bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of race and socioeconomic factors on outcome in hepatocellular carcinoma.
Authors: Muzaffar Mahvish , Naqash Abdul Rafeh 
Published: May 2020

e16657 Background: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer related deaths and sixth leading cause of cancer globally. In USA the incidence of HCC has gradually increased over years.We sought to investigate impact of race and socioeconomic factors on the outcome of HCC in USA. Methods: The SEER database (version 8.3.6) was reviewed for patients with Hepatocellular carcinoma diagnosed between 1990-2016. Cases identified on autopsy or reported only on a death certificate were excluded. Variables included were, age, race, gender, stage, insurance, Pacific Coast Purchased/Referred Care Delivery Areas (PRCDA). Cox proportional hazard regression model was employed to test the association between survival and variables. Results: We identified a total of 87,047 cases of HCC that met the inclusion criteria from SEER database. Mean age was 63.15 yrs.( 63.22-63.07),67% were white,13% black, and others 20%.The Male: Female ratio was 3:1 and 59% of patients belonged to Pacific Coast PRCDA compared to 29% to East PRCDA.43% had localized stage,25% regional, 14% distant and 18% unknown.58% patient had some insurance and 42% were uninsured or unknown status. Patients diagnosed between 1990-2003 had median survival for white (4mos), blacks(3mos), others (7 mos.) (p < .0001) and for the time period 2004-2016, median survival was better,white(13 mos), blacks(10 mons), others(20mos) (p < .001). Conclusions: Outcome for HCC have improved over last two decades, but race and socioeconomic factors continue to impact outcome. Interventions addressing the racial and socioeconomic disparity can result in meaningful improvement in survival. [Table: see text]
Development and validation of a novel ten-gene prognostic signature for hepatocellular carcinoma.
Authors: Zhou Taicheng , Cai Zhihua , Ma Ning , Xie Wenzhuan , Gao Chan , Huang Mengli , Bai Yuezong , Ni Yangpeng , Tang Yunqiang 
Published: May 2020

e16665 Background: Hepatocellular carcinoma (HCC) remains a major challenge for public health worldwide and long-term outcomes remained dismal despite availability of curative treatment. We aimed to construct a multi-gene model for prognosis prediction to inform clinical management of HCC. Methods: RNA-seq data of paired tumor and normal tissue samples of HCC patients from the TCGA and GEO database were used to identify differentially expressed genes (DEGs). DEGs shared by both cohorts along with patients’ survival data of the TCGA cohort were further analyzed using univariate Cox regression and LASSO Cox regression to build a prognostic 10-gene signature, followed by validation of the signature via ICGC cohort and identification of independent prognostic predictors. A nomogram for prognosis prediction was built and Gene Set Enrichment Analysis (GSEA) was performed to further understand the underlying molecular mechanisms. Results: Of 571 patients (70.93% men and 29.07% women; median age [IQR], 65 [56-72] years), a signature of 10 genes was constructed using the training cohort. In the testing and validation cohorts, the signature significantly stratified patients into low- vs high-risk groups in terms of overall survival across and within subpopulations with stage I/II and III/IV disease and remained as an independent prognostic factor in multivariate analyses (hazard ratio range, 0.13 [95% CI, 0.07-0.24; P < 0 .001] to 0.38 [95% CI, 0.2-0.71; P < 0.001]) after adjusting for clinicopathological factors. Prognosis was significantly worse in the high-risk group than in the low-risk group across cohorts (P < 0.001 for all). The 10-gene signature achieved a higher accuracy (C-index, 0.84; AUCs for 1-, 3- and 5-year OS, 0.84, 0.81 and 0.85, respectively) than 8 previously reported multigene signatures (C-index range, 0.67 to 0.73; AUCs range, 0.68 to 0.79, 0.68 to 0.80 and 0.67 to 0.78, respectively) for estimation of survival in comparable cohorts. A nomogram incorporating tumor stage and signature-based risk group showed better predictive performance for 1- and 3- year survival than for 5 year survival. Moreover, GSEA revealed that the pathways related to cell cycle regulation were more prominently enriched in the high-risk group while the low-risk group had higher enrichment of metabolic process. Conclusions: Taken together, we established a robust 10-gene signature and a nomogram to predict overall survival of HCC patients, which may help recognize high-risk patients potentially benefiting from more aggressive treatment.
Mutational landscape and tumor mutation burden (TMB) feature of biliary cancer.
Authors: Yi Bin , Liu Lianke , Song Jinghai , Huang Yingying , Zhang Min , Chen Rongrong , Xia Xuefeng , Jiang Xiaoqing 
Published: May 2020

e16670 Background: Biliary cancer are relatively rare, highly aggressive and have poor prognoses. Most biliary cancers are diagnosed in the advanced and metastatic stages. Chemotherapy is the main treatment of advanced biliary cancer. We focus on gene mutation and tumor mutation burden (TMB) of biliary cancer. Methods: We retrospectively reviewed one hundred and fifty-six cases of biliary cancer. One hundred and fifty-six tumor tissues and 35 plasma samples were subjected to next-generation sequencing (NGS), which enables simultaneously assess snv, indel, rearrangements and cnv variations at least 59 genes (range 59-1021 genes). Results: Fifty-eight patients were intrahepatic cholangiocarcinoma (IHCC), 50 were extrahepatic cholangiocarcinoma (EHCC) and 48 were gall bladder cancer (GBC). From tissue samples, the commonly mutated genes were different in three groups. TP53 was the most frequently mutated gene among the three groups (IHCC 43%, EHCC 58%, GBC 79%). KRAS (33%), TERT (16%), LRP1B (16%), IDH1/2 (10%) were usual in IHCC. KRAS (28%), SMAD4 (20%), STK11 (18%), ARID1A (12%) were usual in EHCC. And ERBB2 (19%), LRP1B (17%), TERT (15%), MLL3 (15%) were usual in GBC. TP53, LRP1B and MLL3 had a higher frequency in GBC than cholangiocarcinoma (p < 0.05), and KRAS was more common in cholangiocarcinoma than GBC (p < 0.05). 72.4% IHCC, 76.0% EHCC and 60.4% GBC had gene mutation associated with target therapies, which involved in multiple signal pathway, such as IDH1/2, FGFR, ERBB1/2/3, MET, PIK3CA, PTEN, BRCA, etc. Thirty-five patients had paired tissue and plasma samples, 21 stage Ⅲ/Ⅳ, 11 stage Ⅱ and 3 unknown. The concordance between tissue and plasma was 53% in all patients and was higher in stage Ⅲ/Ⅳ than stage Ⅱ (p < 0.05). One hundred and thirty-three tissue samples assessed TMB, the mean TMB was highest in the GBC group, followed by EHCC and IHCC (7.1 vs 5.5 vs 3.9 muts/Mb, p < 0.05). The proportion of TMB-H (defined 9.0 muts/Mb as cutoff value) was higher in GBC than IHCC and EHCC. Conclusions: IHCC, EHCC, and GBC have distinctive mutational landscapes and TMB features. It maybe guide different target therapy and immunotherapy strategies in the clinic. ctDNA has promising potential in biliary cancer.
High serum sPD-1 and sPD-L1 levels 1 predict outcome in hepatocellular carcinoma patients treated with radiotherapy.
Authors: Du Shisuo , Chen Genwen , Chen Yixing , Yang Ping , Hu Yong , Zhao Qianqian , Zeng Zhao-Chong 
Published: May 2020

e16672 Background: Accumulating data have shown that soluble (s)PD-1 and sPD-L1 are potential biomarkers for the curative efficacy of chemotherapy in several cancers. However, these markers have not been well established for outcomes in hepatocellular carcinoma (HCC) radiotherapy (RT). Therefore, this study aims to assess sPD-1/sPD-L1 levels before and after RT and their relationship to clinical characteristics and prognoses. Methods: Pre-treatment serum sPD-L1 and sPD-1 levels were measured with an enzyme-linked immunosorbent assay (ELISA) in 281 patients with HCC treated with RT. The association between serum sPD-L1 and sPD-1 levels and prognosis was assessed using survival analysis. Formalin-fixed paraffin-embedded samples were obtained from 40 patients with HCC who underwent surgery. The expression of PD-L1 was evaluated by immunohistochemical analysis. Results: Using multivariate analyses; sPD-L1 and sPD-1 levels were significant independent predictors of disease-free and overall survival. Patients with maximum tumor diameters ≥5 cm and Barcelona clinic liver cancer (BCLC) staging B and C had significantly higher median sPD-1/sPD-L1 serum concentrations compared to patients with smaller tumor sizes and earlier stages. There was a positive correlation (r = 0.377, p < 0.001) between sPD-L1 and sPD-1 levels. High pretreatment sPD-1/sPD-L1 levels were associated with poor prognoses, and increased sPD-1/sPD-L1 levels were associated with disease progression after RT. In post-irradiated tumor tissue, PD-L1 expression was significantly higher than matched, non-irradiated tissue. In addition, higher PD-L1 expression was correlated with decreased cytotoxic T-cell infiltration and poor survival. Therefore, sPD-1/sPD-L1 could be used as noninvasive biomarkers for evaluating HCC malignancy before RT and in predicting the response to RT in HCC patients. Conclusions: High pretreatment serum sPD-L1 and sPD-1 were associated with poor prognoses, and increased serum sPD-L1 levels were associated with the disease progression of HCC patients treated with RT. PD-L1/ PD-1 pathway may be explored as therapeutic targets and potential predictive biomarkers for HCC treated with RT.
Comparing clinicopathologic feature and treatment outcome of patients who underwent surgical resection or liver transplant for nonalcoholic fatty liver disease (NAFLD)-related and non-NAFLD related hepatocellular carcinoma (HCC).
Authors: Chaudhary Surendra Pal , Goyal Lipika , Chase Matthew L , Zhu Andrew X. , Hashemi Nikroo , Reyes Stephanie , Corey Kathleen E , Misdraji Joseph , Clark Jeffrey William 
Published: May 2020

e16675 Background: NAFLD associated HCC is rapidly increasing in frequency worldwide. In this study, we evaluated potential differences in clinical characteristics and outcomes of patients who underwent surgery or liver transplant for NAFLD-associated HCC compared to HCC from other etiologies. Methods: Demographic, clinicopathological features and outcomes of patients with HCC who underwent liver resection or liver transplant at Massachusetts General Hospital and Brigham and Women’s Hospital were collected (January 2004 - April 2018). Of 713 patients screened, 481were eligible: 260 underwent resection [NAFLD (n = 61), viral (n = 150), cryptogenic (CC) (n = 49)]. 221 underwent transplant [(NAFLD (n = 14), viral (n = 201), CC (n = 6)]. Results: In the Resected cohort, NAFLD patients presented with median age of (71.5 years) compared with Viral (63.4) and Cryptogenic (68.4). NAFLD patients had significantly higher Body Mass Index (BMI) > 28.8 39(66%) p = < 0.001, while patients with cryptogenic HCC presented with large tumor size (>5cm) 37(75%) p = 0.001. In multivariate analysis, tumor size 5cm (HR1.78,p = 0.002), R1 or R2 resection (HR 2.48, p = < 0.001and 2.8,p = 0.007), low platelet count (HR 2.8,p = 0.002) and diabetes (HR 1.5,p = 0.025) were poor prognostic factors in resection cohort. Median overall survival (OS) was not significantly different between NAFLD, Cryptogenic and Viral (47.2, 69.7 and 69.0 months, p = 0.18) etiologies, respectively. In the Transplant cohort, NAFLD patients had a median age of 65.5 and cryptogenic, viral (61.3 and 58.5 years) respectively. NAFLD and Cryptogenic HCC patients compared with viral HCC patients had low AFP median 3.7, 3.9 and 7.5 ng/mL(p = 0.012) respectively. In multivariate analysis patients with perineural invasion (HR 20.7,p = 0.009), disease recurrence (HR 2.5,p = 0.001) and high AFP (HR 2.1,p = 0.001) were at higher risk of death among transplant patients. No significant difference in median OS was seen between NAFLD, cryptogenic and viral (69.1,92.3 and 88.0 months, p = 0.38). Conclusions: NAFLD patients had higher BMI and had a lower AFP than viral and CC. NAFLD had similar median OS following resection and transplant when compared to those with Viral and CC.
Anti-Her2neu directed therapy in advanced gall bladder cancer: A prospective, multicenter experience from India.
Authors: Das Chandan Krushna , Patel Amol , Raj Abhishek , Gupta Vineet Govinda , Mehta Prashant , Bhethanabhotla Sainath , Reddy Rakesh , Yadav Ajay 
Published: May 2020

e16682 Background: Prognosis of Gallbladder cancer (GBC) remains unchanged over the last 20 years. Her2neu amplification is present in 17% of cases of advanced GBC. We present our experience of anti Her2 targeted therapy. Methods: This is a multicenter, prospective, observational study conducted in northern India from Sept2017-Sept2019. All consecutive patients were tested for Her2neu by standard techniques or next-generation sequencing (NGS). Trastuzumab or Lapatinib was used as the anti Her2 therapy along with chemotherapy. Outcome measures were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) and compared to historical controls. Data were censored on 31Dec2019. Results: A total of 181 patients were screened; 38 (20.9%) patients were positive for Her2neu or Her3neu. Demographic details are depicted in the table. Her2 was detected by IHC 18 (47%), FISH 6(15.7%) or NGS 14(36.8%). Five patients were positive for Her3 mutation and/or amplification. Twenty-one patients received anti Her2 therapy upfront with chemotherapy. At a median follow-up of 6.8 months, median PFS was 4.1 months for chemotherapy only (n = 85) and 9.7 months for trastuzumab with chemotherapy (n = 21) (HR 0.22; P < 0.05). The median OS was 14 and 6 months in patients with or without trastuzumab-based therapy (HR 0.08 P = 0.001), respectively. Trastuzumab with chemotherapy was well tolerated. Conclusions: Her2neu directed therapy significantly improve ORR, PFS, and OS in GBC with no added toxicities in the first line. It must be evaluated in a randomized phase 3 clinical trials. [Table: see text]
A phase II study of apatinib treatment for advanced biliary tract carcinoma after failure of the standard chemotherapy.
Authors: Wang Chenchen , Guo Weijian , Huang Mingzhu 
Published: May 2020

e16684 Background: There is no standard second-line therapy for advanced biliary tract carcinoma (BTC). Apatinib, a VEGFR2 tyrosine kynase inhibitor, showed an inhibitary effect on tumor formation in BTC tumorgraft mouse model in previous study, with tolerable toxicity in clinical trials for other types of advanced cancer such as gastric cancer. We conducted an exploratory study to evaluate the efficacy and safety of apatinib in patients with advanced BTC. Methods: This is a single-center, single-arm phase II study (NCT03427242). The key inclusion criteria were:(1) histologically confirmed advanced or metastatic BTC; (2) Prior lack of response or intolerance to at least one chemotherapeutic regimens; (3) At least one measurable lesion as defined by RECIST 1.1; (4) No prior use of anti-angiogenic targeted drugs. Eligible patients received oral apatinib 500mg each day continuously until unacceptable toxicity or tumor progression. The primary endpoint was progression free survival (PFS). The secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR) and treatment safety. Results: From Dec 1, 2017 to Jan 31, 2020, a total of 18 patients (12 males and 6 females) had been recruited, and 16 patients who had received the medication of apatinib were included in this analysis. Among these patients, 10 were previously treated with only first-line chemotherapy and 6 were treated with two or more lines of therapy. The median age was 65 (range 45-76) years old. Fourteen patients had received the efficacy evaluation after treatment. Two patients achieved partial response (PR, 14.3%), 6 patients with stable disease (SD, 42.9%),and 6 patients with progressive disease(PD). The ORR and DCR were 14.3% and 57.1%, respectively. At the last follow-up date on Jan 30, 2020, 4 patients are still on apatinib medication. The median PFS was 2.70 months (95% CI, 1.94 - 3.46), and the median OS was 7.03 months (95% CI, 3.16 - 10.9). Grade 3 or 4 adverse events were reported in 7 patients (43.8%). The detailed grade 3 or 4 adverse events were proteinuria in 5 patients, hand-foot syndrome in 2 patients, platelet count decrease in 1 patients, diarrhea in 1 patients and urine bilirubin in 1 patients (Table). Conclusions: For the patients with advanced biliary tract carcinoma, apatinib showed an anti-tumor activity with acceptable safety. Clinical trial information: NCT03427242 . [Table: see text]
Parameters of oxidative metabolism in the blood of patients with pancreatic tumors of different histotypes.
Authors: Goroshinskaya Irina A. , Frantsiyants Elena M. , Aleynov Viacheslav A. , Nemashkalova Ludmila A. , Cheryarina Natalia D. , Trifanov Vladimir S. , Mezentsev Stanislav S. , Grechkin Fedor N. , Duritskiy Maksim N. , Kit Oleg I. , Zhukova Galina V. , Fomenko Yuriy A. , Petrov Dmitry S. 
Published: May 2020

e16697 Background: High mortality rates in patients with pancreatic tumors and especially with neuroendocrine tumors necessitate the study of their molecular features. Our purpose was the comparative analysis of the intensity of lipid peroxidation and functioning of the enzymatic unit of the antioxidant system in the blood of patients with pancreatic tumors depending on the presence of a neuroendocrine component in them. Methods: The study included 42 patients with pancreatic cancer before the treatment and 22 donors. Parameters of lipid peroxidation (LPO) - the content of malondialdehyde (MDA) and diene conjugates, the activity of superoxide dismutase (SOD) and catalase were measured in the plasma and red blood cells, and the content of SOD1, SOD3 and catalase were measured in the blood plasma by ELISA. The results were analyzed depending on the histotype of removed tumors: pancreatic neuroendocrine tumors (n = 12), pancreatic adenocarcinoma (n = 9), pancreatic adenocarcinoma with a neuroendocrine component from 1% to 10-30% (n = 21). Results: The most pronounced changes in the blood oxidative status relative to the group of donors were observed in neuroendocrine cancer: an increase in plasma MDA levels by 30% (p = 0.006), diene conjugates in plasma and red blood cells by 2.6 and 2.9 times (p≤0.0003), a decrease in SOD and catalase activity in red blood cells by 39.7%, and 46.5% (p = 0.000000), reduced (by 20%, p = 0.047) plasma catalase activity and the minimal ratio of activity to content of both antioxidant enzymes (37.2% and 54.8% of donor levels, p < 0.0002). Conclusions: The LPO intensification most typical of neuroendocrine cancer is promoted by more significant inhibition of enzymes of the first-line antioxidant defense in red blood cells and decreased plasma catalase activity, compared to the values in adenocarcinoma.
Real-world analysis of peptide receptor radionuclide therapy (PRRT) in the treatment of neuroendocrine tumors.
Authors: Chau Justin , Yu Nanmeng , Bakeri Hirva , Menda Yusuf , Dillon Joseph S. , Chandrasekharan Chandrikha 
Published: May 2020

e16701 Background: PRRT received FDA approval in 2018 for treatment of somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (GEPNETs) based on NETTER-1 trial data that included only small bowel grade 1 and 2 neuroendocrine tumors. We present real-world data of PRRT outcomes and implementation from a large tertiary treatment center following approval. Methods: Patients treated with PRRT at University of Iowa between Jan 2018 - July 2019 were included in this retrospective study. Patient and tumor characteristics, cumulative dose and cycles of Lu 177 PRRT administered, treatment course, treatment-related toxicity and responses were reviewed, and 1-year progression-free and overall survival rates were calculated. Results: 67 patients received PRRT, of which 61 completed at least 2 doses. Primary tumor sites included small bowel (64.1%), pancreas (20.3%), and lung (9.4%). 43 (64%) had grade 2 NET; 5 had grade 3 (7.4%). 44 (65.6%) completed 4 cycles of PRRT per FDA approval while 10 received 3 cycles (14.9%). Median duration of follow up was 11.7 months. 53 patients received at least 2 doses and at least one imaging procedure post-PRRT. No complete responses were noted. 9 patients were found to have disease progression at last follow up. 1-year progression-free survival was 78% (95% CI 64-88%). 1-year overall survival was 88% (95% CI 75-94%). Of 23 patients who received fewer than 4 cycles, PRRT was discontinued in 4 (5.9%) due to myelosuppression, specifically thrombocytopenia grade 2 and above. 9 patients discontinued therapy due to change in clinical status or progression per treating physician, 2 experienced carcinoid crisis and 2 had renal function deterioration (preexisting renal disease). 5 patients had previously received PRRT with either Y90 or Lu 177 prior to FDA approval and were retreated in our cohort. 5 patients had preexisting renal disease, including one patient on peritoneal dialysis. Conclusions: We noted a higher rate of treatment discontinuation after 3 cycles, possibly due to heavy pretreatment or treatment of patients with advanced disease, not uncommon after a new therapy is approved and implemented into practice. Discontinuation due to myelosuppression or renal dysfunction was minimal, consistent with NETTER-1 data. Our cohort is unique as it included patients who had received prior PRRT as well as others with preexisting renal dysfunction. Despite this, treatment-related toxicity in our cohort was not significantly higher.
Molecular detection of pancreatic neuroendocrine tumors using methylated DNA markers: Discovery and tissue validation.
Authors: Majumder Shounak , Berger Calise K. , Foote Patrick H. , Cao Xiaoming , McGlinch Maria , Gysbers Brianna , Halfdanarson Thorvardur Ragnar , Graham Rondell P. , de la Fuente Jaime , Robran Mariah J , Doering Karen A , Burger Kelli , Mahoney Douglas W. , Taylor William R. , Petersen Gloria M. , Ahlquist David A. , Kisiel John B. 
Published: May 2020

e16705 Background: The prevalence of pancreatic neuroendocrine tumors (PNETs) has increased in the last decade. Despite being clinically asymptomatic PNETs can be biologically aggressive. There is currently no reliable non-invasive diagnostic biomarker for PNETs. In this study we aimed to identify and validate methylated DNA marker (MDM) candidates that differentiate PNET from normal pancreas. Methods: For discovery, reduced representation bisulfite sequencing (RRBS) was performed on DNA extracted from frozen normal pancreas (n = 13) and PNET (n = 51) tissues. Area under the receiver operator characteristic curve (AUC), fold-change, and p-value criteria selected candidates MDMs for blinded validation in independent FFPE tissues from primary PNET (n = 67; solid = 50, cystic = 17), normal pancreas controls (n = 24), and normal buffy coat (n = 36) using methylation specific PCR. MDM distributions in primary PNETs were compared to primary lung (n = 36) and small bowel (n = 36) NETs and metastatic PNET tissue (n = 25). The discrimination accuracy of candidate markers was summarized as the AUC with corresponding 95% confidence intervals (CI). Results: From the RRBS discovery, 31 candidate MDMs were selected for validation. Four MDMs ( SRRM3, HCN2, SPTBN4 and TMC6) achieved individual AUCs ≥0.95 in the validation set (Table). These MDMs were similarly discriminant in metastatic PNET tissue and in primary lung and small bowel NETs. Three out of these 4 MDMs perfectly differentiated PNET tissue from buffy coat with AUC of 1 and may be ideally suited for further development of a blood-based assay. Conclusions: We identified and validated novel MDMs in tissue that discriminate PNETs from controls with normal pancreas and buffy coat with high accuracy. These MDMs also differentiated metastatic PNETs from normal pancreas tissue. Further exploration of these candidate tissue MDMs in plasma can potentially guide diagnosis and management of PNETs. Funding: P30DK084567. [Table: see text]