Primary Hepatic Malignancies Research Articles

Genetic polymorphisms in interleukin-1β (rs1143634) and interleukin-8 (rs4073) are associated with survival after resection of intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is a rare, understudied primary hepatic malignancy with dismal outcomes. Aiming to identify prognostically relevant single-nucleotide polymorphisms, we analyzed 11 genetic variants with a role in tumor-promoting inflammation (VEGF, EGF, EGFR, IL-1B, IL-6, CXCL8 (IL-8), IL-10, CXCR1, HIF1A and PTGS2 (COX-2) genes) and their association with disease-free (DFS) and overall survival (OS) in patients undergoing curative-intent surgery for iCCA. Genomic DNA was isolated from 112 patients (64 female, 48 male) with iCCA. Germline polymorphisms were analyzed with polymerase chain reaction-restriction fragment length polymorphism protocols. The IL-1B +3954 C/C (73/112, hazard ratio (HR) = 1.735, p = 0.012) and the IL-8 -251 T/A or A/A (53/112 and 16/112, HR = 2.001 and 1.1777, p = 0.026) genotypes were associated with shorter OS in univariable and multivariable analysis. The IL-1B +3954 polymorphism was also associated with shorter DFS (HR = 1.983, p = 0.012), but this effect was not sustained in the multivariable model. A genetic risk model of 0, 1 and 2 unfavorable alleles was established and confirmed in multivariable analysis. This study supports the prognostic role of the IL-1B C+3954T and the IL-8 T-251A variant as outcome markers in iCCA patients, identifying patient subgroups at higher risk for dismal clinical outcomes.

18 F-FDG PET/MRI of Primary Hepatic Malignancies: Differential Diagnosis and Histologic Grading

Distinguishing between IHCC and HCC is important because of their differences in treatment and prognosis. The hybrid Positron Emission Tomography/magnetic Resonance Imaging (PET/MRI) system has become more widely accessible, with oncological imaging becoming one of its most promising applications. The objective of this study was to see how well 18F-fluorodeoxyglucose (18F-FDG) PET/MRI could be used for differential diagnosis and histologic grading of primary hepatic malignancies. We retrospectively evaluated 64 patients (53 patients with HCC, 11 patients with IHCC) with histologically proven primary hepatic malignancies using 18F-FDG/MRI. The Apparent Diffusion Coefficient (ADC), Coefficient of Variance (CV) of the ADC, and standardized uptake value (SUV) were calculated. The mean SUVmax value was higher for IHCC (7.7 ± 3.4) than for HCC (5.2 ± 3.1) (p = 0.019). The area under the curve (AUC) was 0.737, an optimal 6.98 cut-off value providing 72% sensitivity and 79% specificity. The ADCcv value in IHCC was statistically significantly higher than in HCC (p=0.014). ADC mean values in HCCs were significantly higher in low-grade tumors than in high-grade tumors. The AUC value was 0.73, and the optimal cut-off point was 1.20x10-6 mm2/s, giving 62% sensitivity and 72% specificity. The SUVmax value was also found to be statistically significantly higher in the high-grade group. The ADCcv value in the HCC low-grade group was found to be lower than in the highgrade group (p=0.036). 18F FDG PET/MRI is a novel imaging technique that can aid in the differentiation of primary hepatic neoplasms as well as tumor-grade estimation.

Cytomorphology of paediatric hepatocellular carcinoma: A useful diagnostic adjunct.

Hepatocellular carcinoma (HCC) is a common primary malignancy of the liver but is rare in the paediatric age group; thus, it may be misdiagnosed as the more common tumour, hepatoblastoma. Management varies in both these tumours, and pathological diagnosis thus plays an important role for definitive therapy. Only a few case reports available in the literature have described the cytological characteristics of paediatric HCC. The present study was thus planned to evaluate the cytomorphological features of paediatric HCC. Cases diagnosed with HCC on ultrasound-guided fine needle aspiration cytology over a period of 14 years were retrieved. The cases were evaluated for detailed cytological features including cellularity, architecture, sinusoidal wrapping, trabecular thickness, necrosis, anisonucleosis, chromatin, nucleoli, nuclear contours, bi- or multinucleation, intranuclear and intracytoplasmic inclusions, naked nuclei, extra-medullary haematopoiesis, monomorphism, and nuclear overlapping. Twelve cases of HCC were included in the study. The median age at diagnosis was 10 years. Serum alpha-fetoprotein level was raised in most of them. Five of the 12 cases were characterised as moderately differentiated, three as poorly differentiated, two as well differentiated, and two as the fibrolamellar type of HCC. Cytohistological correlation was performed in seven cases. Ultrasound-guided fine needle aspiration serves as a useful tool to diagnose paediatric HCC and differentiate it from other primary hepatic malignancies, especially hepatoblastoma which closely mimics HCC in this age group, as serum alpha protein levels and imaging findings are unable to distinguish these two tumours.

Mechanism of sorafenib resistance associated with ferroptosis in HCC.

Hepatocellular carcinoma (HCC) is the most familiar primary hepatic malignancy with a poor prognosis. The incidence of HCC and the associated deaths have risen in recent decades. Sorafenib is the first drug to be approved by the Food and Drug Administration (FDA) for routine use in the first-line therapy of patients with advanced HCC. However, only about 30% of patients with HCC will be benefited from sorafenib therapy, and drug resistance typically develops within 6months. In recent years, the mechanisms of resistance to sorafenib have gained the attention of a growing number of researchers. A promising field of current studies is ferroptosis, which is a novel form of cell death differing from apoptosis, necroptosis, and autophagy. This process is dependent on the accumulation of intracellular iron and reactive oxygen species (ROS). Furthermore, the increase in intracellular iron levels and ROS can be significantly observed in cells resistant to sorafenib. This article reviews the mechanisms of resistance to sorafenib that are related to ferroptosis, evaluates the relationship between ferroptosis and sorafenib resistance, and explores new therapeutic approaches capable of reversing sorafenib resistance in HCC through the modulation of ferroptosis.

Liver directed therapies in primary and metastatic liver cancer: A rural academic institution experience.

e16188 Background: Liver-directed therapies (LDT) are well established in the treatment of primary and secondary hepatic malignancies and are developed for potentially curative intent, bridging for definitive therapy or palliation. They are used either in isolation usually for hepatocellular carcinoma (HCC) or in combination with systemic chemotherapy and/or surgery. We conducted a retrospective study at our academic institution that serves ethnic minorities and patients with high BMI and multiple major co-morbidities. Methods: All patients who underwent liver-directed therapy at ECU Health Medical Center from the year 2010 to 2020 were included in this study. Total of 196 patients were identified of which 96 met the eligibility criteria. That criteria included all patients who have undergone any type of liver directed therapy in primary and mainly metastatic gastrointestinal liver cancer. We conducted descriptive univariate analysis, cox regression and Kaplan-Meier survival analysis. Results: The study cohort had 63% (n=60) with primary HCC and 38% (n=36) with metastatic liver cancer predominantly colorectal cancer. Median age at diagnosis was 68 yrs. (65.3-69.5), 58% were Caucasian, 38% were black and 2% were other ethnic groups. 68% of the patient were male and 31% were female. ECOG performance status of 1 in 60% of the cohort. 50% of the cohort had 3 major comorbidities other than cirrhosis and hepatitis. Mean body mass index (BMI) was >25 kg/m2. 43% of the patient (n=41) had multiple barriers to care. Patients with primary HCC, 45% had hepatitis C and 48 % had non-viral causes in 60 patients. Child- Pugh A in 67% (n=40), B in 30% (18) and C in 3% (n=3). 70% of non-HCC cohort has colorectal and cholangiocarcinoma. All patient in non-HCC group received chemotherapy and 52% of HCC cohort received systemic therapy. 55% (n= 43) of the patients underwent Y-90 and 55% (n= 53) underwent other types of liver directed therapies, most common being TACE. 62% of the patient underwent 1 treatment and 38% had >2 LDT. Multivariate analysis showed that age (p-value, 0.0229) and type of liver directed therapy ( p-value, 0.0212) are statistically significant in the HCC cohort. In the non-HCC cohort, patients with high BMI (P-value=0.0050) had poor outcome and was statistically significant. Conclusions: Liver directed therapy is a reasonable option for patients with HCC and non-HCC metastatic disease. According to our study, it improves median survival in non-HCC patients. It includes rural population with high BMI, major comorbidities and multiple barriers to care. In this study, 38% of patients were African Americans who are usually underrepresented in majority of studies. Limitations of the study include retrospective nature of the analysis and heterogenous group. In future clinical trials, ethnic minorities should be equally represented to advance health equity and to apply real word data to the populations we serve.

Changing survival of intrahepatic cholangiocarcinoma based on Surveillance, Epidemiology, and End Results Database (2000–2018).

e16182 Background: Intrahepatic cholangiocarcinoma (iCCA) is a primary hepatic malignancy arising from peripheral intrahepatic bile ducts with poor survival and increasing incidence. Treatment regimen has changed in the last two decades, whereas new molecular targeted therapies have emerged. The present study aims to characterize changes in treatment outcomes of iCCA using a national representative database. Methods: Data were retrieved from the Surveillance, Epidemiology and End Results (SEER) 18 Research Plus Database. Overall survival (OS) was analyzed based on age, gender, race, histological grade, stage, and treatment. Predictors of OS were evaluated by Cox regression models. Statistical analysis was performed with Stata 15.1 (STATA Corp., College Station, TX, USA). Results: The overall observed OS from 2000 to 2018 at 12, 36, and 60 months were 42.6%, 16.4%, and 10.2%, respectively. The median survival time (MST) increased from 6 to 11 months from 2000-2004 time period to 2015-2018 (p < 0.0001). Such an improved trend was observed in all stage groups (p < 0.0001). Among patients diagnosed after 2015, the 12, 24, and 36 month OS were 45.9%, 26.4% and 17.4 %, respectively; the MST were 25, 13, and 6 months for patients with localized (12-month OS: 72.7%; 36-month OS: 37.5% ), regional (12-month OS: 51.4%; 36-month OS: 18.9%), and distant diseases(12-month OS: 28.2%; 36-month OS: 4.5%), respectively (p < 0.0001). On multivariable analysis, older age, female, grade, stage, whether surgery, chemotherapy or radiotherapy was performed were statistically significant predictors of OS (p < 0.001). Conclusions: Survival outcomes of iCCA improved in the last twenty years in all cancer stages. Age, gender, grade, stage, and whether interventions were performed were prognostic factors.

Integration analysis of miRNA–mRNA expression exploring their potential roles in intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is the second common primary hepatic malignancy tumor. In this study, an integrative analysis of differentially expressed genes (DEGs) and miRNAs from the ICC onset and adjacent normal tissues were performed to explore the regulatory roles of miRNA–mRNA interaction. A total of 1018 DEGs and 39 miRNAs were likely involved in ICC pathogenesis, suggesting the changes in cell metabolism in ICC development. The built network indicated that 30 DEGs were regulated by 16 differentially expressed miRNA. The screened DEGs and miRNA together were probably considered the biomarkers of ICC, and their important roles in ICC pathogenesis remain to be elucidated. This study could provide a good basis to uncover the regulatory mechanism of miRNA and mRNAs in ICC pathogenesis.

Advancing the Field of Pediatric Liver Transplantation: Urgent Action Items Identified During the 2022 Society of Pediatric Liver Transplantation Meeting.

Advancing the Field of Pediatric Liver Transplantation: Urgent Action Items Identified During the 2022 Society of Pediatric Liver Transplantation Meeting.

Management of locally advanced intrahepatic cholangiocarcinoma: a narrative review.

Intrahepatic cholangiocarcinoma (ICC) is an aggressive primary hepatic malignancy, which has increased in incidence over the past decades. While surgical resection is the standard of care for patients with early-staged disease, many patients present with locally advanced and unresectable tumors. Given the importance of locoregional control and the potential for downstaging to resectability, knowledge of advances in the management of locally advanced ICC is critical for optimizing outcomes. This is a narrative review providing an up-to-date summary of the current literature regarding contemporary management of locally advanced ICC including systemic and liverdirected therapies. Along with systemic chemotherapy, several liver-directed therapies including transarterial chemoembolization, transarterial radioembolization, and hepatic artery infusion pumps, targeted therapies, and chemoradiation therapy have demonstrated promising results for improving local disease control and possibly extending survival. Unfortunately, successful downstaging to resection remains uncommon with no single treatment strategy established as standard of care. Although additional randomized controlled data are needed, multidisciplinary management using contemporary systemic and locoregional therapies improves outcomes for patients with locally advanced ICC. The optimal management of locally advanced ICC remains uncertain. Despite this, novel treatment options and ongoing clinical trials are currently contributing to more effective treatment and improved patient outcomes. Future advancements are likely to explore further novel therapies in addition to elucidating optimal patient selection and sequencing of multidisciplinary therapy.

New Insights in the Setting of Transplant Oncology.

Background and Objectives: Liver transplantation (LT) is the best strategy for curing several primary and secondary hepatic malignancies. In recent years, growing interest has been observed in the enlargement of the transplant oncology indications. This paper aims to review the most recent developments in the setting of LT oncology, with particular attention to LT for unresectable colorectal liver metastases (CRLM) and cholangiocellular carcinoma (CCA). Materials and Methods: A review of the recently published literature was conducted. Results: Growing evidence exists on the efficacy of LT in curing CRLM and peri-hilar and intrahepatic CCA in well-selected patients when integrating this strategy with (neo)-adjuvant chemotherapy, radiotherapy, or locoregional treatments. Conclusion: For unresectable CCA and CRLM management, several prospective protocols are forthcoming to elucidate LT's impact relative to alternative therapies. Advances in diagnosis, treatment protocols, and donor-to-recipient matching are needed to better define the oncological indications for transplantation. Prospective, multicenter trials studying these advances and their impact on outcomes are still required.

A Case of Fibrolamellar Hepatocellular Carcinoma at the High Specialty Hospital of Veracruz, Mexico

Fibrolamellar hepatocellular carcinoma is a primary hepatic malignancy, primarily affecting adolescents and young adults without underlying liver disease. We present the case of a 22-year-old male farmer who presents burning pain in the epigastrium with an intensity of 2/10 on the VAS scale, on palpation with the presence of a tumor in the right hypochondrium with ultrasound of the liver and bile ducts with evidence of liver mass in the segment VIII, in addition to exploratory laparoscopy with the discovery of multiple implants in 70% of the liver surface. In the histopathological analysis with morphological findings compatible with fibrolamellar carcinoma. In the laboratory with AST 356 UI/L, ALT 205 UI/L, GGT 930 U/L, LDH 343 UI/L AF 638 UI/L, for which treatment was started with atezolizumab 1200 mg and bevacizumab 1000 mg. Continuing to follow up. Fibrolamellar hepatocellular carcinoma is a variant of hepatocellular carcinoma, which usually presents with non-specific symptoms. The imaging approach is fundamental in the diagnosis, being the anatomopathological confirmation. Despite being low frequency tumors, they should be suspected in all young patients with a palpable mass in the liver.

Tumor Mutational Burden for Predicting Prognosis and Therapy Outcome of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC), the primary hepatic malignancy, represents the second-highest cause of cancer-related death worldwide. Many efforts have been devoted to finding novel biomarkers for predicting both patients' survival and the outcome of pharmacological treatments, with a particular focus on immunotherapy. In this regard, recent studies have focused on unravelling the role of tumor mutational burden (TMB), i.e., the total number of mutations per coding area of a tumor genome, to ascertain whether it can be considered a reliable biomarker to be used either for the stratification of HCC patients in subgroups with different responsiveness to immunotherapy, or for the prediction of disease progression, particularly in relation to the different HCC etiologies. In this review, we summarize the recent advances on the study of TMB and TMB-related biomarkers in the HCC landscape, focusing on their feasibility as guides for therapy decisions and/or predictors of clinical outcome.

Genetics of Hepatocellular Carcinoma: From Tumor to Circulating DNA.

Hepatocellular carcinoma (HCC) accounts for 90% of primary hepatic malignancies and is one of the major causes of cancer-related death. Over the last 15 years, the molecular landscape of HCC has been deciphered, with the identification of the main driver genes of liver carcinogenesis that belong to six major biological pathways, such as telomere maintenance, Wnt/b-catenin, P53/cell cycle regulation, oxidative stress, epigenetic modifiers, AKT/mTOR and MAP kinase. The combination of genetic and transcriptomic data composed various HCC subclasses strongly related to risk factors, pathological features and prognosis. However, translation into clinical practice is not achieved, mainly because the most frequently mutated genes are undruggable. Moreover, the results derived from the analysis of a single tissue sample may not adequately catch the intra- and intertumor heterogeneity. The analysis of circulating tumor DNA (ctDNA) is broadly developed in other types of cancer for early diagnosis, prognosis and monitoring under systemic treatment in order to identify primary and secondary mechanisms of resistance. The aim of this review is to describe recent data about the HCC molecular landscape and to discuss how ctDNA could be used in the future for HCC detection and management.

Risk modeling of single-cell transcriptomes reveals the heterogeneity of immune infiltration in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common primary hepatic malignancies. E2F transcription factors play an important role in the tumorigenesis and progression of HCC, mainly through the RB/E2F pathway. Prognostic models for HCC based on gene signatures have been developed rapidly in recent years; however, their discriminating ability at the single-cell level remains elusive, which could reflect the underlying mechanisms driving the sample bifurcation. In this study, we constructed and validated a predictive model based on E2F expression, successfully stratifying patients with HCC into two groups with different survival risks. Then we used a single-cell dataset to test the discriminating ability of the predictive model on infiltrating T cells, demonstrating remarkable cellular heterogeneity as well as altered cell fates. We identified distinct cell subpopulations with diverse molecular characteristics. We also found that the distribution of cell subpopulations varied considerably across onset stages among patients, providing a fundamental basis for patient-oriented precision evaluation. Moreover, single-sample gene set enrichment analysis revealed that subsets of CD8+ T cells with significantly different cell adhesion levels could be associated with different patterns of tumor cell dissemination. Therefore, our findings linked the conventional prognostic gene signature to the immune microenvironment and cellular heterogeneity at the single-cell level, thus providing deeper insights into the understanding of HCC tumorigenesis.

Did COVID-19 disrupt surgery for patients with pancreatic and hepatic malignancies?

Background: The COVID-19 pandemic began to affect the United States (US) healthcare system in March 2020. By April 2020, multiple government and professional organizations published guidelines to restrict elective operations in an effort to conserve hospital resources. However, the risk of progression made procedures for malignancy more time sensitive than other elective operations. As a result, patients with pancreatic and hepatic malignancies who required surgery were prioritized. However, after two and a half years of the COVID-19 pandemic, only sparse data exist on how the contagion affected the volume of cancer operations in the US. The aim of this study was to evaluate the impact of the COVID-19 pandemic on the national monthly volume of pancreatic and hepatic operations for malignancy. Methods: The Vizient Clinical Database was queried for national data from participating hospitals, which includes 97% of academic medical centers and over 100 oncologic hospitals. These institutions perform the majority of pancreatic and hepatic surgery in America. Data were gathered for 12 months before (March 2019 – February 2020) and 27 months during (April 2020 – June 2022) the COVID-19 pandemic. Patients undergoing major operations for pancreatic, primary hepatic (hepatocellular carcinoma and intrahepatic cholangiocarcinoma), and secondary hepatic (colorectal metastases) malignancies were included. Case volume trends were compared before and during the pandemic using QI Macros Control Charts. Comparison of mean case volume before and during the pandemic was performed using Student’s t Test and Wilcoxon Rank Sum Test in R (Version 4.2.1). Results: A total of 26,662 patients underwent surgery over the 40-month study period for pancreatic (Nf17,724, 66.5%), primary hepatic (Nf7,100, 26.6%), and secondary hepatic (Nf1,838, 6.9%) malignancies. Operations for pancreatic cancer (Figure A) and colorectal liver metastases (Figure C) were unaffected by the pandemic. Operative volumes for primary hepatic malignancies (Figure B) transiently decreased at the beginning of the pandemic, but returned to the pre-pandemic baseline within five months. No statistically significant changes were observed in the mean monthly operative volume before and during the pandemic for pancreatic (433 vs 447, p=0.208), primary hepatic (183 vs 175, p=0.224), or secondary hepatic (44 vs 47, p=0.397) malignancies. Conclusion: The COVID-19 pandemic did not significantly disrupt the volume of operations for pancreatic or secondary hepatic malignancies in the United States. The pandemic transiently decreased the rate of hepatic operations for primary liver tumors, but this rate returned to the pre-pandemic baseline within five months. Surgery for pancreatic and hepatobiliary malignancies was prioritized during the pandemic.

How did COVID-19 influence use of neoadjuvant therapy before surgery for patients with HPB cancers?

Background: The COVID-19 pandemic caused widespread disruption of the United States (US) healthcare system. Medical resources were rationed, and healthcare organizations worked to prevent hospitalizations in both healthy and high-risk patients. Numerous surgical specialties decreased elective operations during the peak of the pandemic, but surgical oncologists were faced with balancing the risks of oncologic progression with exposing immunosuppressed patients to nosocomial COVID-19. In recent years neoadjuvant therapy (NAT) has been increasingly utilized in pancreatic and colorectal malignancies. However, no analyses have determined whether these practice patterns were disrupted by the pandemic. Thus, the aims of this study were to evaluate the effect of COVID-19 on the volume of operations for pancreatic, primary hepatic, and secondary hepatic malignancies in patients who had undergone NAT. Methods: The Vizient Clinical Database was queried for national data from participating hospitals, including 97% of academic medical centers and over 100 oncologic hospitals. These institutions perform the majority of pancreatic and hepatic surgery in America. Data were obtained for 12 months before (March 2019 – February 2020) and 27 months during (April 2020 – June 2022) the COVID-19 pandemic. Patients who underwent neoadjuvant therapy (chemotherapy or immunotherapy) followed by major operations for pancreatic, primary hepatic (hepatocellular carcinoma and intrahepatic cholangiocarcinoma), and secondary hepatic (colorectal metastases) malignancies were included. Case volume trends were compared before and during the pandemic using QI Macros Control Charts. Mean comparison of case volume before and during the pandemic was performed using Student’s t Test and Wilcoxon Rank Sum Test in R (Version 4.2.1). Results: Over the 40-month study period, 6,936 patients received NAT and underwent surgery; 5,594 patients (80.7%) had pancreatic operations, 685 patients (9.9%) underwent surgery for primary hepatic malignancies, and 657 patients (9.5%) had hepatic operations for metastatic colorectal cancer. Pancreatic operations for patients who received NAT steadily increased throughout the study period (Figure A) while hepatic operations for metastatic colorectal cancer after NAT (Figure C) transiently increased 20 months into the pandemic. Operations for primary hepatic malignancies in patients who received NAT were unaffected by the pandemic (Figure B). These findings were confirmed with the average monthly case volume for pancreatic operations increasing during COVID-19 (126 vs 146, p< 0.001). No statistically significant changes were noted in the mean monthly operative volume for primary hepatic malignancies (17 vs 17, p=0.809) or for secondary hepatic malignancies following NAT (15 vs 17, p=0.213). Conclusion: Despite the pandemic, the number of oncologic operations for pancreatic cancer following neoadjuvant therapy (NAT) increased over time, continuing a pre-pandemic trend. A transient increase in oncologic operations for secondary hepatic malignancies following NAT was observed late in the pandemic. The volume of operations following NAT for primary hepatic malignancies was unaffected by the pandemic. The utilization of NAT for operative hepato-pancreato-biliary malignancies was not altered by the COVID-19 pandemic.

NUF2 Drives Cholangiocarcinoma Progression and Migration via Inhibiting Autophagic Degradation of TFR1.

Cholangiocarcinoma (CCA) is the second most common primary hepatic malignancy and associated with poor prognosis. Lack of therapeutic methods for CCA and insensitivity of targeted therapy and immunotherapy make its treatment challenging. NUF2, a component of Ndc80 kinetochore complex, is implicated in the initiation and development of multiple cancers. However, the role and mechanism of NUF2 in CCA is still unclear. In this research, we investigated the biological processes and underlying mechanisms of NUF2 in CCA. We discovered that the expression of NUF2 was upregulated in CCA and negatively correlated with prognosis. Changes in NUF2 levels had an impact on cell proliferation and migration. Moreover, NUF2 functioned as an oncogene to promote the progression of CCA through p38/MAPK signaling by inhibiting p62 binding of TFR1 and affecting its autophagic degradation. In addition, TFR1 promoted CCA progression and Kaplan-Meier analyses uncovered patients with high expression of TFR1 was associated with the poor survival. In conclusion, our study demonstrated that NUF2 promoted CCA progression by regulating TFR1 protein degradation, and the NUF2/TFR1/MAPK axis could be an excellent therapeutic target for CCA.

Profile of Perioperative Coagulation in Major Liver Resection for Cancer: A Prospective Observational Study

Background: The liver plays a key role in the complex and dynamic process of blood coagulation. Consequently, after liver resection the equilibrium between procoagulant and anticoagulant activity is often deranged. Major hepatectomies have been associated with excessive intraoperative blood loss, hemodynamic instability, massive fluid shifts, and coagulopathy. Alterations of the coagulation profile are always present post-operatively even in case of normal pre-operative coagulation function. Cumulative evidence supports the superiority of global coagulation analysis compared with conventional coagulation for clinical decision-making. Aim: The purpose of this study was to assess the perioperative coagulation status of patients undergoing major hepatectomies for primary or metastatic hepatic malignancy. Conventional coagulation tests, plasma levels of coagulation factors, and TGA measurements were used for longitudinal documentation of the coagulation activity. Methods: Patients included in the study were referred for major liver resection which was defined as a resection of three or more liver segments, and were followed up to the 10th post-operative day by serial measurements of conventional coagulation tests, plasma levels of coagulation factors, and thrombin generation assay parameters. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were determined by STA Neoplastin R, and STA-Cephascreen, Fibrinogen by STA-Liquid Fib, D-dimer STA Liatest D-DI Plus, all from Diagnostica Stago, France. Coagulation factor activity for FII, FV, FVII, FVIII, FIX, FX, was measured by clotting assay using coagulation factor deficient plasma, vWFAg , and vWFAc by vWFAg and Innovance vWFAc, from Siemens Healthcare Diagnostics, Germany. Thrombin generation (TG) was assessed in samples of PPP with the TF 5 pM PPP-Reagent on Calibrated Automated Thrombogram (Stago, France). Results: Changes over time for FII, FV, FVII and FX were statistically significant (p <0.05). Factor VIII level was above normal values at baseline. A steady rise was observed for fibrinogen, FVIII, and vWF antigen throughout the study period, but only vWF antigen exhibited statistically significant changes over time. Levels of coagulation inhibitors, AT, PC and PS, decreased significantly during the first postoperative day and then increased reaching baseline values by POD5 for protein C and S, but AT, remained low by POD10. INR increased after surgery, reaching a peak on the first post-operative day and decreasing toward baseline levels from then on (p <0.001). The aPTT remained within normal range throughout the study period (Table 1). TG conducted at baseline, on POD1, POD5, and POD10 showed elevated of Lag time and time to peak at baseline, whereas the rest thrombin generation parameters were within reference range. ETP decreased significantly over time, reaching lower values by POD5 and sustaining those low values by POD10. Peak height fluctuated in a similar manner, but changes over time did not bear any statistical significance. Lag-time, which was prolonged at baseline, exhibited a steady rise throughout the study period, bearing borderline statistical significance (Table 2) . A statistically significant positive correlation was detected between AT and time to Peak (ttPeak) at baseline, however any other significant difference between coagulation factors, natural coagulation inhibitors, and TGA parameters was observed. Conclusion: This study shows that patients with hepatic malignancy have systematic endothelial activation and hyper-coagulability as indicated by increased FVIII levels and lag time prolongation in thrombin generation. These patients are in a hyper-coagulable state in the early post-operative period, as shown by increased vWF, FVIII, D-dimer, fibrinogen and decreased levels of natural coagulation inhibitors AT, PC, and PS. Measurements of INR, PT, aPTT are not useful in this setting and could be misleading. Global coagulation analysis may be more appropriate for clinical guidance. To the best of our knowledge this is the first report in literature documenting the pre-existing coagulation disturbances in patients with hepatic carcinoma and their impact on the coagulation status after major hepatectomy. However, the clinical implications of our findings deserve further investigation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effects of agomelatine on rat liver regeneration following partial hepatectomy

ABSTRACT Primary or metastatic hepatic malignancies are common. Partial hepatectomy (PH) is the primary treatment for both benign and malignant hepatic neoplasms; it also is used for living donor liver transplantation. The regenerative potential of the liver after PH is 70–80% in humans. We investigated the protective and therapeutic effects of agomelatine (AGM) on rat liver regeneration following PH. We used 32 rats distributed equally into four groups: group 1, sham control; group 2, PH group; group 3, administered 20 mg/kg AGM orally once/day for 7 days following PH; group 4, administered 20 mg/kg AGM orally once/day 3 days before and 7 days following PH for 10 days. Liver samples were analyzed for antioxidants and free radicals. Tissue samples were processed and stained with hematoxylin and eosin to assess histopathological status and stained immunohistochemically for Ki-67. We found that PH reduced antioxidant enzymes and increased tissue reactive oxygen species, whereas AGM treatment had the opposite effect on these parameters. Our biochemical and histopathological findings were consistent. PH caused sinusoid congestion and dilation. Intensity of Ki-67 immunostaining of hepatocytes was increased in group 2, whereas these were reduced in group 4. Intensity of Ki-67 immunostaining of hepatocytes was increased in group 2, whereas it was reduced in the group 4 compared to group 1. We found that AGM was hepatoprotective following PH due to its antioxidant and free radical scavenger properties.

EIF3H stabilizes CCND1 to promotes intrahepatic cholangiocarcinoma progression via Wnt/β-catenin signaling.

Cholangiocarcinoma (CCA) is a group of tumors that arise along the human biliary duct tree, ranking second in primary hepatic malignancies. Intrahepatic CCA (iCCA) represents about 10%-20% of CCAs. There is an increasing body of evidence suggesting that iCCAs' incidence and mortality have been increasing globally over the past few decades. In this study, we found that the EIF3H expression level in iCCA tissues was significantly increased compared to the adjacent non-cancerous tissues by immunohistochemistry analysis (IHC). A similar tendency of EIF3H mRNA and protein level was confirmed in iCCA cell lines using RT-qPCR and Western blot. EIF3H has been identified as a critical molecule that plays a pro-neoplasmic role in iCCA both in vivo and in vitro, such as proliferation, migration, and anti-apoptosis. Mechanistically, we found that EIF3H knockdown can promote the degradation of CCND1 and the proteolysis of CCND1 is mediated by ubiquitin-proteasome system (UPS). Thus, we come to the conclusion that EIF3H promotes proliferation and migration of iCCAs, inhibiting apoptosis of iCCA cells at the same time by stabilizing the CCND1 protein structure. Our findings provide insights into the mechanism of tumorigenesis role of EIF3H in iCCAs and a potential therapeutic target for iCCA treatment.