bluuebunny/crossref_metadata_2025_split huggingface dataset:
Retrospective analysis of outcomes in patients with non metastatic cholangiocarcinoma: A single network experience.
Authors: Mamadgi Jyothika , Lundeen Kristina , Hasan Shaakir , Patruni Sunita , Khattab Ahmed , Yellala Amulya , Kirichenko Alexander V. , Raj Moses S. 
Published: May 2019

e15643 Background: Biliary tract cancers are rare cancers with an annual incidence of about 8,000. In resected non-metastatic BTCs (NM-BTCs), cure rates decrease significantly due to local and distant recurrence. However, guidelines to use adjuvant therapies are not well established due to the lack of well-structured phase three randomized trials, given the rarity of the disease. We present a retrospective study analyzing outcomes of NM-BTCs managed within Allegheny Health Network (AHN) with specific focus on patients who underwent resection and received different adjuvant treatment modalities. Methods: Data of all patients with NM-BTCs treated at AHN from January 2012 to December 2017 was collected and outcomes analyzed for patients treated with surgery vs no surgery We then sub-stratified the patients who received surgery into three groups based on the modality of adjuvant therapy. Group 1 included patients with no additional therapy , Group 2 with adjuvant chemotherapy and Group 3 with adjuvant chemotherapy+radiation. We compared Mean Progression-Free Survival (PFS) and Overall Survival (OS) in these three groups. Results: Of the 59 NM-BTCs treated at AHN, 32(52.4%) underwent surgery. The OS for surgical vs non-surgically treated patients was 23 vs 17 months (p = 0.008) and PFS 26 vs 19 months (P = 0.06) respectively. Of the resected –patients, PFS for patients in Group1 vs Group2 vs Group3 was 16 vs 21 vs 34 months (pooled P = 0.05) and OS was 19 vs 22 vs 19 months respectively (pooled P = 0.5). PFS for patients in Group1 vs Group (2+3),i.e, patients treated surgery only vs surgery+ any adjuvant treatment was 16 vs 28 months (P = 0.1), OS was 19 vs 22 months (P = 0.7)respectively. PFS in patients in Group 3 vs Group (1+2),i.e, patients treated with adjuvant chemotherapy+radiation vs others was 34 vs 19 months. (p = 0.0183) respectively. Conclusions: This analysis revealed a statistically significant improvement in OS in patients with NM-BTCs who received surgery. There was a trend towards improvement in PFS/OS in patients who received adjuvant therapy, though not statistically-significant. Use of adjuvant chemotherapy+radiation resulted in statistically significant improvements in PFS as compared to other treatment modalities.
Prediction of hepatocellular carcinoma patient survival using machine learning classification rules.
Authors: Zhou Wei , Chen Huan , Han Wenbo , He Ji , Zhang Henghui 
Published: May 2019

e15649 Background: The outcome prediction of hepatocellular carcinoma (HCC) is conventionally determined by evaluating tissue samples obtained during surgical removal of the primary tumor focusing on their clinical and pathologic features. Recently, accumulating evidence suggests that cancer development is comprehensively modulated by the host’s immune system underlying the importance of immunological biomarkers for the prediction of HCC prognosis. However, an integrated predictive algorism incorporating clinical characteristic and immune features still remain to be established. 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, (Shanghai, China) from 2015 through April 2018. Characteristics such as CD8+, CD163+, tumor-infiltrating lymphocytes (TILs) were obtained for further model construction used to predict the status of 3 survival indexes: Overall Survival (OS ,≤ 24 or > 24 month), Progression Free Survival (PFS, ≤ 6 or > 6 month), and Recurrence/Death (RD). Mutual information and coefficient between each feature and the survival indexes were tested to remove low scoring features after data cleaning and standardization. Furthermore, recursive features selection was preformed to obtain the optimal features combination. Finally, supervised learning techniques include either boosting or bagging strategy were used to fit and predict model with a grid-search method optimizing the parameters. Meanwhile, a cross validation procedure with 0.2 proportion of test cohort was randomly carried out for 10 times to evaluate the model. Results: We finally confirmed 15 biomarkers from the 46 candidates as features for the survival status prediction by using a 221 patients cohort. Among them, the top 10 most important biomarkers, included both clinical and immune attributes. The AUC of our model for survival indexes (OS, PFS, RD) was ranged from 0.76 (RD) to 0.8 (PFS), and the accuracy was above 0.85. Conclusions: We describe the integrative analysis of the clinical and immune features which collectively contribute to the survival index of HCC. Machine learning techniques, such as Gradient Boosting and random forest classifier , have a great promise for using in HCC cancer survival prediction.
Tumor size and location affecting the treatment selection for solitary small recurrent hepatocellular carcinoma (≤3.0 cm) after initial hepatectomy.
Authors: Chen Shu-Ling , Peng Zhenwei , Xiao Han , Wei Mengchao , Kuang Ming 
Published: May 2019

e15660 Background: We aimed to investigate the optimal treatment modality between radiofrequency ablation (RFA) and repeated hepatectomy in the treatment of solitary recurrent HCC (rHCC) after hepatectomy, considering the influence of tumor size and location. Methods: From Jan 2009 to Dec 2016, 630 consecutive patients with solitary small rHCC (≤3.0cm) after initial hepatectomy who underwent RFA or repeated hepatectomy were enrolled in three tertiary referral centers. Patients were divided into four groups according to tumor size (≤ 2.0cm or > 2.0cm) and location (central or peripheral) respectively. Overall survival (OS) and recurrence-free survival (RFS) rates were compared between RFA and repeated hepatectomy in these four groups. Results: For central rHCC ≤ 2.0cm, the OS and RFS rates at 5 years after RFA were significantly higher than those after repeated hepatectomy (69.9% vs 53.1%, P= 0.001; 56.2% vs 42.6%, P= 0.038). For central rHCC > 2.0cm, the 5-year OS and RFS rates were not significantly different between repeated hepatectomy and RFA (55.9% vs 48.2%, P= 0.080; 27.0% vs 19.2%, P= 0.103). For peripheral tumors ≤ 2.0cm (58.8% vs. 47.7%, P= 0.001; 45.2% vs. 25.6%, P= 0.001) or > 2.0cm (62.6% vs. 45.4%, P= 0.001; 44.7% vs. 21.1%, P= 0.010), the OS and RFS rates at 5 years after repeated hepatectomy were both significantly higher than those after RFA. Complications were more common in patients after repeated hepatectomy than RFA, especially for central tumors. Conclusions: RFA might be the optimal treatment for patients with central rHCC ≤ 2.0 cm whereas repeated hepatectomy should be recommended for patients with peripheral tumors.
The heterogeneity of genomic biomarkers for immune checkpoint inhibitor in therapy-naïve primary hepatocellular carcinoma and their metachronous metastases.
Authors: Sun Yun-Fan , Zhou Jian , Jia Fan 
Published: May 2019

e15665 Background: Immune checkpoint blockade (ICB) has delivered unprecedented success in treating patients with metastatic cancers to extend overall survival, yet only a small percentage of patients respond. Immune-relevant genomic biomarkers, such as tumor mutation burden (TMB), neoantigen, and human leukocyte antigen class I (HLA-I) are emerging as potential predictors for immunotherapy response. However, little is known about their heterogeneity in metastatic cancer patients. In this study, we aim to characterize these immune-relevant genomic biomarkers in primary and matched metastatic hepatocellular carcinoma (HCC). Methods: Two cohorts of samples were included in this study. Cohort 1: a total of 24 pairs of surgical resected primary and matched metastatic HCC tissue. Cohort 2: 29 surgical resected primary HCC tissue from patients with long-term relapse-free survival. All samples were characterized using whole exome sequencing and RNA sequencing. We compared TMB, neoantigen and HLA-I genotype between primary and matched metastatic tumors, as well as between primary tumors with or without postoperative metastatic relapse. Results: The TMB of primary HCC with metastatic relapse was significantly higher than that with long-term relapse-free survival (Mean, 32 vs 17 mutations/Mb, P< 0.05), while neoantigen and HLA-I genotype failed to show statistical difference. Paired comparison between primary and matched metastatic tumors indicated that both TMB and neoantigen were significantly decreased in metastases ( P< 0.05). We further categorized metastases into two subgroups based on their HLA-I genotype. HLA-I homozygosity in at least one locus (homozygous) occurred in 9 metastases, while the rest metastases showed maximal heterozygosity at HLA-loci (heterozygous). HLA-I heterozygous metastases were associated with significantly higher neoantigen load compared with HLA-I homozygous metastases ( P< 0.05). Conclusions: High TMB might be a poor prognostic factor in patients with resected HCC and a potential predictor for postoperative adjuvant therapy with ICB. Metastatic HCC showed lower antigenicity than the corresponding primary tumors. Therefore, they might not show the same responsiveness to immunotherapy as primary tumor did. However, our HLA-I genotype analysis provides evidence that HLA-I heterozygosity has potential implication for predicting response of metastatic HCC to ICB.
Genomic landscape of HBV-related hepatocellular carcinoma in south China patients with high mutational frequency of TP53 and TERT promoter.
Authors: Ye Jiazhou , Wang Yinguang , Liang Rong , Wu Xue , Shao Yang , Wu Feixiang 
Published: May 2019

e15670 Background: Development of hepatocellular carcinoma (HCC) is a complex process with accumulations of polygene abnormalities and multi-pathway misregulation. Hepatitis B virus (HBV) exposure can cause liver damage and promote hepatocarcinogenesis via various biological effects. We aimed to investigate the molecular mechanisms underlying the etiology of HBV-related HCC development, and provide new insights into novel molecular targets. Methods: 84 HBV-positive HCC patients from Guangxi Province, South China, who underwent hepatic resection, were enrolled in this study. Genomic alterations were analyzed in pair-matched tumor and adjacent normal tissue using a hybridization capture-based next-generation sequencing (NGS) assay targeting 422 cancer-relevant genes. Results: In total, 691 somatic mutations, 166 copy number variations and 10 gene fusions were detected in 81 (96.4%) of 84 tumor samples. The most commonly mutated gene is TP53 in this cohort (84% of the patients), which is much higher than its frequency in the reported overall HCC patients. TERT promoter has somatic mutations in 32% of the patients, reactivation of which has been implicated in multiple cancer types. Dysfunction in the cell cycle control pathway (TP53, RB1, CCND1, CDKN2A and CCNE1) was dominant, followed by PI3K/AKT cascade (PIK3CA, AKT3, MTOR, TSC1 and TSC2), while genes of WNT signaling pathway (CTNNB1, APC and AXIN2) were mutated at a lower frequency. In addition, 69 variants in 25 DNA damage repair (DDR) genes were identified in 37 (45.7%) patients. Patients with DDR mutations had a higher tumor mutation burden (TMB) than those without DDR mutations. Conclusions: This study revealed a unique genomic landscape of HBV-related HCC. Besides TP53 being the highest mutated gene, a significant fraction of patients was identified with TERT promoter mutations, suggesting that TERT may play a role in HBV-related hepatocarcinogenesis as a novel molecular marker. Furthermore, the most common biological processes affected by HBV status in HCC were cell cycle control, PI3K/AKT and WNT signaling pathways. The possible synergistic effects of HBV in hepatocarcinogenesis warrant further investigations.
Molecular profiling by circulating tumor DNA (ctDNA) and benefit from anti-PD-1 in HCC.
Authors: Carmagnani Pestana Roberto , Abugabal Yehia I. , Xiao Lianchun , Hassan Manal , Hassan Reham Abdel wahab , Girard Lauren , Raghav Kanwal Pratap Singh , Morris Jeffrey , Rashid Asif , Qayyum Aliya , Meric-Bernstam Funda , Wolff Robert A. , Yao James C. , Amin Hesham M. , Kaseb Ahmed Omar 
Published: May 2019

e15679 Background: Molecular profiling has defined actionable mutations in HCC, and has the potential to be used for selection of targeted therapies, as well as for the characterization of predictive biomarkers from approved treatments. Noninvasive strategies are critical to HCC given the challenge of obtaining liver biopsies. We investigated whether profiling by ctDNA could provide predictive and/or prognostic information for HCC patients (pt) treated with immune checkpoint inhibitors. Methods: We analyzed blood samples from 22 HCC pt who underwent treatment with anti-PD-1 using comprehensive genomic testing of ctDNA with a commercially-available platform (Guardant Health, CA). Demographic and treatment data were retrospectively collected with the goal of correlating treatment outcomes and drug response (by imaging and/or AFP) with molecular abnormalities. Results: 17/22 (77.3%) were men; median age was 66 years. 21 patients received nivolumab and 1 received pembrolizumab. 9 were HCV positive and 5 were HBV positive. 15/22 patients had > 1 alteration identified. The median number of alterations/pt was 3 (range, 1-8). TP53 was the common altered gene (n = 11) followed by CTNBB1 (n = 8) , TERT (n = 5) KRAS (n = 3) , GNAS (n = 2). Mutations were also seen (n = 1) in KIT, PIK3CA, PTEN, EGFR, NTRK, FGFR2 among others. 6 pt (27.3%) had AFP response and 8 (36.4%) achieved disease control > 12 weeks. Mutations involving KIT, PIK3CA and PTEN were associated with shorter progression-free (PFS) (p < .001 for all) and overall survival (OS) (p = .028 for all), whereas GNAS mutation was associated with shorter PFS (p = 0.019) but not OS. No differences in OS or PFS was observed for other alterations, including the presence of CTNNB1 mutation. There were no correlations between specific alterations and objective tumor response (either by imaging or AFP). 32% of pt were progression-free at 6 months. Median OS was not reached, and 62% were alive after 1 year. Conclusions: Identifying non-invasive predictive biomarkers of benefit to immunotherapy is a priority in HCC. Our data suggest that specific ctDNA alterations can provide predictive information for survival (OS and PFS) on immune checkpoint inhibitors. Further larger studies are warranted for confirmation.
Meta-analysis of prognostic biomarkers for pancreatic neuroendocrine tumors (PNETs).
Authors: Zhu Mojun , Halfdanarson Thorvardur Ragnar , Gould Rothberg Bonnie Elyssa 
Published: May 2019

e15688 Background: PNETs are marked by histological heterogeneity and variable clinical outcomes. Other than Ki67 index, reliable circulating or tissue biomarkers for prognosis do not exist. Methods: PubMed was searched through 01/31/2017. Inclusion criteria were: 1) prospective/retrospective cohort with defined source population, boundary dates, and justifications for exclusions; 2) assay of primary tumors; 3) clear descriptions of methods including techniques and controls; 4) use of multivariate proportional hazards modeling adjusted for prognostic factors including but not limited to stage or grade; and 5) reporting adjusted hazard ratios (HR) with 95 % confidence intervals and P values. Studies with < 50 % PNETs were excluded. PNET-specific data was summarized in the table. Results: A total of 2958 manuscripts were identified and 462 manuscripts were reviewed. Only 23 multivariate studies met all inclusion criteria. These altogether analyzed 24 unique targets and 14 were associated with survival. Conclusions: This meta-analysis identified 14 markers associated with survival of PNET patients. Future studies should adhere to the REMARK criteria and incorporate the 2017 WHO grading system for multivariate analysis. 1. I-immunohistochemistry, F-fluorescence in situ hybridization, E-enzyme linked immunosorbent assay, M- methylation specific PCR, P-polymerase chain reaction; 2. O-overall survival, F-disease free survival, S-disease specific survival, P- progression free survival.[Table: see text]
Methylation and mRNA analysis of differential genes between primary tumor and liver metastasis in pancreatic neuroendocrine neoplasm.
Authors: Feng Mengyu , Qiu Jiangdong , Cao Zhe , Yang Gang , Liu Yueze , Zhang Taiping 
Published: May 2019

e15689 Background: The liver metastasis of pNEN is rare, and the underlying mechanisms remain unclear. The objective of this study is to compare the DNA methylation status and mRNA expression between primary tumor and liver metastasis in pNEN, aiming to find the potential gene responsible for liver metastasis in pNEN. Methods: The liver metastasis of pNEN is rare, and the underlying mechanisms remain unclear. The objective of this study is to compare the DNA methylation status and mRNA expression between primary tumor and liver metastasis in pNEN, aiming to find the potential genes responsible for liver metastasis in pNEN. Results: The differential methylation counts in the two patients were 17756 and 214321 respectively, indicating 1975 and 26176 differential genes (|diff.Beta| > 0.14, at least one sample FPKM > 0). mRAN analysis revealed 1302 and 3729 differential mRNAs (|log2fold change| > 1, Q value < 0.05). When combining these results together, 106 and 1513 genes were discovered, and the two patients had 39 differential genes in common. 13 genes with high mutation frequency in pNEN and 52 relevant pathways were selected in literatures. Among the 39 genes, only four genes were involved in these pathways: GREM1, PAX5, CLDN11 and FGFR2. However, only FGFR2 had both decreased methylation and increased mRNA expression in the two patients, and pyrosequencing confirmed that methylation position in FGFR2 was in accordance with results from methylation microarrays. Conclusions: The present study reveals that the gene expression varies greatly between primary tumor and liver metastasis in pNEN. The decreased methylation and increased mRNA expression of FGFR2 may play an important role in liver metastasis and further mechanisms are worthy of exploring.
First real-world experience of peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors (NET) since US FDA approval.
Authors: Konda Bhavana , Rogers Sherise C. , Grenade Cassandra Natalie , Verschraegen Claire F. , Zhou Ye , Goyal Ashima , Natwa Mona , Wright Chadwick , Hussein Akram , Barr Hallie , Konate Dramane , Brown Andrew , Batdorf Rochelle , Williams Bonnie , Zhao Songzhu , Wei Lai , Shah Manisha H. 
Published: May 2019

e15691 Background: PRRT using 177Lu-DOTATATE was US FDA approved in Jan 2018, and real world data in the US is lacking. Methods: We retrospectively reviewed medical records of patients who began PRRT 03/14/18 - 10/01/18 at our institution. 177Lu-DOTATATE was administered at a dose of 200mCi over 20-30 min every 8 weeks for 4 doses. Infusion of arginine-lysine 25gm/25gm in 1-liter normal saline was given over 4 hours starting 30 min prior to treatment, in addition to intravenous palonosetron 0.25mg. Results: 51 patients received at least 1 of 4 doses and 40/51 were no longer on active therapy. 28/40 received all 4 doses and 12/40 discontinued treatment after < 4 doses. 25/40 were evaluable for response per RECIST v1.1. 16/25 (64%) had GI NET, 3/25 (12%) pancreatic NET, 4/25 (16%) atypical lung carcinoid, 1/25 (4%) multifocal NET, and 1/25 (4%) had paraganglioma. 28% had grade 1, 56% grade 2, and 8% (2/25) had grade 3 (Ki 67: 25% and 40%) NET. 12/25 (48%) had received ≥2 prior systemic therapies not including somatostatin analogs, and 10/25 (40%) had ≥1 prior liver-directed therapy. Median follow-up from date of last PRRT was 61.5 days. Objective response (partial response) rate was 16% (4/25; table). 18/25 (72%) had stable disease and 3/25 (12%) had progressive disease. Most adverse events (AEs) were grade 1-2 and included fatigue, nausea, abdominal pain, and cytopenias. ≥Grade 3 AEs requiring treatment discontinuation included symptomatic gastric outlet obstruction (2/51), small bowel obstruction (1/51), ischemic enteritis (1/51), confusion/bone pains (1/51), liver failure (1/51), and severe neutropenia (1/51). All patients with ≥grade 3 AEs had a high tumor burden at baseline. Conclusions: 177Lu-DOTATATE is an effective and safe treatment in advanced NET, and our results are consistent with NETTER 1 data.[Table: see text]
Video-based patient education on carcinoid syndrome: Positive knowledge and behavior shift for patients.
Authors: Roc Anne , Turell Wendy , Goldstein Grace , Wolin Edward M. 
Published: May 2019

e15697 Background: Carcinoid syndrome (CS) negatively affects quality of life (QOL), compromising physical, daily, and emotional functioning. Reticence to discuss symptoms, particularly debilitating diarrhea, perpetuates negative QOL, as does confusion of CS symptoms with other conditions and dietary challenges. To address these needs, we created video-based patient education activities with the Carcinoid Cancer Foundation (CCF) to empower patients with information and resources on CS facts, diagnosis, medical management, eating well and self-care. Methods: Two 1-hour patient education activities were broadcast live online and on-demand in 2017 and 2018 at CancerCoachLive.com , carcinoid.org, and Facebook Live for 6+ months. Features included panel discussions, slides, live polling and Q&A, and video vignettes of real patient experiences. Knowledge-focused test questions were administered at 3 time points (pre-activity, immediate post-activity, and 8-week [follow-up] post). Behavioral and communication-focused questions were also asked at follow up. Data from these questions, live poll responses, and learner-submitted questions pre-event and during live Q&A were analyzed to determine engagement, lessons learned and continuing patient needs. Results: In total, 1,893 patients took part in the activities, and attracted 39,821 Facebook engagements (“views”). Respondents (n = 116-119) reported: 57%, improved communication with their healthcare providers (HCPs) regarding CS; 44%, improved feeling of being “in-control” of health care decision; 31%, improved care behaviors for their health. Improved communication with their HCPs were specific to: their disease and symptoms, treatments, and diet. Changes in behaviors included: dietary changes, more “involved” in care decisions, asking questions of HCPs, and proactively learning about CS. Knowledge improvements were observed on 7 of 8 questions on CS facts, diet, and treatment (5 of 7 statistically significant; average effect size = 1.16; n averaged 382 pre and 96 post). Conclusions: Patient education on CS can yield immediate and sustained gains in knowledge and behavior, which may improve diagnosis, treatment, and improve patient QOL.