Don't Judge a Book by Its Cover: The Role of Statins in Liver Cancer.

Statins, which are inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, are an effective pharmacological tool for lowering blood cholesterol levels. This property makes statins one of the most popular drugs used primarily to prevent cardiovascular diseases, where hyperlipidemia is a significant risk factor that increases mortality. Nevertheless, studies conducted mainly in the last decade have shown that statins might prevent and treat liver cancer, one of the leading causes of cancer-related mortality worldwide. This narrative review summarizes the scientific achievements to date regarding the role of statins in liver tumors. Molecular biology tools have revealed that cell growth and proliferation can be inhibited by statins, which further inhibit angiogenesis. Clinical studies, supported by meta-analysis, confirm that statins are highly effective in preventing and treating hepatocellular carcinoma and cholangiocarcinoma. However, this effect may depend on the statin's type and dose, and more clinical trials are required to evaluate clinical effects. Moreover, their potential hepatotoxicity is a significant caveat for using statins in clinical practice. Nevertheless, this group of drugs, initially developed to prevent cardiovascular diseases, is now a key candidate in hepato-oncology patient management. The description of new drug-statin-like structures, e.g., with low toxicity to liver cells, may bring another clinically significant improvement to current cancer therapies.

Refining Liver Biopsy in Hepatocellular Carcinoma: An In-Depth Exploration of Shifting Diagnostic and Therapeutic Applications.

The field of hepatocellular carcinoma (HCC) has faced significant change on multiple levels in the past few years. The increasing emphasis on the various HCC phenotypes and the emergence of novel, specific therapies have slowly paved the way for a personalized approach to primary liver cancer. In this light, the role of percutaneous liver biopsy of focal lesions has shifted from a purely confirmatory method to a technique capable of providing an in-depth characterization of any nodule. Cancer subtype, gene expression, the mutational profile, and tissue biomarkers might soon become widely available through biopsy. However, indications, expectations, and techniques might suffer changes as the aim of the biopsy evolves from providing minimal proof of the disease to high-quality specimens for extensive analysis. Consequently, a revamped position of tissue biopsy is expected in HCC, following the reign of non-invasive imaging-only diagnosis. Moreover, given the advances in techniques that have recently reached the spotlight, such as liquid biopsy, concomitant use of all the available methods might gather just enough data to improve therapy selection and, ultimately, outcomes. The current review aims to discuss the changing role of liver biopsy and provide an evidence-based rationale for its use in the era of precision medicine in HCC.

The Role of Immunohistochemistry in the Differential Diagnosis between Intrahepatic Cholangiocarcinoma, Hepatocellular Carcinoma and Liver Metastasis, as Well as Its Prognostic Value.

Intrahepatic cholangiocarcinoma (iCCA) is the second most frequent primary hepatic malignant tumor, after hepatocellular carcinoma (HCC). Its incidence has risen worldwide, yet the only potentially curative treatment, surgical resection, is seldom applicable, and the median overall survival remains extremely low. So far, there are no personalized therapy regimens. This study investigated whether routine immunohistochemical stains have diagnostic and/or prognostic value in iCCA. Clinical, imaging, and pathology data were retrospectively gathered for patients diagnosed with iCCA, HCC, or liver metastases assessed using liver needle biopsies. Three study groups with an equal number of cases (n = 65) were formed. In the iCCA group, CK19, CA19-9, CK7, and CEA demonstrated the highest sensitivities (100%, 100%, 93.7%, and 82.6%, respectively). The most relevant stains used for diagnosing HCCs were Glypican 3, CD34 (sinusoidal pattern), and Hep Par 1, with corresponding sensitivities of 100%, 100%, and 98.2%. The immunohistochemical panels for diagnosing metastatic tumors were chosen after correlating the clinical data and morphologic H&E aspects. Moderate/intensely positive CK7 expression and absent/low amount of intratumoral immune cells were favorable prognostic factors and correlated with increased overall survival in both the univariate analysis and the multivariate regression adjusted for age, existence of cirrhosis, number of tumors, and tumor differentiation.

PD-L1 expression on immune cells, but not on tumor cells, is a favorable prognostic factor for patients with intrahepatic cholangiocarcinoma.

Cholangiocarcinoma, the second most common liver malignancy, after hepatocarcinoma is highly aggressive and usually diagnosed in advanced cases. In the era of personalized medicine, targeted therapy protocols are limited for cholangiocarcinoma and the only potential curative treatment, surgical resection, is seldom applicable.This retrospective study included all cases with pathology-confirmed intrahepatic cholangiocarcinoma admitted in a tertiary healthcare facility during a 10-year timeframe. Clinical information, laboratory values, imaging studies, and survival data were retrieved, and PD-L1 immunostaining was performed on representative pathology slides, for each case. From the total of 136 included cases (49 surgical resections and 87 liver biopsies), 38.97% showed PD-L1 positivity on tumoral cells, 34.8% on tumor infiltrating immune cells, 10.11% on epithelial cells within the peritumoral area and 15.95% on immune cells from the peritumoral area. Overall survival was significantly higher in the first two scenarios. However, after adjusting for age, tumor number, tumor size, and tumor differentiation in a multivariate analysis, only PD-L1 positivity on tumor infiltrating immune cells remained a favorable prognostic for survival. High immune cell counts also correlated with increased overall survival.Our study demonstrated that PD-1/PD-L1 checkpoint pathway in the microenvironment of intrahepatic cholangiocarcinoma bears prognostic significance. PD-L1 expression on immune cells, in both resection and biopsy specimens, might be a strong independent predictor for a favorable outcome.

Pulmonary complications of portal hypertension: The overlooked decompensation.

The systemic nature of cirrhosis and portal hypertension has long been recognized, and the amount of data characterizing the interplay between each system is becoming ever so complex. Lung involvement was among the first described associated entities in cirrhosis, with reports dating back to the late nineteenth century. However, it appears that throughout the years, interest in the pulmonary complications of portal hypertension has generally faded, especially in contrast to other decompensating events, as expertise in this field has primarily been concentrated in highly experienced tertiary care facilities and liver transplantation centers. Despite affecting up to 10%-15% of patients with advanced liver disease and having a proven prognostic impact, hepato-pulmonary syndrome, porto-pulmonary hypertension, and hepatic hydrothorax are frequently misdiagnosed, mistreated, or misinterpreted. This lack of precision might adversely impact patient care, referral to expert centers, and, ultimately, liver disease-related mortality and successful transplantation odds. The present minireview aims to increase awareness of the pulmonary complications of chronic liver disease by providing a brief overview of each of the three entities. The paper focuses on the essential theoretical aspects, addressing the most critical knowledge gaps on the one hand and, on the other hand, critically discussing one key issue for each complication.

Novel approaches in search for biomarkers of cholangiocarcinoma.

Cholangiocarcinoma (CCA) arises from the ductular epithelium of the biliary tree, either within the liver (intrahepatic CCA) or more commonly from the extrahepatic bile ducts (extrahepatic CCA). This disease has a poor prognosis and a growing worldwide prevalence. The poor outcomes of CCA are partially explained by the fact that a final diagnosis is challenging, especially the differential diagnosis between hepatocellular carcinoma and intrahepatic CCA, or distal CCA and pancreatic head adenocarcinoma. Most patients present with an advanced disease, unresectable disease, and there is a lack in non-surgical therapeutic modalities. Not least, there is an acute lack of prognostic biomarkers which further complicates disease management. Therefore, there is a dire need to find alternative diagnostic and follow-up pathways that can lead to an accurate result, either singlehandedly or combined with other methods. In the "-omics" era, this goal can be attained by various means, as it has been successfully demonstrated in other primary tumors. Numerous variants can reach a biomarker status ranging from circulating nucleic acids to proteins, metabolites, extracellular vesicles, and ultimately circulating tumor cells. However, given the relatively heterogeneous data, extracting clinical meaning from the inconsequential noise might become a tall task. The current review aims to navigate the nascent waters of the non-invasive approach to CCA and provide an evidence-based input to aid clinical decisions and provide grounds for future research.

Serum levels of soluble programmed death-ligand 1 (sPD-L1): A possible biomarker in predicting post-treatment outcomes in patients with early hepatocellular carcinoma.

BACKGROUND: There have been great advances in hepatocellular carcinoma management over the last years. However, there are still no prognostic biomarkers that can identify patients who will benefit the most from curative treatments. We aimed to investigate whether sPD-L1 levels measured before curative treatment is a prognostic biomarker of survival in patients with HCC. METHODS: HCC patients from a prospectively collected database were selected and soluble programmed death-ligand1(sPD-L1) levels were determined. The association of sPD-L1 levels and overall survival (OS) and disease-free survival (DFS) was assessed. RESULTS: One hundred twenty-one patients with HCC were included. The best cut-off value of sPD-L1 for both DFS and OS was 96 pg/mL. Patients with a high sPD-L1 value (>96 pg/mL) had a shorter disease free survival and OS (hazard ratio 5.42, 95% confidence interval 2.28-12.91, p < 0.001, and hazard ratio 9.67, 95% confidence interval 4.33-21.59, p < 0.001). High sPD-L1 levels were associated with mortality independently from other known survival predictors. We found a positive correlation between sPD-L1 and PD-L1 expression in cancer cells (p = 0.01). In 16 out of 38 patients, sPD-L1 levels decreased from baseline value on week 6 after treatment and in 22 out of 38 patients, sPD-L1 levels increased from the baseline value. However, fluctuations of sPD-L1 in time had no influence on survival (p = 0.148). CONCLUSION: We conclude that a high sPD-L1 level is a biomarkerfor a poor outcome in HCC. The predictive value of sPD-L1 levels for a successful anti-PD1/PD-L1 therapy should be investigated in the future.

Percutaneous ultrasound guided PEG-coated gold nanoparticles enhanced radiofrequency ablation in liver.

To investigate the effects of PEG-coated gold nanoparticles on ablation zone volumes following in vivo radiofrequency ablation of porcine liver. This prospective study was performed following institutional animal care and committee approval was used. Radiofrequency ablations were performed in the livers of ten Sus scrofa domesticus swines. During each ablation, 10 mL (mL) of Peg-coated gold nanoparticles at two different concentrations (0.5 mg/mL and 0.01 mg/mL) were injected through the electrode channel into the target zone. For the control group, 10 mL of physiological saline was used. Five to ten minutes after each ablation, contrast enhanced ultrasound (CEUS) was performed to evaluate the volume of the coagulation zone. On day five we performed another CEUS and the animals were sacrificed. Treated tissues were explanted for quantification of the ablation zones' volumes. Hematoxylin and eosin (H&E) staining was also performed for histologic analysis. A total of 30 ablations were performed in the livers. The mean coagulation zone volume as measured by CEUS on day 5 after RFA was: 21.69 ± 3.39 cm3, 19.22 ± 5.77 cm3, and 8.80 ± 3.33 cm3 for N1, N2 and PS respectively. The coagulation zone volume after N1 and N2 treatments was significantly higher compared to PS treatment (p < 0.001 and p = 0.025 respectively). There was no difference between N1 and N2 treatment (p = 0.60). In our proof-of concept, pilot study we have shown for the first time that when injected directly into the target tissue during RFA, gold nanoparticles can substantially increase the coagulation zone.

Percutaneous ultrasound guided radiofrequency and microwave ablation in the treatment of hepatic metastases. A monocentric initial experience.

AIM: Percutaneous radiofrequency (RFA) and microwave ablation (MWA) are currently the best treatment options forpatients with liver metastases (LM) who cannot undergo a liver resection procedure. Presently, few studies have evaluated theefficacy of tumor ablation in beginner's hands but none at all in hepatic metastasis. Our aim was to report the initial experiencewith ultrasound as a tool to guide tumor ablation in a low volume center with no experience in tumor ablation. MATERIAL AND METHODS: We conducted a retrospective cohort study, on a series of 61 patients who had undergone percutaneous US-guided ablations for 82 LM between 2010 and 2015. Long term outcome predictors were assessed using univariate and multivariate analysis. RESULTS: Complete ablation was achieved in 86.9% of cases (53/61). All MWA sessions (20/20) attained ablation margins >5mm, compared to 79% (49/62) for RFA sessions (p=0.031). Ablation time was significantly shorter for MWA, with a median duration of 10 minutes (range: 6-12) vs. 14 minutes (range: 10-19.5, p=0.003). There was no statistically significant difference in local tumor progression (LTP)-free survival rates between MWA and RFA (p=0.154). On univariate analysis, significant predictors for local recurrence were multiple metastases (p=0.013) and ablation margins <5 mm (p<.001), both retaining significance on multivariate analysis. Significant predictors for distant recurrence on both univariate and multivariate analysis were multiple metastases (p<0.001) and non-colorectal cancer metastases (p<0.05). CONCLUSION: A larger than 5 mm ablation size is critical for local tumor control. We favor the use of MWA due to its ability to achieve ablation in significantlyshorter times with less incomplete ablations.

Prognostic Factors after Percutaneous Radiofrequency Ablation in the Treatment of Hepatocellular Carcinoma. Impact of Incomplete Ablation on Recurrence and Overall Survival Rates.

AIMS: To report on the long-term impact of tumor and non-tumor related parameters on local recurrence, distant recurrence and survival in patients with naïve or recurrent type hepatocellular carcinoma (HCC) treated by radiofrequency ablation (RFA). METHODS: We performed 240 RFA sessions on 133 patients with 156 HCC nodules developed on a background of liver cirrhosis and analyzed the outcomes. RESULTS: Contrast-enhanced ultrasound performed one month after RFA showed complete ablation in 119 out of 133 (89.65%) patients. With a median follow-up of 46 months, 3-, 5- and 7-year survival rates were 61.7%, 35.7%, and 22.6%, respectively. Previous ethanol injection and histological grade were significantly related to local tumor progression. Child-Pugh class, incomplete ablation, histological grade, previous ethanol injection, alpha-fetoprotein level before the treatment, and local recurrence were all significantly related to distant recurrence. Multivariate analysis demonstrated that age, Child-Pugh class, distant recurrence and multiple incomplete ablations were significantly related to survival. CONCLUSION: Radiofrequency ablation could be locally curative for HCC, resulting in a survival longer than 7 years. Previous ethanol injection and incomplete ablations were strongly associated with poor outcomes.