marcella , Lee Kathrine , Yang Andrew , He Aiwu Ruth
Published: January 2019

310

Background: HCC is the sixth most common cancer and the second leading cause of cancer-related death worldwide. Most HCCs develop in severely damaged liver. Methods: The effect of multiple treatment options on liver function (LF) and disease outcome of patients (pts) with HCC (n = 380) were examined retrospectively. Pt LF (Child Pugh score [CPS]) was assessed at time of diagnosis (dx) and then after treatment. Kaplan Meier with log rank and Chi square test was used for comparisons. Results: Our cohort of 380 pts had the following demographics: 74% were male and 26% female; 42% were African American, 26% Caucasian, 13% Asian, and 8% undetermined. The mean age at dx was 62.7 yrs; 17% and 61% of pts were between 40-55 and 56-70 yrs, respectively. Only 2% were below 40 yrs, and 19.6% were above 70 yrs of age. About half of pts smoked (55%) or drank (54%). Regarding viral infection, 17% had Hep B, 52% Hep C, 3% both, and 26% neither. Risky behavior correlated with age of dx: pts aged 56-70 yrs of age had the highest of both (p < 0.05). Cirrhosis and vascular invasion were seen in 66% and 40% of pts, respectively. Stage I/II HCC was seen in 38% and stage III/IV in 68% of pts. Median OS was significantly higher for stage I/II pts (p < 0.001). Pts who had no change or improvement in LF had longer median OS vs. pts who had declining LF (p < 0.001). Considering all treatment scenarios including local and systemic therapy, LF improved in 13%, did not change in 41%, and worsened in 46% of pts. LF decline in pts receiving various treatments was as follows: 53%, sorafenib (SFB); 39%, TACE; 53% radiation; 58% TACE/Y-90/SFB; and 32%, immunotherapy independent of prior treatment. However the degree in LF decline, as dictated by a ΔCPS of > 4, 3 to 4, or 1 to 2 points, did not by itself correlate with significant changes in median OS. Conclusions: The outcome of pts with HCC depends on disease stage and LF. Most pts experience LF decline during treatment. The degree of LF decline is independent of median OS, but maintaining LF is significantly beneficial for OS. Balancing survival benefit with liver toxicities is critical to the successful treatment of pts with advanced HCC.
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

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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.
Myeloid-deprived suppressor cell mediated the prognostic value of platelet-to-lymphocyte ratio for advanced hepatocellular carcinoma patients.
Authors: Li Xing , Wu Xiang-yuan , Jiang Nan , Xing Yan-Fang , Wu Dong-hao , Dong Min
Published: January 2019

331

Background: Myeloid Deprived Suppressor Cell (MDSC) has been recoganized as a promising target for hepatocellular carcinoma (HCC). However, targeted therapy on MDSC failed to display convincing efficacy. Optimization of patient selection to find the most potential beneficiaries might be a solution to this issue. In the present study, we aimed to identify clinical parameters relevant to MDSC level in HCC patients for future MDSC targeted therapy. Methods: In the present study, a series of 55 HCC patients (prospective group) and 20 healthy donors were analyzed investigating frequencies of MDSC in peripheral blood mononuclear cells (PBMC). Results: As a result, we found that MDSC level was increased in HCC patients compared to healthy donors (10.33% vs 1.54%, p< 0.0001). The monocytes (r2= 0.2875, p< 0.0001), neutrophils (r2= 0.3630, p< 0.0001) and platelet counts (r2= 0.0828, p= 0.0331) in circulation was positively associated with MDSC level. Then, the prognostic value of the above predictors was determined in a retrospective database of 243 HCC patients (retrospective group). The baseline characteristics of prospective and retrospective group were similar. Platelet-to-lymphocyte ratio (PLR) were confirmed to be an independent predictor for OS ( p= 0.003) with the rest parameters presented negative results. Then, advanced HCC patients were divided into two groups based on PLR value ≤111.23 or > 111.23 according to ROC analysis. Patients with low PLR presented higher 3-month survival rate (57.6% vs 37.6%) compared with patients with high PLR. PLR was associated with aggressive behavior of malignancies, such as distant metastasis and portal vein thrombosis. Conclusions: In summary, the present study firstly indentified blood platelet counts was a predictor of MDSC level in PBMC for HCC patients. And, patients with higher PLR might be the optimal patient subgroup for MDSC targeted therapy.
MicroRNA-1291 effects on pancreatic cancer (PC) cells sensitivity to arginine deprivation and chemotherapy through modulation of ASS1 and GLUT1.
Authors: Kim Edward Jae-hoon , Tu Mei-Juan , Duan Zhijian , Gonzalez Frank J , Bold Richard J. , Yu Aiming
Published: January 2019

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Background: Cancer cells are reprogrammed to become addicted to a continuous supply of nutritional glucose and semi-essential amino acids like arginine, to drive synthesis of critical macromolecules for proliferation, tumorigenesis and metastasis. This dependence on nutritional supply makes cancer cells potentially vulnerable to deprivation by agents like pegylated arginine deiminase (ADI-PEG) which converts arginine back to citrulline. However, this vulnerability depends on limited ability of cancer cells to make arginine. PC cells that express high levels of argininosuccinate synthase 1 (ASS1), the rate limiting enzyme in cellular arginine synthesis, appear to be resistant to ADI-PEG. Our recent study showed that miR-1291 modulates factors in nutrient metabolism including ASS1 and GLUT1. We have developed a novel method to bioengineer miR-1291 agents for treatment. The aim of the current study was to evaluate if miR-1291 could enhance efficacy of metabolism-targeting drugs in PC. Methods: Cell proliferation was measured by CellTiter-Glo assay. Mature miR-1291 levels were determined by stem-loop reverse transcription real-time PCR assay. GLUT1 and ASS1 protein levels in miR-1291-treated pancreatic cancer cell lines were assessed by Western blot. Glucose uptake in AsPC-1 and PANC-1 cell lines was determined with a fluorescent probe, 2-NBDG. Results: A bioengineered pre-miR-1291 was processed to high levels of mature miR-1291 in PC cells. L3.3 and PANC-1 cells endogenously express high levels of ASS-1 and are resistant to arginine deprivation by ADI-PEG. ASS1 protein was downregulated by miR-1291 in L3.3 and PANC-1 cells and sensitized pancreatic cancer cells to ADI-PEG. In addition, miR-1291 significantly downregulated the protein levels of GLUT1 in AsPC-1 cells, leading to a lower glucose uptake capacity and a greater sensitivity to chemotherapy. Conclusions: Our results demonstrate that miR-1291 sensitizes PC cells to arginine deprivation and chemotherapy through downregulation of ASS1 and GLUT1. These results provide new insight into the mechanistic actions of miR-1291 and provide a new strategy for treatment of pancreatic cancer.
Treatment adherence, healthcare resource utilization, and costs in patients with gastrointestinal neuroendocrine tumors (GI NETs).
Authors: Cai Beilei , Broder Michael , Chang Eunice , Yan Jessie Tingjian , Benson Al Bowen
Published: January 2019

337

Background: This study aimed to assess treatment adherence, healthcare resource utilization and costs in patients with GI NETs who initiated pharmacologic treatments. Methods: In 2 US commercial claims databases, patients ≥18 years with ≥1 inpatient or ≥2 outpatient claims for GI NETs were identified. The first claim for pharmacologic treatments (e.g. somatostatin analogues [SSAs], cytotoxic chemotherapy [CC], targeted therapy) following diagnosis and between 7/1/2009 and 12/31/2013 was defined as the index date. A 6-month clean period before index date and a 6-month pre- and a ≥1-year post-index enrollment were required. Proportion of days covered (PDC) was calculated during the follow up period. Outcomes were reported separately for patients with 1 and 2 years of post-index enrollment. Descriptive statistics including means, standard deviations, and frequencies and percentages for continuous and categorical data, respectively, were reported. Results: Of 1,322 patients with 1-year of follow-up, 847 initiated SSAs, 397 CC, 35 targeted therapies, 2 interferon, and 41 various combinations. Due to sample sizes, remaining results focus only on SSAs and CC. Mean PDC (SD) was 0.669 (0.331) for SSAs and 0.466 (0.236) for CC; SSA users had 20.5 (13.5) office visits and 0.59 (1.03) hospitalizations, CC users had 30.5 (19.8) and 0.89 (1.45) office visits and hospitalizations respectively; total annual cost for SSA-treated patients during the 1st year was $99,691 (82,423) and $134,912 (116,078) for CC. Among 685 patients with 2 years of follow-up, the annual mean costs in the second year were $8,071 and $58,944 lower than the first year for SSAs and CC, respectively. Conclusions: In this descriptive non-comparative study, we reported the resource utilization and costs associated with different treatment therapies. Overall, costs were higher in the first year than in the second year. This 2-database study offers new information on the magnitude and trends in the cost of pharmacologically treated GI NETs. Additional research with a larger sample size would be needed to better understand real-world utilization and costs for GI NET patients treated with different pharmacological therapies.
Liver regeneration after hemihepatectomy in patients with hepatocellular carcinoma.
Authors: Gong Wen-Feng , Zhong Jian-Hong , Ma Liang , Xiang Bang-De , Li Le-Qun
Published: January 2019

339

Background: We explored clinical factors associated with extent of liver regeneration after hemihepatectomy to treat hepatocellular carcinoma (HCC), as well as how the extent of regeneration influences postoperative recovery of liver function. Methods: In this prospective study of 125 patients who underwent hemihepatectomy, future liver remnant volume (as a percentage of functional liver volume, %FLRV) and remnant liver volume were measured preoperatively and at 1, 5, 9 and 13 weeks postoperatively. Logistic regression was used to identify clinical factors associated with liver regeneration. Influence of liver regeneration on postoperative liver function was evaluated. Results: After hepatectomy, 1 of 125 patients (0.8%) died within 3 months, 13 (10.4%) experienced liver failure and 99 (79.2%) experienced complications. %FLRV was able to predict liver failure with an area under the receiver operating characteristic curve of 0.900, and a cut-off value of 42.7% showed sensitivity of 85.7% and specificity of 88.6%. Postoperative median growth ratio was 21.3% at 1 week, 30.9% at 5 weeks, 34.6% at 9 weeks and 37.1% at 13 weeks. Multivariate analysis identified three predictors associated with liver regeneration: FLRV < 601 cm3 (OR 0.230, 95%CI 0.074-0.717), %FLRV (OR 0.271, 95%CI 0.077-0.960) and liver cirrhosis (OR 7.740, 95%CI 2.748-21.798). At postoperative weeks 1 and 5, liver function indicators were significantly better among patients showing high extent of regeneration than among those showing low extent, but these differences disappeared by postoperative week 9. Conclusions: FLRV, %FLRV and liver cirrhosis strongly influence extent of liver regeneration after hepatectomy. %FLRV values below 42.7% are associated with greater risk of post-hepatectomy liver failure.