IntroductionWith recent expansion of oral small molecule inhibitors, the drug development studies need to provide insight into optimal dose selection for these agents with vastly different mechanism and pharmacokinetic considerations compared to our traditional chemotherapy agents. Currently there is one published meta-analysis that examines intermittent and alternative dosing of oral small molecule inhibitors and it is unclear what guidance is available for treatment personalization beyond package insert labeling for patients undergoing toxicities from treatment.MethodsA systematic review of oral small molecule inhibitors with intermittent dosing was conducted in the National Library of Medicine PubMed database. Studies were selected based on predefined inclusion/exclusion criteria. Data was extracted to summarize findings on available guidance for intermittent or alternative dosing of oral small molecule inhibitors. Studies were categorized based on food and drug administration (FDA) approved or non-FDA approved agents, and further characterized by comparison of different dosing schemas.ResultsFifty-five trials were included in the final review and data analysis. Thirty-three trials were phase 1 trials, 26 trials for FDA approved agents and 29 non-FDA approved agents. Most trials reported on agents used in solid tumors, particularly renal cell carcinoma, with most trials examining sunitinib. Of the 55 trials, 28 compared different dosing strategies with 26 of the 28 trials examining efficacy outcomes with 27 of the 28 trials examining safety outcomes.ConclusionsThis systematic review found limited guidance for clinicians in optimizing dosing for intermittently dosed oral small molecule inhibitors.

Liver cancer is a global health challenge, causing a significant social-economic burden. Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer, which is highly heterogeneous in terms of molecular and cellular signatures. Early-stage or small tumors are typically treated with surgery or ablation. Currently, chemotherapies and immunotherapies are the best treatments for unresectable tumors or advanced HCC. However, drug response and acquired resistance are not predictable with the existing systematic guidelines regarding mutation patterns and molecular biomarkers, resulting in sub-optimal treatment outcomes for many patients with atypical molecular profiles. With advanced technological platforms, valuable information such as tumor genetic alterations, epigenetic data, and tumor microenvironments can be obtained from liquid biopsy. The inter- and intra-tumoral heterogeneity of HCC are illustrated, and these collective data provide solid evidence in the decision-making process of treatment regimens. This article reviews the current understanding of HCC detection methods and aims to update the development of HCC surveillance using liquid biopsy. Recent critical findings on the molecular basis, epigenetic profiles, circulating tumor cells, circulating DNAs, and omics studies are elaborated for HCC diagnosis. Besides, biomarkers related to the choice of therapeutic options are discussed. Some notable recent clinical trials working on targeted therapies are also highlighted. Insights are provided to translate the knowledge into potential biomarkers for detection and diagnosis, prognosis, treatment response, and drug resistance indicators in clinical practice.

Hepatocellular carcinoma (HCC) is the deadliest emergent health issue around the globe. The stronger oncogenic effect, proteins, and weakened immune response are precisely linked with a significant prospect of developing HCC. Several conventional systemic therapies, antiangiogenic therapy, and immunotherapy techniques have significantly improved the outcomes for early-, intermediate-, and advanced-stage HCC patients, giving new hope for effective HCC management and prolonged survival rates. Innovative therapeutic approaches beyond conventional treatments have altered the landscape of managing HCC, particularly focusing on targeted therapies and immunotherapies. The advancement in HCC treatment suggested by the Food and Drug Administration is multidimensional treatment options, including multikinase inhibitors (sorafenib, lenvatinib, regorafenib, ramucirumab, and cabozantinib) and immune checkpoint inhibitors (atezolizumab, pembrolizumab, durvalumab, tremelimumab, ipilimumab, and nivolumab), in monotherapy and in combination therapy to increase life expectancy of HCC patients. This review highlights the efficacy of multikinase inhibitors and immune checkpoint inhibitors in monotherapy and combination therapy through the analysis of phase II, and III clinical trials, targeting the key molecular pathways involved in cellular signaling and immune response for the prospective treatment of advanced and unresectable HCC and discusses the upcoming combinations of immune checkpoint inhibitors-tyrosine kinase inhibitors and immune checkpoint inhibitors-vascular endothelial growth factor inhibitors. Finally, the hidden challenges with pharmacological therapy for HCC, feasible solutions for the future, and implications of possible presumptions to develop drugs for HCC treatment are reported.

Hepatocellular carcinoma (HCC) is a high mortality neoplasm which usually appears on a cirrhotic liver. The therapeutic arsenal and subsequent prognostic outlook are intrinsically linked to the HCC stage at diagnosis. Notwithstanding the current deployment of treatments with curative intent (liver resection/local ablation and liver transplantation) in early and intermediate stages, a high rate of HCC recurrence persists, underscoring a pivotal clinical challenge. Emergent systemic therapies (ST), particularly immunotherapy, have demonstrate promising outcomes in terms of increase overall survival, but they are currently bound to the advanced stage of HCC. This review provides a comprehensive analysis of the literature, encompassing studies up to March 10, 2024, evaluating the impact of novel ST in the early and intermediate HCC stages, specially focusing on the findings of neoadjuvant and adjuvant regimens, aimed at increasing significantly overall survival and recurrence-free survival after a treatment with curative intent. We also investigate the potential role of ST in enhancing the downstaging rate for the intermediate-stage HCC initially deemed ineligible for treatment with curative intent. Finally, we critically discuss about the current relevance of the results of these studies and the encouraging future implications of ST in the treatment schedules of early and intermediate HCC stages.

Immune-oncology-based regimens have shown efficacy in advanced HCC and have been implemented as standard of care as first-line therapy. Their efficacy, including high response rates, and safety justify their evaluation in earlier disease stages. Following negative results for adjuvant sorafenib in the global STORM trial in 2015, 4 global phase 3 trials, featuring different immune checkpoint inhibitor combinations, entered in parallel the race in the adjuvant setting. The IMbrave050 trial, comparing adjuvant atezolizumab in combination with bevacizumab to active surveillance following curative-intent resection or ablation, was the first to report, fast-tracking the results of the first interim analysis and demonstrating an improvement in recurrence-free survival. The trial has provoked a discussion on the horizon of expectations from adjuvant treatment and the clinical relevance of efficacy endpoints. Moreover, major pathological responses reported from early phase 2 data in the neoadjuvant setting provide a strong rationale for the evaluation of these concepts in phase 3 trials. In this review, we summarize current evidence and outline future directions for systemic therapies in early-stage HCC.

Recent scientific interest has been directed towards age-related diseases, driven by the significant increase in global life expectancy and the growing population of individuals aged 65 and above. The ageing process encompasses various biological, physiological, environmental, psychological, behavioural, and social changes, leading to an augmented susceptibility to chronic illnesses. Cardiovascular, neurological, musculoskeletal, liver and oncological diseases are prevalent in the elderly. Moreover, ageing individuals demonstrate reduced regenerative capacity and decreased tolerance towards therapeutic interventions, including organ transplantation. Liver diseases, such as non-alcoholic fatty liver disease, alcoholic liver disease, hepatitis, fibrosis, and cirrhosis, have emerged as significant public health concerns. Paradoxically, these conditions remain underestimated despite their substantial global impact. Age-related factors are closely associated with the severity and unfavorable prognosis of various liver diseases, warranting further investigation to enhance clinical management and develop novel therapeutic strategies. This comprehensive review focuses specifically on age-related liver diseases, their treatment strategies, and contemporary practices. It provides a detailed account of the global burden, types, molecular mechanisms, and epigenetic alterations underlying these liver pathologies.

Multi-target inhibitors represent useful anticancer agents with superior therapeutic attributes. Here in, two novel series of benzimidazole-triazole hybrids were designed, synthesised as multi-target EGFR, VEGFR-2 and Topo II inhibitors, and evaluated for anticancer activity. Compounds 5a and 6g were the most potent analogues against four cancer cell lines, HepG-2, HCT-116, MCF-7 and HeLa, and were further evaluated for EGFR, VEGFR-2, and Topo II inhibition. Compound 5a was especially good inhibitor for EGFR (IC₅₀ = 0.086 µM) compared to Gefitinib (IC₅₀ = 0.052 µM), moderate VEGFR-2 inhibitor (IC₅₀ = 0.107 µM) compared to Sorafenib (IC₅₀ = 0.0482 µM), and stronger Topo II inhibitor (IC₅₀ = 2.52 µM) than Doxorubicin (IC₅₀ = 3.62 µM). Compound 6g exhibited moderate EGFR and VEGFR-2 inhibition and weaker Topo II inhibition. DNA binding assay, cell cycle analysis, apoptotic induction, molecular docking, and physicochemical studies were additionally implemented to explore the plausible mechanism of the active compounds.

Most cases of hepatocellular carcinoma (HCC) are able to be diagnosed through regular surveillance in an identifiable patient population with chronic hepatitis B or cirrhosis. Nevertheless, 50% of global cases might present incidentally owing to symptomatic advanced-stage HCC after worsening of liver dysfunction. A systematic search based on PUBMED was performed to identify relevant outcomes, covering newer surveillance modalities including secretory proteins, DNA methylation, miRNAs, and genome sequencing analysis which proposed molecular expression signatures as ideal tools in the early-stage HCC detection. In the face of low accuracy without harmonization on the analytical approaches and data interpretation for liquid biopsy, a more accurate incidence of HCC will be unveiled by using deep machine learning system and multiplex immunohistochemistry analysis. A combination of molecular-secretory biomarkers, high-definition imaging and bedside clinical indexes in a surveillance setting offers a comprehensive range of HCC potential indicators. In addition, the sequential use of numerous lines of systemic anti-HCC therapies will simultaneously benefit more patients in survival. This review provides an overview on the most recent developments in HCC theranostic platform.

There are five fibroblast growth factor receptors (FGFRs), namely, FGFR1-FGFR5. When FGFR binds to its ligand, namely, fibroblast growth factor (FGF), it dimerizes and autophosphorylates, thereby activating several key downstream pathways that play an important role in normal physiology, such as the Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase, phosphoinositide 3-kinase (PI3K)/AKT, phospholipase C gamma/diacylglycerol/protein kinase c, and signal transducer and activator of transcription pathways. Furthermore, as an oncogene, FGFR genetic alterations were found in 7.1% of tumors, and these alterations include gene amplification, gene mutations, gene fusions or rearrangements. Therefore, FGFR amplification, mutations, rearrangements, or fusions are considered as potential biomarkers of FGFR therapeutic response for tyrosine kinase inhibitors (TKIs). However, it is worth noting that with increased use, resistance to TKIs inevitably develops, such as the well-known gatekeeper mutations. Thus, overcoming the development of drug resistance becomes a serious problem. This review mainly outlines the FGFR family functions, related pathways, and therapeutic agents in tumors with the aim of obtaining better outcomes for cancer patients with FGFR changes. The information provided in this review may provide additional therapeutic ideas for tumor patients with FGFR abnormalities.

Vascular endothelial growth factors (VEGFs) are the key regulators of vasculogenesis in normal and oncological development. VEGF-A is the most studied angiogenic factor secreted by malignant tumor cells under hypoxic and inflammatory stress, which made VEGF-A a rational target for anticancer therapy. However, inhibition of VEGF-A by monoclonal antibody drugs led to the upregulation of VEGF-D. VEGF-D was primarily described as a lymphangiogenic factor; however, VEGF-D's blood angiogenic potential comparable to VEGF-A has already been demonstrated in glioblastoma and colorectal carcinoma. These findings suggested a role for VEGF-D in facilitating malignant tumor growth by bypassing the anti-VEGF-A antiangiogenic therapy. Owing to its high mitogenic ability, higher affinity for VEGFR-2, and higher expression in cancer, VEGF-D might even be a stronger angiogenic driver and, hence, a better therapeutic target than VEGF-A. In this review, we summarized the angiogenic role of VEGF-D in blood vasculogenesis and its targetability as an antiangiogenic therapy in cancer.

Hepatocellular carcinoma (HCC) is an exceedingly prevalent malignancy with an exceptionally poor prognosis. Targeted therapy is an effective treatment option for patients with advanced HCC. However, there have been no bibliometric analyses of targeted therapies for HCC.

This study aimed to assess the current status and future directions of targeted therapy for HCC to provide future scholars with clearer research contents and popular themes. Methods: Literature on targeted therapy for HCC from 2008 to 2022 was obtained from the Web of Science (WoS) and assessed using bibliometric methodology. Additionally, the VOS viewer was applied in the visualization study to conduct bibliographic coupling, co-authorship, co-citation, and co-occurrence analyses of publications.

A total of 10,779 papers were subsequently selected. Over the past 15 years, there has been a progressive increase in the number of publications on an annualized basis. China released the most publications in the field, whereas the United States had the highest H-index. Cancers published the most papers. Fudan University had the greatest sway in this area. Studies could be divided into 5 clusters: "Gene and expression research," "Mechanism study," "Nanoparticle study," "Targeted drug research," and "Clinical study."

In the upcoming years, more papers on targeted therapy for HCC are expected to be released, demonstrating the potential for this topic to flourish. Particularly, "Clinical study" is the following trendy topic in this field. Other research subfields may likewise exhibit a continuous tendency towards balanced development.

The burden of hepatocellular carcinoma (HCC) continues to pose a significant global health problem. Several systemic therapies have recently been shown to improve survival for patients with unresectable disease. However, evidence to support the use of neoadjuvant or adjuvant systemic therapies in patients with resectable disease is limited, despite the high risk of recurrence. Neoadjuvant and adjuvant systemic therapies are being investigated for their potential to reduce recurrence after resection and improve overall survival. Our review identified various early-phase clinical trials showing impressive preliminary signals of pathologic complete response in resectable disease, and others suggesting that neoadjuvant therapies-particularly when combined with adjuvant strategies-may convert unresectable disease to resectable disease and cause significant tumor necrosis, potentially decreasing recurrence rates. The role of adjuvant therapies alone may also play a part in the management of these patients, particularly in reducing recurrence rates. Heterogeneity in trial design, therapies used, patient selection, and a scarcity of randomized phase III trials necessitate the cautious implementation of these treatment strategies. Future research is required to identify predictive biomarkers, optimize the timing and type of therapeutic combinations, and minimize treatment-related adverse effects, thereby personalizing and enhancing treatment strategies for patients with resectable and borderline resectable HCC.

Despite maximizing techniques and patient selection, liver resection and ablation for HCC are still associated with high rates of recurrence. To date, HCC is the only cancer with no proven adjuvant or neoadjuvant therapy used in association to potentially curative treatment. Perioperative combination treatments are urgently needed to reduce recurrence rates and improve overall survival. Immunotherapy has demonstrated encouraging results in the setting of adjuvant and neoadjuvant treatments for non-hepatic malignancies. Conclusive data are not yet available in the context of liver neoplasms. However, growing evidence suggests that immunotherapy, and in particular immune checkpoint inhibitors, could represent the cornerstone of an epochal change in the treatment of HCC, improving recurrence rates and overall survival through combination treatments. Furthermore, the identification of predictive biomarkers of treatment response could drive the management of HCC into the era of a precision medicine. The purpose of this review is to analyze the state of the art in the setting of adjuvant and neoadjuvant therapies for HCC in association with loco-regional treatments in patients not eligible for liver transplantation and to hypothesize future scenarios.

Hepatocellular carcinoma (HCC) is a primary liver tumor that typically occurs in the setting of chronic liver disease/cirrhosis. Treatment modalities for HCC have evolved and given the variety of treatment options, a multi-disciplinary approach requiring input from surgical, medical, and radiation oncology, hepatology, and interventional radiology is necessary. Multiple advances have been made over the last decade regarding treatment of HCC, especially advanced disease. Resection and transplantation remain as cornerstone curative-intent treatment options. For patients who are not candidates for curative-intent therapy, exciting progress has been made in molecular and cellular approaches to systemic therapy for HCC including immunotherapies and tyrosine kinase inhibitors. Although the prognosis for advanced HCC remains poor, the armamentarium of therapies has increased, and valuable years of life can be gained with these therapies. While the main therapeutic modality for early-stage disease remains resection, multimodal immunotherapy has emerged as first-line treatment for advanced disease. We herein review different clinical and molecular treatment modalities related to the treatment of HCC, as well as provide insights into future directions for HCC treatment. We highlight how research and progress are needed to move into a new era of molecular and cellular treatments.

Hepatocellular carcinoma (HCC) remains one of the most common malignancies and the third cause of cancer-related death worldwide, with surgery being the best prognostic tool. Among the well-known causative factors of HCC are chronic liver virus infections, chronic virus hepatitis B (HBV) and chronic hepatitis virus C (HCV), aflatoxins, tobacco consumption, and non-alcoholic liver disease (NAFLD). There is a need for the development of efficient molecular markers and alternative therapeutic targets of great significance. In this review, we describe the general characteristics of HCC and present a variety of targeted therapies that resulted in progress in HCC therapy.

Angiogenesis forms new vessels from existing ones. Abnormal angiogenesis, which is what gives tumor microenvironments their distinctive features, is characterised by convoluted, permeable blood vessels with a variety of shapes and high perfusion efficiency. Tumor angiogenesis controls cancer growth by allowing invasion and metastasis and is highly controlled by signalling networks. Therapeutic techniques targeting VEGF, PDGF, FGF Notch, Angiopoietin, and HGF signalling restrict the tumor's vascular supply. Numerous pathways regulate angiogenesis, and when one of those processes is blocked, the other pathways may step in to help. VEGF signalling inhibition alone has limits as an antiangiogenic therapy, and additional angiogenic pathways such as FGF, PDGF, Notch, angiopoietin, and HGF are important. For the treatment of advanced solid tumors, there are also new, emerging medicines that target multiple angiogenic pathways. Recent therapies block numerous signalling channels concurrently. This study focuses on 'alternative' methods to standard antiangiogenic medicines, such as cyclooxygenase-2 blocking, oligonucleotide binding complementary sites to noncoding RNAs to regulate mRNA target, matrix metalloproteinase inhibition and CRISPR/Cas9 based gene edition and dissecting alternative angiogenesis mechanism in tumor microenvironment.

Dovitinib has been investigated as an anti-tumor drug due to its ability to inhibit multiple receptor tyrosine kinases. Dovitinib free base has a poor water solubility leading to poor absorption. Salts and lipid-based formulations have been used to improve drug availability. Here, we investigated the physiochemical properties of the dovitinib free base in the presence of some pharmaceutical excipients. We sought to study the effect of acidic counterions on the aqueous solubility and lipophilicity of dovitinib and how pH, buffer species, and cyclodextrin (CD) influenced dovitinib stability. pH-solubility studies were performed by titration against five different acids. Aqueous solubility of dovitinib salt depended on the counterion. Lactic acid greatly increased the aqueous solubility of dovitinib. The counterion effect on the solubility was also investigated in the aqueous complexing media. Unexpected synergistic solubilization was found with γ-CD/phosphoric acid and γ-CD/maleic acid. The counterion did not affect the lipophilicity of dovitinib at physiological pH. Accelerated degradation of dovitinib was carried out at high temperature. Stability was studied across a range of pH values, buffer species and in the presence of two CDs. Dovitinib was most stable at pH 4 in the phosphate buffer species. γ-CD stabilized the drug at relatively low pH.