bluuebunny/crossref_metadata_2025 huggingface dataset:
Preoperative serum artemin (ARTN) as a predictive biomarker of recurrence following curative resection for hepatocellular carcinoma (HCC).
Authors: Feng Sophie , Sim Hao-Wen , Bucur Roxana , Aggarwal Reenika , Abreu Phillipe , Ray Monali , Herman Michael , Cheng Dangxiao , Chen Zhuo , Zhang Wenjiang , Greig Paul David , Wei Alice Chia-chi , Moulton Carol-Anne , McGilvray Ian M. , Cleary Sean P. , Gallinger Steven , Sapisochin Gonzalo , Knox Jennifer J. , Liu Geoffrey , Chen Eric Xueyu
Published: February 2020

571

Background: Tumor-induced generation of splenic erythroblast- like cells (Ter-cells) has been shown to promote tumor progression. These Ter-cells produce the glial-line derived neurotropic factor, ARTN. We investigated the association of pre-operative serum ARTN and the risk of recurrence in HCC patients (pts) undergoing curative resection. Methods: Blood samples were collected prior to surgery as part of an institutional molecular epidemiologic study. Serum ARTN concentration was measured using an enzyme-linked immunosorbent assay (ELISA). Demographics, pathological variables known to be associated with outcomes and clinical outcomes were collected. Uni- and multi-variate analysis were conducted. The optimal cutpoint method was used to define high and low ARTN concentrations. Cox models (hazard ratios, HR) were used to compare progression-free (PFS, primary endpoint), and overall survival (OS) of pts with high vs low serum ARTN. Results: Pre-operative blood samples were available for 58 pts. Median age was 63 years (range: 25-85 years); 74% were male and 50% were Asian. Etiology of liver disease was hepatitis B (43%) and hepatitis C (22%); 43% of tumors were ≤5cm, and vascular invasion was seen in 62%. A baseline alpha-fetoprotein (AFP) of > 100 mcg/L was observed in 36% pts. Median follow-up was 18.9 months. Median ARTN concentration was 0.322 ng/mL. The optimal ARTN concentration cut-off was 0.206 ng/mL. Median PFS for pts with high ( > 0.206 ng/mL) vs low (≤0.206 ng/mL) ARTN was 15.7 vs 55 months (p = 0.04) respectively. Three year PFS was 34% vs 55%, and three year OS 54% vs 91% for high vs low groups. Univariate analysis found that high ARTN concentration (HR 2.44, p = 0.05) and multifocal tumors were associated with a worse PFS. In a multivariate analysis adjusted for AFP > 100mcg/L, vascular invasion, hepatitis status and multifocal tumors, high ARTN remained a negative prognostic factor for PFS, aHR 3.32 (95% CI: 1.22-9.05, p = 0.02). Conclusions: A high pre-surgery serum ARTN is associated with earlier recurrence in HCC pts undergoing curative resection. ARTN should be further studied in HCC to determine its value as a prognostic marker.
Role of Wnt5a in suppressing invasiveness of hepatocellular carcinoma via epithelial mesenchymal transition.
Authors: Wakizaka Kazuki , Kamiyama Toshiya , Orimo Tatsuya , Shimada Shingo , Nagatsu Akihisa , Asahi Yoh , Sakamoto Yuzuru , Kamachi Hirofumi , Mitsuhashi Tomoko , Taketomi Akinobu
Published: February 2020

573

Background: Wnt signaling pathway includes canonical pathway and non-canonical pathway. Wnt/β-Catenin pathway as canonical pathway is associated with the development of hepatocellular carcinoma (HCC). On the other hand, the association between aberrant activation of non-canonical pathway activated by Wnt5a and tumor progression of HCC is not well-known. We investigated the significance of the expression of Wnt5a in HCC. Methods: Immunohistochemical staining of Wnt5a was performed on the specimen of 243 patients who underwent hepatic resection for HCC. We investigated whether the expression of Wnt5a correlated with the clinicopathological factors, survival, and recurrence in HCC patients. The expression of Wnt5a in human HCC cell lines HLE, HLF, HepG2 and Huh7 was investigated by western blotting. The effects of overexpression or knockdown of Wnt5a on cell lines were evaluated by proliferation assay and invasion assay and changes in epithelial mesenchymal transition (EMT) related molecules were studied by western blotting. Results: The Wnt5a expression was positive in 63 patients (25.9%) and negative in 180 patients (74.1%). The Wnt5a negative was significantly associated with poorly differentiation (P = 0.003) and vascular invasion positive (P = 0.046). By univariate analysis, Wnt5a negative (P = 0.020) was identified as a significant prognostic factor of OS. Multivariate analysis of OS showed that Wnt5a negative (HR 1.895, 95% CI 1.053-3.409, P = 0.033) was identified as an independent prognostic factor. In the HCC cell lines, the Wnt5a expression was lower in HLE and HLF than in HepG2 and Huh7. Knockdown of Wnt5a by shRNA increased the proliferation and invasiveness in Huh7 with high expression of Wnt5a. As a result, the expression of E-cadherin decreased. In HLF with low expression of Wnt5a, overexpression of Wnt5a inhibited the invasiveness and the expression of vimentin decreased. Conclusions: Wnt5a negative was associated with poorly differentiation and vascular invasion, and was independent poor prognostic factor in HCC patients. Wnt5a may be a tumor suppressor involved in EMT mediated changes of invasiveness.
Genomic characterization of HBV-infected hepatocellular carcinoma patients using circulating tumor DNA.
Authors: Lin Daniel , Ye Zhong , Wang Chun , Wei Qiang , Bingshan Li , Posey James , Yang Hushan
Published: February 2020

575

Background: Hepatocellular carcinoma (HCC) is a leading cause of mortality, with Hepatitis B virus (HBV) infection as a dominant etiology. Surgery or ablation may be curative for early-stage HCC. Thus, effective detection strategies are needed. We investigated genomic aberrations in circulating tumor DNA (ctDNA) as a potential diagnostic marker of HCC in HBV-infected patients. Methods: We identified early stage (BCLC 0-A) HCC cases (n = 21) and cancer-free controls (n = 15) from a cohort of Asian patients with HBV, undergoing surveillance at Thomas Jefferson University Hospital between 2013-2017. Blood samples were collected. Circulating cell-free DNA was isolated from plasma and assayed by capture-based next-generation sequencing of a targeted panel of 23 genes implicated in HCC pathogenesis. Sequencing data analysis and somatic mutation identification were conducted using a computational pipeline. Using area under the curve (AUC) in receiver operating characteristic analysis, we evaluated gene alterations and clinical factors (age, gender, cirrhosis) in an exploratory early detection HCC model. Results: Mutant ARID1A, ATM, CDKN2A, CTNNB1, ERBB2, TP53 genes were increased in HCC cases relative to non-cancer patients (85.7% vs 53.3%, P = 0.058; 42.9% vs 6.7%, P = 0.025; 38.1% vs 6.7%, P = 0.051; 42.9% vs 0%, P = 0.005; 52.4% vs 13.3%, P = 0.016; 100% vs 66.7%, P = 0.008, respectively). HCC patients had higher prevalence of cirrhosis than controls (90.5% vs. 60%, P = 0.046). Using the 6 mutant genes alone, the AUC for discriminating HCC from non-cancer patients was 0.827 (95% confidence interval [CI]: 0.701-0.953), which was greater than the AUC for discriminating cirrhosis from non-cirrhosis (0.531). When the 6 mutant genes were combined with clinical factors, the AUC of the exploratory HCC detection model increased to 0.914 ( P= 0.045). Conclusions: We identified 6 genomic aberrations in ctDNA that were more prevalent in HCC patients compared with non-cancer patients. Combining these alterations with clinical factors may identify HCC in HBV-infected patients at an early stage. These findings warrant further validation in future studies.
Gamma-synuclein as a potential novel prognostic marker promoting tumor cell migration in biliary tract carcinoma.
Authors: Takemura Yusuke , Ojima Hidenori , Oshima Go , Shinoda Masahiro , Kitago Minoru , Yagi Hiroshi , Abe Yuta , Hori Shutaro , Nishimura Yoko , Kubota Naoto , Masuda Yuki , Hibi Taizo , Sakamoto Michiie , Kitagawa Yuko
Published: February 2020

577

Background: Biliary tract carcinoma (BTC) is a highly malignant tumor, but the detailed pathological mechanism of its development and progression remain ill-defined. Gamma-synuclein (SNCG) promotes invasive behavior in pancreatic cancer and a range of other cancers, and SNCG expression is reportedly a prognostic factor. However, the role of SNCG in BTC remains unknown. Consequently, we investigated the clinicopathological significance and function of SNCG in BTC. Methods: Using surgically resected BTC specimens from 149 patients with adenocarcinoma [extrahepatic cholangiocarcinoma (ECC) (n =98); intrahepatic cholangiocarcinoma (ICC) (n =51)], we immunohistochemically evaluated SNCG positivity and checked for correlations with clinicopathological factors and outcomes. Furthermore, cell lines with high expressions of SNCG were selected from 17 BTC cell lines by using immunohistochemistry and qPCR. Cell proliferation and migration assays were then performed in the presence and absence of SNCG (silenced using). Results: SNCG expression was found in 32 of 149 (21.4%) BTC patients. SNCG expression was significantly correlated with poorly differentiated tumor ( P = 0.001) and lymph node metastases ( P = 0.001). SNCG positivity was also correlated with poorly differentiated tumor in both ECC and ICC ( P = 0.008 and P = 0.03, respectively), but was correlated with lymph node metastases only in ECC ( P = 0.003). Multivariate analyses identified SNCG expression as an independent prognostic factor of poor overall survival ( P = 0.008) and poor recurrence-free survival (RFS) ( P = 0.006). SNCG expression in both ECC and ICC was significantly associated with poor prognosis in univariate analysis, and multivariate analysis identified SNCG as an independent prognostic factor of poor RFS for ECC (P = 0.03). High SNCG expression was found in 3 BTC cell lines (NCC-BD1, NCC-BD3, and NCC-CC6-1). Functional analysis revealed that SNCG silencing by siRNA suppressed cell migration significantly in NCC-BD1 and NCC-CC6-1 and downregulated cell proliferation in NCC-CC6-1. Conclusions: Our results suggest that SNCG may promote tumor cell activity and is potentially a novel prognostic marker in BTC.
Circulating free DNA (cfDNA) and tissue next-generation sequencing analysis in a phase II study of infigratinib (BGJ398) for cholangiocarcinoma with FGFR2 fusions.
Authors: Makawita Shalini , Kelley Robin Kate , Roychowdhury Sameek , Weiss Karl Heinz , Abou-Alfa Ghassan K. , Macarulla Teresa , Sadeghi Saeed , Waldschmidt Dirk , Zhu Andrew X. , Goyal Lipika , Yong Wei-Peng , Borbath Ivan , El-Khoueiry Anthony B. , Philip Philip Agop , Moran Susan , Ye Yining , Soifer Harris S. , Li Gary , Berman Craig , Javle Milind M.
Published: February 2020

579

Background: Fibroblast growth factor receptor 2 (FGFR2) alterations occur in 11% of cholangiocarcinomas, 85% of which are fusions. A multicenter, open-label, phase II study is currently evaluating the efficacy of infigratinib, a selective FGFR1–3 tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma containing FGFR2 fusions. We report detailed biomarker analyses from this study. Methods: Patients with advanced or metastatic cholangiocarcinoma containing FGFR2 fusions whose disease had progressed following cisplatin- or gemcitabine-based therapy were eligible. Patients received oral infigratinib 125 mg once daily on days 1–21 every 28 days. Comprehensive genomic profiling (CGP) was performed on tumor tissue and cfDNA collected prior to the start of therapy. The primary endpoint was investigator-assessed overall response rate (ORR) [RECIST version 1.1]. Data cut-off (prespecified): August 8, 2018. Trial registration: NCT02150967. Results: At data cut-off, 71 patients with FGFR2 fusions were included (62% women; median age 53 years; 55% received ≥2 prior lines of therapy). Median duration of treatment was 5.5 months. ORR (confirmed and unconfirmed) was 31.0% (95% CI 20.5–43.1%) and confirmed ORR was 26.9% (95% CI 16.8–39.1%). 33 unique FGFR2 fusion genes were identified in 71 enrolled patients. The most common fusion gene partner was BICC1 (32%; 23/71). Pathogenic variants in 9 other druggable genes were identified in 32% of patients (13/37) who underwent CGP. FGFR2 fusions were concordant in 67% (8/12) of patients with tumor tissue and cfDNA at screening. Conclusions: The large assortment of FGFR2 fusion genes identified in this study underscores the diversity of FGFR2 rearrangements that may drive cholangiocarcinoma. Although cfDNA analysis was performed in a minority, these preliminary data suggest that cfDNA analysis may be valuable for the identification of FGFR2 fusions and to study intratumoral heterogeneity. Clinical trial information: NCT02150967.
Comparison of the clinical features, treatment patterns, and tumor mutations of patients with intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinoma.
Authors: Pappas Leon , Reyes Stephanie , Lanka Aishwarya , Shroff Rachna T. , Le Tri Minh , Rahma Osama E. , Bocobo Andrea Grace , Borad Mitesh J. , DeLeon Thomas , Mody Kabir , Roth Marc Thomas , Peters Mary Linton Bounetheau , Goff Laura Williams , Boyhen Kylie , VanCott Christine , Horick Nora , Zhu Andrew X. , Javle Milind M. , Kelley Robin Kate , Goyal Lipika
Published: February 2020

580

Background: Though studies indicate that the genomic profiles of ICC and ECC are distinct, the clinical features that differentiate them still remain to be well characterized. The purpose of this study was to further analyze these differences and patient treatment patterns in a multi-center cohort. Methods: A retrospective chart review was performed at 8 institutions on patients (pts) with ICC or ECC diagnosed after June 2009. Data on demographics, risk factors, treatments, pathology and overall survival (OS) were collected. Tumor genotyping results from CLIA-certified tissue assays were analyzed. Fisher’s exact, Wilcoxon rank sum and log-rank tests were used to compare sub-groups. Results: In a database of 737 pts with cholangiocarcinoma, 538(73%) had ICC and 199(27%) had ECC. Pts with ICC more often presented in later stages, had tumors > 5cm at resection (p < 0.0001) and had metastases to the liver, lymph nodes, lung and/or bone (p < 0.01). Pts with ICC more often received liver directed therapy, targeted therapy and multiple lines of systemic therapy and they more often enrolled in a clinical trial (all p < 0.01). Pts with ECC were more likely to be male, undergo surgery, receive adjuvant chemotherapy and/or chemoradiation (all p < 0.05). Mutation profiling performed in 381 (52%) pts (ICC/ECC = 301/80) showed that pts with ICC were more likely to have IDH1 mutations and FGFR2 fusions, whereas pts with ECC were more likely to have KRAS, APC, SMAD4, WNT, TGFb and TP53 mutations (all < 0.05). Factors that did not differ significantly between pts with ICC and ECC include race, rates of primary sclerosing cholangitis, median diagnosis CA19-9 levels and R1 resection rate. Median OS from diagnosis was 18.9 months in ICC and 17.3 months in ECC (p = 0.8471). Conclusions: While pts with ICC and ECC have some similarities in their clinical features, differences in metastases patterns and molecular profiling significantly impact their management such that pts with ICC receive more liver-directed therapy, targeted therapy and more lines of systemic therapy. Further prospective studies are needed as referral patterns to tertiary care centers may have impacted these results.
Patient-derived organoids for personalized drug screening in intrahepatic cholangiocarcinoma.
Authors: Antonia Ricardo J. , Toriguchi Kan , Karelehto Eveliina , Annuar Dania , Timmerman Luika , Tbeileh Noura , Mattis Aras N. , Corvera Carlos U. , Hirose Kenzo , Nakakura Eric K. , Donner David B. , Warren Robert S.
Published: February 2020

581

Background: Despite standard treatment with gemcitabine and cisplatin, median survival for unresectable Intrahepatic Cholangiocarcinoma (ICC) is < 1 year. Clearly, novel therapeutic strategies are urgently needed. The paucity of targetable mutations in ICC and the as yet unproven benefit of genetically targeted drugs led us to ask whether a reliable clinical benefit may be revealed by patient-specific therapeutic testing in novel models of ICC. Here we describe our ability to establish patient-derived three-dimensional organoid cultures (PDO) that enable individualized identification of active single agents or drug combinations in surrogate models of ICC. Methods: To model patient-specific drug responses, we used the freshly resected ICCs from small samples of single patient tumors to generate PDXs and PDOs, small spheroidal clusters of tumor cells grown in vitro. We have employed a high-throughput drug screening platform using AI-enhanced robotics (Yamaha Motor Corporation) to identify and distribute single, uniformly sized PDOs into 384-well ultra-low adherent plates. This is coupled with a TECAN D300e drug dispenser that rapidly delivers nanoliter volumes of a 34-drug panel, thereby facilitating rapid, reliable drug response analyses. Results: Our data show that PDOs retain characteristic genomic and histological features of the patients’ tumors. Drug responses were specific to each patient tumor, but PDOs from all patients responded to a greater or lesser degree to mTOR inhibition, suggesting that this pathway is important in ICC. The responses of PDO to the mTOR inhibitor Sapanisertib (INK128), was recapitulated in the same patient’s PDX. Further, INK128 was synergistic with gemcitabine in patient 970 PDOs as well as in vivo in PDX also from patient 970. Conclusions: As it is believed that PDX can predict patient responses to drugs, our results suggest that PDO may also predict patient drug responses. The establishment of PDO may allow economical patient-specific, high throughput drug screens that could ultimately inform clinical practice.

[Table: see text]
Association of objective response by mRECIST with better overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC) treated with systemic therapies: A systematic review and meta-analysis of randomized controlled trials.
Authors: Kudo Masatoshi , Chiba Yasutaka , Meyer Tim , Lencioni Riccardo , Llovet Josep M.
Published: February 2020

586

Background: EASL guidelines for management of HCC recommends assessing tumor response according to mRECIST at all stages of the disease (EASL guidelines, J Hep 2018). Several studies have reported that objective response by mRECIST predicted overall survival (OS) but definitive data are still lacking. Methods: The PubMed database and ASCO meeting library were searched for full reports of randomized trials in patients with advanced HCC treated by systemic therapy up to August 31, 2018. We search strategy used the following terms: HCC, mRECIST, OS and objective response rate (ORR). We assess the association between ORR and OS in a meta-analysis of pooled data by using random effects model comparing patients achieving objective response (complete or partial response) versus non responders (stable disease, progressive disease) and displayed the results as per hazard ratio (HR, 95% CI). Results: Among 14 articles assessing response by mRECIST to systemic therapies in randomized studies in advanced HCC, 4 studies (5 trials) including 1,463 patients were considered eligible. Systemic therapies tested included lenvatinib, sorafenib, brivanib and nintedanib. Overall, ORR as per mRECIST ranged from 11.5% to 18.8%, being the median OS for responders of 18.5 to 27.2 mo (as opposed 8.9 to 11.4 for non-responders). As per random effects model, the HR for overall survival (responders versus non responders) was 0.47 (95% confidence interval 0.34–0.66, p<0.001). Conclusions: Objective response by mRECIST to systemic therapies in patients with advanced HCC is significantly and strongly associated to OS. Patients achieving an objective response can expect a significantly longer OS.
Nationwide survey of pancreaticobiliary maljunction focusing on biliary cancer incidence in Japan.
Authors: Shimada Mitsuo , Ishibashi Hiroki , Morine Yuji , Kubota Masayuki , Fujii Hideki ,   Japanese Study Group on Pancreaticobiliary Maljunction
Published: February 2020

587

Background: Pancreaticobiliary maljunction (PBM) is known to be a unique entity closely related to biliary carcinogenesis. We herein report update analysis of PBM focusing on biliary cancer as third report of Japan-nationwide survey. Methods: From 1990 to 2015, 3,419 patients with PBM were registered at 141 medical institutions in Japan. 3,289 (1,344 pediatric and 1,945 adult patients) out of 3,419 patients were fully investigated, according to presence of bile duct dilatation (BDD), age (pediatric or adult), etc. Results: In pediatric patients, only 3 cases with BDD (0.124%) had bile duct cancers. On the other hand, in adults, biliary cancer incidence was 21.1% in patients with BDD and 43.5% in patients without BDD. The rates were extremely high in comparison with 0.0174% of Japanese prevalence of biliary cancer 2013. The cancer incidences of bile duct, gallbladder and both in adults with BDD/without BDD were 6.7%/4.1%, 13.0%/37.3%, and 1.4%/2.1%, respectively. In patients without associated biliary cancers, extrahepatic bile duct resection (EHBDRx) combined with cholecystectomy was performed in 89.5% of adults with BDD, while, in only 31.2% adults without BDD. Regarding the new biliary cancer occurrence of patients having follow-up data, the rate was 0.3% in 354 patients with BDD who underwent EHBDRx, while that was 4.0% in 75 patients without BDD who underwent simple cholecystectomy. In patients without BDD, cancer incidence (6.7%) in the late period (2010 to 2015) was higher than those (3.3% and 3.5%) in early and middle period (1990 to 1999, and 2000 to 2009). Conclusions: This updated nationwide survey of PBM revealed characteristics of associated and newly occurred biliary cancers, and could be widely used as a reference data for diagnosis and treatment of PBM.
Significance of frailty in prognosis after hepatectomy in older patients with hepatocellular carcinoma.
Authors: Yamada Shinichiro , Shimada Mitsuo , Morine Yuji , Imura Satoru , Ikemoto Tetsuya , Arakawa Yusuke , Saito Yu , Yoshikawa Masato , Miyazaki Katsuki
Published: February 2020

590

Background: An aging society has come, and “Frailty” is becoming increasingly important in surgery. Recently, clinical frail scale (CFS), which is simple criteria for frailty, has been reported to be useful for prognostic prediction of non-cardiac surgery (Ann Surg. 2018). Herein we report a new knowledge about frailty for patients with hepatocellular carcinoma (HCC) undergoing hepatectomy. Methods: Eighty-one patients over 75 years who underwent hepatectomy for HCC between 2007 and 2018 were enrolled in this study. Frailty was diagnosed as CFS≥4, and patient were divided into 2 groups, frailty (n = 17) and no frailty (n = 64). Clinicopathological factors were compared between 2 groups. Results: Patients’ background, such as age, gender, preoperative comorbidity, and liver function showed no significant difference between 2 groups. Regarding tumor factors, frailty group showed significant larger tumor diameter, more advanced stage (p < 0.05) and tendency of high PIVKA-II (p = 0.15) compared with no frailty group. Frailty group showed significant high CRP level (p < 0.01), high modified Glasgow prognostic score (mGPS, p = 0.04) and tendency of high neutrophil-lymphocyte ratio (NLR, p = 0.14). Frailty group also showed tendency of higher rate of postoperative complication (p = 0.11) and longer postoperative hospital stay (p = 0.09). Overall and disease-free survival rate were significantly worse in frailty group (p = 0.03). In univariate analysis for overall survival, AFP≥10, PIVKA-II≥400, frailty and mGPS high (1, 2) were prognostic factor. Multivariate analysis revealed that frailty was independent prognostic factor. In univariate analysis of disease-free survival, only frailty was detected as prognostic factor. Conclusions: Frailty is an independent prognostic factor for HCC patients who underwent hepatectomy.
Receipt and survival outcomes by age following second-line therapy for metastatic CRC (mCRC): Analysis of 5,289 patients from the ARCAD Clinical Trials Program.
Authors: McCleary Nadine Jackson , Harmsen William S. , VanCutsem Eric , Sobrero Alberto F. , Goldberg Richard M. , Tabernero Josep , Seymour Matt , Saltz Leonard B. , Giantonio Bruce J. , Dirk Arnold , Rothenberg Mace L. , Koopman Miriam , Schmoll Hans-Joachim hans-joachim , Pitot Henry C. , Hoff Paulo Marcelo , Falcone Alfredo , De Gramont Aimery , Shi Qian , Lichtman Stuart M.
Published: February 2020

6

Background: Rates and survival outcomes for second-line therapy for mCRC for OA vs. YA are poorly understood. Methods: Pts with available subsequent treatment data after progression from 10 1st line trials were included. Associations between key clinical/disease characteristics, time to initial progression (TTiP) and rate of receipt of second-line therapy were evaluated. Time to progression (TTP) and overall survival (OS) were compared between OA and YA who were enrolled on second-line trials by Cox regression, adjusting for age, sex, ECOG PS, number of metastatic sites, presence of metastasis in lung/liver/peritoneum. Results: OA comprised 16.4% of first-line trials. OA and ECOG PS >0 were less likely to receive second-line therapy than YA. Odds of receiving second-line therapy decreased by 11% for each additional decade of life in multivariate analysis (p=0.0117). OA enrolled in second-line trials experience similar mTTP and mOS as YA (5.1 vs. 5.2mos; 11.6 vs 12.4mos, respectively). Conclusions: OA are less likely to receive 2nd line therapy for mCRC. We did not observe a statistical difference in survival outcomes for OA vs. YA following second-line therapy. Further study is needed to examine unmeasured factors, including comorbidity and functional status given observed inferior outcomes among adults with ECOG PS >0, and consideration given to inclusion of geriatric assessment to select OA likely to benefit from 2nd line therapy for mCRC.

[Table: see text]
Do socioeconomic factors really have an impact on early detection of hepatocellular carcinoma and colorectal cancer?
Authors: Albawaliz Anas , Zafar Yousaf , Kaur Anahat , Madhusudhana Sheshadri , Shrestha Anuj
Published: February 2020

60

Background: Improving surveillance in hepatocellular carcinoma (HCC) and colorectal cancer (CRC) is an important topic in the field of gastroenterology and oncology due to significant benefit associated with early detection and better outcomes. Multiple studies have been undertaken to assess the association between the socioeconomic status of the population and adherence to HCC/CRC screening. Most of these studies used self-reporting surveys and faced limitations due to reporting bias. We aimed to assess the relevance of socioeconomic factors in the diagnosis of HCC and CRC in Jackson County, Missouri by means of a census-based survey. Methods: We retrospectively studied 190 HCC and 690 CRC cases at our institution using a census-based analysis, which consisted of geocoding home addresses of patients and then attaching block level census variables for household occupancy, education level and household income. Statistical analysis was performed using Cox proportional hazard model and ordinal logistic regressions. Results: We did not find a statistically significant association between socioeconomic factors and adherence to surveillance guidelines for HCC and CRC. USPSTF-2019 guidelines for CRC and AASLD-2018 guidelines for HCC screening were taken into account. Variables that were analyzed included high school education or better (p = 0.5), four-person households with one or more workers (p = 0.08) and income less than 25 thousand dollars (p = 0.58). Study results were risk adjusted for age, race, and gender. Separate ordinal logistic regression analysis was done to also adjust for the stage at the time of eventual cancer diagnosis, no statistically significant result was obtained. Conclusions: Our study showed no association between demographic variables and participation in HCC or CRC surveillance. The study is limited by a relatively small sample size confined to local patients seen at our institution. Multicenter census-based surveys and meta-analyses need to be conducted to determine whether socioeconomic factors really have an appreciable impact on early screening and detection of HCC and CRC.
Trends of survival based on race and ethnicity in gastrointestinal tract neuroendocrine tumor.
Authors: Goksu Suleyman Yasin , Beg Muhammad Shaalan , Sanford Nina Niu , Fangman Benjamin David , Herrman Sarah , Bacik Goksu Busra , Verma Udit , Sanjeevaiah Aravind , Jones Amy Little , Kainthla Radhika , Kazmi Syed Mohammad Ali
Published: February 2020

607

Background: There is paucity of data about racial/ethnic disparities in gastrointestinal tract neuroendocrine tumors (GiNET). We aimed to study the race/ethnic differences in disease characteristics and survival in GiNET. Methods: We analyzed the SEER database to identify cases with non-pancreatic GiNET between 2004 and 2015. We evaluated trends in incidence and outcomes between Hispanic, non-Hispanic/non-Black (NH/NB) and non-Hispanic Black (NHB). Kaplan-Meier method and cox regression model were performed for overall survival (OS) after adjusting for stage, grade, gender, race/ethnicity, and surgery. Results: 25,826 cases were included, 12.7% were Hispanic, 18.5% NHB and 68.8% NH/NB; males comprised 46.8%, 50.5%, 41.9%, respectively (p < 0.001). The overall incidence of GiNET increased two-folds in the ten years. The highest increase in incidence was observed in appendiceal NET followed by small intestine NET, and this increase was observed mostly among Hispanic population. NH/NB cases were older ( > 65 years) (31.3% vs. 23.3% vs. 23.5%; p < 0.001) and presented with metastatic disease (17.8% vs. 12.7%, 12.0%; p < 0.001). On multivariate analysis Hispanic population had significantly better OS than NH/NB and NHB (HR: 1.25 95% CI: 1.14-1.37 and HR: 1.15 95% CI: 1.033-1.28, respectively). For stage-4 low- and intermediate-grade GiNET, OS was better if surgery was performed (p < 0.001), and this trend was most pronounced among Hispanic as compared to NH/NB (HR 1.35, 95% CI 1.07-7.71). Conclusions: The incidence of GiNET had increased two-fold in the last ten years with the highest increase in Hispanic. However, Hispanic had significantly better overall survival than NH/NB and NHB population.[Table: see text]
A real-world observational study of somatostatin analogue use and costs in Canada.
Authors: Cheung Winson Y. , Feuilly Marion , Laforty Callahan , Liovas Anna , McKechnie Heather , Loree Jonathan M.
Published: February 2020

608

Background: Somatostatin analogue (SSA) use is indicated in acromegaly and neuroendocrine tumours for symptomatic relief and tumour control. Two long-acting SSAs (lanreotide and octreotide) are currently available, but comparative real-world data on their use are limited. This study evaluated SSA use and costs in Canada. Methods: Claims data from the IQVIA Private Drug Plan (PDP), Ontario Drug Benefit (ODB) program and Régie de l’assurance-maladie du Québec (RAMQ) were compiled. Injection burden, rescue medication use and costs were compared (using unpaired t-test or Wilcoxon test) over a 12-month period from first SSA prescription. Patients (pts) were eligible if the first prescription was dispensed Sept. 2015–Jun. 2018. Results: 908 pts were included: lanreotide 120 mg, N=375; octreotide long-acting release (LAR) 30 mg, N=533. Lanreotide treatment was associated with a lower weighted average injection burden for 12 months when compared to octreotide (12.54 vs 13.44 injections/pt, respectively; p<0.0001). Pts receiving lanreotide also had lower mean use of rescue medications than those treated with octreotide (0.01 vs 0.05 claims/pt/year), although this difference was greatest during the first month of treatment (mean difference: 0.19; p<0.0001), after which differences in rescue medication use were only significant (p<0.05) at Months 5 and 6. Mean total annual costs (rescue medication + LAR) were lower for lanreotide than octreotide ($27,829.35/pt [N=373] vs $31,255.49/pt [N=530], respectively, p<0.0001). Conclusions: In the absence of clinical trials directly comparing the SSAs, factors driving treatment selection are unclear. Findings from our real-world observational study suggest treatment with lanreotide to be less burdensome and costly than octreotide and may inform treatment discussions with pts. References1. Ipsen Biopharmaceuticals. Somatuline Autogel Product Monograph. 2018. Available at: https://cnetscanada.org/wp-content/uploads/2018/06/Somatuline-Product-Monograph.pdf; 2. Novartis Pharmaceuticals Canada Inc. Sandostatin LAR Product Monograph. 2018. Available at: http://www.ask.novartispharma.ca/download.htm?res=sandostatin_scrip_e.pdf&resTitleId=789.
Implications of neuroendocrine tumor and diabetes mellitus on patient outcomes and care: A matched case control study.
Authors: Karlin Nina J. , Kosiorek Heidi E. , Buras Matthew , Rone Kelley , Verona Patricia M. , Coppola Kyle , Cook Curtiss B.
Published: February 2020

612

Background: The aim of this study was to examine the impact of diabetes mellitus (DM) on survival in neuroendocrine tumor and the impact of neuroendocrine tumor on glycemic control in DM. Methods: Patients with newly diagnosed neuroendocrine tumor with and without DM were matched 1:1 according to age, gender, and year of cancer diagnosis (2005-2017). The file was linked to the electronic medical record to obtain information on DM and neuroendocrine tumor therapies and laboratory results. There were 59 matched pairs (total 118 patients) included in the analysis. We compared characteristics between cases and controls and assessed survival with the Kaplan-Meier method and Cox proportional hazards model. Mixed models compared hemoglobin A1c and glucose levels over time. Results: Median age of patients at diagnosis was 67 (40-86); 41% had stage IV disease. Women constituted 49% of the study population; 22% had pancreatic neuroendocrine tumor and 45% had another GI primary neuroendocrine tumor. No differences in race/ethnicity, marital status, alcohol or tobacco use were detected between cancer patients with and without DM. Mean BMI was significantly different between DM and non-DM patients (31.0 [7.90] versus 26.4 [5.27]); p = 0.011. Among those with DM, mean HbA1c during the year following cancer diagnosis was 7.3%. Mean glucose was significantly different between DM (159.1 [43.5] versus non-DM pts 117 [31.5]); p < 0.001. Median follow-up time was 32.8 (2.4-165.4) months in alive patients. Three year survival was estimated at 72% (95% CI: 60-86%) for DM patients versus 80% (95% CI: 70-92%) in non-DM patients by Kaplan Meier method (p = 0.82 log rank test). Hazard ratio (stratification for matched pairs) = 1.33 (95% CI: 0.56 – 3.16; p = 0.51). Conclusions: DM did not adversely impact survival in patients with neuroendocrine tumor. Neuroendocrine tumor and its treatment did not affect glycemic control. This should be reassuring to oncologists and endocrinologists who treat patients with neuroendocrine tumors and diabetes.
Outcomes after high-dose radiation in management of neuroendocrine neoplasms.
Authors: Chen Katherine , Whitman Julia , Paciorek Alan , Nakakura Eric K. , Fidelman Nicholas , Feng Mary Uan-Sian , Bergsland Emily K. , Anwar Mekhail
Published: February 2020

616

Background: In this study, we analyze outcomes after the use of high-dose radiation therapy (RT) in management of neuroendocrine neoplasms (NENs) at a high-volume center. Methods: We performed a retrospective review of patients who received high-dose RT (defined as biologically effective dose (BED) >40, α/β = 10) for their NEN. Patients with small cell lung cancer and Merkel cell carcinoma were excluded, given their unique treatment paradigms. Results: 61 patients completed a radiation course with BED >40 for their NEN (median BED 70, range 44-180). Most tumors were gastroenteropancreatic in origin (n = 20); additional primary sites included lung (n = 11), head and neck (n = 10), cervix (n = 6), other (n = 9) and unknown (n = 5). 56% (n = 34) had well-differentiated (WD) neuroendocrine tumors, and 44% (n = 27) had poorly-differentiated (PD) neuroendocrine carcinomas. Disease stage at the time of RT was localized/locally advanced (LLA, n = 27), or metastatic/recurrent (MR, n = 34). The intent of RT was definitive (n = 18), post-operative (n = 10), for oligoprogression (n = 18), or purely palliative (n = 15). 48 patients had follow-up imaging at a median follow-up of 20 months after radiation. Outcomes were grouped by differentiation and stage, with median time to progression (mTTP) in months (Table). 8% of patients had local progression, while 44% developed new metastases, including 38% of WD-LLA, 47% of PD-LLA, 37% of WD-MR, and 67% of PD-MR disease with progressively shorter median time to progression (26, 10, 8, and 3 months, respectively). Conclusions: These data suggest that focal, high-dose radiation has a role in the management of NENs. Local failure is rare in patients with both WD-LLA and PD-LLA disease. The predominant pattern of failure is development of new metastases, which appear to occur sooner and more frequently in patients with PD and MR disease. [Table: see text]
Efficacy of somatostatin analog (SSA) monotherapy for well-differentiated grade 3 (G3) gastroenteropancreatic neuroendocrine tumors (NETs).
Authors: McGarrah Patrick Walsh , Hobday Timothy J. , Starr Jason Scott , Kendi Ayse T. , Graham Rondell P. , Sonbol Mohamad Bassam , Halfdanarson Thorvardur Ragnar
Published: February 2020

617

Background: Currently, there is no published data on the efficacy of SSAs for well-differentiated G3 NETs. Randomized trials have demonstrated a progression-free survival (PFS) benefit and limited tumor response for lower grade 1-2 NETs, but the optimal systemic therapy for metastatic/unresectable G3 NETs is unknown. We sought to evaluate the efficacy of SSAs in G3 NETs. Methods: We performed a retrospective analysis of Mayo Clinic patients treated with SSAs for metastatic/unresectable G3 NETs, querying data from 1992 - present. Inclusion criteria were: centrally reviewed pathology confirming well-differentiated morphology, G3 based on WHO classification, SSA monotherapy, and radiological data available to assess response. Patients who had prior lines of treatment were included as long they subsequently were treated with single-agent SSA. Poorly-differentiated tumors were excluded. The primary endpoint was PFS. Best overall response was determined by radiographic regression, stabilization, or progression of tumor size. Results: Ninety patient records were reviewed, with 14 meeting inclusion criteria (diagnosed 2014 – 2018). Median Ki-67 proliferative index was 25%. Two patients (14%) had a partial response to SSA therapy, five (36%) had stable disease, and seven (50%) had progressive disease. The estimated median PFS was 4.4 months (95% CI 2.9 – 24). Of the 7 patients with stable disease or partial response, the median time to progression was 8.7 months. Three patients had stable disease for greater than 9 months (24, 29 and 42 months, respectively). Overall survival was not estimable. There was no association of Ki-67 index with PFS based on a proportional hazards model. Conclusions: This is the first report on the efficacy of SSAs for G3 NETs. Although half of the patients in our series had at least stable disease, the PFS was modest at only 4.4 months. Given their favorable side-effect profile compared to cytotoxic chemotherapy, SSAs may present an attractive option to be further explored in a prospective fashion. We are presently updating this data by reassessing response using RECIST criteria.
A phase II trial of atezolizumab and bevacizumab in patients with advanced, progressive neuroendocrine tumors (NETs).
Authors: Halperin Daniel M. , Liu Suyu , Dasari Arvind , Fogelman David R. , Bhosale Priya , Mahvash Armeen , Dervin Shannon , Estrella Jeannelyn , Cortazar Patricia , Maru Dipen M. , Mckenna Edward Francis , Wistuba Ignacio Ivan , Schulze Katja , Futreal Phillip Andrew , Darbonne Walter C. , Yun Cindy , Hwu Patrick , Yao James C.
Published: February 2020

619

Background: Neuroendocrine tumors (NETs) are relatively rare and heterogeneous tumors arising throughout the aerodigestive tract, which are incurable and life-limiting when metastatic. Prior studies of checkpoint inhibitors in NET patients have yielded minimal evidence of efficacy. Historically, effective therapies for advanced, progressive NET yield response rates less than 10% and progression-free survival (PFS) durations of approximately 11 months, as compared to approximately 4.5 months with placebo. Methods: We undertook a phase II basket study of atezolizumab in combination with bevacizumab in patients with rare cancers, and present here the data from the pancreatic NET (pNET) cohort and extrapancreatic NET (epNET) cohort, each of which included 20 patients with grade 1-2 NET that was progressive under any prior therapy. Patients received 1200mg of atezolizumab and 15mg/kg of bevacizumab IV q 21 days. The primary endpoint was confirmed objective response by RECIST 1.1. Results: The confirmed objective response rate with this combination was 20% (95% CI 6-44%) in the pNET cohort and 15% (95% CI 3-38%) in the epNET cohort. The median PFS in the pNET cohort is 19.6 months (95% CI 10.6-NR), while it was 14.9 months (95% CI 6.1-NR) in the epNET cohort, 1-year PFS was 75% and 52%, respectively. The combination was well-tolerated in this patient population, with the most common related treatment-emergent adverse events being hypertension (47.5%), proteinuria (37.5%), and fatigue (35%). The most common related grade 3/4 adverse events were hypertension (20%) and proteinuria (7.5%). Conclusions: The combination of atezolizumab and bevacizumab demonstrated moderate clinical activity in patients with advanced NETs. As pre-treatment and on-treatment biopsies were obtained for all patients, correlations with immune infiltration, mutations, and transcriptome alterations should provide additional insight into the mechanisms of response and resistance. Clinical trial information: NCT03074513.
Impact of race on incidence and survival from colorectal cancer in young adults in the United States.
Authors: Mukhija Dhruvika , Nagpal Sajan
Published: February 2020

62

Background: Multiple studies have reported an increasing incidence of colorectal cancer (CRC) in young( < 45 years)adults.However, the impact of race on the incidence, tumor location and survival in adults < 45 years with CRC has not been explored. Methods: Using Surveillance,Epidemiology and End Results database,we identified patients with CRC and abstracted data on patient demographics,tumor location and survival between 1973-2014, and compared these variables in patients 18-44 years with those > 45 years. Cases where CRC was not the first/only malignancy were excluded.Categorical variables were compared using the Chi-square test and overall survival was analyzed using Kaplan-Meier method. Results: Overall, 453,019 patients were included (27, 352 < 45,and 425,667 >45 years). 81.7% among those > 45 years were caucasian, as compared to 74.3% < 45 years of age. Among those < 45, 14.3% were black, 10.3% were Asian/Pacific Islander (API) and 1.1% were American Indian/Alaska Native (compared to 10.1%, 7.5% and 0.6% respective in adults > 45) (p < 0.0001*) (Table). 73.1% of those < 45 had left sided disease (descending, sigmoid colon and rectum) as compared to 60.1% in those > 45 (p < 0.0001*).Survival was poorer for non-white patients (black, API and AI) (94 months, 95%CI 90-100) as compared to white patients (153 months, 95%CI 145-161) overall, and individually for the < 45 and >45 years subgroups as well. Conclusions: Racial distribution in patients with CRC differs significantly among patients < 45 as compared to older adults,with incidence in young American Indian/Alaska Natives approaching 2 times that of older adults,and 1.5 times in young Blacks and Asian/Pacific Islanders.Non-white races have poorer survival across all age groups.With rates of CRC rising sharply in young adults, underlying reasons for these differences require further investigation to better channelize efforts for education and screening.

[Table: see text]
Weight loss as an untapped early detection marker in pancreatic cancer.
Authors: Hue Jonathan J. , Markt Sarah C. , Kyasaram Ravi Kumar , Shanahan John , Rao Goutham , Winter Jordan Michael
Published: February 2020

643

Background: Pancreatic cancer has the worst survival of common cancers and there are no reliable early detection tests. While prior reports link unintentional weight loss (>5% decrease from baseline) to pancreatic cancer, there has never been a study documenting the frequency of this presenting sign using raw patient weight data. Methods: Patients at our institution with a pancreatic neoplasm (n=288) were queried using ICD-9 code 157.9 and ICD-10 code C25.9. Retrospective review identified 95 patients with pancreatic ductal adenocarcinoma and two or more prediagnosis weights (>7 days apart). Date of diagnosis was defined by the date of positive biopsy or encounter with surgical or medical oncology. Standard statistical analysis was performed. Results: Among the 95 patients, there was a slight preponderance of female (65.3%) and Caucasian (54.7%) patients. The median age at diagnosis was 71 (range: 41-90) and the median BMI was 25.6 kg/m2 (range: 15.4-49.5). 9.5% presented with clinical stage I disease, 27.3% with stage II, 9.5% with stage III, and 53.7% with stage IV. Within 1 year of diagnosis (range: 9-365 days), median weight loss was 7.1% of body weight (range: 0.2-34.5%). In this period, 71.6% of patients lost greater than 5% body weight and 32.6% lost over 10% (Table). In the 6 months before diagnosis (range: 9-180 days), median weight loss was 6.4% (range: 0.2-24.2%). A subgroup analysis of early (I, II) and late stage (III, IV) patients showed that those with late stage at presentation lost significantly more prediagnosis weight compared to the early stage patients (median 8.2% vs 5.6%, p=0.02) in a median of 175 days. Prior to diagnosis of late stage patients, 80.0% lost over 5% body weight and 38.3% lost over 10%. Conclusions: Diagnosis of pancreatic cancer is preceded by weight loss in the majority of cases, even at an early stage. Monitoring unintentional weight loss in otherwise asymptomatic patients may be an inexpensive and practical way to detect pancreatic cancer. [Table: see text]