bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatic and hematological toxicity associated with selective internal radiation therapy (SIRT): A meta-analysis of randomized clinical trials.
Authors: Manne Ashish , Behring Michael , Manne Upender , Jacob Rojymon , Paluri Ravi Kumar 
Published: February 2020

546 Background: For advanced hepatocellular cancers (HCCs) and colorectal cancers (CRCs) with liver metastasis, the impact of selective internal radiation therapy(SIRT) with yttrium-90 on survival outcomes is not established. A meta-analysis of randomized clinical trials (RCT) was performed to determine the relative risk (RR) of hepatic and hematological toxicities with the use of SIRT, compared to therapies not including SIRT. For patients with advanced HCC or CRC, we assessed the RR of high grade (grades 3 and 4) hyperbilirubinemia, fatigue, leucopenia, thrombocytopenia and elevated liver enzymes (AST and ALT) with use of SIRT. Methods: Citations from PubMed/Medline, clinical trials.gov, package inserts, and abstracts from major conferences were reviewed to include RCTs comparing arms with or without SIRT. Potential publication bias was assessed using the Egger test for funnel plot asymmetry. There was no publication bias and the trials were of high quality per Jadad scoring. Patients in control arms received trans-arterial chemo-embolization (TACE) or sorafenib for HCC or FOLFOX for CRC. The proportion and 95% confidence intervals (CIs) for patients with adverse events were derived for each arm of each study and used to calculate the RR. For the meta-analysis, both the fixed-effects model and the random-effects model were considered; the method proposed by DerSimonian and Laird was used to estimate the random-effects model. Results: The RR of grade 3/4 leucopenia was consistently high across high with the use of SIRT across all the studies (RR 2.05, 95% CI (1.22-3.42), p-value 0.027). The risk of hepatic dysfunction and fatigue was higher with SIRT but not statistically significant. Conclusions: Since SIRT is associated with increased risk of high-grade leukopenia, caution is advised in selecting patients with HCC’s with underlying decompensated cirrhosis or with CRCs and on cytotoxic therapy. Proper selection of patients would reduce toxicities from SIRT alone or SIRT in combination with systemic chemotherapy.
Role of precision medicine for patients with advanced biliary tract cancers.
Authors: Hollebecque Antoine , Nabi Oumrou , Ducreux Michel , Boige Valerie , Scoazec Jean-Yves , Rouleau Etienne , Boileve Alice , Smolenschi Cristina , Verlingue Loic , Matias Margarida , Burtin Pascal , Prieux-Klotz Caroline , Massard Christophe , Malka David 
Published: February 2020

552 Background: Biliary tract cancers (BTC) are rare and heterogeneous cancers with poor prognosis. Several actionable genomic targets have been described in BTC but data on the efficacy of targeted therapies remain limited. The main objectives of this retrospective study was to evaluate the frequency of actionable genomic alterations among BTC and the impact of targeted therapy. Methods: We performed a retrospective analysis on BTC patients seen at Gustave Roussy (IGR) from Dec 2011 to Jul 2019. All clinical and genomic reports were reviewed. Results: The study population included 212 patients with the main following characteristics: median age 61 years, female 51%, intrahepatic cholangiocarcinoma 57%, median of 2 previous lines. Of 212 BTC patients, 170 patients had a genomic profile based on archival tissue or a new tumor biopsy (IGR panel n = 120; Foundation One panel n = 92 ). 124 patients (73%) had at least one genomic alteration and 68 (40%) patients had genomic alteration considered as actionable. The most common actionable targets were FGFR2 rearrangement/mutation (n = 24, 35.3%), HER2/3 mutations (n = 9, 13.2%) and IDH1/2 mutations (n = 7, 10.3%). Of those 68 patients, 58 received the matched targeted therapy: FGFR inhibitor n = 24, HER2/3 inhibitors n = 9, Akt/PIK3CA/mTOR inhibitors n = 7, IDH1 inhibitor n = 6. In the treated population, the objective response rate was 36.2% and the disease control rate 85.1%. Progression-free survival (PFS) was 6.2 months compared to 2.8 months (p = 0.02) for patients who did not received targeted treatment. Overall survival (OS) was 17.7 months compared to 11.0 months (p = 0.03) for patients who did not received targeted treatment. Conclusions: Actionable genomic targets are frequent among BTC. Profiling-directed therapies resulted in a 36% response rate, a 85% tumor control rate and a 6.2 months PFS which compare favorably to second-line chemotherapy. A randomized trial is required to confirm the benefit of precision medicine in BTC.
Real-world efficacy and safety of immune checkpoint inhibitors in advanced hepatocellular carcinoma: Experience of a tertiary Asian center.
Authors: Ng Kennedy , Wong Lawrence Wen Jun , Choo Su Pin , Tai David Wai-Meng , Tan Sze Huey , Ang Andrea Jing Shi , Lee Joycelyn Jie Xin 
Published: February 2020

559 Background: Immune checkpoint inhibitor (ICI) use in advanced hepatocellular carcinoma (HCC) is increasing. Real-world data on efficacy and safety however is lacking, more so when used in patients who fall out of standard clinical trial criteria. Methods: We conducted a retrospective review of all patients with advanced HCC seen at our centre who received at least one dose of an ICI between May 2015 - June 2018. Data cutoff was 31 Dec 2018. Responses were evaluated using RECIST v1.1 criteria. Results: 114 patients fulfilled inclusion criteria. Median age was 66 years and 88.6% were male. 96.5% had an ECOG PS of 0 – 1. 64.9% received an ICI within a clinical trial setting. 62.3% received monotherapy ICI. 19.6% of patients had Child-Pugh B disease on initiation of ICI, and 69.3% had an ALBI Grade of 2. 50.0% were known to have hepatitis B and 11.4% had hepatitis C. Baseline HBV VL ranged from undetectable to 8210000 IU/mL. 30.7% received prior systemic treatment, most commonly sorafenib (82.9%). Over a median follow-up duration of 5.7 months (0.03 - 42.4), ORR was 18.4%, and disease control rate (DCR) was 51.8%. Median PFS was 2.6 months (1.7 - 3.9), and median OS was 13.9 months (7.0 - 16.2). 5 patients (23.8%) had response duration of more than 18 months. 35.1% received further systemic therapy after ICI. On multivariable analyses, age ≥ 65 years, higher albumin level and lower bilirubin level were associated with increased OS. 68.0% of patients experienced adverse events (AEs) of any grade, 12.0% of these being grade 3 - 4. No grade 5 adverse events were observed. Use of antiviral therapy was associated with a lower risk of hepatic AEs (p = 0.04) whilst high baseline HBV VL was not associated with an increased risk of reactivation or hepatic AEs. Conclusions: In the real-world setting, responses and adverse event profiles to ICI use are comparable to those observed in clinical trials despite a more heterogenous population base. The expansion of indications for ICI use in advanced HCC beyond current approvals warrants greater study.
Real-world data on treatment patterns of advanced CRC in third-line and beyond.
Authors: Flood William A. , Kozlovsky Vlad , Margolis Neil , Reddy Sandeep K. 
Published: February 2020

56 Background: NCCN guidelines state “regorafenib (Stivarga) [REG], and Trifluridine+Tipiracil (Lonsurf) [LON] are treatment options for patients who have progressed through all available regimens”. Available clinical trial data has not established whether recycling of prior regimens (oxaliplatin/irinotecan/5FU) with exchange of biologics (bevacizumab, ziv-aflibercept, cetuximab, panitumumab) is superior to changing class of therapy with oral well tolerated agents such as REG and LON. Methods: Data from a pre-authorization platform used by multiple commercial insurance companies in the US (Eviti) was analyzed. 6325 treatment plans of advanced CRC patients were evaluated. Analysis for request for use of REG and LON was limited to third-line and later of therapy in patients with a diagnosis of advanced CRC patients. Results: Of 394 treatment plans beyond second-line of therapy, REG was preferred over LON (239 v 155). Excluding growth factors, anti-emetics, and leucovorin, REG and LON were the 9th and 13th most frequently requested drugs in this clinical setting. Irinotecan was the most commonly requested drug in this setting at >10x the frequency of REG. Ramucirumab was requested more often than REG, and Pembrolizumab, Nivolumab, and Ziv-aflibercept were more requested than LON. HEOR models that included expected supportive care drugs and medication complication management fees estimated the cost of REG at $62,515 per patient versus LON at $26,596 with similar duration of therapy. Conclusions: Therapeutic preferences exist in third-line and later treatment of advanced CRC patients which cannot be fully explained by clinical trial outcome differences, HEOR cost differences, or NCCN guideline preferences. Recycling of chemotherapy and biologics in the late line setting is common and occurs more frequently than switching to a drug regimen with an alternative mechanism of action.
Clinical outcomes of hepatocellular carcinoma patients with Child-Pugh class B treated with stereotactic body radiation therapy.
Authors: Baclay J Richelcyn , Toesca Diego Augusto Santos , von Eyben Rie , Minneci Madeline , Pollom Erqi L. , Chang Daniel Tandel 
Published: February 2020

560 Background: Caution is usually employed in the treatment of patients with hepatocellular carcinoma (HCC) due to the inherent liver radiosensitivity, especially in patients with Child Pugh (CP) B and C classes. This study aims to review the outcomes of patients treated with SBRT for CP class B with HCC. Methods: Medical records of all patients with HCC and compromised liver function (CP class B) treated with SBRT between 2003 and 2018 were retrieved after institutional review board approval. Clinical, laboratory, and treatment-related data were collected and analyzed for their correlation to toxicity and survival. Liver function was assessed prior to SBRT and at 1, 3 and 6 months after treatment using the CP score classification. Patients were censored for toxicity after extensive tumor progression in the liver, new liver-directed therapies, or liver transplant. Time-to-events were calculated from date of SBRT. Results: A total of 22 patients were identified, but 3 were excluded for incomplete follow-up. Median follow-up time was 33 months (range: 11-95 months). At baseline, 13 (68%) patients had a CP score of 7, and 6 (32%) had a CP score of 8. The median PTV volume was 94 cc (range: 14-710 cc). The median prescribed dose was in 5 fractions (range: 35-45 Gy in 3-5 fractions). After SBRT, 8 (42%) patients presented with worsening in CP score, with a mean increase of 1.5 points (95% CI, 0.6-2.5; p = 0.005) at the first month of follow-up, but followed by recovery in liver function with change in CP score not statistically different from baseline at 3- or 6-month follow-up times (p = 0.35 and p = 0.13, respectively). Eight patients (42%) presented with acute hepatobiliary toxicity, with six of those presenting with ≥grade 2 toxicity. Patients with CP score change ≥2 points (n = 6) showed a significantly higher incidence of acute grade 2 or higher hepatobiliary toxicity (p = 0.001) with a trend toward worse overall survival (33 vs. 51 months, p = 0.45). Conclusions: In our cohort, SBRT demonstrated to be safe for patients with Child Pugh Class B liver function.
Proteomic features of HCC tumors reveal clinically distinct subtypes independent of somatic mutations.
Authors: Yim Sun Young , Shim Jaejun , Jeong Yun Seong , Sohn Bo Hwa , Kim Ji Hoon , Lee Ju-Seog 
Published: February 2020

561 Background: Recent massive sequencing studies of HCC genomes revealed many new genetic alterations that might be accountable for HCC development and provided comprehensive view of malignant disease. However, genomic profiling of tumors is limited by a loose correlation between genetic alterations and their functional products such as proteins and metabolites. To overcome current limitation, we generated genomic and proteomic data together from HCC tumors and performed integrated analysis of both data sets. Methods: We analyzed proteomic data and genomic data such as somatic mutations, mRNA expression, miRNA expression, and copy number alterations from 300 HCC tumors to uncover most correlated genomic alterations with proteins. Clinical significance of identified key protein features were validated in multiple independent cohorts of HCC patients. Results: Analysis revealed three subtypes of HCC with substantial difference in proteomic patterns. Based on proteomic characteristics, three subtypes were named to mesenchymal (MES), metabolically active (MA), and kinase-active and genome stable (KAGS) subtypes. When assessed clinical relevance, the overall survival rate of patients in MES subtype was significantly worse than those in MA and KAGS subtype (P = 0.001). Poor clinical outcomes of mesenchymal subtype is validated in multiple independent cohorts (in total of >500 patients). Gene network analysis with integrated genomic and proteomic data further revealed association of subtypes with currently available treatments of HCC such as sorafenib and immunotherapy. In addition, multiple in-depth analysis of integrated data identified potential therapeutic target candidates for each subtype. Functional validation with cell lines demonstrated that some of candidates are essential for survival of HCC cells. Conclusions: HCC is classified into three subtypes by integrating genomic and proteomic data. These analyses has identified potential therapeutic targets as well as biomarkers associated with therapeutic targets. Our study demonstrated merit of integrated analysis of proteomic data with genomic data to uncover potential driver genes of HCC development.
Association of CXCR2+ granulocytic myeloid derived suppressor cells with the development of cholangiocarcinoma: A possible target for intervention.
Authors: Ullman Nicholas A. , Ruffolo Luis I. , Jackson Katherine M. , Chacon Alexander , Jewell Rachel , Georger Mary , Belt Brian A. , Linehan David 
Published: February 2020

565 Background: Cholangiocarcinoma (CCA) is the second most common primary liver malignancy, with increasing incidence. Currently, surgical resection offers the only chance for cure, however the prognosis remains poor in part due to high rates of unresectability, recurrence, and poor response to conventional therapy. Thus, new systemic therapies represent an unmet medical need. Few preclinical models exist for identifying and testing new targeted or immune based therapies. Here we present our findings of the immune infiltrate in human CCA tumor microenvironment (TME) and a spontaneous murine model that faithfully recapitulates human disease. Methods: Histology and immunohistochemistry (IHC) staining was performed on human CCA and adjacent normal liver. Mice with targeted hepatic Kras activation and loss of p53 (KPPC) spontaneously develop CCA. KPPC hepatic tumors and normal livers from littermate controls underwent histological and gene expression studies. Flow cytometric analysis was performed on bone marrow, spleen, peripheral blood, CCA tumors and normal littermate livers. Results: Digital IHC quantification of archival human CCA specimens demonstrated elevated levels of CD15+CXCR2+ granulocytic myeloid derived suppressor cells (G-MDSC) compared to adjacent normal liver (p = < 0.05). In addition, the CXCR2 ligand, CXCL5, was significantly elevated in CCA tumors compared to adjacent normal liver. In KPPC mice, flow cytometric analysis of hepatic tumors showed an abundance of CD45+ leukocytes comprised of immunosuppressive G-MDSC vs normal littermate controls (p = 0.0007) which recapitulates human disease. qRT-PCR demonstrated significantly increased expression of G-csf, Csf1, Cxcl1, Cxcl2, and Cxcl5 (p = < 0.0001) in CCA KPPC tumors compared to normal livers. Accordingly, granulocytes in KPPC mice were elevated in both the bone marrow and blood compared to normal littermate controls. Conclusions: These data suggest CCA co-opts the ELR+ cytokine/CXCR2 axes to mobilize and recruit immunosuppressive G-MDSC to the TME. Targeted therapy against tumor infiltrating neutrophils can be tested in this pre-clinical model to inform clinical translation.
Survival outcomes according to the tumor mutation burden and PD-L1 expression in hepatobiliary tumors.
Authors: Sánchez-García Jorge , Lopez-Verdugo Fidel , Gagnon Andrew , Alonso Diane , Fujita Shiro , Rodriguez-Davalos Manuel , Lewis Mark Andrew , Gill David Michael , Gilroy Richard , Haslem Derrick S. , Yeatman Timothy Joseph , Krong Jake , Dong Li , Dow Sean , Zendejas-Ruiz Ivan R , Thota Ramya 
Published: February 2020

566 Background: Hepatobiliary (HB) tumors are aggressive tumors with emerging evidence for increasing sensitivity to immune checkpoint inhibitors (ICI). Tumor mutation burden (TMB) was found to be a quantitative biomarker associated with production of neoantigens within the tumor and predict the sensitivity to immune therapy. Herein, we explore the TMB, microsatellite instability (MSI) and PD-L1 expression as a potential biomarker of response to immune therapy in HB tumors. Methods: We retrospectively assessed all patients with hepatobiliary malignancies who have undergone next generation sequencing (NGS) between October 2009 and June 2019. We then analysed the tumor mutation burden and PD-L1 of these tumors and also identified frequency of patients with no clinically actionable mutations. Results: In our total 61 patients with HB tumors predominantly were male (62.3%) with mean age of 63 years. Thirty-four patients had hepatocellular carcinoma, 22 patients had cholangiocarcinoma and 5 patients had gallbladder carcinoma. The most common risk factors were smoking status, cirrhosis, alcohol consumption and hepatitis C virus. The mean TMB reported was 3.2 (1.16 – 7.35). MSI was identified in 13 patients and one was indeterminate. Only 17 patients had PD-L1 positive. At least, 37 patients had one clinically actionable mutation while 24 patients had no clinically actionable mutations. Mean overall survival was 16.6 months, but no statistically significant difference was found by high PD-L1 (3 vs 3.7 months, p=0.3) expression. Conclusions: Our data suggests the TMB in HB tumors is low in general irrespective of their underlying risk factors. We also noted more than half had microsatellite stable tumors and PD-L1 expression. Future larger studies are needed to evaluate TMB, MSI and PD-L1 as a potential biomarker in hepatobiliary tumors to help select patients that will benefit from immune therapy.
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.