bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel pretreatment model identifying high-risk of refractoriness after transcatheter arterial chemoembolization in unresectable hepatocellular carcinoma.
Authors: Yin Xin , Hu Ke Shu , Lu Shen Xin , Tang Bei , Ren Zhenggang 
Published: May 2020

e16641 Background: Refractoriness to transcatheter arterial chemoembolization is common during the therapeutic process of hepatocellular carcinoma, which is an intractable issue and may compromise the prognosis. We aim to establish a pre-treatment model to identify patients with high risks of refractoriness. Methods: From 2010 to 2016, 824 patients who had initially underwent at least two sessions of transcatheter arterial chemoembolization in Zhongshan Hospital, Fudan University were retrospectively enrolled. These patients were randomly allocated into a training cohort and a validation cohort. The pre-treatment scoring model was established based on the clinical and radiological variables using logistic regression and nomogram. The discrimination and calibration of the model were also evaluated. Results: Logistic regression identified vascularization pattern, ALBI grade, serum alpha-fetoprotein level, serum γ- glutamyl transpeptidase level and major tumor size as the key parameters related to refractoriness. The p-TACE model was established using these variables (risk score range: 0-19.5). Patients were divided into six risk subgroups based on their scores ( < 4, ≥4, ≥7, ≥10, ≥13, ≥16). The discriminative ability, as determined by the area under receiver operating characteristic curve was 0.784 (95% confidence interval: 0.741-0.827) in the training cohort and 0.743 (95% confidence interval: 0.696-0.789) in the validation cohort. Moreover, satisfactory calibration was confirmed by Hosmer-Lemeshow test with P values of 0.767 and 0.913 in the training cohort and validation cohort. Conclusions: This study presents a pre-treatment model to identify patients with high risks of refractoriness after transcatheter arterial chemoembolization and shed light on clinical decision making.
PD-1 targeted immunotherapy for advanced hepatocellular cancer: Current utilization and outcomes in the United States.
Authors: Uhlig Johannes , Stein Stacey , Kim Kevin 
Published: May 2020

e16647 Background: Novel oncological treatment strategies for hepatocellular carcinoma (HCC) include immunotherapies targeting programmed death protein 1 (PD-1). To date there is scarce data on the current real-world clinical utilization of immunotherapy for HCC in the US. Methods: The Flatiron Health EHR-derived de-identified database was queried in October 2019 for adult patients with advanced HCC. PD-1 targeted immunotherapy (PD-1 IMT) included Nivolumab and Pembrolizumab. Overall survival (OS) was evaluated using Cox proportional hazards models. Multivariable analyses adjusted for patient demographics (age, gender, race), documented liver disease risk factors (obesity, diabetes, alcohol abuse, hepatitis), documented liver disease complication (ascites, encephalopathy), local HCC treatment (resection, radiofrequency ablation, transarterial chemoembolization [TACE], transarterial radioembolization [TARE]) and systemic Sorafenib. Subgroup analyses were performed in patients with documented clinical performance status (Eastern Cooperative Oncology Group; ECOG) and albumin/bilirubin results (all measured nearest to HCC diagnosis). Results: A total of 2,912 patients with advanced HCC were included, of which n = 345 (11.8%) received PD-1 IMT. Utilization of PD-1 IMT continuously increased from 2004, accounting for 20.9% of all cases in 2018/19. Patients treated with and without PD-1 IMT were comparable regarding demographics, comorbidities and liver disease. PD-1 IMT was more commonly administered at academic centers (20.3% vs. 13% in non-academic centers, p < 0.001), and in patients receiving Sorafenib, TACE, TARE or HCC resection (vs. none of these treatments, each p < 0.05). Median follow-up time was 36.1 months. In univariate analyses, administration of PD-1 IMT was associated with longer OS (vs. no PD-1 IMT; HR = 0.67, 95% CI: 0.58-0.78, p < 0.001; OS rates in the table). In multivariable analyses, PD-1 IMT receipt was an independent prognosticator (vs. no PD-1 IMT; HR = 0.54, 95% CI: 0.46-0.63, p < 0.001). In a subset of n = 1560 patients, this effect persisted after adjustment for ECOG, albumin and bilirubin results (HR = 0.58; 95% CI: 0.48-0.69, p < 0.001). Conclusions: PD-1 targeted immunotherapy is increasingly used for advanced HCC, accounting for up to 20.9% of cases in 2018/19. After adjustment for potential confounders, immunotherapy was associated with an overall survival benefit. [Table: see text]
Co-mutations of KRAS/BRAF and TP53 or the high tumor mutation burden to predict survival in patients with biliary tract carcinoma.
Authors: Guo Lingling , Kou Xiaoxia , Song Panpan , Zhang Xiaoyu , Zhang Hongjuan , Qiu Jinrong 
Published: May 2020

e16650 Background: Biliary tract carcinoma (BTC), including cholangiocarcinoma and gallbladder carcinoma, is the second most common type of hepatobiliary cancer. Patients with BTC always show poor prognosis, here we revealed the molecular landscape of BTC in the Chinese population and evaluated the role of different mutations in informing prognosis. Methods: Formalin-Fixed Paraffin-Embedded (FFPE) or freshly-sampled tumor tissues from 59 BTC patients were conducted next-generation sequencing of 620 genes related to oncogenesis. Tumor mutation burden (TMB) value represents the number of non-synonymous mutations per mega base pairs in each sample. Kaplan-Meier survival curves were generated and compared using the log-rank test. Results: Altogether, 59 patients have mutations mainly in TP53, Ras/Raf, PI3K, CDK signaling pathways and SWI/SNF complex. The most frequently mutated gene was TP53(53%), followed by KRAS(23%), ARID1A(17%), ATM(12%), CDKN2A(10%), SMAD4(8%), BRCA2(8%), STK11(7%), BRAF(5%), IDH1(5%) and FGFR3 (3%). Noticeably, only one patient with FGFR2 fusion was detected. The Median TMB of these patients is 2.80 Muts/Mbp (0-36.52 Muts/Mbp). Existing data showed that KRAS/BRAF alterations were associated with a worse overall survival (OS) (median OS 166d vs. 294d, p= 0.063). Further analysis indicated that RAS/BRAF mutations were often co-current with TP53 alternations. And patients with coaltered RAS/BRAF and TP53 demonstrated the worst prognosis (media OS 123d vs. 294d, p= 0.087). In addition, a higher TMB ( > 2.80 Muts/Mb) was also associated with a worse survival (median OS 174d vs. 355d, p= 0.085). Conclusions: We identified KRAS/BRAF, or co-mutations with TP53 and high TMB could predict poor prognosis in BTC patients. These findings will be useful for clinical decision making in patients with refractory biliary tract cancer and for risk stratification of patients in future clinical studies.
Risk score and prognostication modeling based on mRNA expressivity in the tumor microenvironment of hepatocellular carcinoma.
Authors: Lee Sunyoung S. , Mohamed Yehia I. , Lee Sung Hwan , Baird Andrew , Dolan Jillian , furqan fateeha , Kaseb Ahmed Omar 
Published: May 2020

e16658 Background: Stromal elements in the tumor microenvironment (TME) impact prognosis and response to therapy. Advances in mRNA-sequencing improved understanding of gene expressivity, but few models exist to model prognosis in association with mRNA expression. Methods: Clinical data and mRNA-seq of 256 patients (pts) with hepatocellular carcinoma (HCC) were obtained from TCGA. The expressivity of 191 genes enriched in cellular and structural components of the TME and clinical data were analyzed using machine learning, multivariable COX model, and Kaplan-Meier (KM) analysis to model risk score (RS) for prediction of prognosis. Results: Prognostication was modeled with higher risk score (RS) representing worse prognosis. Gene expression associated with poor (P) and good (G) in stage 1 and 2 HCC was identified (refer to presentation). RS (stage 1) = 5.997 - 0.589 × (Age at diagnosis−7.979E-06) - 4.818 × (P/G−0.009); RS (stage 2) = -5.704 - 0.780 × (Age at diagnosis−9.383E-06) + 7.228 × (P/G−0.004). Based on RS, pts were clustered into 2 groups in each stage - high and low RS groups, showing two KM curves with P < 0.05, HR = 3.213 (95% CI 2.212 – 4.347) in stage 1; HR = 2.733 (95% CI 2.131 – 3.426) in stage 2, confirming the validity of RS modeling. Analysis of immune profiles in high and low RS groups shows that expression of genes associated with immunosuppressive factors, desmoplastic reaction, neutrophils, and co-inhibitory factors of T-cells are higher in high RS group in both stages (p < 0.05). Conclusions: Machine learning-assisted mathematical modeling of RS and gene analysis identified TME-related genes and gene groups that are strongly associated with worse prognosis in stage 1 and 2 of HCC. RS could potentially prognosticate pts in the clinic with available genomic profiles.
NTRK gene fusions in bilio-pancreatic cancers.
Authors: Demols Anne , Perez-Casanova Luis , Rocq Laureen , Charry Manon , De Nève Nancy , Verrellen Audrey , Ramadhan Ali , Van Campenhout Claude , De Clercq Sarah , Maris Calliope , Closset Jean , Lucidi Valerio , Salmon Isabelle , D'Haene Nicky 
Published: May 2020

e16664 Background: Gene fusions involving one of the 3 neurotrophic tyrosine receptor kinases ( NTRK) have been identified in approximately 1% of solid tumors and inhibitors of TRK have been shown to have anti-tumor activity regardless of tumor type. NTRK gene fusions have been previously reported in bilio-pancreatic tumors. It is of interest therefore to determine incidence and molecular characteristics of NTRK gene fusions in these patients. Methods: Formalin-fixed paraffin-embedded archival blocks from surgical resections, biopsies or cytological samples of biliary tract tumors (BTC) including intra-hepatic (IH), extra-hepatic (EH), perihilar cholangiocarcinoma (PH) and gallbladder tumors (G), and pancreatic adenocarcinoma (PA) were retrieved from the tumor bank of CUB Hôpital Erasme between JAN 2010 and OCT 2019. A two-step diagnostic method incorporating immunohistochemistry (IHC) screening followed by NGS analysis was used. Pan–TRK IHC (monoclonal antibody clone EPR17341 [AbCam, Cambridge, MA]) was used for the screening method. Staining intensity (negative, weak, moderate or strong) pattern (diffuse, focal or rare positive cells), and localization (cytoplasmic or nuclear) were evaluated. The presence of at least weak staining tumor cells led to testing by a RNA-based NGS panel (Oncomine Focus Assay ThermoFisher Scientific). Results: For BTC, 162 archival tumors samples have been selected. 149 samples were suitable to perform IHC.17 samples were IHC positive including 9 IH, 3 PH, 2 EH and 3 G tumor samples. Intensity of staining was weak in 16 samples and moderate in one. Staining location was cytoplasmic (14/17), nuclear (2/17), and nuclear+cytoplasmic (1/17). Pattern of staining was rare positive cells (2/17), focal (4/17) and diffuse (11/17). NGS testing of the 17 IHC positive samples revealed a single NTRK3 gene fusion ( ETV6(4)- NTRK3(14)). In this PH tumor, IHC had a weak focal cytoplasmic and nuclear staining. Overall in the patients screened by IHC and confirmed by NGS, percentage of NTRK fusions was 0.67 %. For PA, 319 archival tumor samples have been selected and 297 were suitable for IHC. 19 samples were IHC positive. Intensity of staining was weak in 18 samples and moderate in one. Staining location was cytoplasmic (18/19) and nuclear (1/19). Pattern of staining was focal in 2 cases and diffuse in 17 cases. No fusion was detected by NGS. Conclusions: NTRK gene fusions are rare in bilio-pancreatic cancers but testing is of high interest due to the emergence of possible treatment with specific TRK inhibitors. These results support the use of NGS to confirm positive IHC results during diagnostic screening.
BRAF mutation in Chinese biliary tract cancer patients.
Authors: Li Wendong , Cui Yanzhi , Yin Fei , Peng Li , Liu Xiaogang , Shen Yunzhi , Guo Yuntong , Wen Shiwang , Shi Junping , Lei Mengping , Javle Milind M. , Wang Kai , Jiang Da 
Published: May 2020

e16678 Background: Biliary tract cancers (BTCs) are a group of relatively rare invasive carcinomas including gallbladder carcinoma (GBC), intrahepatic (ICC), hilar (HCCA), and extrahepatic (ECC) cholangiocarcinoma. In the ROAR basket trial, dabrafenib, a BRAF inhibitor, combined with trametinib, a MEK inhibitor, demonstrated promising efficacy in patients with BTCs with an overall response rate (ORR) of 41% and a favorable safety profile. The frequency of BRAF mutations reported in BTC varies widely, and BRAF V600E mutations have been reported in 0% to 20% of BTCs. However, the frequencies of BRAF mutations in Chinese BTCs are not clear. Methods: A total of 926 BTC patients (203 ECC, 195 GBC, 59 HCCA, and 469 ICC) were included in this study. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues and matching blood samples from these patients were collected and sequenced using next-generation sequencing (NGS) targeting 450 cancer genes. Genomic alterations including single nucleotide variants, insertions and deletions, copy number variations, and fusions were assessed. The testing was carried out by a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: BRAF activating mutations were detected in 5.5% of Chinese BTC patients. There were 5.1% in ICC cases, 8.9% in ECC cases, 5.1% in HCCA cases, and 3.1% in GBC cases. BRAF V600E, the most common hotspot mutation, was detected in ICC and GBC with frequencies of 1.5% and 0.5%, respectively. No BRAF V600E was detected in ECC or HCCA. The top-ranked co-mutation genes with BRAF were TP53 (54%), ARID1A (40%), and SMAD4 (32%). Compared with BRAF wild-type cohort, the frequencies of ARID1A and SMAD4 mutations were significantly higher in patients with BRAF mutations cohort (40% vs 17%, P< 0.001; 32% vs 14%, P< 0.001), while KRAS mutations were mutually exclusive with BRAF mutations. Conclusions: To our knowledge, this is the largest BTCs cohort used to study the characterization of BRAF mutations in the Chinese patients. BRAF mutations occurred in 5.5% of patients, and BRAF V600E in 0.9%. These patients could benefit from treatment with a BRAF inhibitor combined with a MEK inhibitor. Analysis of BRAF V600E should be considered in patients with BTCs, especially in ICC and GBC. Clinical trial information: NCT03892577 .
Initially unresectable hepatocellular carcinoma treated by combination therapy of tyrosine kinase inhibitor and anti-PD-1 antibody followed by resection.
Authors: Sun Hui-Chuan , Zhu Xiao-Dong , Huang Cheng , Shen Ying-Hao , Ji Yuan , Ge Ning-Ling , Tan Chang-Jun , Zhou Jian , Fan Jia 
Published: May 2020

e16690 Background: Combination of tyrosine kinase inhibitor (TKI) and anti-PD-1 antibody showed a high tumor response for advanced hepatocellular carcinoma (HCC). We are aiming to study the effect of combination therapy followed by resection in pts with initially unresectable HCC. Methods: 60 consecutive pts with unresectable or advanced HCC were treated with combination therapy as first-line treatment, including 2 in BCLC-A (China Liver Cancer stage [CNLC]-Ib), and 13 in BCLC-B (CNLC-IIa and IIb), 26 in BCLC-C (vascular invasion, CNLC-IIIa) and 19 in BCLC-C (extrahepatic metastasis, CNLC-IIIb). Tumor response and resectability were evaluated by imaging every 2 months (± 1 week). The criteria of resectability included: (1) R0 resection can be achieved; (2) remnant liver volume ≥ 40%; (3) Child-Pugh score is 5; (4) no contra-indications for hepatectomy. Results: Conversion to resectable HCC was identified in 11 (18.3%) pts after combination therapy. Of them, 2 pts are still under treatment for immune-related adverse events, and 9 underwent hepatectomy as of January 2020. Of the 9 pts, the initial tumor was unresectable because of macro-vascular invasion (n = 6, 1 Vp3, 3 Vp4, 1 hepatic vein, 1 inferior vena cava), extrahepatic metastasis (n = 1, right adrenal gland), tumor nodules ≥ 4 (n = 1) and recurrent HCC within 2 months after first resection (n = 1). The TKIs used were lenvatinib (n = 6) and apatinib (n = 3); anti-PD-1 antibodies used were pembrolizumab (n = 4), sintilimab (n = 3), camrelizumab (n = 1) and nivolumab (n = 1). The median interval between start of combination therapy and resection was 99 days (range, 73–251). The median post-operative hospital stay was 14 days (range, 11–68). The prevalence of post-hepatectomy liver dysfunction (the criteria by ISGLS) is 5 (55.6%) pts, and the post-operative complications (by Clavien–Dindo classification) occurred in 4 (44.4%) pts, including grade I in 1, grade IIIa in 2, and grade V in 1 (died from immune-related adverse events). Tumor response (RECIST v1.1) evaluated before surgery were PR (n = 5), SD (n = 3), and PD (n = 1). Pathological CR (pCR) was found in 5 (55.6%) cases. After a median follow up of 72 days (range, 11–184), tumor recurrence were diagnosed in 1 patient, and mortality without tumor recurrence in 1 patient, the other 7 cases remained tumor-free. Conclusions: This is to date the largest cohort of pts underwent R0 resection after combination therapy for initially un-resectable HCC. The combination of a TKI and anti-PD-1 antibody is feasible as a conversion therapy.
Characteristics of growth factors in the blood allowing determination of neuroendocrine component in pancreatic diseases.
Authors: Frantsiyants Elena M. , Kaplieva Irina V. , Surikova Ekaterina I. , Neskubina Irina V. , Bandovkina Valeria A. , Trepitaki Lidia K. , Pogorelova Yulia A. , Nemashkalova Ludmila A. , Aleynov Viacheslav A. , Trifanov Vladimir S. , Grechkin Fedor N. , Sanamyants Sergey V. , Kit Oleg I. , Nepomnyashchaya Evgeniya M. , Petrov Dmitry S. , Fomenko Yuriy A. 
Published: May 2020

e16693 Background: Insulin-like growth factors I and II (IGF-I and II), transforming growth factor β (TGFβ) and its receptor (TGFβR2) are involved in cancer pathogenesis. At the same time, the features of these parameters in the blood related to the disease nature have yet to be determined. The purpose of the study was to analyze the dynamics of IGF-I, IGF-II, TGFβ and TGFβR2 in the blood of patients with pancreatic cancer. Methods: The study included male patients with pancreatic adenocarcinoma T1-3N0-1M0 (A, n = 18), pancreatic neuroendocrine tumors (NET, n = 12) and pancreatic adenocarcinoma with the neuroendocrine component T1-3N0-1M0 (A+NEC, n = 12) before the treatment. Healthy males (n = 21) were controls. Blood levels of IGF-I and IGF-II were measured by ELISA using standard test systems (Meddiagnost, Germany), as well as levels of TGFβ (BenderMedSystem, Austria) and TGFβR2 (RayBiotech, USA). Results: Patients with pancreatic cancer showed increased blood levels of IGF-II: in PA – by 1.9 times (p˂0.05), in NET – by 2.7 times and in A+NEC – by 3.4 times compared to values in healthy donors. TGFβ was elevated only in patients with A by 1.5 times (p˂0.05). TGFβR2 in the blood of patients with NET and A+NEC was increased by 4.8 and 4.5 times respectively, while in patients with A it was similar to control values. The TGFβ/TGFβR2 ratio was calculated; A+NEC was prognosed in patients with its level of 1.32±0.2. Conclusions: High blood levels of IGF-II were registered in patients with pancreatic cancer. The TGFβ/TGFβR2 ratio served as informative laboratory tests to predict the nature of pancreatic disease.
Cohort 1 results of a phase I study of autolytic immunotherapy of metastatic neuroendocrine neoplasms using intralesional rose bengal disodium.
Authors: McGregor Mark , Price Timothy Jay , Cehic Gabby , Kirkwood Ian D. , Sebben Ruben , Reid Jessica J. , Neuhaus Susan , Wachter Eric Andrew , Maddern Guy 
Published: May 2020

e16694 Background: Metastatic neuroendocrine neoplasms (mNEN’s) originating in the gastrointestinal tract are frequently slow growing yet both symptom and disease control remain important. Treatment options include resection, chemoablation, systemic somatostatin analogues (SSA) or peptide receptor radionuclide therapy (PRRT), but additional options are needed, especially when available options have been exhausted. Intralesional (IL) rose bengal disodium (PV-10), an autolytic immunotherapy under development for solid tumors, is being investigated as a potential option for treatment-refractory patients (pts) with hepatic metastases. Methods: This phase 1 study is evaluating the safety, tolerability and objective response resulting from percutaneous administration of PV-10 in 12 pts with progressive mNEN refractory to SSA and PPRT; pts must have at least one injectable hepatic lesion (1.0-3.9 cm in longest diameter) not amenable to resection or other potentially curative therapy. In Cohort 1 (n = 6) pts received PV-10 to a single hepatic lesion per treatment cycle, and could receive PV-10 to additional uninjected hepatic lesions ≥6 weeks after prior injection. The primary endpoint is safety. Secondary endpoints include objective response rate assessed by independent review of contrast enhanced CT and by 68Ga-DOTATATE PET. Results: Cohort 1 has fully enrolled, with 4 of 6 pts male, median age 65 yrs, range 47-72. Primary sites were: small bowel 3, pancreas 2, caecal 1. NET grade: Gd1 = 5, Gd2 = 1. All pts had progressed on prior SSA and PRRT. Median baseline CgA was 645 (range 30-2819). One pt received 4 PV-10 treatment cycles, 1 received 2 cycles, and 4 received a single cycle. Toxicity was acceptable, including transient pain post procedure, carcinoid flare and nausea. A partial response of injected lesions was observed in 50% of pts (injected lesion progression in 1 pt), with an overall response of stable disease achieved in 84% of pts by RECIST 1.1 (progressive disease in 1 pt). Progression free survival (PFS) was not reached by CT (range 2.4-25.3+ months), and was 6.1 months by PET. Median overall survival (OS) was ≥22.5 months, with three subjects alive at the data cut-off of Jan 2020 (range 18.1-33.8 months). Conclusions: Hepatic IL PV-10 elicited no safety concerns with encouraging evidence of both local response of injected tumors and prolonged systemic disease control in some pts. Enrolment to Cohort 2 is nearing completion where an additional 6 pts may receive injection of multiple lesions per treatment cycle. Clinical trial information: NCT00986661 .