Irreversible Electroporation in Liver Cancers and Whole Organ Engineering

Liver cancers contribute significantly to cancer-related mortality worldwide and liver transplants remain the cornerstone of curative treatment for select, early-stage patients. Unfortunately, because of a mismatch between demand and supply of donor organs, liver cancer patients must often wait extended periods of time prior to transplant. A variety of local therapies including surgical resection, transarterial chemoembolization, and thermal ablative methods exist in order to bridge to transplant. In recent years, a number of studies have examined the role of irreversible electroporation (IRE) as a non-thermal local ablative method for liver tumors, particularly for those adjacent to critical structures such as the vasculature, gall bladder, or bile duct. In addition to proving its utility as a local treatment modality, IRE has also demonstrated promise as a technique for donor organ decellularization in the context of whole-organ engineering. Through complete non-thermal removal of living cells, IRE allows for the creation of an acellular extra cellular matrix (ECM) scaffold that could theoretically be recellularized and implanted into a living host. Here, we comprehensively review studies investigating IRE, its role in liver cancer treatment, and its utility in whole organ engineering.

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Predicting Clinical Efficacy of Vascular Disrupting Agents in Rodent Models of Primary and Secondary Liver Cancers: An Overview with Imaging-Histopathology Correlation

Diagnostics ◽

10.3390/diagnostics10020078 ◽

2020 ◽

Vol 10 (2) ◽

pp. 78 ◽

Cited By ~ 1

Author(s):

Yewei Liu ◽

Shuncong Wang ◽

Xiaohui Zhao ◽

Yuanbo Feng ◽

Guy Bormans ◽

...

Keyword(s):

Clinical Trials ◽

Liver Cancer ◽

Human Liver ◽

Cellular Differentiation ◽

Liver Tumors ◽

Pancreatic Tumors ◽

Imaging Biomarkers ◽

Vascular Disrupting Agents ◽

Liver Cancers ◽

Vascular Disrupting

Vascular disrupting agents (VDAs) have entered clinical trials for over 15 years. As the leading VDA, combretastatin A4 phosphate (CA4P) has been evaluated in combination with chemotherapy and molecular targeting agents among patients with ovarian cancer, lung cancer and thyroid cancer, but still remains rarely explored in human liver cancers. To overcome tumor residues and regrowth after CA4P monotherapy, a novel dual targeting pan-anticancer theragnostic strategy, i.e., OncoCiDia, has been developed and shown promise previously in secondary liver tumor models. Animal model of primary liver cancer is time consuming to induce, but of value for more closely mimicking human liver cancers in terms of tumor angiogenesis, histopathological heterogeneity, cellular differentiation, tumor components, cancer progression and therapeutic response. Being increasingly adopted in VDA researches, multiparametric magnetic resonance imaging (MRI) provides imaging biomarkers to reflect in vivo tumor responses to drugs. In this article as a chapter of a doctoral thesis, we overview the construction and clinical relevance of primary and secondary liver cancer models in rodents. Target selection for CA4P therapy assisted by enhanced MRI using hepatobiliary contrast agents (CAs), and therapeutic efficacy evaluated by using MRI with a non-specific contrast agent, dynamic contrast enhanced (DCE) imaging, diffusion weighted imaging (DWI) are also described. We then summarize diverse responses among primary hepatocellular carcinomas (HCCs), secondary liver and pancreatic tumors to CA4P, which appeared to be related to tumor size, vascularity, and cellular differentiation. In general, imaging-histopathology correlation studies allow to conclude that CA4P tends to be more effective in secondary liver tumors and in more differentiated HCCs, but less effective in less differentiated HCCs and implanted pancreatic tumor. Notably, cirrhotic liver may be responsive to CA4P as well. All these could be instructive for future clinical trials of VDAs.

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Complications of thermal ablation of hepatic tumors: Comparison of radiofrequency and microwave techniques.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e15040 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e15040-e15040 ◽

Cited By ~ 1

Author(s):

Xiang Jing ◽

Jianmin Ding ◽

Jibin Liu ◽

Yandong Wang ◽

Fengmei Wang ◽

...

Keyword(s):

Liver Cancer ◽

Thermal Ablation ◽

Liver Tumors ◽

Major Complication ◽

Mortality Rates ◽

Complication Rates ◽

Hepatic Tumors ◽

Ablation Therapy ◽

Liver Cancers ◽

Significant Difference

e15040 Background: The efficacy and safety of radiofrequency ablation (RFA) have been reported in the literatures, which are considered as frontline choice for treatment of liver cancer. Recently, microwave ablation (MWA) has emerged and gained great attention over RFA. However, in comparison to RFA, the safety of MWA for treatment of liver cancer has not been fully reported in the literatures. Studies with large clinical data sets are still needed to understand the technique and avoid the complications. The objective of this study was to retrospectively investigate the common complications of thermal ablations of liver tumors using both RFA and MWA techniques, and compare the safety between these two procedures. Methods: This retrospective study protocol was approved by our institutional ethics committee to allow investigators to review the existing patient’s medical records. A total of 879 patients with hepatic tumors underwent thermal ablation. There were 323 cases having the RFA procedures and 556 cases having MWA procedures. The complications of thermal ablations of liver tumors were compared using both RFA and MWA techniques. Results: A total of 1,030 thermal ablation sessions was performed in 879 patients with a total of 1,652 tumors. There were 323 patients with 562 tumors received a total of 376 RFA with averaged 1.16±0.48 sessions per patient. The other 556 patients with 1,090 tumors received a total of 654 MWA with averaged1.18±0.51 sessions per patient. The mortality rates were 0.31% (1/323) and 0.36% (2/556) in RFA and MWA group. In RFA and MWA group, the major complication rates were 3.5% (13/376) and 3.1% (20/654) (Table 1), meanwhile the minor complication rates were 5.9% (22/376) and 5.7% (37/654). There was no statistical significant difference for the mortality rates, the major complications, the minor complications between the RFA and MWA groups (P>0.05). Conclusions: Thermal ablation therapy in the treatment of liver cancers is relatively safe with low mortality and low incidence of serious complications. The types and incidences of complications caused by RFA and MWA are similar and comparable for safety consideration in clinical settings.

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YAP and TAZ Heterogeneity in Primary Liver Cancer: An Analysis of Its Prognostic and Diagnostic Role

International Journal of Molecular Sciences ◽

10.3390/ijms20030638 ◽

2019 ◽

Vol 20 (3) ◽

pp. 638 ◽

Cited By ~ 13

Author(s):

Matthias Van Haele ◽

Iván Moya ◽

Ruçhan Karaman ◽

Guy Rens ◽

Janne Snoeck ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cancer ◽

Liver Tumors ◽

Primary Liver Cancer ◽

Hippo Pathway ◽

Disease Free Survival ◽

Decisive Role ◽

Binding Motif ◽

Keratin 19 ◽

Liver Cancers

Primary liver cancer comprises a diverse group of liver tumors. The heterogeneity of these tumors is seen as one of the obstacles to finding an effective therapy. The Hippo pathway, with its downstream transcriptional co-activator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), has a decisive role in the carcinogenesis of primary liver cancer. Therefore, we examined the expression pattern of YAP and TAZ in 141 patients with hepatocellular carcinoma keratin 19 positive (HCC K19+), hepatocellular carcinoma keratin 19 negative (HCC K19−), combined hepatocellular–cholangiocarcinoma carcinoma (cHCC-CCA), or cholangiocarcinoma (CCA). All cHCC-CCA and CCA patients showed high expression levels for YAP and TAZ, while only some patients of the HCC group were positive. Notably, we found that a histoscore of both markers is useful in the challenging diagnosis of cHCC-CCA. In addition, positivity for YAP and TAZ was observed in the hepatocellular and cholangiocellular components of cHCC-CCA, which suggests a single cell origin in cHCC-CCA. Within the K19− HCC group, our results demonstrate that the expression of YAP is a statistically significant predictor of poor prognosis when observed in the cytoplasm. Nuclear expression of TAZ is an even more specific and independent predictor of poor disease-free survival and overall survival of K19− HCC patients. Our results thus identify different levels of YAP/TAZ expression in various liver cancers that can be used for diagnostics.

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Mitochondrial Dynamics and Liver Cancer

Cancers ◽

10.3390/cancers13112571 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2571

Author(s):

María Isabel Hernández-Alvarez ◽

Antonio Zorzano

Keyword(s):

Liver Cancer ◽

Liver Tumors ◽

Mitochondrial Dynamics ◽

Primary Liver Cancer ◽

Mitochondrial Morphology ◽

Mitochondrial Dynamic ◽

Mitochondrial Homeostasis ◽

Liver Cancers ◽

Rising Incidence ◽

Novel Therapeutic Strategies

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer. Due to its rising incidence and limited therapeutic options, HCC has become a leading cause of cancer-related death worldwide, accounting for 85% of all deaths due to primary liver cancers. Standard therapy for advanced-stage HCC is based on anti-angiogenic drugs such as sorafenib and, more recently, lenvatinib and regorafenib as a second line of treatment. The identification of novel therapeutic strategies is urgently required. Mitochondrial dynamics describes a group of processes that includes the movement of mitochondria along the cytoskeleton, the regulation of mitochondrial morphology and distribution, and connectivity mediated by tethering and fusion/fission events. In recent years, mitochondrial dynamic processes have emerged as key processes in the maintenance of liver mitochondrial homeostasis. In addition, some data are accumulating on the role played by mitochondrial dynamics during cancer development, and specifically on how such dynamics act directly on tumor cells or indirectly on cells responsible for tumor aggression and defense. Here, we review the data that suggest mitochondrial dynamics to be involved in the development of liver tumors.

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Biological and Phytochemical Screening of Fumaria indica extract on Chemically Induced Hepatocellular Carcinoma with Reference to Biochemical Parameters

International Journal of Pharmaceutical Quality Assurance ◽

10.25258/ijpqa.10.2.1 ◽

2019 ◽

Vol 10 (02) ◽

Author(s):

Irfan Aziz ◽

Birendra Shrivastava ◽

Chandana Venkateswara Rao2 ◽

Sadath Ali

Keyword(s):

Free Radicals ◽

Liver Disease ◽

Liver Cancer ◽

Early Stage ◽

Food Additives ◽

Ethanolic Extract ◽

Hepatoprotective Activity ◽

Control Group ◽

Industrial Chemicals ◽

Toxic Industrial Chemicals

Liver disease or liver cancer is the sixth most common cancer and the third leading cause of cancer mortality in the world. Hepatitis viral infection, food additives, alcohol, fungal toxins (aflatoxins), toxic industrial chemicals, air and water pollutants are the major risk factors of liver cancer. Moreover, due to high tolerance of liver, HCC is seldom detected at an early stage and once detected treatment faces a poor prognosis in most cases.Fumaria indica possesses hepatoprotective activity as evidenced by the significant and dose dependent restoring the activities of entire liver cancer marker enzymes, diminution in tumor incidence, decrease in lipid peroxidation (LPO) and increase in the level of antioxidant enzymes (GSH, CAT, SOD, GPx and GST) through scavenging of free radicals, or by enhancing the activity of antioxidant, which then detoxify free radicals. These factors protect cells from ROS damage in NDEA and CCl4-induced hepatocarcinogenesis. Histopathological observations of liver tissues too correlated with the biochemical observations. Thus, present investigation suggested that the Fumaria indica would exert a chemoprotective effect by reversing the oxidant-antioxidant imbalance during hepatocarcinogenesis induced by NDEA and CCl4. Besides Fumaria indicais very much effective in preventing NDEA-induced multistage hepatocarcinogenesis possibly through antioxidant and antigenotoxic nature, which was confirmed by various liver injury and biochemical tumour markers enzymes. The hepatoprotective activity of a Fumaria indicaof 50 % ethanolic extract was studied using rats. The animals received a single intraperitoneal injection of N-nitrosodiethylamine 200mg/kg body wt followed by subcutaneous injection of CCl4 in a dose of 3 ml/kg body wt. Fumaria indica extract dose dependently and significantly the increase in serum hepatic enzyme levels after NDEAand CCl4 treatment compared to the toxin control group. The results of this study confirmed the antioxidant and hepatoprotective activity of the Fumaria indicaextract against carbon tetrachlorideand N-nitrosodiethylamine induced hepatotoxicity in rats. In addition to this, studies on molecular aspect of hepatoprotective therapy will give mechanistic information in hepatoprotective therapy and also critical balance should be there between the animal model and clinical research. The hepatoprotective properties of Fumaria indicashould provide useful information in the possible application in hepatic liver disease.

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Evaluation of non-targeting, C- or N-pH (low) insertion peptide modified superparamagnetic iron oxide nanoclusters for selective MRI of liver tumors and their potential toxicity in cirrhosis

RSC Advances ◽

10.1039/c9ra02430a ◽

2019 ◽

Vol 9 (25) ◽

pp. 14051-14059

Author(s):

Abdulrahman Ahmed Mahmood ◽

Jianqi Zhang ◽

Rufang Liao ◽

Xiwei Pan ◽

Dan Xu ◽

...

Keyword(s):

Iron Oxide ◽

Liver Cancer ◽

Contrast Agent ◽

Cancer Diagnosis ◽

Liver Tumors ◽

Superparamagnetic Iron Oxide ◽

Mri Contrast Agent ◽

Potential Toxicity ◽

Mri Contrast ◽

Specific Enhancement

The acid-responsive pHLIP modified SPION as an MRI contrast agent for liver cancer diagnosis requires the validation of both the tumor-specific enhancement and a safe profile in cirrhosis.

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Hepatic Arterial Buffer Response in Liver Radioembolization and Potential Use for Improved Cancer Therapy

Cancers ◽

10.3390/cancers13071537 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1537

Author(s):

Stephan Walrand ◽

Michel Hesse ◽

Philippe d’Abadie ◽

François Jamar

Keyword(s):

Animal Studies ◽

Liver Tumors ◽

Clinical Trial Design ◽

Normal Liver ◽

Dose Ratio ◽

Liver Cancers ◽

Tumoral Cell ◽

Flow Enhancement ◽

Curative Intention ◽

Tumoral Cells

Liver radioembolization is a treatment option for unresectable liver cancers, performed by infusion of 90Y or 166Ho loaded spheres in the hepatic artery. As tumoral cells are mainly perfused via the liver artery unlike hepatic lobules, a twofold tumor to normal liver dose ratio is commonly obtained. To improve tumoral cell killing while preserving lobules, co-infusion of arterial vasoconstrictor has been proposed but with limited success: the hepatic arterial buffer response (HABR) and hepatic vascular escape mechanism hamper the arterioles vasoconstriction. The proposed project aims to take benefit from the HABR by co-infusing a mesenteric arterial vasodilator: the portal flow enhancement inducing the vasoconstriction of the intra sinusoids arterioles barely impacts liver tumors that are mainly fed by novel and anarchic external arterioles. Animal studies were reviewed and dopexamine was identified as a promising safe candidate, reducing by four the hepatic lobules arterial flow. A clinical trial design is proposed. A four to sixfold improvement of the tumoral to normal tissue dose ratio is expected, pushing the therapy towards a real curative intention, especially in HCC where ultra-selective spheres delivery is often not possible.

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The Emerging Factors and Treatment Options for NAFLD-Related Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers13153740 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3740

Author(s):

Chunye Zhang ◽

Ming Yang

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cancer ◽

Fatty Liver ◽

Early Stage ◽

Primary Liver Cancer ◽

Treatment Options ◽

Underlying Mechanism ◽

Diagnostic Methods ◽

T Cell Therapy ◽

Nonalcoholic Fatty Liver

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, followed by cholangiocarcinoma (CCA). HCC is the third most common cause of cancer death worldwide, and its incidence is rising, associated with an increased prevalence of obesity and nonalcoholic fatty liver disease (NAFLD). However, current treatment options are limited. Genetic factors and epigenetic factors, influenced by age and environment, significantly impact the initiation and progression of NAFLD-related HCC. In addition, both transcriptional factors and post-transcriptional modification are critically important for the development of HCC in the fatty liver under inflammatory and fibrotic conditions. The early diagnosis of liver cancer predicts curative treatment and longer survival. However, clinical HCC cases are commonly found in a very late stage due to the asymptomatic nature of the early stage of NAFLD-related HCC. The development of diagnostic methods and novel biomarkers, as well as the combined evaluation algorithm and artificial intelligence, support the early and precise diagnosis of NAFLD-related HCC, and timely monitoring during its progression. Treatment options for HCC and NAFLD-related HCC include immunotherapy, CAR T cell therapy, peptide treatment, bariatric surgery, anti-fibrotic treatment, and so on. Overall, the incidence of NAFLD-related HCC is increasing, and a better understanding of the underlying mechanism implicated in the progression of NAFLD-related HCC is essential for improving treatment and prognosis.

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CLINICAL APPLICATIONS OF ELECTROCHEMOTHERAPY

10.5644/pi2019.181.01 ◽

2019 ◽

Author(s):

Gregor Serša

Keyword(s):

Biomedical Applications ◽

Liver Tumors ◽

Checkpoint Inhibitors ◽

Combined Treatment ◽

Local Treatment ◽

Industrial Applications ◽

Interleukin 12 ◽

Nice Guidelines ◽

Or Gene

Electroporation has several biomedical and industrial applications. The biomedical applications are in the field of drug or gene delivery. Electrochemotherapy utilizes electroporation for the increased delivery of cytotoxic drugs like bleomycin or cisplatin into tumors. The use of electrochemotherapy has spread throughout Europe for the treatment of cutaneous tumors or metastases. It is in the NICE guidelines and is becoming standard ablative technique in treatment of cancer. The technological advancements have also enabled the use of electrochemotherapy for the treatment of deep seated tumors, such as soft tissue or liver tumors. Clinical studies demonstrate good effectiveness on fibrosarcomas, colorectal liver metastases and hepatocellular carcinoma. However, electrochemotherapy is a local treatment that also induces moderate local immune response. This so called “in situ vaccination” induced by electrochemotherapy can be exploited in combined treatment with immune checkpoint inhibitors or electrogene therapy with immunostimulating effect. Therefore, gene electrotransfer of plasmid coding for interleukin 12 (IL-12), in combination with electrochemotherapy could result in transformation of electrochemotherapy from local into systemic treatment. This is also of our current interest, and we are undertaking steps to bring this idea from preclinical into clinical testing.

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