Androgen receptors in hepatocellular carcinoma and surrounding liver: relationship with tumor size and recurrence rate after surgical resection

Background: Hepatocellular carcinoma is cancer with many new cases and the highest mortality rate. Chemotherapy is the most commonly used method for the clinical treatment of hepatocellular carcinoma. Natural products have become clinically important chemotherapeutic drugs due to their great potential for pharmacological development. Many sesquiterpene lactone compounds have been proven to have antitumor effects on hepatocellular carcinoma. Objective: Britanin is a sesquiterpene lactone compound that can be considered for the treatment of hepatocellular carcinoma. The present study aimed to investigate the antitumor effect of britanin. Methods: BEL 7402 and HepG2 cells were used to study the cytotoxicity and antitumor effects of britanin. Preliminary studies on the nuclear factor kappa B pathway were conducted by western blot analysis. A BEL 7402-luc subcutaneous tumor model was established for the in vivo antitumor studies of britanin. In vivo bioluminescence imaging was conducted to monitor changes in tumor size. Results: The results of the cytotoxicity analysis showed that the IC50 values for britanin in BEL 7402 and HepG2 cells were 2.702μM and 6.006μM, respectively. The results of the colony formation demonstrated that the number of cells in a colony was reduced significantly after britanin treatment. And the results of transwell migration assays showed that the migration ability of tumor cells was significantly weakened after treatment with britanin. Tumor size measurements and staining results showed that tumor size was inhibited after britanin treatment. The western blot analysis results showed the inhibition of p65 protein expression and reduced the ratio of Bcl-2/Bax after treatment. Conclusion: A series of in vitro and in vivo experiments demonstrated that britanin had good antitumor effects and provided an option for hepatocellular carcinoma treatment.

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MRI Features for Predicting Microvascular Invasion of Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

Liver Cancer ◽

10.1159/000513704 ◽

2021 ◽

Vol 10 (2) ◽

pp. 94-106

Author(s):

Seung Baek Hong ◽

Sang Hyun Choi ◽

So Yeon Kim ◽

Ju Hyun Shim ◽

Seung Soo Lee ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Size ◽

Meta Analysis ◽

Diagnostic Odds Ratio ◽

Microvascular Invasion ◽

Hepatobiliary Phase ◽

Phase Imaging ◽

Arterial Enhancement ◽

Mri Features ◽

Peritumoral Enhancement

Purpose: Microvascular invasion (MVI) is an important prognostic factor in patients with hepatocellular carcinoma (HCC). However, the reported results of magnetic resonance imaging (MRI) features for predicting MVI of HCC are variable and conflicting. Therefore, this meta-analysis aimed to identify the significant MRI features for MVI of HCC and to determine their diagnostic value. Methods: Original studies reporting the diagnostic performance of MRI for predicting MVI of HCC were identified in MEDLINE and EMBASE up until January 15, 2020. Study quality was assessed using QUADAS-2. A bivariate random-effects model was used to calculate the meta-analytic pooled diagnostic odds ratio (DOR) and 95% confidence interval (CI) for each MRI feature for diagnosing MVI in HCC. The meta-analytic pooled sensitivity and specificity were calculated for the significant MRI features. Results: Among 235 screened articles, we found 36 studies including 4,274 HCCs. Of the 15 available MRI features, 7 were significantly associated with MVI: larger tumor size (>5 cm) (DOR = 5.2, 95% CI [3.0–9.0]), rim arterial enhancement (4.2, 95% CI [1.7–10.6]), arterial peritumoral enhancement (4.4, 95% CI [2.8–6.9]), peritumoral hypointensity on hepatobiliary phase imaging (HBP) (8.2, 95% CI [4.4–15.2]), nonsmooth tumor margin (3.2, 95% CI [2.2–4.4]), multifocality (7.1, 95% CI [2.6–19.5]), and hypointensity on T1-weighted imaging (T1WI) (4.9, 95% CI [2.5–9.6]). Both peritumoral hypointensity on HBP and multifocality showed very high meta-analytic pooled specificities for diagnosing MVI (91.1% [85.4–94.8%] and 93.3% [74.5–98.5%], respectively). Conclusions: Seven MRI features including larger tumor size, rim arterial enhancement, arterial peritumoral enhancement, peritumoral hypointensity on HBP, nonsmooth margin, multifocality, and hypointensity on T1WI were significant predictors for MVI of HCC. These MRI features predictive of MVI can be useful in the management of HCC.

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Small Neuroendocrine Tumors of the Whole Gastrointestinal Tract Performed Endoscopic or Surgical Resections Also Show Positive for Lymphovascular Invasion

Digestion ◽

10.1159/000517282 ◽

2021 ◽

pp. 1-8

Author(s):

Haruna Miyashita ◽

Takuji Yamasaki ◽

Yoshihiro Akita ◽

Yoshitaka Ando ◽

Yuki Maruyama ◽

...

Keyword(s):

Surgical Resection ◽

Neuroendocrine Tumors ◽

Tumor Size ◽

Lymphovascular Invasion ◽

Distant Metastases ◽

High Rate ◽

Ki 67 ◽

Primary Endpoints ◽

Invasion Impact ◽

Prognostic Stratification

Background and Aims: In gastrointestinal neuroendocrine tumors (GI-NETs), tumor size and grading based on cellular proliferative ability indicate biological malignancy but not necessarily clinically efficient prognostic stratification. We analyzed tumor size- and grading-based prevalence of lymphovascular invasion in GI-NETs to establish whether these are true biological malignancy indicators. Methods: We included 155 cases (165 lesions), diagnosed histologically with GI-NETs, that had undergone endoscopic or surgical resection. Patient age, sex, method of treatment, tumor size, invasion depth, lymphovascular invasion positivity according to Ki-67 index-based neuroendocrine tumor grading, distant metastases, and outcome were evaluated. The primary endpoints were the prevalence of lymphovascular invasion according to tumor size and grading. Results: Overall, 24.8% were positive for lymphovascular invasion. There was a high rate of lymphovascular invasion positivity even among grade 1 cases (22.8%). The rate of lymphovascular invasion was 3.4% for grade 1 cases <5 mm, with a lymphovascular invasion rate of 8.7% for those 5–10 mm. Lymphovascular invasion ≤10% required a tumor size ≤8 mm, and lymphovascular invasion ≤5% required a tumor size ≤6 mm. A cutoff of 6 mm was identified, which yielded a sensitivity of 79% and a specificity of 63%. Even small GI-NETs grade 1 of the whole GI tract also showed positive for lymphovascular invasion. Conclusions: GI-NETs ≤10 mm had a lymphovascular invasion prevalence exceeding 10%. The lymphovascular invasion impact in GI-NET development is incompletely understood, but careful follow-up, including consideration of additional surgical resection, is crucial in cases with lymphovascular invasion.

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Is the Rationale of Anatomical Liver Resection for Hepatocellular Carcinoma Universally Adoptable? A Hypothesis-Driven Review

Medicina ◽

10.3390/medicina57020131 ◽

2021 ◽

Vol 57 (2) ◽

pp. 131

Author(s):

Young-Jen Lin ◽

Cheng-Maw Ho

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Microenvironment ◽

Surgical Resection ◽

Tumor Recurrence ◽

Hepatic Metastases ◽

Vascular Supply ◽

Tumor Ablation ◽

Supporting Evidence ◽

En Bloc ◽

Margin Width

Surgical resection is the first-line curative treatment modality for resectable hepatocellular carcinoma (HCC). Anatomical resection (AR), described as systematic removal of a liver segment confined by tumor-bearing portal tributaries, may improve survival by reducing the risk of tumor recurrence compared with non-AR. In this article, we propose the rationale for AR and its universal adoption by providing supporting evidence from the advanced understanding of a tumor microenvironment and accumulating clinical experiences of locoregional tumor ablation therapeutics. AR may be advantageous because it completely removes the en-bloc by interrupting tumor vascular supply and thus extirpates the spreading of tumor microthrombi, if they ever exist, within the supplying portal vein. However, HCC is a hypervascular tumor that can promote neoangiogenesis in the local tumor microenvironment, which in itself can break through the anatomical boundary within the liver and even retrieve nourishment from extrahepatic vessels, such as inferior phrenic or omental arteries. Additionally, increasing clinical evidence for locoregional tumor ablation therapies, such as radiofrequency ablation, predominantly performed as a non-anatomical approach, suggests comparable outcomes for surgical resection, particularly in small HCC and colorectal, hepatic metastases. Moreover, liver transplantation for HCC, which can be considered as AR of the whole liver followed by implantation of a new graft, is not universally free from post-transplant tumor recurrence. Overall, AR should not be considered the gold standard among all surgical resection methods. Surgical resection is fundamentally reliant on choosing the optimal margin width to achieve en-bloc tumor niche removal while balancing between oncological radicality and the preservation of postoperative liver function. The importance of this is to liberate surgical resilience in hepatocellular carcinoma. The overall success of HCC treatment is determined by the clearance of the theoretical niche. Developing biomolecular-guided navigation device/technologies may provide surgical guidance toward the total removal of microscopic tumor niche to achieve superior oncological outcomes.

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Prognostic and clinicopathological significance of hypoxia-inducible factors 1α and 2α in hepatocellular carcinoma: a systematic review with meta-analysis

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920987071 ◽

2021 ◽

Vol 13 ◽

pp. 175883592098707

Author(s):

Carolina Méndez-Blanco ◽

Paula Fernández-Palanca ◽

Flavia Fondevila ◽

Javier González-Gallego ◽

José L. Mauriz

Keyword(s):

Hepatocellular Carcinoma ◽

Subgroup Analysis ◽

Tumor Size ◽

Vasculogenic Mimicry ◽

Disease Free Survival ◽

Clinicopathological Features ◽

Hypoxia Inducible Factors ◽

Free Survival ◽

Node Metastasis ◽

Clinicopathological Significance

Background: Hepatocellular carcinoma (HCC) is a highly recurrent tumor after resection and has been closely related to hypoxia. Hypoxia-inducible factors 1α and 2α (HIF-1α and HIF-2α) have been shown to contribute to tumor progression and therapy resistance in HCC. We evaluated the prognostic and clinicopathological significance of HIF-1α and HIF-2α in HCC patients. Methods: We systematically searched Embase, Cochrane, PubMed, Scopus and Web of Science (WOS) from inception to 1 June 2020 for studies evaluating HIF-1α and/or HIF-2α expression in HCC. Selected articles evaluate at least one factor by immunohistochemistry (IHC) in HCC patients who underwent surgical resection, and its relationship with prognosis and/or clinicopathological features. Study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CDR42020191977). We meta-analyzed the data extracted or estimated according to the Parmar method employing STATA software. We evaluated the overall effect size for the hazard ratio (HR) and odds ratio (OR) with 95% confidence interval (CI), as well as heterogeneity across studies with the I2 statistic and chi-square-based Q test. Moreover, we conducted subgroup analysis when heterogeneity was substantial. Publication bias was assessed by funnel plot asymmetry and Egger’s test. Results: HIF-1α overexpression was correlated with overall survival (OS), disease-free survival (DFS)/recurrence-free survival (RFS) and clinicopathological features including Barcelona Clinic Liver Cancer (BCLC), capsule infiltration, intrahepatic metastasis, lymph node metastasis, tumor–node–metastasis (TNM), tumor differentiation, tumor number, tumor size (3 cm), vascular invasion and vasculogenic mimicry. We also detected a possible correlation of HIF-1α with alpha-fetoprotein (AFP), cirrhosis, histological grade, tumor size (5 cm) and albumin after subgroup analysis. Initially, only DFS/RFS appeared to be associated with HIF-2α overexpression. Subgroup analysis denoted that HIF-2α overexpression was related to OS and capsule infiltration. Conclusions: HIF-1α and HIF-2α overexpression is related to poor OS, DFS/RFS and some clinicopathological features of HCC patients, suggesting that both factors could be useful HCC biomarkers.

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Abstract No. 210 KEYNOTE-937 trial in progress: adjuvant pembrolizumab for hepatocellular carcinoma and complete radiologic response after surgical resection or local ablation

Journal of Vascular and Interventional Radiology ◽

10.1016/j.jvir.2021.03.216 ◽

2021 ◽

Vol 32 (5) ◽

pp. S92-S93

Author(s):

A. Vogel ◽

A.X. Zhu ◽

A. Cheng ◽

T. Yau ◽

J. Zhou ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Surgical Resection ◽

Local Ablation

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Effect of timing of surgical resection of primary hepatocellular carcinoma on survival outcomes in elderly patients and prediction of clinical models

BMC Gastroenterology ◽

10.1186/s12876-021-01815-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yongfei He ◽

Tianyi Liang ◽

Shutian Mo ◽

Zijun Chen ◽

Shuqi Zhao ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Liver Cancer ◽

Elderly Patients ◽

Surgical Resection ◽

Influencing Factors ◽

The Elderly ◽

Primary Hepatocellular Carcinoma ◽

Surgical Timing ◽

Duration Of Surgery

Abstract Background The effect of time delay from diagnosis to surgery on the prognosis of elderly patients with liver cancer is not well known. We investigated the effect of surgical timing on the prognosis of elderly hepatocellular carcinoma patients undergoing surgical resection and constructed a Nomogram model to predict the overall survival of patients. Methods A retrospective analysis was performed on elderly patients with primary liver cancer after hepatectomy from 2012 to 2018. The effect of surgical timing on the prognosis of elderly patients with liver cancer was analyzed using the cut-off times of 18 days, 30 days, and 60 days. Cox was used to analyze the independent influencing factors of overall survival in patients, and a prognostic model was constructed. Results A total of 232 elderly hepatocellular carcinoma patients who underwent hepatectomy were enrolled in this study. The cut-off times of 18, 30, and 60 days were used. The duration of surgery had no significant effect on overall survival. Body Mass Index, Child-Pugh classification, Tumor size Max, and Length of stay were independent influencing factors for overall survival in the elderly Liver cancer patients after surgery. These factors combined with Liver cirrhosis and Venous tumor emboli were incorporated into a Nomogram. The nomogram was validated using the clinical data of the study patients, and exhibited better prediction for 1-year, 3-year, and 5-year overall survival. Conclusions We demonstrated that the operative time has no significant effect on delayed operation in the elderly patients with hepatocellular carcinoma, and a moderate delay may benefit some patients. The constructed Nomogram model is a good predictor of overall survival in elderly patients with hepatectomy.

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