bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterizing PD-L1/PD-1 expression in hepatocellular carcinoma and implications on postresection treatment response.
Authors: Farha Mark , Green Michael , El Naqa Issam 
Published: May 2019

e15626 Background: Despite recent progress in the treatment of liver cancer, its outcomes remain poor and recurrence rates are as high as 70% in 5 years. Here we seek to use PD-1 and PD-L1 expression to characterize the tumor immune microenvironment and determine whether the expression profile can be associated with response to specific treatments and be applied to personalize treatment regimens in the post-resection setting. Methods: Patients in the study had a mean age of 59, and the majority were caucasian (73%). Most were classified as Child-Pugh A (60%) and TNM stage 1-2 disease (63%). RNA Seq by Expectation Maximization (RSEM) values from the TCGA hepatocellular carcinoma (HCC) dataset for the PD-1 and PD-L1 genes were collected and normalized. RSEM values above the median were labeled “high”, while values below the median were labeled “low”. Corresponding clinical and demographic data were recorded. Survival analysis and multivariate Cox regression analyses were performed, and the Estimation of STromal and Immune cells in MAlignant Tumors using Expression data (ESTIMATE) scores were included to further characterize the tumor purity and the immune cell infiltration. Results: The median post-treatment survival of all patients was 32.4 months. Significant covariates impacting survival were age (HR = 1.05), AJCC TNM stage (HR = 1.61), and high PD-L1 expression (HR = 0.37). When stratified by ESTIMATE, the PD-1 high/PD-L1 high patient cohort had a mean immune score of 450, which was significantly higher than the other cohorts and the only positive score. Furthermore, when patients in this cohort were treated with chemotherapy, radiation, or sorafenib, their time-to-death was 20 months longer than patients from the same cohort treated with local embolization or ablation. Conclusions: We have provided data suggesting a survival advantage for patients with a positive ESTIMATE immune score and high PD-L1 and PD-1 expressions when treated with chemo, radiation, or sorafenib. Existing data suggests that immunotherapy can further synergize with these treatments in HCC and offer another promising approach to improve survival after resection for about 30% of HCC patients with this immune profile.
FOXO1, an AKT downstream substrate, plays a role as tumor suppressor in HCC pathogenesis.
Authors: Zhang Shu , Chen Xin 
Published: May 2019

e15627 Background: Hepatocellular carcinoma (HCC) represents the fifth most common tumor types in the world. However, the signaling pathways underlying hepatic pathogenesis are still poorly understood. Activation of PI3K/AKT signaling cascade has been implicated in HCC development. It has been well-established that the mammalian target of rapamycin complex 1 (mTORC1), is a major downstream effector of AKT. The reason why mTORC1 can be consistently activated is partly due to inactive mutations of a negative element regulating mTORC1, tuberous sclerosis 2 (TSC2), found in 10% human HCCs. Beyond TSC2, forkhead Box O transcription factor 1 (FOXO1), is another AKT substrate. It has been proved that FOXO1 plays a crucial role in the insulin signal pathway and liver regenerationrelying on AKT isoforms. However, the role of FOXO1 in HCC development has not been well established. Methods: FOXO1 expression was analyzed in human liver cancer from TCGA database and multiple HCC cell lines were used to verify the mechanism of how FOXO1 regulate HCC cell growth downstream of AKT activation and we further confirmed the role of FOXO1 in HCC development in vivo. Results: By using TCGA database the mRNA level of FOXO1 significantly decreases among the FOXO family, comparing tumor tissue to the surrounding tissue. The overall survival rate favors patients with high FOXO1 expression. The inhibition efficacies of MK2206, a pan-AKT inhibitor, in both TSC2 wide type cells and TSC2-null ones are not significantly different, indicating TSC2 is not the only target downstream of AKT. As FOXO1 is another major target, we knockdown endogenous FOXO1 in the same HCC cell lines, the activation of mTORC1 was no longer inhibited. Furthermore, we overexpress the activated FOXO1 (FOXO1 AAA) in TSC2-null HCC cell lines. Cell growth are significantly prohibited, implicating FOXO1 is a tumor suppressor in HCC cells. Overexpression of activated FOXO1 can also delay AKT depended HCC in met/β-catenin FVB mice model. Conclusions: AKT/mTORC1 can be a classic molecular pathway for HCC pathogenesis. Nevertheless, the parallel substrate of AKT, FOXO1, may also be an important factor in the TSC2 independent way.
The efficacy and safety of lenvatinib in patients who did not meet the inclusion criteria of the phase 3 trial (REFLECT trial) in real-world practice in Japan: A nationwide multicenter study in Japan.
Authors: Tsuchiya Kaoru , Kurosaki Masayuki , Marusawa Hiroyuki , Abe Takehiko , Ogawa Chikara , Sohda Tetsuro , Kimura Hiroyuki , Kondo Masahiko , Tsuji Keiji , Furuta Koichiro , Shigeno Masaya , Joko Kouji , Narita Ryoichi , Uchida Yasushi , Yoshida Hideo , Akahane Takehiro , Kobashi Haruhiko , Mitsuda Akeri , Kojima Yuji , Izumi Namiki ,   Japanese Red Cross Liver Study Group
Published: May 2019

e15629 Background: Lenvatinib (LEN) has been approved as a single agent for patients with unresectable hepatocellular carcinoma (u-HCC) since Mar 2018 in Japan. We conducted a nationwide multicenter study and especially focused on the efficacy and safety in the patients who did not meet the inclusion criteria of the phase 3 trial (REFLECT trial). Methods: A total of 202 patients received LEN from March 2018 at 21 sites in Japan was registered. Tumour assessments in accordance with modified RECIST were done using dynamic CT or MRI within 4-8 weeks and every 6-8 weeks thereafter. Adverse events (AEs) were graded according to the CTCAE ver4.0. Results: In this study, 128 of 202 (63%) patients did not meet the inclusion criteria of the REFLECT trial. For the reasons, 69 patients received TKI therapy before LEN, 37 patients were Child-Pugh B, 6 patients showed main portal vein invasion,13 patients had HCC which occupied ≥ 50% of liver, and 22 patients were with lower platelet ( < 75 × 10⁹ per L) . Median observation time was 4.1 months in all patients, 22 patients died, and median overall survival (OS) was not reached. As the 2nd-line therapy (after sorafenib), 45 patients received LEN and 24 patients did as the 3rd-line (after regorafenib). The OS between TKI naïve and experienced patients was not significantly different, even though baseline albumin level and ALBI score were significantly lower in TKI experienced patients than TKI naïve (p = 0.001 and 0.005). Objective response rate (ORR) and disease control rate (DCR) of TKI naïve patients were 37% and 84%, while those of TKI experienced were 27% and 76%. Child-Pugh B patients (n = 36) had significantly shorter OS than Child-Pugh A (p = 0.01) and median OS in Child-Pugh B patients was 6.1 months. Drug discontinuation due to AEs and elevated aspartate aminotransferase were significantly higher in Child-Pugh B patients (p = 0.005 and 0.001). The OS, treatment duration and drug discontinuation were not significantly different between patients with or without lower platelets. ORR and DCR in patients with lower platelets (n = 22) were 18% and 63%. Conclusions: The response rate of LEN in patients who experienced TKI therapies was similar to that in TKI naïve patients. The median OS in Child-Pugh B patients was 6.1 months and elevated aspartate aminotransferase during LEN was frequently reported in such patients. The OS and treatment duration were not significantly different between patients with or without lower platelets at the cut off of < 75 × 10⁹ per L.
Can artificial intelligence support the clinical decision making for Barcelona clinic liver cancer stage 0/a hepatocellular carcinoma in China?
Authors: Chen Ze-bin , Chen Shu-Ling , Liang Rui-Ming , Peng Zhen-Wei , Shen Jing-Xian , Zhu Wan-Jie , Li Bin , Peng Sui , Kuang Ming 
Published: May 2019

e15634 Background: Artificial intelligence (AI) is emerging as a revolutionary technology with the power to transform healthcare. IBM Watson for Oncology (WFO), as an AI clinical decision support system (CDSS), has been investigated about its impact on clinical decision making in some cancer types and shown potential to be an effective CDSS in cancer care. However, the feasibility of WFO in Chinese patients with hepatocellular carcinoma (HCC) has not been reported. Methods: Artificial intelligence (AI) is emerging as a revolutionary technology with the power to transform healthcare. IBM Watson for Oncology (WFO), as an AI clinical decision support system (CDSS), has been investigated about its impact on clinical decision making in some cancer types and shown potential to be an effective CDSS in cancer care. However, the feasibility of WFO in Chinese patients with hepatocellular carcinoma (HCC) has not been reported. Results: The overall concordance rate was 60.5%, with 53.7% and 61.4% in BCLC stage 0 and A respectively. After the MDT re-review, the overall, BCLC stage 0 and A concordance rate increased to 67.3%, 65.9% and 67.3%. The main discordance was that MDT recommended more aggressive treatment options (eg. hepatectomy) than WFO did. The increase in concordance rate may be due to the progress of treatment of HCC in the past 5 years. Conclusions: With the concordance and reasonability verified by MDT in this study, WFO may provide practical reference in BCLC stage 0/A HCC. Localization is required to cover the disparity in guideline and patient characteristics between China and the US.
Histone deacetylase 6-EGFR axis in recurrent hepatocellular carcinoma.
Authors: Yeh Yao-Tsung , Dai Hong-Ying , Wang Shen-Nien , Chang-Chien Pin-Jou 
Published: May 2019

e15638 Background: Alterations of histone deacetylases (HDACs) and related signaling have been increasingly associated with cancer development and treatment. Among those HDACs, HDAC6 uniquely functions in maintaining mRNA stability of certain genes. The aim of this study was to determine the clinical impacts and associated mechanisms of HDAC6 in hepatocellular carcinoma (HCC). Methods: Immunohistochemistry is firstly applied to analyze the distribution patterns of HDAC6 in 122 patients and the obtained results are statistically analyzed with clinicopathological characteristics and patient survival. XTT, flowcytometery, transwell assay, real-time PCR, IF, IB, immunoprecipitation (IP), and RNA-IP are used to determine the bio-impacts and underlying mechanisms of HDAC6 in liver cancer cells. Results: Both cytoplasmic and nuclear staining of HDAC6 proteins were mainly decreased in cancerous lesions. Nevertheless, increased cytoplasmic HDAC6 staining was positively correlated with disease recurrence (p = 0.002). Increased nuclear frequency, but not cytoplasmic intensity, of HDAC6 was associated with a poor survival rate in HCC patients (p = 0.041). Restoration of HDAC6 expression increased the proliferation, S phase, migration and invasion of the HepJ5, Huh7 and Mahlavu cells, lacking detectable HDAC6 expression. More interestingly, ectopic HDAC6 overexpression increased a ligand-independent expression of p-AKT, beta-catenin and cyclin D, and subsequently promoted the entry of beta-catenin into the nucleus. Both transcripts and proteins of the EGFR, a dominant trigger of AKT signaling, were unexpectedly increased upon HDAC6 restoration in HepJ5, Huh7 and Mahlavu cells. The expression of EGFR was not restored by treatment with MG132 (proteasome inhibitor) in HepJ5, Huh7 and Mahlavu cells, and HDAC6-specific siRNA decreased both HDAC6 and EGFR expression in Hep3B and SK-Hep1 cells, having detectable HDAC6 and EGFR expression. IP and RNA-IP analysis revealed that HDAC6 interacted with HuR and increased EGFR mRNA stability. Accordingly, the expression of HDAC6 and EGFR were positively correlated in cancerous lesions. Conclusions: Our results suggest that the contribution of HDAC6 to recurrent HCC may act through its maintenance of EGFR mRNA stability. HDAC6 may serve as a rational treatment target in recurrent HCC.
First-in-class hafnium oxide nanoparticles NBTXR3 in the treatment of liver cancers.
Authors: Chajon Enrique , Pracht Marc , Rolland Yan , De Baere Thierry , Nguyen France , Bronowicki Jean-Pierre , Vendrely Veronique , Sa Cunha Antonio , Baumann Anne-Sophie , Valérie Laurent , Rio Emmanuel , Le Sourd Samuel , Gustin Pierre , Perret Christophe , Peiffert Didier , Deutsch Eric 
Published: May 2019

e15642 Background: Hafnium oxide nanoparticles, NBTXR3, increase the effect of radiotherapy (RT) by enhancing local energy dose deposit within tumor cells, resulting in increased cell death compared to the same dose of RT alone. NBTXR3 efficacy was demonstrated in a phase II/III study in soft tissue sarcoma (NCT02379845) and is currently evaluated in other solid tumors including liver cancers. The use of this radio enhancer is particularly relevant in liver cancer management, a difficult to treat heterogenous population, due to the presence of underlying liver dysfunction. Methods: Phase I/II study of NBTXR3 activated by RT in patients (pts) with HCC (with/without portal vein tumor thrombus) or liver metastasis (mets) [NCT02721056]. The dose escalation part followed a 3+3 design with tested dose levels equivalent to 10%, 15%, 22% and 33% of baseline tumor volume. Patients were treated with a single intralesional injection (ILI) of NBTXR3 followed by Stereotaxic Body RT (SBRT: 45 Gy/3 fractions/5 to 7 days). Determination of recommended dose(s) and early dose limiting toxicities (DLT) were primary endpoints. Secondary endpoints include assessment of global safety profile, liver function evaluated by Child-Pugh score (CPS), AST to Platelet Ratio Index (APRI), and response rate (mRECIST/RECIST 1.1). Results: The 4 levels of ILI dose escalation were finalized (n = 17): 6 pts at 10% (2 SBRT doses tested due to organs constraints), 4 pts at 15% and 22% (due to fiducial displacement and ILI shift) and 3 pts at 33% were included. ILIs were successful and SBRT was delivered as planned with no observed DLT or NBTXR3-related SAE at all levels. Only one grade 1 AE (fatigue) related to NBTXR3 was reported at dose level 33%. No relevant change of CPS or APRI was observed over time. Among 7 evaluable HCC pts the best target lesion responses by mRECIST were: 3 CR and 4 PR and among 5 evaluable mets pts: 2 PR, 1 SD and 2 PD. Conclusions: This study demonstrated the feasibility and good tolerance of the first in class NBTXR3 ILI. These results have supported a protocol amendment adding a higher dose of NBTXR3 (42% of the tumor volume). This innovative approach might constitute a valuable solution for patients with unresectable liver tumors and liver dysfunction. Clinical trial information: NCT02721056.
Dynamic changes in the immune infiltrate within hepatocellular carcinoma tumor correlate with response to PD-1 blockade.
Authors: Marron Thomas Urban , Desland Fiona , Lavin Yonit , Schwartz Myron E. , Tabrizian Parissa , Fernandez Nicholas , Kim Joel , Tabachnikova Alexandra , Kamphorst Alice O. , Schanoski Alessandra Soares , Brown Brian , Kenigsberg Effi , Sung Max W. , Taouli Bachir , Rahman Adeeb , Merad Miriam 
Published: May 2019

e15644 Background: Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths in men worldwide, and is the most rapidly rising cause of cancer mortality in the US. Patients with resectable disease experience high rates of locoregional recurrence, and there are few effective systemic treatment options available. PD-1 blockade was recently approved for 2nd line therapy, and there are promising response rates seen in the 1st-line setting. However, only 20% of patients achieve significant response, thus we must investigate further the tumor-immune microenvironment to understand how to better modulate the immune system in this highly immunosuppressive organ. Methods: We used mass cytometry (CyTOF) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to study protein and transcriptomics of untreated tumor and tumor adjacent tissue, on a single-cell level. Results: Paired CyTOF analysis of 10 tumor lesions/adjacent tissues identified a significant increase in frequency of CD4+ T cells and T regulatory cells, a significant decrease in NK cells and neutrophils, and no difference in CD8+ T cells, macrophages, or dendritic cells (DCs) in the tumor microenvironment compared to the adjacent liver tissue. We also analyzed four patients who received nivolumab and subsequently went on to have their liver tumors resected; two out of the four patients treated had near-complete necrosis of their tumors (radiographically and histologically). Of note, the tumors of the two patients with significant pathologic response contained a significantly higher number of CD103+ tissue resident CD8+ and CD4+ T cells, compared to adjacent tissue. Moreover, activated CD8+ T cells (TIGIT+, PD-1+, TIM3+, and/or CD38+) were significantly higher in the tumor of nivolumab responders, indicating a tumor-specific response. We will also present single cell transcriptomic analyses of T cell and myeloid populations in responders and non-responders. Interestingly, high levels of nivolumab were detected on PD-1+ T cells in the tumor in all 4 patients; we will discuss transcriptional differences between nivolumab-targeted T cells in responders and non-responder patients. Conclusions: Based on this preliminary data we will be opening a clinical trial of neoadjuvant PD-1 blockade in HCC (NCT# pending) in March 2019.
Liver resection in elderly patients over the age of 70 with primary liver cancer: A retrospective analysis.
Authors: Tan Elinor , Sandroussi Charbel 
Published: May 2019

e15647 Background: Liver surgery in the elderly remains controversial amidst growing incidence in developed countries. This study compares perioperative outcomes of elderly with non-elderly patients undergoing curative hepatectomy for primary liver malignancies. Methods: 310 patients underwent liver resection for primary tumours between 2000 and 2018. There were 71 elderly (≥70 years) and 239 non-elderly patients ( < 70 years). Survival analyses, stratified according to pathology (Hepatocellular carcinoma (HCC), n = 262 and Cholangiocarcinoma (CC) n = 48), were compared between the elderly and non-elderly group. Multiple regression analyses were performed to evaluate independent predictors of major complications and overall survival. Results: Elderly patients had higher frailty score (modified Frailty Index, mean, 1.14 v 0.51, p < 0.001), more comorbidities (Comorbidities ≥4: 28% v 14%, p = 0.005), had non viral-induced primary liver cancers (Non-Hep B Non-Hep C: 65% v 19%, p < 0.001) with lower AST (p = 0.014) and ALT (p = 0.004) levels. 46% of patients underwent major hepatectomy and were similar between both groups (p = 0.502). The overall complication rate and duration of stay were comparable (p > 0.05). Post-Hepatectomy Liver Failure occurred in 10 (3%) patients with no difference between both groups (p > 0.05). There were 11 (4%) postoperative deaths with higher mortality in the elderly group (8% v 2%, p = 0.011). Multiple logistic regression revealed that MELD ≥11 (OR 2.415, p = 0.480) and a positive surgical margin (OR 2.549, p = 0.024) were independent predictors for major complications. The overall survival (OS) and disease free survival (DFS) for both HCC and CC were similar between elderly and non-elderly group respectively (HCC: 5-yr OS, 62% v 68.5%, p = 0.712; 5-yr DFS, 30.4% v 38.8%, p = 0.323; CC: 5-yr OS, 62.2% v 48.3%, p = 0.919; 5-yr DFS, 43.6% v 28.2%, p = 0.618). Multiple Cox regression revealed that albumin < 40g/L (HR 2.533, p = 0.002) and the presence of vascular invasion (HR 2.417, p = 0.004) were independent predictors of poor survival. Conclusions: Long-term survivals were comparable between the elderly and non-elderly patients following surgical treatment for primary liver cancers. Low albumin and vascular invasion predicted poor survival. Age alone should not be a contraindication to liver surgery. Major complications may be minimised by carefully selecting patient and paying particular attention to the MELD score in elderly patients with primary liver disease. Further prospective studies are required to confirm the findings here.
Transcriptional characterization of microenvironment and their prediction role for the prognosis of hepatocellular carcinoma after surgery.
Authors: Chen Kehe , Wei Haiming , Liu Tianqi , Chen Zhenxiang , Pan Deng , Huang Jingning , Gao Ting , Huang Min , Ren Xiaoshuang , Zhang Jiao , Mao Beibei , Yang Ying , Han Wenbo , Zheng Hongbo , Zhang Henghui 
Published: May 2019

e15650 Background: Hepatocellular carcinoma (HCC) is one of the most common prevalent fatal cancers worldwide with poor prognosis due to high incidence of recurrence. For patients with HCC, surgical treatment is a potentially cutative therapy. However, the puzzle in the therapy was the rapid recurrence after surgery. The purpose of this study was to integrate the impact of different immune context present in HCC microenvironment on patients’ prognosis, provide the molecular prediction clue of HCC recurrence. Methods: RNA targeted sequencing was performed on 12 primary tumor specimens from HCC patients. Transcripts of 395 immune related genes expressed in FFPE tumor samples were analyzed. The lima package was used to analyze the different expressed genes (DEGs) between patients with different prognosis. The gene set variance analysis (GSVA) analysis was performed to explore gene sets enrichment related to the recurrence post-resection. Results: 15 DEGs were detected in tissue samples between the two groups (group A: patients who relapsed within one year after surgery; group B: patients who hadn't relapsed beyond two years after surgery). The Antigen processing pathway enrichment may associate with the favorable prognosis (p < 0.05). HLA-A gene expression in group A was lower than that in group B; The gene expression of IL23A, TP63, ALOX15B, BUB1, CXCR2, CCL20, CLEC4C, PTK7, MPO, IL1B, MMP9, GAGE2C, GAGE2A, GAGE2E, DMBT1, FOXM1 in group A was higher than that in group B. Additionally, the combination of 3 genes (TP63, IL23A and BUB1) can distinguish the patients recurrent within 1 year or beyond 2 years post-resection. The joint diagnostic equation is logit (Y = 1) = 0.073 +0.740 *(TP63) + 0.589 * (IL23A)+0.959(BUB1), (Optimal threshold: 0.667, specificity: 1, sensitivity: 0.833). Conclusions: Our results suggest that RNA-seq of immune related genes from FFPE sample can effectively profile the specific landscape of tumor immune microenvironment and predict the survival of HCC. 3 genes’ expression (TP63, IL23A and BUB1) might correlate with recurrence in HCC patients after surgery.