bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disassociation of ARID1A with genomic ancestry and prognostic impact in an admixed cohort of Brazilian patients with gastric cancer (GC).
Authors: Freitas Helano C. , Nunes Diana Noronha , Bartelli Thais Fernanda , de Amorim Maria Galli , Araujo Luiza Ferreira , Jesus Victor Hugo Fonseca , Begnami Maria D. , da Silva Israel Tojal , Defelicibus Alexandre , Valieris Renan , Boneti Bianca Salgado , Caires Elizabete Maria Pereira de Andrade , Dias-Neto Emmanuel 
Published: May 2019

e15585 Background: Loss of expression of ARID1A, a tumor suppressor gene involved in chromatin remodeling and transcription activation, has been associated with worse prognosis in Asian GC patients (Yang et al. 2016). Mutations in ARID1A have been found in 8-27% of GC, usually leading to gene/protein inactivation. Here we evaluated the possible involvement of ARID1A mutations and clinical characteristics, while considering genomic ancestry and survival, in a cohort of Brazilian GC patients. Methods: We included 112 pts diagnosed with GC and treated at AC Camargo Cancer Center before 2013. The study was approved by local IRB. Genomic DNA was used for capture-based enrichment of a customized gene panel including 99 genes. Libraries were sequenced in the NextSeq 500 platform (Illumina), using paired-end reads (2x75bp). For ancestry inference we used a set of ancestry informative markers, covered by target and off-target reads, described by Elhaik et al. (2014). Results: Median age was 64y (37-91), 63% were male, M:F ratio was 1.73. Most cases were classified as Diffuse (47.3%) followed by Intestinal (41.1%), Mixed (2.7%) and 8.9% were deemed unclassifiable by Lauren´s classification. 22.3% were stage I, 20.5% stage II, 42.9% stage III and 14.3% stage IV. 11.6% were in the GEJ and 80.4% were in corpus/antrum. Five patients were EBV positive (4.5%). Genomic ancestry was as follows: 55.4% European, 27.7% Asian, 8.9% African and 8% were highly admixed ( < 50% of any ancestry). ARID1A was mutated in 19% of cases and showed no association with age at diagnosis (p = 0.21), gender (p = 0.76), tumor location (p = 0.55), staging (p = 0.42), Lauren (p = 0.14) or EBV (p = 0.42). ARID1A had no impact on overall survival (OS) (HR 1.17; 95%CI 0.59-2.31; p = 0.6) or disease-free survival (DFS) (HR 1.24; 95%CI 0.66-2.32; p = 0.5), including the subgroup with Asian genomic background: OS-Asia (HR 1.08; 95%CI 0.31-3.81; p = 0.9), DFS-Asia (HR 1.15; 95%CI 0.32-4.12; p = 0.8). Conclusions: ARID1A is a common driver in GC among Brazilian patients. Unlike in Asians, ARID1A was not prognostic in this Brazilian cohort even in the subgroup with a predominant ( > 50%) Asian genomic ancestry.
Treatment modalities and oncological outcomes in a cohort of patients with advanced gastric cancer in Mexico.
Authors: Valenzuela Ana Karen , Meneses Medina Mónica Isabel , Camargo Vanessa Rosas , Verduzco-Aguirre Haydee Cristina , Hernandez-Felix Jorge Humberto , Huitzil Melendez Fidel David 
Published: May 2019

e15590 Background: Gastric cancer (GC) represents the third leading cause of cancer related death in Mexico. Treatment modalities and outcomes have been infrequently reported in our population. Methods: we retrospectively reviewed medical records from all consecutive patients with histologically confirmed metastatic GC treated from January 2005 to December 2015 at our institution. EG junction primaries were excluded. Overall survival (OS) was estimated by Kaplan Meier method from histological diagnosis to dead or last date of follow up and compared by Log-rank test. P value < 0.05 was considered significant. Results: 172 patients were included: 53.5% women, median age 55 years. Lauren’s classification: diffuse 57%, intestinal 20%, 3% mixed and 20% non-specified. Signet ring cells were found in 66% of cases. 37% have T4 tumors. Treatment modalities: 22% none treatment, 12% palliative care, 48% systemic chemotherapy at any time of disease course, 29% initial palliative surgery (derivative o gastrectomy), gastrectomy at any time in 14% (n 24). An R0 resection was achieved in 6/24 of patients. For those patients who received systemic chemotherapy (n 83) objective response rate was 34% and disease control rate 70%. Median OS according to treatment is shown in table. Only 35% of patients received second line chemotherapy and 7% a third line. Conclusions: patients with advanced GC have a dismal prognosis in our center. A third of patients present with terminal disease and are ineligible for oncological treatment. Chemotherapy can be offered to less than a half of patients. Palliative gastrectomy is offered to 12%. Multimodal therapy is associated with the best survival but could be offered to less than 10% of patients. [Table: see text]
Chemotherapy (CT) or chemoradiation (CTRT) in postoperative (simple cholecystectomy) carcinoma gall bladder (GBC) with residual disease, unsuitable for revision surgery.
Authors: Agrawal Sushma , Alam Nawed , Rastogi Neeraj , Das KJ Maria , Lal Punita 
Published: May 2019

e15594 Background: Approximately 25% patients of GBC present after SC. Revision surgery is the standard of care, which is possible only in few patients because of delayed presentation ( > 3 months after SC), major vessels encasement by residual lymph-nodes or medical reasons. It is unclear whether these patients should be offered CT /CTRT/ CT followed by consolidation CTRT. The purpose of this analysis is to evaluate whether single modality or dual modality is required in these patients. Methods: Records of GBC patients with SC (non-metastatic based on a staging CECT abdomen) registered between January 2008 - December 2016 were retrieved. Based on the presence and extent of residual disease, they were risk stratified into 3 groups: (1) No residual disease [NRD], (2) LR1: residual disease in GB bed, peri-portal and peri-choledochal lymph-nodes, (3) LR2: residual disease in GB bed, peri-portal and peri-choledochal, coeliac, superior mesenteric or paraaortic lymph-nodes. Patients were either offered CT or CTRT due to lack of any guidelines and according to physician discretion. Those receiving CT were offered 6 cycles of Cisplatin and Gemcitabine. Patients in Consolidation CTRT arm received 3-4 cycles of Cisplatin and Gemcitabine followed by consolidation CTRT (Concurrent Capecitabine daily with RT upto 50.4Gy/28#/5.5 weeks). Response assessment was according to RECIST criteria (CR, PR, SD, PD). Overall survival (OS) was computed by Kaplan Meier method. Results: Out of 300 patients with SC, 87 had the inclusion criteria mentioned above and rest were metastatic. At a median follow-up of 21 months (range 2-129 months), the median OS was not reached (NR) for NRD (n = 17) ( both CT and CTRT), 19 months for LR1 (n = 33) (27 mo with CTRT and 19 mo with CT, p = 0.003) and 14 months for LR2 (14 mo with CTRT and 18 mo with CT, p = 0.29). The median OS was NR, 17 mo, 16 mo and 9 mo for CR (n = 30), PR(n = 31), SD (n = 5), PD (n = 5), p = 0.001. Conclusions: While NRD should be offered single modality, Consolidation CTRT benefits LR1 but not LR2. Risk stratification according to residual disease burden after SC is a prognostic marker for OS.
Development of radiotherapeutic rhenium-188 liposomes in alginate microspheres (Rhe-LAMs) for treatment of liver tumors and technetium-99m liposomes in alginate microspheres (Tech-LAMs) for image-guided treatment planning.
Authors: Bitar Ryan D. , Lopera Jorge , Bao Ande , Merlo Jaclyn , Cigarroa Francisco , Phillips William 
Published: May 2019

e15599 Background: Radio-embolic agents such as beta-emitting yttrium-90 spheres have been widely adopted as a modality for liver cancer therapy; however, their production can be timely and costly, shunting to the lungs may occur, and post-procedural visualization is limited. Alginate, a polysaccharide which can easily be formed into microspheres, has already been investigated for drug delivery applications; however, we propose utilizing alginate to manufacture radioembolic microspheres for intra-arterial delivery to liver tumors: Rhenium-188/186-labeled liposomes in alginate microspheres (Rhe-LAMS) as a radioembolic agent for the treatment of liver tumors and technetium-99m labeled liposomes in alginate microspheres (Tech-LAMs) as an agent for nuclear image-guided pre-treatment planning for liver cancer patients. Methods: Liposomes were manufactured and labeled with either Re-188/186 or Tc-99m. The liposomes were then mixed with alginate solution and then cross-linked with CaCl2 to form microspheres. Microsphere diameter was evaluated via light microscopy, and retention of radioactivity was measured over time via dosimeter. Microspheres containing free Re-186/Tc-99m (i.e. no liposomes) were also constructed for control comparison. To test in vivo stability, Tech-LAMs were intra-arterially injected into the liver of rabbits for nuclear imaging. Results: 2 ml batches of Rhe-LAMS/Tech-LAMS of 20-80 microns could be manufactured in 3 hours. Radiolabeling efficiency of the liposomes reached 85% and retention of radioactivity in microspheres reached 75%. After overnight incubation, 90% activity was retained. Control microspheres showed a retention of < 5%. In vivo imaging revealed absent activity in the lungs and high embolic activity in the liver. Conclusions: Our novel method demonstrated success regarding radioactivity retention and embolization capabilities. We envision this method to be a quickly-producible, cost-efficient, and effective means for radioembolization of liver tumors that could be adopted by any radiopharmacy.
Tumor mutation burden in biliary tract cancers with ERBB family or DNA damage repair gene mutations.
Authors: Zhang Yongjie , Shen Ningjia , Yu Wenlong , Fu Xiaohui , Song Jia , Zhao Jing , Zhang Yuzi , Cai Shangli 
Published: May 2019

e15602 Background: Biliary tract cancers (BTCs) are aggressive malignancies associated with resistance to chemotherapy. Though immunotherapy presents a promising results based on several studies, the overall response rate is relative low. Tumor mutation burden (TMB) has been considered as a predictive biomarker of immunotherapy. However, the association between common mutations and TMB in BTCs are still unclear. Methods: We analyzed 76 BTC samples (32 cholangiocarcinoma and 44 gallbladder cancer patients) from the Cancer Genome Altas (TCGA) by whole-exome sequencing and 408 samples (276 cholangiocarcinoma and 132 gallbladder cancer patients) from Chinese clinical cohort by 381-gene targeted sequencing. The association between ERBB family members or DNA damage repair (DDR) genes and TMB was explored, respectively. TMB was defined as total number of somatic non-synonymous mutations in coding region. Results: The mutation frequency of ERBB genes was similar between the TCGA cohort and the clinical cohort (cholangiocarcinoma, 13.6% vs 10.9%; gallbladder cancer, 21.9% vs 17.4%). However, DDR mutation rate from the TCGA data was greater than that from the clinical data without consideration the pathological type (cholangiocarcinoma, 40.9% vs 21.0%; gallbladder cancer, 62.5% vs 29.5%). In cholangiocarcinoma, any ERBB gene mutation was associated with higher TMB level in TCGA cohort (P = 0.0013) and clinical cohort (P = 0.0008). Any DDR gene mutation also significantly contributed to higher TMB in two cohorts (TCGA cohort, P = 0.0001; clinical cohort, P = 0.0139). In gallbladder cancer, the same result was discovered on the significant association between ERBB genes statue and higher TMB in both two data (TCGA cohort, P = 0.0370; clinical cohort, P = 0.0008). On the contrary, higher TMB level was observed in patients carrying any DDR alterations (P = 0.0017) in TCGA cohort, but the association was not found in Chinese cohort (P = 0.2660). Besides, prognosis analysis was performed on patients in TCGA cohort. Cholangiocarcinoma patients harboring any ERBB gene mutation represent significantly poorer overall survival (median, 10.6 vs. 40.1 months; HR, 3.37; P = 0.0186). Conclusions: Chinese BTC patients may exhibit distinct gene mutations. These findings were the supplement of better comprehending BTC genomic characteristics. Further studies are needed to evaluate the efficacy of immunotherapy in BTC patients with ERBB or DDR mutation in Chinese clinical cohort.
Derazantinib (DZB) provides antitumor efficacy regardless of line of therapy in patients (pts) with FGFR2-fusion positive advanced intrahepatic cholangiocarcinoma (iCCA).
Authors: Droz Dit Busset Michele , El-Rayes Bassel F. , Harris William Proctor , Damjanov Nevena , Masi Gianluca , Rimassa Lorenza , Bhoori Sherrie , Niger Monica , Personeni Nicola , Braiteh Fadi S. , Lonardi Sara , Braun Stephan , Engelhardt Marc , Saulay Mikael , Schwartz Brian E. , Kazakin Julia , Shaib Walid Labib , Mazzaferro Vincenzo , Papadopoulos Kyriakos P. 
Published: May 2019

e15607 Background: FGFR2 fusions are prevalent in 13-22% of iCCA and known oncogenic drivers. DZB is a kinase inhibitor with potent pan-FGFR activity. In a non-comparative Phase 2a study, DZB was administered to 29 pts with FGFR2-fusion positive advanced, inoperable iCCA, either as first-line (1L) (n = 2), 2L (n = 13), 3L (n = 10), 4L (n = 2) or 5L therapy (n = 2). The objective response rate (ORR) with DZB was 21%, disease-control rate (DCR) 83% and median PFS 5.7 months (Mazzaferro et al. 2018 BJC). Data from biliary tract cancer studies suggest decreasing treatment effects of chemotherapy with increasing lines of treatment. Here, we present a post-hoc analysis of outcomes of pts treated with DZB in 1L/2L (n = 15) compared to pts treated post-2L (n = 14). Methods: Pts received 300 mg DZB QD PO. Eligibility criteria included locally confirmed, positive testing of FGFR2 fusion expression (FISH or NGS), ECOG PS 0-1. Objective responses were determined using RECIST 1.1. Disease control rate was defined as CR, PR or SD. Results: The mean age of pts treated in 1L/2L was 66y and 55y in post-2L; 73% were females in 1L/2L and 50% in post-2L treatment; other demographic variables were balanced between groups (87% vs 86% of liver target lesions, median baseline lesion size of 97.5 mm vs 109.5 mm, ECOG PS0 was 60% vs 71%). Of 15 1L/2L group pts, 12 (80%) had prior platinum-based chemotherapy as compared to all 14 pts in the post-2L group. In the 1L/2L and post-2L groups, ORR was 20% and 21%, DCR was 80% and 86%, and a reduction in sum of the largest diameter of target lesions was observed in 60% and 64% of pts, respectively. Median PFS was 5.5 mo (95% CI, 1.9-11.9) and 6.2 mo (3.6-9.2) for the 1L/2L and post-2L groups, respectively. Types of drug-related adverse events were similar in 1L/2L and post-2L. Conclusions: Anti-tumor efficacy of DZB in iCCA patients measured either by ORR, DCR, tumor shrinkage or PFS was numerically similar irrespective of treatment line. These data suggest that DZB is an effective treatment option that can be applied early in the treatment continuum of iCCA patients or at later stages to offer anti-tumor efficacy and disease control. Clinical trial information: 01752920.
The combination of the NT157 and sorafenib as a new therapeutic option for hepatocellular carcinoma.
Authors: Guo Hui , Wang Yu , Yu SZ , Li WY 
Published: May 2019

e15610 Background: Sorafenib, which was the only choice of systemic therapy in the past ten years in HCC. But sorafenib alone achieves limited efficacy. Reversing sorafenib resistance was difficulty for oncologist. Based on previous study, we investigated whether NT157 augmented antitumor activity of sorafenib and underlying mechanisms. Methods: HCC cell lines and xenografts were employed to determine antitumor activity of NT157 combined with sorafenib and explore underlying mechanisms. Results: NT157 inhibited proliferation and induced apoptosis in dose and time dependent manner in HCC cells. HCC tumor was efficiently inhibited by NT157 in vivo. Mechanistic investigations elucidated NT157 induced phosphorylation of IRS1 by ERK pathway, and blockade of Stat3 pathway was independent of ERK pathways. NT157-activated p-ERK committed them to degradation by proteasome. CCL20 and CXCL8 were selected as efficacy markers by sequence, which effectively and minimal invasively predict efficacy. No major toxicity of liver, kidney and hemogram was observed, but SII (systemic immune-inflammation = N*P/L) was much lower, implying NT157 may influence immune and inflammatory reaction. Combination of NT157 and sorafenib increased percentage of apoptotic cells, c-caspase3 and PARP. Besides, sorafenib can reverse transient elevation of p-ERK by NT157, which may be potential mechanism of two drugs performing synergy. In vivo tumor volume and weight decreased in combination group compared with monotherapy. NT157 decreased p-AKT, which was overexpressed in resistant cell, implying NT157 may reverse sorafenib resistance by inhibiting AKT. To explore mechanism of sorafenib resistance in HCC, we established sorafenib-resistant HCC cell. Combination of two drugs inhibited cell viability, increased the percentage of apoptotic cells and activated of caspase3 and PARP cleavage in resistant cell. Conclusions: Our findings demonstrate NT157 displays potent antitumor effect in HCC via blockade IRS1 and STAT3 pathways. Combination of NT157 and sorafenib has potential therapeutic effect, even in sorafenib-resistant HCC cell. These findings identify a novel therapeutic strategy for HCC using a combination of NT157 and sorafenib.
Association of the ratio of CD8+ and CD163+ lymphocytes with clinical outcome in hepatocellular carcinoma.
Authors: Chen Huan , Xin Haibei , Wu Lihong , Chen Yanhui , Luo Hongli , Li Nan , Zhang Henghui 
Published: May 2019

e15613 Background: Within the tumor microenvironment (TME), infiltrating lymphocytes and myeloid cells including tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) are key players involved in liver cancer progression. The purpose of the study was to explorer whether distinct infiltrated immune cell features differentially affect clinical outcome in hepatocellular carcinoma (HCC). Methods: We obtained respectable stage II HCC specimens, along with adjacent para-tumor tissues from 221 patients who underwent surgical resection at Eastern Hepatobiliary Surgery Hospital, (in Shanghai, China) from 2015 through April 2018. CD8+, CD163+ and CD66B+ tumor-infiltrating lymphocytes (TILs) in the cancer area (CA) and stroma area (SA), as well paratumor stroma area, were analyzed by multiple immunohistochemistry. Results: Hierarchical clustering analysis of immune cell densities revealed that all HCC samples can be classified into three distinct groups. The three immune oncology types (IO-types) were characterized by a strong CD8 T cell density in CA and SA region (IO-1), an intermediate state of CD8 and CD163+ (IO-2), and a strong CD163+ macrophage density in IO-3. Remarkably increasing risks of mortality and recurrence, as well as elevated AST, ALP, GGT and AFP levels, were identified in IO-3 group, when compared with IO-1 group. We then identified that percentages of CA-CD8+ TILs in the tumor sample and SA-CD163+ macrophages in the para-tumor region showed opposite distribution pattern among the three IO types, suggesting a predictive role for CD8/TAM ratio in HCC cohort. Therefore, we next classified all HCC samples into two subgroups, according to the levels of tumor-CA-CD8/paratumor-SA-CD163 ratio. Expectedly, higher rate of CD8/CD163 represented significantly improved overall survival (OS) and progression free survival (PFS), verses lower rate of CD8/CD163. Further association studies suggested that the two subgroups correlated with HBV DNA, tumor size, and microvascular invasion (MVI). Of note, a prognostic signature combining portal vein tumor thrombus (PVTT) and CD8/CD163 ratio discriminated HCC patients into four subtypes with increasing risk of mortality and recurrence. Conclusions: The current results indicated that the CD8/CD163 is a novel, independent prognostic factor for a lower rate of disease recurrence and favorable OS in patients with resectable HCC.
A novel preclinical model of cholangiocarcinoma based on human aberrant FBXW7 expression.
Authors: Wang Jingxiao , Wang Haichuan , Peters Michele , Ding Ning , Ribback Silvia , Utpatel Kirsten , Evert Matthias , Cigliano Antonio , Dombrowski Frank , Song Xinhua , Cossu Antonio , Xu Meng , Che Li , Gordan John Dozier , Calvisi Diego , Chen Xin 
Published: May 2019

e15624 Background: Pre-clinical models that mimic human genetic events occurring in intrahepatic cholangiocarcinoma (iCCA) are limited. The ubiquitin ligase F-box and WD repeat domain-containing 7 (FBXW7) is recognized as a tumor suppressor in many cancer types. Methods: Firstly, we determined the FBXW7 mutation frequency (n = 120) and mRNA expression (n = 87) in a collection of human iCCA. Based on the preliminary findings in human data, we generated a mouse model by hydrodynamic tail vein injection of activated/myristylated (myr-)AKT with Fbxw7ΔF, a dominant negative form of Fbxw7. Subsequently, we investigated the role of established targets of Fbxw7, namely Notch2, Yap, and c-Myc in this novel mouse model and in human CCA cell lines. Results: FBXW7 mRNA expression is almost ubiquitously downregulated (71/82; 86.6%) in human iCCA specimens, while only 0.8% of samples showed FBXW7 somatic mutations. In vivo, co-expression of AKT and Fbxw7ΔF triggered the development of iCCA lesions and mice were euthanized by 15 weeks post-injection due to high tumor burden. At the molecular level, a strong induction of FBXW7 canonical targets, including Yap, Notch2, and c-Myc oncoproteins, was detected. However, only c-Myc was consistently confirmed as a FBXW7 target in human CCA cell lines. Interestingly, selected ablation of c-Myc completely impaired iCCA formation in AKT/Fbxw7ΔF mice, whereas deletion of either Yap or Notch2 delayed cholangiocarcinogenesis in the same model. Furthermore, in human iCCA specimens, a strong, inverse correlation between the expression levels of FBXW7 and c-Myc was observed. Conclusions: Downregulation of FBXW7 is almost ubiquitous in human iCCA and cooperates with AKT to induce cholangiocarcinogenesis in mice. This pre-clinical mouse model could be used to test novel therapeutics targeting c-Myc, Notch2, and/or Yap.