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Article ; Online: γδ T Cells: A Game Changer in the Future of Hepatocellular Carcinoma Immunotherapy.

Papadakos, Stavros P / Arvanitakis, Konstantinos / Stergiou, Ioanna E / Koutsompina, Maria-Loukia / Germanidis, Georgios / Theocharis, Stamatios

International journal of molecular sciences

2024 Volume 25, Issue 3

Abstract: Hepatocellular carcinoma (HCC) remains a global health challenge with limited treatment options and a poor prognosis for advanced-stage patients. Recent advancements in cancer immunotherapy have generated significant interest in exploring novel ... ...

Abstract	Hepatocellular carcinoma (HCC) remains a global health challenge with limited treatment options and a poor prognosis for advanced-stage patients. Recent advancements in cancer immunotherapy have generated significant interest in exploring novel approaches to combat HCC. One such approach involves the unique and versatile subset of T cells known as γδ T cells. γδ T cells represent a distinct subset of T lymphocytes that differ from conventional αβ T cells in terms of antigen recognition and effector functions. They play a crucial role in immunosurveillance against various malignancies, including HCC. Recent studies have demonstrated that γδ T cells can directly recognize and target HCC cells, making them an attractive candidate for immunotherapy. In this article, we aimed to explore the role exerted by γδ T cells in the context of HCC. We investigate strategies designed to maximize the therapeutic effectiveness of these cells and examine the challenges and opportunities inherent in applying these research findings to clinical practice. The potential to bring about a revolutionary shift in HCC immunotherapy by capitalizing on the unique attributes of γδ T cells offers considerable promise for enhancing patient outcomes, warranting further investigation.
MeSH term(s)	Humans ; Carcinoma, Hepatocellular/pathology ; Liver Neoplasms/pathology ; Receptors, Antigen, T-Cell, gamma-delta ; T-Lymphocytes ; Immunotherapy
Chemical Substances	Receptors, Antigen, T-Cell, gamma-delta
Language	English
Publishing date	2024-01-23
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25031381
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Article: The Liver Cancer Immune Microenvironment: Emerging Concepts for Myeloid Cell Profiling with Diagnostic and Therapeutic Implications.

Arvanitakis, Konstantinos / Mitroulis, Ioannis / Chatzigeorgiou, Antonios / Elefsiniotis, Ioannis / Germanidis, Georgios

Cancers

2023 Volume 15, Issue 5

Abstract: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide [ ... ]. ...

Abstract	Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide [...].
Language	English
Publishing date	2023-02-28
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15051522
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Article: How Far beyond Diabetes Can the Benefits of Glucagon-like Peptide-1 Receptor Agonists Go? A Review of the Evidence on Their Effects on Hepatocellular Carcinoma.

Arvanitakis, Konstantinos / Koufakis, Theocharis / Kotsa, Kalliopi / Germanidis, Georgios

Cancers

2022 Volume 14, Issue 19

Abstract: Hepatocellular carcinoma (HCC) is characterized by poor survival rate and quality of life, while available treatments remain generally limited. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) originally emerged as drugs for the management of ... ...

Abstract	Hepatocellular carcinoma (HCC) is characterized by poor survival rate and quality of life, while available treatments remain generally limited. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) originally emerged as drugs for the management of diabetes, but have also been shown to alleviate cardiorenal risk. Furthermore, they have demonstrated a wide range of extraglycemic effects that led to their evaluation as potential therapies for a variety of diseases beyond diabetes, such as obesity, neurogenerative disorders and nonalcoholic fatty liver disease. Given the presence of the GLP-1 receptor in hepatocytes, animal data suggest that GLP-1 RAs could regulate molecular pathways that are deeply involved in the genesis and progression of HCC, including inflammatory responses, tumor cell proliferation and oxidative stress, through direct and indirect effects on liver cells. However, future studies must assess several aspects of the benefit-to-risk ratio of the use of GLP-1 RAs in patients with HCC, including co-administration with approved systemic therapies, the incidence of gastrointestinal side effects in a high-risk population, and weight loss management in individuals with poor nutritional status and high rates of cancer cachexia. In this narrative review, we discuss the potential role of GLP-1 analogs in the treatment of HCC, focusing on the molecular mechanisms that could justify a possible benefit, but also referring to the potential clinical implications and areas for future research.
Language	English
Publishing date	2022-09-24
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14194651
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Article: Tumor-Associated Macrophages in Hepatocellular Carcinoma Pathogenesis, Prognosis and Therapy.

Arvanitakis, Konstantinos / Koletsa, Triantafyllia / Mitroulis, Ioannis / Germanidis, Georgios

Cancers

2022 Volume 14, Issue 1

Abstract: Hepatocellular carcinoma (HCC) constitutes a major health burden globally, and it is caused by intrinsic genetic mutations acting in concert with a multitude of epigenetic and extrinsic risk factors. Cancer induces myelopoiesis in the bone marrow, as ... ...

Abstract	Hepatocellular carcinoma (HCC) constitutes a major health burden globally, and it is caused by intrinsic genetic mutations acting in concert with a multitude of epigenetic and extrinsic risk factors. Cancer induces myelopoiesis in the bone marrow, as well as the mobilization of hematopoietic stem and progenitor cells, which reside in the spleen. Monocytes produced in the bone marrow and the spleen further infiltrate tumors, where they differentiate into tumor-associated macrophages (TAMs). The relationship between chronic inflammation and hepatocarcinogenesis has been thoroughly investigated over the past decade; however, several aspects of the role of TAMs in HCC development are yet to be determined. In response to certain stimuli and signaling, monocytes differentiate into macrophages with antitumor properties, which are classified as M1-like. On the other hand, under different stimuli and signaling, the polarization of macrophages shifts towards an M2-like phenotype with a tumor promoting capacity. M2-like macrophages drive tumor growth both directly and indirectly, via the suppression of cytotoxic cell populations, including CD8+ T cells and NK cells. The tumor microenvironment affects the response to immunotherapies. Therefore, an enhanced understanding of its immunobiology is essential for the development of next-generation immunotherapies. The utilization of various monocyte-centered anticancer treatment modalities has been under clinical investigation, selectively targeting and modulating the processes of monocyte recruitment, activation and migration. This review summarizes the current evidence on the role of TAMs in HCC pathogenesis and progression, as well as in their potential involvement in tumor therapy, shedding light on emerging anticancer treatment methods targeting monocytes.
Language	English
Publishing date	2022-01-04
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14010226
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Article ; Online: The effects of sodium-glucose cotransporter 2 inhibitors on hepatocellular carcinoma: From molecular mechanisms to potential clinical implications.

Arvanitakis, Konstantinos / Koufakis, Theocharis / Kotsa, Kalliopi / Germanidis, Georgios

Pharmacological research

2022 Volume 181, Page(s) 106261

Abstract: Hepatocellular carcinoma (HCC) occurs in the setting of prolonged liver inflammation, hepatocyte necrosis and regeneration in patients with cirrhosis. Despite the progress made in the medical management of the disorder during the past decades, the ... ...

Abstract	Hepatocellular carcinoma (HCC) occurs in the setting of prolonged liver inflammation, hepatocyte necrosis and regeneration in patients with cirrhosis. Despite the progress made in the medical management of the disorder during the past decades, the available pharmacological options remain limited, leading to poor survival rates and quality of life for patients with HCC. Sodium-glucose cotransporter 2 inhibitors (SGLT2) originally emerged as drugs for the treatment of hyperglycemia; however, they soon demonstrated important extra-glycemic properties, which led to their evaluation as potential treatments for a wide range of non-metabolic disorders. Evidence from animal studies suggests that SGLT2i have the potential to modulate molecular pathways that affect hallmarks of HCC, including inflammatory responses, cell proliferation, and oxidative stress. The impressive benefits of neurohormonal modulation observed with SGLT2i in congestive heart failure set the stage for human trials in cirrhotic ascites. However, future studies need to evaluate several aspects of the benefit to risk ratio of such a therapeutic strategy, including the co-administration with antineoplastic agents and diuretics, infections, use in hospitalized individuals, renal safety and hypovolemia. In this narrative review, we discuss the putative role of SGLT2i in the treatment of patients with HCC, starting with the mechanisms that could justify a possible benefit and ending with potential clinical implications and areas for future research.
MeSH term(s)	Animals ; Humans ; Blood Glucose ; Carcinoma, Hepatocellular/drug therapy ; Hypoglycemic Agents/therapeutic use ; Liver Neoplasms/drug therapy ; Quality of Life ; Sodium-Glucose Transporter 2 Inhibitors/adverse effects
Chemical Substances	Blood Glucose ; Hypoglycemic Agents ; Sodium-Glucose Transporter 2 Inhibitors
Language	English
Publishing date	2022-05-16
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	1003347-6
ISSN	1096-1186 ; 0031-6989 ; 1043-6618
ISSN (online)	1096-1186
ISSN	0031-6989 ; 1043-6618
DOI	10.1016/j.phrs.2022.106261
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Zs.A 721: Show issues

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Article: Tumor-Associated Neutrophils in Hepatocellular Carcinoma Pathogenesis, Prognosis, and Therapy.

Arvanitakis, Konstantinos / Mitroulis, Ioannis / Germanidis, Georgios

Cancers

2021 Volume 13, Issue 12

Abstract: Hepatocellular carcinoma represents the most prevalent primary liver cancer worldwide, and it is either caused by intrinsic genetic mutations or by a multitude of extrinsic risk factors. Even though the interplay between chronic inflammatory changes and ... ...

Abstract	Hepatocellular carcinoma represents the most prevalent primary liver cancer worldwide, and it is either caused by intrinsic genetic mutations or by a multitude of extrinsic risk factors. Even though the interplay between chronic inflammatory changes and hepatocarcinogenesis has been at the forefront of clinical investigation for the past few decades, the role of tumor-associated neutrophils (TANs) in HCC development still remains ambiguous. On the one hand, N1 TANs exhibit an anti-tumorigenic activity, mediated by direct or indirect tumor cell lysis, whereas on the other hand, N2 TANs have been correlated with increased HCC growth, invasiveness, and metastasis. The association of an elevated Neutrophil-to-Lymphocyte Ratio (NLR) with poor prognosis in patients with HCC, has been recently brought into spotlight, consolidating its widespread use as a reliable biomarker. Due to the decisive involvement of TANs in HCC pathogenesis and development, the utilization of various neutrophil-centered anticancer treatment modalities has been under clinical experimentation, selectively targeting and modulating the processes of neutrophil recruitment, activation, and migration. This review summarizes current evidence on the role of TANs in HCC pathogenesis and progression, as well as in their potential involvement in tumor therapy, shedding light on emerging anticancer treatment methods targeting neutrophils.
Language	English
Publishing date	2021-06-10
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13122899
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Article: Unraveling the Significance of EPH/Ephrin Signaling in Liver Cancer: Insights into Tumor Progression and Therapeutic Implications.

Papadakos, Stavros P / Stergiou, Ioanna E / Gkolemi, Nikolina / Arvanitakis, Konstantinos / Theocharis, Stamatios

Cancers

2023 Volume 15, Issue 13

Abstract: Liver cancer is a complex and challenging disease with limited treatment options and dismal prognosis. Understanding the underlying molecular mechanisms driving liver cancer progression and metastasis is crucial for developing effective therapeutic ... ...

Abstract	Liver cancer is a complex and challenging disease with limited treatment options and dismal prognosis. Understanding the underlying molecular mechanisms driving liver cancer progression and metastasis is crucial for developing effective therapeutic strategies. The EPH/ephrin system, which comprises a family of cell surface receptors and their corresponding ligands, has been implicated in the pathogenesis of HCC. This review paper aims to provide an overview of the current understanding of the role of the EPH/ephrin system in HCC. Specifically, we discuss the dysregulation of EPH/ephrin signaling in HCC and its impact on various cellular processes, including cell proliferation, migration, and invasion. Overall, the EPH/ephrin signaling system emerges as a compelling and multifaceted player in liver cancer biology. Elucidating its precise mechanisms and understanding its implications in disease progression and therapeutic responses may pave the way for novel targeted therapies and personalized treatment approaches for liver cancer patients. Further research is warranted to unravel the full potential of the EPH/ephrin system in liver cancer and its clinical translation.
Language	English
Publishing date	2023-06-30
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15133434
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Article: Adverse pregnancy outcomes in women with celiac disease: a systematic review and meta-analysis.

Arvanitakis, Konstantinos / Siargkas, Antonios / Germanidis, Georgios / Dagklis, Themistoklis / Tsakiridis, Ioannis

Annals of gastroenterology

2022 Volume 36, Issue 1, Page(s) 12–24

Abstract: Background: The aim of this meta-analysis was to evaluate the risk of adverse pregnancy outcomes in women affected with celiac disease (CD), and to further estimate the impact of early disease diagnosis and subsequent adherence to a gluten-free diet ( ... ...

Abstract	Background: The aim of this meta-analysis was to evaluate the risk of adverse pregnancy outcomes in women affected with celiac disease (CD), and to further estimate the impact of early disease diagnosis and subsequent adherence to a gluten-free diet (GFD) on obstetric complications. Methods: A systematic search for English language observational studies was conducted in Medline, Scopus, and the Cochrane Library, from inception till April 2022, to identify relevant studies reporting on the incidence of adverse pregnancy outcomes in women with CD. Odds ratios (OR) and relative risks (RR) with 95% confidence intervals (CIs) were used to combine data from case-control and cohort studies, respectively. The quality of the included studies was assessed using the Newcastle-Ottawa scale. Results: In total, 14 cohort and 4 case-control studies were included and our analysis demonstrated that the risk for spontaneous abortion (RR 1.35, 95%CI 1.10-1.65), fetal growth restriction (RR 1.68, 95%CI 1.34-2.10), stillbirth (RR 1.57, 95%CI 1.17-2.10), preterm delivery (RR 1.29, 95%CI 1.12-1.49), cesarean delivery (RR 1.10, 95%CI 1.03-1.16) and lower mean birthweight (mean difference -176.08, 95%CI -265.79 to -86.38) was significantly higher in pregnant women with CD. The subgroup analysis demonstrated that only undiagnosed CD increased risk for fetal growth restriction, stillbirth, preterm delivery and lower mean birthweight, whereas early diagnosis of CD was not linked to any adverse pregnancy outcomes. Conclusions: Undiagnosed CD is associated with a higher risk of adverse pregnancy outcomes. Early CD diagnosis and appropriate management with GFD may ameliorate these associations.
Language	English
Publishing date	2022-12-08
Publishing country	Greece
Document type	Journal Article
ZDB-ID	2032850-3
ISSN	1108-7471
ISSN	1108-7471
DOI	10.20524/aog.2022.0764
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Zs.A 2455: Show issues

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Article ; Online: Management of type 2 diabetes in patients with compensated liver cirrhosis: Short of evidence, plenty of potential.

Arvanitakis, Konstantinos / Koufakis, Theocharis / Kalopitas, Georgios / Papadakos, Stavros P / Kotsa, Kalliopi / Germanidis, Georgios

Diabetes & metabolic syndrome

2023 Volume 18, Issue 1, Page(s) 102935

Abstract: Background and aims: Treatment of type 2 diabetes (T2D) in patients with compensated cirrhosis is challenging due to hypoglycemic risk, altered pharmacokinetics, and the lack of robust evidence on the risk/benefit ratio of various drugs. Suboptimal ... ...

Abstract	Background and aims: Treatment of type 2 diabetes (T2D) in patients with compensated cirrhosis is challenging due to hypoglycemic risk, altered pharmacokinetics, and the lack of robust evidence on the risk/benefit ratio of various drugs. Suboptimal glycemic control accelerates the progression of cirrhosis, while the frequent coexistence of nonalcoholic fatty liver disease (NAFLD) with T2D highlights the need for a multifactorial therapeutic approach. Methods: A literature search was performed in Medline, Google Scholar and Scopus databases till July 2023, using relevant keywords to extract studies regarding the management of T2D in patients with compensated cirrhosis. Results: Metformin, sodium-glucose co-transporter-2 inhibitors (SGLT2i), and glucagon-like peptide-1 receptor agonists (GLP-1 RA) are promising treatment options for patients with T2D and compensated liver cirrhosis, offering good glycemic control with minimal risk of hypoglycemia, while their pleiotropic actions confer benefits on NAFLD and body weight, and decrease cardiorenal risk. Sulfonylureas cause hypoglycemia, thus should be avoided, while in specific studies, dipeptidyl peptidase-4 inhibitors have been correlated with increased risk of decompensation and variceal bleeding. Despite the benefits of thiazolidinediones in nonalcoholic steatohepatitis, concerns about edema and weight gain limit their use in compensated cirrhosis. Insulin does not exert hepatotoxic effects and can be administered safely in combination with other drugs; however, the risk of hypoglycemia should be considered. Conclusions: The introduction of new hepatoprotective diabetes drugs into clinical practice, including tirzepatide, SGLT2i, and GLP-1 RA, sets the stage for future trials to investigate the ideal therapeutic regimen for people with T2D and compensated cirrhosis.
MeSH term(s)	Humans ; Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 2/drug therapy ; Diabetes Mellitus, Type 2/chemically induced ; Non-alcoholic Fatty Liver Disease/complications ; Non-alcoholic Fatty Liver Disease/drug therapy ; Esophageal and Gastric Varices/chemically induced ; Esophageal and Gastric Varices/complications ; Esophageal and Gastric Varices/drug therapy ; Gastrointestinal Hemorrhage/chemically induced ; Gastrointestinal Hemorrhage/complications ; Gastrointestinal Hemorrhage/drug therapy ; Hypoglycemic Agents/therapeutic use ; Sodium-Glucose Transporter 2 Inhibitors/therapeutic use ; Hypoglycemia/chemically induced ; Liver Cirrhosis/complications ; Liver Cirrhosis/drug therapy ; Glucagon-Like Peptide 1 ; Glucagon-Like Peptide-1 Receptor
Chemical Substances	Hypoglycemic Agents ; Sodium-Glucose Transporter 2 Inhibitors ; Glucagon-Like Peptide 1 (89750-14-1) ; Glucagon-Like Peptide-1 Receptor
Language	English
Publishing date	2023-12-28
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2273766-2
ISSN	1878-0334 ; 1871-4021
ISSN (online)	1878-0334
ISSN	1871-4021
DOI	10.1016/j.dsx.2023.102935
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Article: Pathophysiology and Clinical Management of Dyslipidemia in People Living with HIV: Sailing through Rough Seas.

Papantoniou, Eleni / Arvanitakis, Konstantinos / Markakis, Konstantinos / Papadakos, Stavros P / Tsachouridou, Olga / Popovic, Djordje S / Germanidis, Georgios / Koufakis, Theocharis / Kotsa, Kalliopi

Life (Basel, Switzerland)

2024 Volume 14, Issue 4

Abstract: Infections with human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) represent one of the greatest health burdens worldwide. The complex pathophysiological pathways that link highly active antiretroviral therapy (HAART) and ... ...

Abstract	Infections with human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) represent one of the greatest health burdens worldwide. The complex pathophysiological pathways that link highly active antiretroviral therapy (HAART) and HIV infection per se with dyslipidemia make the management of lipid disorders and the subsequent increase in cardiovascular risk essential for the treatment of people living with HIV (PLHIV). Amongst HAART regimens, darunavir and atazanavir, tenofovir disoproxil fumarate, nevirapine, rilpivirine, and especially integrase inhibitors have demonstrated the most favorable lipid profile, emerging as sustainable options in HAART substitution. To this day, statins remain the cornerstone pharmacotherapy for dyslipidemia in PLHIV, although important drug-drug interactions with different HAART agents should be taken into account upon treatment initiation. For those intolerant or not meeting therapeutic goals, the addition of ezetimibe, PCSK9, bempedoic acid, fibrates, or fish oils should also be considered. This review summarizes the current literature on the multifactorial etiology and intricate pathophysiology of hyperlipidemia in PLHIV, with an emphasis on the role of different HAART agents, while also providing valuable insights into potential switching strategies and therapeutic options.
Language	English
Publishing date	2024-03-28
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662250-6
ISSN	2075-1729
ISSN	2075-1729
DOI	10.3390/life14040449
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