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Challenges and Opportunities in Hepatocellular Carcinoma

Challenges and Opportunities in Hepatocellular Carcinoma

Valle, A., & Carvalho, A. O. (2023)

Abstract

Hepatocellular carcinoma is the most common liver neoplasm in dogs and can be treated by the Viscum album therapy in a curative or palliative way. The objective is to report a hepatocellular carcinoma case in a dog treated by homeopathic therapy, extending to Palliative Care, with a 24-month survival. A 12-year-old Schnauzer male with a history of a liver nodule was treated by intravenous and subcutaneous applications of V. album in different dynamization and combinations, chromotherapy, and oral homeopathic medicines. The tumor growth was controlled, and the health condition of the patient was stable while the medication was given as prescribed. However, as application frequency was reduced, tumor growth increased, and health deterioration was verified. Nevertheless and contrary to expectations, the patient had a 24-month survival. Therefore, these findings point to the potential of V. album on enhancing the quality of life, controlling tumor growth, and prolonging survival in patients with hepatocellular carcinoma. Patients under continuous treatment would benefit better from these properties.

Valle, A. M. B., De Rebouças Carvalho, A. C., Rahme, S., Araújo, A. C. T., Malard, P. F., & Brunel, H. D. S. S. (2023)

Abstract

Hepatocellular carcinoma (HCC) is a type of neoplasm of high-frequency occurrence and late diagnosis. Therefore, medicine must act in a multidisciplinary and preventive manner to give patients a better prognosis. Homeopathy appears as a possible therapeutic tool to treat these patients, emphasizing significant results regarding quality of life and longevity. This article aimed to evaluate the effect of homeopathic dilutions of Ruta graveolens in the D35 potency on the in vitro cell viability and nitric oxide quantification of hepatocellular carcinoma cells (HepG2). The results showed a critical cytotoxic activity and high production of nitric oxide of the cells when the medicine to the culture. These results indicate that Ruta D35 has action potential in inhibiting HepG2 tumor cell growth, being an important and promising therapeutic tool for treating patients diagnosed with hepatocellular carcinoma if these results be confirmed in vivo.

Valle, A. M. B., De Rebouças Carvalho, A. C., Rahme, S., Araújo, A. C. T., Malard, P. F., & Brunel, H. D. S. S. (2023b)

Abstract

Homeopathy has become increasingly known and used in various treatments, showing excellent clinical results. One of its most common indications is to help treat chronic diseases, directly improving patients’ quality of life, especially those with cancer. Hepatocellular carcinoma is a disease that depends on different factors for its development and the success of its treatment. In this context, searching for new therapeutic tools is essential, and homeopathy seems promising. Therefore, Anonna muricata (soursop/graviola) and Handroanthus impetiginosus (purple ipe) have been studied due to their action potential against tumor cells. This study aimed to evaluate the effect of these medicines combined in 1.1mL ampoules, in homeopathic dilutions, on HepG2 (hepatocellular carcinoma) cells through in vitro tests. Cells were cultivated in 75 cm² culture bottles in an oven with controlled temperature and CO2 quantity (37 ºC, 5% CO2). Then, cells were plated in 96-well plates where treatment was performed using the products at different concentrations. After 48 hours of treatment, cell viability analyses were performed by MTT and quantification of the nitric oxide released using the Griess reaction. Treatment with the Anonna muricata D5 (1×10-5) + Handroanthus impetiginosus D5 (1×10-5) formulation resulted in decreased cell viability and increased nitric oxide production by these cells. These findings indicate that this medicine showed an antitumor effect and can be an ally in treating this type of pathology.

Valle, A. M. B., De Rebouças Carvalho, A. C., Rahme, S., Araújo, A. C. T., Malard, P. F., & Brunel, H. D. S. S. (2023a)

Abstract

Hepatocellular carcinoma is a type of cancer with a high mortality rate since it is primarily diagnosed in an advanced stage. Therefore, searching for therapies that help in this treatment becomes increasingly important. Therapies comprising Complementary Medicine have become more popular and have shown beneficial effects in treating various types of cancer. Homeopathy, a therapy established for more than 200 years to treat various diseases, has become the target of several studies, especially regarding chronic diseases, which are difficult to control by conventional medicine. This study evaluated the effect of the homeopathic dilution of Chelidonium majus D35 (1×10-35) in hepatocellular carcinoma cells (HepG2). Cells were cultivated in an oven at 37 ºC, 5% CO2, and then trypsinized and plated in 96-well plates for product addition. Chelidonium majus D35 was added in triplicate to each well at three different concentrations. The concentrations tested were 20, 40, and 60 µL/mL. After 48 hours of incubation with the product, cell viability was measured by MTT, and it was possible to observe a decrease in the groups that received the treatment compared to the control.

A decrease in cell viability was recorded compared to the control of cells without treatment, indicating a cytotoxic effect of Chelidonium majus D35 on tumor cells. Different studies confirm this result due to the evaluation of biologically active compounds present in extracts of Chelidonium majus D35 that control cell proliferation and induce apoptosis. The results of the in vitro tests performed were satisfactory.

Ding, L., Sioshansi, S., Malik, H., Franquet-Elia, E., McIntosh, L. J., Ruppell, E., Licho, R., Kim, Y., Goldstein, A., Mittal, K., Wang, M., Gultawatvichai, P., Mehta, S., Foley, K., Wilson, S., Bishop-Jodoin, W., & Fitzgerald, T. J. (2022)

Abstract

Yttrium-90 (Y-90) therapy has become an important component to the care of patients with primary hepatic malignancies and lesions that have metastasized to the liver. Therapy is administered through an intra-arterial procedure after an interventional procedure is performed using an albumin labeled product to ensure therapy will be delivered to the target volume of interest with minimal migration from the target of choice. In the past, dose to target has been measured by activity delivered and qualitative deposition of dose on metabolic imaging post application. Imaging tools such as single positron emission computer tomography (SPECT) and digital positron emission tomography have given us insight into quantitative dose to volumetric tumor target and dose to normal tissue. Recent validation of computational software has provided voxel-based dosimetry similar to applied processes established in radiation oncology planning systems. This development presents an opportunity to create dose volume analysis similar to teletherapy and brachytherapy dose delivery for Y-90 therapy. In this case report, we review Y-90 dosimetry on a patient with dual diagnosis of a locally advanced high-risk adenocarcinoma of the prostate which required treatment to the para-aortic lymph nodes located in the same axial plane with renal parenchyma. Although not clinically anticipated, hepatocellular carcinoma was serendipitously discovered at the time of staging for prostate cancer. Treatment dosimetry of the hepatocellular carcinoma is reviewed in retrospect with voxel-based commercial software. Same day SPECT study suggested dose localized to the liver, however voxel planning software confirmed unintentional dose to additional structures including the right kidney and uninvolved liver which influenced radiation therapy treatment planning for prostate carcinoma. With modern available tools, post therapy dosimetry for Y-90 can be performed in a manner similar to volumetric dosimetry used in radiation oncology and provide valuable dose volume analysis of dose delivered to target and additional tissue.

Rabei, R., & Fidelman, N. (2023)

Abstract

The aim of this review is to explore the implications of frailty in the treatment of patients with hepatocellular carcinoma (HCC). Frailty, a multidimensional geriatric syndrome, has been increasingly recognized as an important predictor of adverse outcomes and mortality in various patient populations. This review specifically focuses on the prevalence of frailty in the cirrhotic population and its role as a prognostic tool for procedural and surgical outcomes of transplantation, hepatectomy and liver-directed therapies. Understanding the impact of frailty on HCC treatment can help guide clinicians in optimizing management strategies and improving patient outcomes.

Valle, A. M. B., De Rebouças Carvalho, A. C., Rahme, S., Araujo, A., Malard, P. F., & Brunel, H. D. S. S. (2023)

Abstract

Homeopathy has been increasingly standing out for its proven clinical benefits and for providing a course of treatment with fewer side effects to patients, thus promoting a better quality of life for them. Homeopathic therapy can be used in different contexts and is an additional alternative for treating cancer patients in Integrative Medicine. Within this context, hepatocellular carcinoma has a high mortality rate and, in most cases, is diagnosed in advanced cases. Therefore, this study evaluated the in vitro efficacy of the association of the homeopathic medicines Taraxacum officinale and Lycopodium clavatum against HepG2 cells. For this purpose, cells were grown in 75 cm² flasks and then plated in 96-well plates. The treatment with Taraxacum D4 + Taraxacum D8 + Taraxacum D12 and Taraxacum D5 + Lycopodium D6 at concentrations of 20, 40, and 60 µL/mL was added to each well. After 48 hours of incubation in an oven at 37ºC, 5% CO2, cells were subjected to the cell viability test by MTT. A decrease in viability was observed compared to the control group (cells without treatment). In addition, the medicine Taraxacum officinale was more effective in decreasing cell viability than the other medicines in the three conditions tested. In conclusion, the homeopathic medicine Taraxacum D4 + Taraxacum D8 + Taraxacum D12, in accord of potencies, is promising against hepatocellular carcinoma cells and can be used to aid in the treatment of this type of cancer.

Siddiqui, A., Agrawal, A., Kumar, P., Ghotekar, L., & Taneja, S. (2022)

Abstract

Gluten, in genetically susceptible individuals induces an immune mediated enteropathy called Celiac disease (CD). It is an established cause of malabsorption, with the worldwide prevalence being 1% in the general population. It is found across all age groups, from infants to the elderly with 20% patients being diagnosed in the seventh decade of life. It has varying clinical presentations ranging from silent asymptomatic forms which are diagnosed during screening to life threatening forms with severe malabsorption to atypical presentations, with the symptom spectrum extending beyond the gastrointestinal tract which are more common in adults. High index of suspicion, robust screening and testing, followed by strict adherence to gluten free diet is a must to curb and cure the disease. Patients tend to face difficulties not only during diagnosis, but also with compliance and availability of a gluten free diet, in addition to significant economic and psychosocial burden, which is more predominant in developing countries. Screening of high-risk groups like first-degree relatives of celiac disease, patients with severe malnutrition, other autoimmune diseases, refractory anaemia and irritable bowel syndrome should be done to enhance case detection. In low middle income countries, judicious resource utilisation takes precedence, hence, tackling a multifactorial disease such as celiac disease becomes challenging. Repeated follow ups, awareness among patients and doctors, encouragement, availability of testing and dietary counselling is necessary for management of the disease in such settings. Improving sanitation and feeding practices may also play role in decreasing incidence, considering childhood GI infections are a well-established risk factor. Increased availability of serological tests (IgA/IgG anti-tTG, anti -EMA and anti-DGP), biopsy, genetic testing and other newer modalities under research have improved the diagnostic accuracy. Poor compliance increases the risk of GI malignancy, non-Hodgkin’s lymphoma, Hepatocellular carcinoma and MALToma. Hence adherence is a must to prevent complications. A wide variety of treatment modalities are being evaluated to bring into force alternative strategies for management. Only providing gluten free diet is often not sufficient for improvement of nutritional status in patients with CD. Hence, micronutrient supplementation should also be encouraged to meet the unmet needs.

Manusov, E. G., Diego, V. P., Abrego, E., Herklotz, K., Almeida, M., Mao, X., Laston, S., Blangero, J., & Blangero, S. W. (2023)

Abstract

Non-alcoholic fatty liver disease (NAFLD) encompasses a range of liver conditions, from benign fatty accumulation to severe fibrosis. The global prevalence of NAFLD has risen to 25-30%, with variations across ethnic groups. NAFLD may advance to hepatocellular carcinoma, increases cardiovascular risk, is associated with chronic kidney disease, and is an independent metabolic disease risk factor. Assessment methods for liver health include liver biopsy, magnetic resonance imaging, ultrasound, and vibration-controlled transient elastography (VCTE by FibroScan). Hepatic transaminases are cost-effective and minimally invasive liver health assessment methods options.

This study focuses on the interaction between genetic factors underlying the traits (hepatic transaminases and the FibroScan results) on the one hand and the environment (depression) on the other. We examined 525 individuals at risk for metabolic disorders. We utilized variance components models and likelihood-based statistical inference to examine potential GxE interactions in markers of NAFLD, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and the AST/ALT ratio, and Vibration-Controlled Transient Elastography (VCTE by FibroScan). We calculated the Fibroscan-AST (FAST) score (a score that identifies the risk of progressive non-alcoholic steatohepatitis (NASH) and screened for depression using the Beck Depression Inventory-II (BDI-II). We identified significant G x E interactions for AST/ALT ratio x BDI-II, but not AST, ALT, or the FAST score. Our findings support that genetic factors play a role in hepatic transaminases, especially the AST/ALT ratio, with depression influencing this relationship. These insights contribute to understanding the complex interplay of genetics, environment, and liver health, potentially guiding future personalized interventions.

Hays, P. (2022b)

Abstract

Cancer stems cells are cells in tumors that have self-renewing capabilities and proliferation, and are partly responsible for tumor growth, metastasis and drug resistance, and have been associated with multidrug resistance and epithelial-mesenchymal transition. mRNA stemness index or mRNAsi is a machine learning tool that uses the application of algorithms to find associations between cancer stemness and tumor prognostic signatures. mRNAsi predicts gene mutation status and identifies tumor signaling pathways. Clinical tier grading is a common feature for stratifying the presenting features and symptoms of patients in several diseases. This study is a review article that summarizes studies in lung cancer, gastric cancer, hepatocellular carcinoma and glioblastoma that use mRNA stemness index machine learning tools to identify differentially expressed genes, characterize the tumor microenvironment and tumor mutational burden, and determine clinical endpoints. A prognostic signature is shown in this paper as determined by mRNAsi high and low values, and a clinical tier grading system is proposed that categorizes cancer stemness presenting characteristics. This clinical grading tier system demonstrates a relationship between cancer stemness and immune checkpoint inhibitor efficacy. This type of tiered system for cancer patients and the accompanying workflow proposed may prove useful to oncologists, and has not been performed before, and is unique in the literature.

Ding, L., Sioshansi, S., Yang, G., McIntosh, L., Ruppell, E., Licho, R., Kim, Y., Goldstein, A., Mittal, K., Wang, M., Mehta, S., Foley, K., Smith, K. C., Jodoin, M. B., & FitzGerald, T. (2023b)

Abstract

This paper is a follow-up report concerning a patient treated with Yttrium-90 to a hepatocellular carcinoma. The radiation therapy dose distribution was published as a case report in 2022, https://doi.org/10.18103/mra.v10i11.3379. The hepatic target volume for directed therapy abutted the right kidney and this report provides clinical follow up information on the patient relative to renal function on unintentional radiation renal dose. Yttrium-90 therapy has become an important therapy component for patient care directed to multiple malignancies with emphasis on treating lesions in close proximity to the hepatic parenchyma. The targets are treated with an intra-arterial approach with a goal of applying target directed radiation therapy. Historically, prior to the development of voxel-based dose volume computation software, dose to target was prescribed as activity of isotope delivered with a qualitative assessment of isotope delivery based on images obtained from single positron emission computer tomography. As a qualitative image, single positron emission computer tomography served as an image reference and qualitative surrogate for representing radiation dose. Today, commercial software is available to fuse single positron emission computer tomography images into radiation oncology planning images and calculate dose to volume in a manner similar to how radiation oncology physics dosimetry teams calculate radiation dose to target volume for external therapy and brachytherapy with image guidance. In this particular case, we demonstrated that the proximity of the right kidney to the target resulted in unintentional radiation dose to renal parenchyma evaluated using voxel-based dosimetry. In this report, we review progressive decrease in renal function with blood urea nitrogen/creatinine of 45 and 2.75 respectively with continued normal liver function. Although potentially multi-factorial in origin, the decrease in renal function is at a time point consistent with radiation injury. In this paper we review radiation oncology dose volume constraints for renal tolerance and strategies for patient care moving forward. The goal is to provide additional knowledge of this issue and provide an additional knowledge layer for patient safety with emphasis on improving patient outcomes.

Chen, P., & Han, S. (2022b)

Abstract

Hepatitis B (HBV) in special populations within this article is considered as acute on chronic liver failure due to HBV, coinfection with Hepatitis C (HCV), Hepatitis D (HDV), or Human Immunodeficiency Virus (HIV), and HBV infection in patients who are in immunosuppressive states due to specific therapies and liver transplant recipients. Patients within these special populations are at higher risk of liver-related complications such as fibrosis, accelerated cirrhosis, acute on chronic liver failure, and/or development of hepatocellular carcinoma (HCC). Given their respective complex pathophysiology, specific treatment approaches are required for each population. With the introduction of effective antiviral HBV therapies over the past decade and the respective treatment options for the special population diseases, patient outcomes have seen improvement. With the advent of HCV direct antivirals, treatment of HBV-HCV coinfection has been more successful and consistently shown high rates of sustained virologic response. Treatment of HBV-HDV coinfection remains primarily as interferon-based, though new promising therapies have shown greater improvement in viral suppression. HBV-HIV coinfection has also shown promising results given overlapping mechanisms for treatment and specific regimens should be chosen to decrease risk of resistance. HBV reactivation in patients undergoing immunosuppressive therapies have been reported and guidelines recommend close monitoring and in certain cases, HBV antiviral therapy prophylaxis. With the effective HBV therapies, the perception of HBV as a contraindication for liver transplant has been diminishing and prolonged graft survival with effective antiviral therapies have shown promising outcomes.

Hamdan, A., Omar, A., Salameh, R., & Hani, P. (2023)

Abstract

Cholangiocarcinoma, an adenocarcinoma arising from the epithelium of biliary ducts, is considered the second most common hepatic malignancy after hepatocellular carcinoma with increasing incidence over the past 3 decades. Many imaging modalities with correlation to clinical presentation are used for the diagnosis and staging of cholangiocarcinoma. However, the diagnosis of cholangiocarcinoma is still challenging due to the presence of some benign and malignant conditions that mimic the clinical presentation and radiological findings of this disease. One of those mimics is the condition of intrabiliary hydatid cyst rupture which can cause biliary obstructive symptoms over weeks with radiological findings that may be indistinguishable from those of cholangiocarcinoma and specifically klatskin tumor when found at the bifurcation of the common hepatic duct. In such a confusing situation, the correct preoperative diagnosis and potential treatment of the disease could both be made possible using Endoscopic Retrograde Cholangiopancreatography avoiding unrequired surgical interventions.