The predictive value of tumor infiltrating leukocytes in Hepatocellular Carcinoma: A systematic review and meta-analysis.

BACKGROUND: For Hepatocellular carcinoma (HCC) surgery either through resection or transplantation often provides the only chance for cure. Since hepatocarcinogenesis and postsurgical prognosis is not only dependent on cirrhosis but also on immune activation and exhaustion, many studies have investigated tumor infiltrating leukocyte (TIL) subsets. This systematic review and meta-analysis aims at describing the cell groups and their predictive power regarding overall (OS), disease free (DFS) and recurrence free survival (RFS). MATERIAL AND METHODS: A systematic search of the PubMed database was conducted (PROSPERO 172324). Data on CD3+, CD8+, Treg, B cells, macrophages, neutrophil and NK-cells were collected from Pubmed and related references up to December 2018. Overall (OS), disease-free (DFS) and recurrence free survival (RFS) in dependence of high vs. low infiltration rates were compared using a random effects meta-analysis. RESULTS: Altogether data from 3541 patients enrolled in 20 publications were included. Except for Tregs and Neutrophils, heterogeneity analysis was found to be moderate to high across the studies. High CD3+, CD8+, NK-cell infiltration predicted better survival (OS, DFS and RFS; p < 0.05). Higher Treg and Neutrophil infiltration predicted lower OS and DFS. For Macrophages and B cells no difference in survival could be found. DISCUSSION: As with other solid tumors immune infiltration has a great influence on survival after resection. However, a considerable publication bias cannot be ruled out in mostly retrospective analyses. Nevertheless, in light of novel immune modulatory treatments this opens a new avenue towards effective and well-tolerated adjuvant treatment.

Development of novel biological resection criteria for safe and oncologically satisfying resection of hepatocellular carcinoma.

OBJECTIVE: To develop criteria for safe and oncologically satisfying liver resection in case of early hepatocellular carcinoma with a 5-year overall survival (OS) similar to liver transplantation. SUMMARY BACKGROUND DATA: Liver resection (LR) and liver transplantation (LT) are potentially curative treatment options for hepatocellular carcinoma. Generally, LT achieves better OS. Due to organ shortage, however not all patients can receive a LT. METHODS: To decide which patients to resect and which to transplant we have developed biological resection criteria (BRC) as a compound out of mGPS (modified Glascow Prognostic Scale) and the Kings-Score (for HCV cirrhosis). These are based on routine clinical values that reflect both liver function and tumor biology/immunology. RESULTS: 276 patients were analyzed. Patients undergoing LR within BRC (inBRC) had a significantly better overall (73.6% vs. 35.4%, (p < 0.001)) and disease-free survival (54.7% vs. 17.2%, (p < 0.001)) as compared to patients outside the BRC (outBRC). The predictive value of BRC was independent of tumor burden. In a subgroup analysis outBRC patients had significantly worse outcome after major resection. In LT patients BRC had no predictive value. CONCLUSIONS: BRC may be a valuable tool to predict survival after LR for HCC. Patients resected inBRC may achieve comparable survival as LT. LR in outBRC patients are unlikely to be curative. All outBRC patients should be monitored closely for salvage LT.

CyberKnife Radiosurgery - Value as an Adjunct to Surgical Treatment of HCC?

INTRODUCTION: CyberKnife radiosurgery (CK) is an effective tool for the treatment of malignancies. Its greatest potential is in high-dose radiosurgery delivered to targets in organs that move with respiration, e.g., liver tumors. For hepatocellular carcinoma (HCC), however, surgical treatment (resection, transplantation) is most likely to produce long-term survival; for non-resectable tumors, therapies other than radiosurgery are typically recommended. This study evaluated the long-lasting anti-tumor effects of CK combined with surgery in patients with HCC. MATERIALS AND METHODS : Eighteen patients (three women, 15 men) were included in this prospective observational study. They received 21 single-fraction CK treatments (26 Gy). Patient characteristics, treatment effects, tumor response (according to the Response Evaluation Criteria In Solid Tumors (RECIST) grading) and survival were measured for a median period of 29 months. RESULTS: Local tumor control was achieved in 15 patients, with complete and partial remission observed in 10 and five patients, respectively. One patient was treated for two separate lesions in one session, and one received three treatments each separated by two-year intervals; both patients are tumor-free. Two patients showed minimal response, and in one patient local tumor viability could not be excluded by MRI. Nine patients had HCC recurrence, all distant to the treated site. Nine patients died during follow-up, including two with clear relation to tumor progress. Tumor-free survival was 79.4% after one year and 29.8% after three years, and the corresponding overall survival was 84.8% and 66%. CONCLUSION : This study shows the high effectiveness of single-session frameless CyberKnife radiosurgery for treatment of hepatocellular carcinoma and reconfirms previous results of fractioned radiotherapy of HCC. It also demonstrates the potential of radiosurgery to be combined with surgical concepts.