Liver transplantation for hepatocellular carcinoma

Background
Hepatocellular carcinoma (HCC) (about 85–90% of primary liver cancer) is particularly prevalent in China because of the high prevalence of chronic hepatitis B infection. HCC is the fourth most common malignancy and the third leading cause of tumor-related deaths in China. It poses a significant threat to the life and health of Chinese people.

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Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China (2017 Edition).

Background: Primary liver cancer, around 90% are hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people. Summary: Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer (2017 Edition) in 2018, additional high-quality evidence has emerged with relevance to the diagnosis, staging, and treatment of liver cancer in and outside China that requires the guidelines to be updated. The new edition (2019 Edition) was written by more than 70 experts in the field of liver cancer in China. They reflect the real-world situation in China regarding diagnosing and treating liver cancer in recent years. Key Messages: Most importantly, the new guidelines were endorsed and promulgated by the Bureau of Medical Administration of the National Health Commission of the People’s Republic of China in December 2019.

/pdf/guidelines-for-the-diagnosis-and-treatment-of-hepatocellular-4npmgt9l96.pdf

Guidelines for the Diagnosis and Treatment of Hepatocellular Carcinoma (2019 Edition).

Hepatocellular carcinoma (HCC) is the fifth most common cancer globally and the fourth most common cancer in men in Korea, where the prevalence of chronic hepatitis B infection is high in middle-aged and elderly patients. These practice guidelines will provide useful and constructive advice for the clinical management of patients with HCC. A total of 44 experts in hepatology, oncology, surgery, radiology and radiation oncology in the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2014 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. (Gut Liver 2019;13:227-299)

2018 Korean Liver Cancer Association-National Cancer Center Korea practice guidelines for the management of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide and its incidence continues to rise. While cirrhosis underlies most cases of HCC, many molecular pathways are implicated in HCC carcinogenesis, including the TERT promoter mutation, Wnt/β-catenin, P53, Akt/mTOR, vascular endothelial growth factor receptor (VEGFR), and endothelial growth factor receptor (EGFR)/RAS/MAPK pathways. While the most widely used staging and treatment algorithm for HCC-the Barcelona Clinic Liver Cancer (BCLC) system-does not recommend systemic molecular therapy for early HCC, a variety of treatment options are available depending upon the stage of HCC at diagnosis. Determining the best treatment options must take into account not only the burden and extent of HCC, but also the patient's performance status, underlying liver function, extra-hepatic disease and co-morbidities. Radiofrequency or microwave ablation, liver resection, or liver transplantation, all potential curative therapies for HCC, should be the first-line treatments when possible. For patients who are not candidates of curative treatments, locoregional therapies such as transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and stereotactic body radiation (SBRT) can improve survival and quality of life. Sorafenib, a multi-kinase VEGF inhibitor, is the most widely used systemic chemotherapy approved as a first-line agent for unresectable or advanced HCC. Clinical trials are underway directed towards molecular therapies that target different aspects of the hepatocellular carcinogenesis cascade. Ideally, the goal of future therapy should be to target multiple pathways in the HCC cascade with combination treatments to achieve personalized care aimed at improving overall survival.

Goals and targets for personalized therapy for HCC

Background and Aim:  To evaluate the evidence comparing radiofrequency ablation (RFA) and surgical resection (RES) on the treatment of hepatocellular carcinoma (HCC) using meta-analytical techniques.



Methods:  Literature search was undertaken until March 2011 to identify comparative studies evaluating survival rates, recurrence rates, and complications. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were calculated with either the fixed or random effect model.



Results:  These studies included a total of 877 patients: 441 treated with RFA and 436 treated with RES. The overall survival was significantly higher in patients treated with RES than RFA at 1, 3 and 5 years (respectively: OR: 0.50, 95% CI: 0.29–0.86; OR: 0.51, 95% CI: 0.28–0.94; OR: 0.62, 95% CI: 0.45–0.84). In the RES group the 1, 3, and 5 years recurrence-free survival rates were significantly higher than the RFA group (respectively: OR: 0.65, 95% CI: 0.44–0.97; OR: 0.65, 95% CI: 0.47–0.89; OR: 0.52, 95% CI: 0.35–0.77). RFA had a higher rate of local recurrence (OR: 4.08, 95% CI: 2.03–8.20). For tumors ≤ 3 cm RES was better than RFA in the 3-year overall survival rates (OR: 0.38, 95% CI: 0.16–0.89).



Conclusions:  Surgical resection was superior to RFA in the treatment of HCC. However, the findings have to be carefully interpreted due to the lower level of evidence.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1440-1746.2011.06947.x

Clinical outcomes of radiofrequency ablation and surgical resection for small hepatocellular carcinoma: A meta-analysis

Purpose To evaluate the clinical efficacy and safety of radiofrequency ablation (RFA) with surgical re-resection (SRR) in patients with postoperative recurrent hepatocellular carcinoma (RHCC) meeting the Milan criteria. Methods A literature search was performed to identify comparative studies addressing outcomes of both RFA and SRR for RHCC meeting the Milan criteria. Pooled odds ratios (OR) with 95% confidence intervals (95% CI) were calculated using either the fixed effects model or the random effects model. Results Five nonrandomized controlled trials were included in the analysis. These studies included a total of 543 patients: 243 treated with RFA and 300 treated with SRR. The SRR group had a better 3-year recurrence-free survival rate compared with RFA group (OR 0.44, 95%CI 0.25-0.77, p=0.004). However, there were no obvious differences between RFA and SRR group in overall survival (OS) rates, re-recurrence rate and OS rates with tumors ≤ 3cm. What's more, the RFA group had a safety advantage with less complications of Clavien classification grade II or higher compared with SRR group (OR 0.21, 95%CI 0.05-0.94, p=0.04). Conclusions RFA seemed to be superior to SRR in the treatment of patients with RHCC meeting the Milan criteria on account of clinical safety. However, these findings have to be carefully interpreted due to the lower level of evidence.

Is radiofrequency ablation equal to surgical re-resection for recurrent hepatocellular carcinoma meeting the Milan criteria? A meta-analysis.

A major cause of gynecological cancer ‐related deaths worldwide, ovarian cancer is characterized by heterogeneity in both tumor cells and the tumor microenvironment (TME). Our study aimed to characterize tumor cell heterogeneity and the infiltration of M2 tumor‐associated macrophages (TAMs) in the ovarian cancer TME by single‐cell RNA‐Seq (scRNA‐Seq) analysis combined with bulk RNA sequencing (bulk RNA‐Seq). Several highly variable genes were identified in ovarian cancer tissues, and tumor cell heterogeneity and infiltrating immune tumor cell heterogeneity were characterized in ovarian cancer cells. M2 TAMs in the TME were the predominant phenotype of TAM. Further, M2 TAM infiltration in the TME was negatively correlated with poor prognosis of ovarian cancer patients. Four M2 TAM‐associated genes (SLAMF7, GNAS, TBX2‐AS1, and LYPD6) correlated with the prognostic survival of ovarian cancer patients. Knockdown of SLAMF7 or GNAS mRNA repressed malignancy and cisplatin resistance of ovarian cancer cells. ScRNA‐Seq combined with bulk RNA‐Seq identified the same four genes associated with M2 TAMs. The prognostic risk score model based on these four genes may hold favorable predictive value for the prognosis of ovarian cancer patients.

Ovarian cancer‐specific dysregulated genes with prognostic significance: scRNA‐Seq with bulk RNA‐Seq data and experimental validation

e16236 Background: Neuroendocrine neoplasms (NENs) is a heterogeneous and rare tumor type. To date, most genomic profiling studies on NENs have mainly focused on pancreatic NENs (PanNENs), less is known about nonpancreatic NENs (NP-NENs). We explored the molecular characteristics, tumor mutational burdens (TMB) and microsatellite instability (MSI) in Chinese NENs patients based on different primary lesions to discover genomic profiles. Methods: We retrospectively analyzed molecular characteristics, TMB and MSI in 155 Chinese NENs patients from laboratory of Simcere Diagnosis (Nanjing, China) during 2019 to 2022. Tissue and plasma samples were profiled using the 551-gene panel next-generation sequencing (NGS). Results: The median age of 155 patients was 61 years old (range, 22-85 years old), the male to female ratio was 1.63:1. 118 cases with known primary lesions could be divided into PanNENs(n=22) and NP-NENs (n=96). There were no differences in age and ratio of PanNENs and NP-NENs. The most common SNV and indel mutations were TP53(23%), DAXX (22.7%), MEN1 (18.2%), KRAS (18.2%), ATM (13.6%), SMAD4 (13.6%) and TSC2 (13.6%) in PanNENs, in which CDK4/6 amplifications were often detected (31.8%, 27.3%). Gene fusions rarely occurred in this cohort. For NP-NENs, we identified TP53 (58.3%), MUC16 (29.2%), RB1(31.3%), LRP1B (22.9%), SMARCA4 (10.4%), SPTA1 (10.4%) and FAT3 (10.4%) as the most common SNV and indel mutations, with MYC (26%) and CDK4 (15.6%) amplifications. CCNE1 high-level amplification was especially common in digestive system NENs. Multiple gene fusions were found in NP-NENs. 13/155 (8.4%) patients carried pathogenic/likely pathogenic germline mutations in MUTYH(n=3), MSH3 (n=2), FANCG (n=2), RAD51D (n=1), CDH1 (n=1), ERCC3 (n=1), ATM (n=1), MEN1 (n=1), RECQL4 (n=1), most of them were associated with DNA damage repair (DDR) pathway. 92.3% (12/13) patients were NP-NENs with only one PanNENs harboring MUTYH germline mutation. 155 NEN patients could be evaluated for TMB, 24 (15.5%) patients had TMB≥10Muts/Mb, 7% (10/24) were lung-derived NENs. TMB was significantly higher in NP-NENs compared to PanNENs (4.26 muts/Mb vs. 2.13muts/Mb, P<0.01). 138 patients could be evaluated for MSI status, only one NEN whose primary site was liver was MSI-H, the others were all MSS. Conclusions: Our data showed that PanNENs and NP-NENs had different mechanisms of tumorigenesis: DAXX and MEN1 alterations commonly identified in PanNENs primarily mediate DDR and PI3K-mTOR pathway. Frequent TP53, RB1 and CCNE1 aberrations in NP-NENs were associated with CDK signaling pathway. TMB was low in almost all NENs exclude lung-derived NENs. It revealed distinct drivers in different subtypes, potentially being used as relevant therapeutic targets.

Comprehensive analysis of molecular characteristics, TMB, and MSI in Chinese patients with neuroendocrine neoplasms.

Background: To investigate the characteristics of circular RNA hsa-circ-0006969 in breast cancer and identify it as a novel biomarker for breast cancer. Methods: Three breast cancer (BC) patient tissues were selected to perform human circRNA microarray analysis. GeneSpring 13.0 (Agilent) software was applied for analyzing the data. Another 116 BC patients were recruited for verification. Hsa-circ-0006969 was found as a potential circRNA for BC diagnostic biomarker. The structure of hsa-circ-0006969 was predicted by circPrimer1.2 software. MiRanda v3.3, RNA hybrid 2.1, and Cytoscape 3.6.0 were used for predicting the networks of circRNA-miRNA. T-test, Curve regression, and ROC analysis were applied to certify the diagnostic values of hsa-circ-0006969. Using SPSS25.0 software to perform the Statistical analysis. Results: 546 higher expression and 1475 lower expression circRNAs were identified. Four circRNAs were filtrated for further verification. Hsa-circ-0006969 was significantly low expressed in BC tissues and peripheral blood. Hsa-circ-0006969 was confirmed as higher diagnostic correlation with BC tissues (AUC = 0.965) and peripheral blood (AUC = 0.842), with Grade 1 (AUC = 0.639), ER-positive (AUC = 0.612), TNM I (AUC = 0.693), TNM II (AUC = 0.712), TNM III (AUC = 0.757), TNM early stage(I, II) (AUC = 0.709). Hsa-circ-0006969 presented more effective diagnostic values for tumor metastasis (AUC = 0.784) compared with CA153 (AUC = 0.752). Conclusion: Hsa-circ-0006969 could be a novel biomarker for the diagnosis and treatment of BC. 

/pdf/identification-of-circular-rna-hsa-circ-0006969-as-a-novel-1cuvomtn.pdf

Xiao-hang Li

Papers

Clinical outcomes of radiofrequency ablation and surgical resection for small hepatocellular carcinoma: A meta-analysis

Is radiofrequency ablation equal to surgical re-resection for recurrent hepatocellular carcinoma meeting the Milan criteria? A meta-analysis.

Ovarian cancer‐specific dysregulated genes with prognostic significance: scRNA‐Seq with bulk RNA‐Seq data and experimental validation

Comprehensive analysis of molecular characteristics, TMB, and MSI in Chinese patients with neuroendocrine neoplasms.

Identification of Circular RNA hsa-circ-0006969 as a Novel Biomarker for Breast Cancer