Quantitation of sinusoid-like vessels in hepatocellular carcinoma: Its clinical and prognostic significance.
Abstract
Angiogenesis is crucial for tumor growth and metastasis. Hepatocellular carcinoma (HCC) is a typical hypervascular tumor. However, the relationship between tumor vascularity and the outcome of patients with HCC has not been evaluated. To clarify whether tumor angiogenesis is related to the prognosis of patients, immunohistochemical staining, using anti-von Willebrand factor (vWF) and anti-CD34, was applied in resected specimens from 43 cases of HCC. In nonmalignant tissue, staining was confined to vessels in the portal tract and to a few periportal sinusoids with both of the endothelial markers applied. In tumor tissue, however, sinusoid-like vessels reacted intensively with anti-CD34 but not with anti-vWF. The intratumor microvessel density (MVD) highlighted by anti-CD34 was 297 +/- 88 (per 0.74 mm2), which was significantly higher than that highlighted by anti-vWF (4 +/- 7). When only the MVD highlighted by anti-CD34 was analyzed, tumor diameter larger than 2 cm, poor differentiation (Edmondson's II to IV), and portal invasion were significantly related to the subgroup with MVD > or = 290. Overall survival curves of patients with MVD < 290 were better, and these patients were more likely to remain tumor free. Cox hazards model revealed intratumor MVD and Edmondson's grade to be independent prognostic factors for the overall survival of patients. These results demonstrated for the first time that tumor angiogenesis assessed by anti-CD34 was correlated with the outcome of patients with HCC, suggesting a potential role for anti-CD34 in the diagnosis and treatment of HCC. (Hepatology 1997 Nov;26(5):1216-23)
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Adrenocortical carcinoma with multiple liver metastases controlled by bland transarterial embolization and surgery resulting in long-term survival
2022, Radiology Case ReportsAdrenocortical carcinoma (ACC) is a rare malignant tumor with a poor prognosis. Local recurrence or distant metastases occur in more than 50% of cases. Patients with metastases have limited treatment options, and <15% have a 5-year survival time. Herein, we describe a 44-year-old woman with ACC and who underwent retroperitoneal tumor resection. Multiple liver and lung metastases were found 1-year postresection. Mitotane therapy started as systemic treatment. Lung metastases were controlled but liver metastases were progressive. The liver metastases were treated by performing 2 resections and 6 bland transarterial embolization (bland TAE), and are presently controlled with only 2 liver metastases of <20 mm. The present case showed that bland TAE can achieve long-term prevention of the progression of liver metastases of ACC. The ultraselective bland TAE for selective embolization supported by the latest computed tomography analysis techniques during arteriography could minimize liver damage caused by embolization and allowed multiple treatments which prolonged survival. We conclude that bland TAE can be effective for controlling liver metastases of ACC.
Predicting HCC Response to Multikinase Inhibitors With In Vivo Cirrhotic Mouse Model for Personalized Therapy
2021, Cellular and Molecular Gastroenterology and HepatologyHepatocellular carcinoma (HCC) arises in a cirrhotic, pro-angiogenic microenvironment. Inhibiting angiogenesis is a key mode of action of multikinase inhibitors and current non-cirrhotic models are unable to predict treatment response. We present a novel mouse cirrhotic model of xenotransplant that predicts the natural biology of HCC and allows personalized therapy.
Cirrhosis was induced in NOD Scid gamma mice with 4 months of thioacetamide administration. Patient derived xenografts (PDXs) were created by transplant of human HCC subcutaneously into non-cirrhotic mice and intra-hepatically into both cirrhotic and non-cirrhotic mice. The applicability of cirrhotic PDXs for drug testing was tested with 16 days of either sorafenib or lenvatinib. Treatment response was evaluated by MRI.
8 out of 19 (42%) human HCC engrafted in the cirrhotic model compared with only 3 out of 19 (16%) that engrafted in the subcutaneous non-cirrhotic model. Tumor vasculature was preserved in the cirrhotic model but was diminished in the non-cirrhotic models. Metastasis developed in 3 cirrhotic PDX lines and was associated with early HCC recurrence in all 3 corresponding patients (100%), compared with only 5 out of 16 (31%) of the other PDX lines, P = .027. The cirrhotic model was able to predict response and non-response to lenvatinib and sorafenib respectively in the corresponding patients. Response to lenvatinib in the cirrhotic PDX was associated with reduction in CD34, VEGFR2 and CLEC4G immunofluorescence area and intensity (all P ≤ .03).
A clinically relevant cirrhotic PDX model preserves tumor angiogenesis and allows prediction of response to multikinase inhibitors for personalized therapy.
Gadoxetic acid-enhanced MRI of macrotrabecular-massive hepatocellular carcinoma and its prognostic implications
2021, Journal of HepatologyDespite the clinical and genetic significance of macrotrabecular-massive hepatocellular carcinoma (MTM-HCC), its characteristics on imaging have not been described. This study aimed to characterise MTM-HCC on gadoxetic acid-enhanced MRI and to evaluate the diagnostic accuracy and prognostic value of these imaging characteristics.
We enrolled 3 independent cohorts from 2 tertiary care centres. The 3 cohorts consisted of a total of 476 patients who underwent gadoxetic acid-enhanced MRI and surgical resection for treatment-naïve single HCCs. Independent review of histopathology and MRI by 2 reviewers was performed for each cohort, and inter-reader agreement was evaluated. Based on the result of MRI review in the training cohort (cohort 1), we developed 2 diagnostic criteria for MTM-HCC and evaluated their prognostic significance. The diagnostic performance and prognostic significance were validated in 2 validation cohorts (cohorts 2 and 3).
We developed 2 diagnostic MRI criteria (MRIC) for MTM-HCC: MRIC-1, ≥20% arterial phase hypovascular component; MRIC-2, ≥50% hypovascular component and 2 or more ancillary findings (intratumoural artery, arterial phase peritumoural enhancement, and non-smooth tumour margin). MRIC-1 showed high sensitivity and negative predictive value (88% and 95% in the training cohort, and 88% and 97% in the pooled validation cohorts, respectively), whereas MRIC-2 demonstrated moderate sensitivity and high specificity (47% and 94% in the training cohort, and 46% and 96% in the pooled validation cohorts, respectively). MRIC-2 was an independent poor prognostic factor for overall survival in both training and pooled validation cohorts.
Using gadoxetic acid-enhanced MRI findings, including an arterial phase hypovascular component, we could stratify the probability of MTM-HCC and non-invasively obtain prognostic information.
Macrotrabecular-massive hepatocellular carcinoma (MTM-HCC) is a histopathologic subtype of HCC characterised by aggressive biological behaviour and poor prognosis. We developed imaging criteria based on liver MRI that could be used for the non-invasive diagnosis of MTM-HCC. HCCs showing imaging findings of MTM-HCC were associated with poor outcomes after hepatic resection.
Selective devascularization treatment for large hepatocellular carcinoma: Stage 2A IDEAL prospective case series
2019, International Journal of SurgeryRapid growth and invasiveness of hepatocellular carcinoma (HCC) largely depends on its vascularity and active angiogenic capacity. That feature was used to control the tumor in the past with some limitations. These deficiencies were addressed in our new procedure by hepatic artery ligation and extrahepatic collaterals division (HALED) of the liver lobe containing large HCC. This study tried to assess the feasibility, safety and the short term effects of HALED.
This is a prospective stage 2a development IDEAL (Idea, Development, Exploration, Assessment and Long-term monitoring) case series. It included adult patients with large-sized HCC (diameter > 5 cm) subjected to HALED carried out in our center during five years' trial evaluating one-month postoperative outcomes. Patients will be reported prospectively in a sequential order with explanation of reasons for rejected cases and description of changes to technique or indication as the procedure evolved. This study registry number is NCT03129685 at the ClinicalTrials.gov.
The first HALED operation was carried out safely on 2013, followed by nineteen patients by 2018. Patients' mean age (±standard deviation) was 62·45 (±9·27), range 38–76 years. Eleven (55%) patients had tumors diameter > 10 cm 13 (65%) patients were advanced BCLC stage. Seven modifications were made on the technique and indications of the procedure towards stability. According to the modified response evaluation criteria in solid tumors, 13 patients (65%) attained complete response. Operative mortality was 5% (one patient) and major morbidity was 10% (two patients). Liver infarction and abscess formation were not noticed in this study.
Our forerunner study showed that HALED for large HCC is safe and induces tumor necrosis. Further long-term studies are suggested before starting the 2b stage.
Angiopoietin-like protein 3 and 4 expression 4 and their serum levels in hepatocellular carcinoma
2017, CytokineCitation Excerpt :Taken together, searching for novel molecular diagnostic markers reflecting the progression or metastasis of HCC is urgent in this higly aggressive cancer. Noteworthy HCC is a hypervascular tumor and researches demonstrated the a pivotal role of angiogenesis during hepatic carcinogenesis [9]. Angiogenesis could be net result of a balance between the positive and negative regulators of neovascularization [10].
Hepatocellular carcinoma (HCC) is the 6th most common cancer and the 3rd leading cause of cancer causing death allover the world. The aim of this research to explore the clinical relevance of blood angiopoietin-like protein-3 (ANGPTL3) and ANGPTL4 expression and their proteins levels as non invasive biomarkers in cirrhotic and HCC patients and their influence on the clinicopathological features of HCC.
This work comprised 200 patients with chronic hepatitis (120 cases complicated with cirrhosis, 80 patients with primary HCC) and 100 controls. circulating ANGPTL3 and ANGPTL4 expression was estimated by real-time polymerase chain reaction (RT-PCR). ANGPTL3 and ANGPTL4 protein levels were determined by enzyme-linked immunosorbent assay (ELISA).
The circulating ANGPTL3 and ANGPTL 4 expression was significantly elevated in HCC cases compared to chronic hepatitis patients and controls. There were much more serum ANGPTL3 and ANGPTL4 values in HCC and chronic hepatitis patients as compared to controls, but we couldn't detect this significance between chronic hepatitis and HCC cases as regards ANGPTL4. By Multiple stepwise linear regression analysis, an increased ANGPTL3 expression, alpha-fetoprotein (AFP), serum ANGPTL 3 levels, Child–Pugh grade were significantly assosciatedassociated with increased risk of HCC. Logistic regression analysis revealed that ANGPTL 3 expression and AFP levels were the only pridectorspredictors of HCC (odd's ratio (OR) = 8.9; 8.6 respectively, P = 0.003). Receiver operator characteristic (ROC) demonsterated that serum ANGPTL3 and ANGPTL4 levels were usufuluseful biomarkers discriminating chronic hepatitis cases from controls (AUC = 0.820,0.887, respectively P < 0.001). However, they fail to discriminate HCC patients from chronic hepatitis patients (P = 0.27,0.12 respectively). Moreover, ANGPTL3 and ANGPTL 4 expression were promising biomarkers discriminating chronic hepatitis cases from controls and those HCC cases from chronic hepatitis patients (P < 0.001). Combined ANGPTL3 expression and serum level wasn't useful in discriminating HCC patient from chronic hepatitis (P = 0.09). In contrast, combined ANGPTL4 expression and serum level was an useful biomarker discriminating HCC cases from chronic hepatitis.
ANGPTL3 and ANGPTL 4 expression and serum levels can be promising non invasive biomarkers in diagnosis of chronic hepatitis and HCC especially their expression could be useful in discriminating HCC from chronic hepatitis patients.
Candesartan attenuates angiogenesis in hepatocellular carcinoma via downregulating AT1R/VEGF pathway
2016, Biomedicine and PharmacotherapyAngiotensin II type 1 receptor (AT1R) was reported to express in many types of tumors, promoting tumor growth and angiogenesis. We herein examined AT1R expression in liver cancer and the potential antitumor effects of AT1R antagonist Candesartan in liver cancer. We found that AT1R expression was positively correlated with VEGF-A expression and microvascular density (MVD) in 40 HCC patients. Angiotensin II and Candesartan neither had effects on the proliferation of liver cancer cells in vitro. However, Angiotensin II upregulated AT1R protein expression and promoted production of VEGF-A in liver cancer cells in a dose-dependent manner. Candesartan was able to reverse this process in a dose-dependent manner. Moreover, Candesartan downregulated the expression of VEGF-A in SMMC-7721 bearing xenografts in mice and inhibited tumor growth and angiogenesis in vivo. Our data suggested that AT1R antagonist Candesartan might be useful to suppress liver cancer by inhibiting angiogenesis.