Search Results (170)

Histotripsy is a novel, noninvasive, non-thermal technology invented in 2004 for the precise destruction of biologic tissue. It offers a powerful alternative to more conventional thermal or surgical interventions. Using short-pulse, low-duty cycle ultrasonic waves, histotripsy creates cavitation bubble clouds that selectively and precisely destroy targeted tissue in a predefined volume while sparing critical structures like bile ducts, ureters, and blood vessels. Such precision is of value when treating tumors near vital structures. The FDA has cleared histotripsy for the treatment of all liver tumors. Major medical centers are currently spearheading clinical trials, and some institutions have already integrated the technology into patient care. Histotripsy is now being studied for a host of other cancers, including primary kidney and pancreatic tumors. Preclinical murine and porcine models have already revealed promising outcomes. One of histotripsy’s primary advantages is its non-thermal mechanical actuation. This feature allows it to circumvent the limitations of heat-based techniques, including the heat sink effect and unpredictable treatment margins near sensitive tissues. In addition to its non-invasive ablative capacities, it is being preliminarily explored for its potential to induce immunomodulation and promote abscopal inhibition of distant, untreated tumors through CD8+ T cell responses. Thus, it may provide a multilayered therapeutic effect in the treatment of cancer. Histotripsy has the potential to improve precision and outcomes across a multitude of specialties, from oncology to cardiovascular medicine. Continued trials are crucial to further expand its applications and validate its long-term efficacy. Due to the speed of recent developments, the goal of this review is to provide a comprehensive and updated overview of histotripsy. It will explore its physics-based mechanisms, differentiating it from similar technologies, discuss its clinical applications, and examine its advantages, limitations, and future. Full article

A young adult patient presented to the gastrointestinal outpatient department with a suspected hepatic tumor. The patient was in a traffic accident ten years ago and underwent splenectomy and distal pancreatectomy at another medical institution. The physical examination was unremarkable. The liver function tests and tumor markers were within normal limits, with the alpha-fetoprotein level at 1.38 ng/mL. Both hepatitis B surface antigen and anti-HCV were negative. Based on the clinical history, intrahepatic splenosis was suspected first. Dynamic computed tomography revealed a 2.3 cm lesion exhibiting suspicious early wash-in and early wash-out enhancement patterns. As previous studies have reported, this finding makes hepatocellular carcinoma and metastatic lesions the major differential diagnoses. For further evaluation, dynamic magnetic resonance imaging was performed, and similar enhancing features were observed, along with restricted diffusion. As hepatocellular carcinoma still could not be confidently ruled out, the patient underwent an ultrasound-guided biopsy. The diagnosis of intrahepatic splenosis was confirmed by the pathologic examination. Intrahepatic splenosis is a rare condition defined as an acquired autoimplantation of splenic tissue within the hepatic parenchyma. Diagnosis can be challenging due to its ability to mimic liver tumors in imaging studies. Therefore, in patients with a history of splenic trauma and/or splenectomy, a high index of suspicion and awareness is crucial for accurate diagnosis and for prevention of unnecessary surgeries or interventions. Full article

Background: Transarterial radioembolization (TARE) with Yttrium-90 microspheres is an established therapy for unresectable hepatocellular carcinoma (HCC). However, its clinical efficacy compared to transarterial chemoembolization (TACE) remains unclear. Methods: We retrospectively reviewed 279 consecutive patients undergoing TARE (n = 104) or TACE (n = 175) at four tertiary centers. Patients with metastatic disease, locally advanced HCC, or Child–Pugh (CP) C were excluded. Data on treatment, adverse events, survival outcomes (median overall survival [mOS], and objective response rates [by modified Response Evaluation Criteria in Solid Tumors; mRECIST]) were collected. Results: The median follow-up of the cohort was 27 months (IQR 13–50), the mean age was 67.6 ± 10.1 years, and 207 (74.2%) were male. The cohort was balanced in age, performance status, CP class, and HCC etiology. Maximum tumor diameter was significantly larger in the TARE cohort compared to the TACE cohort (4.4 vs. 3.1 cm, p < 0.001), including within the BCLC 0/A (4.2 vs. 2.7 cm, p = 0.001) and BCLC B (5.0 vs. 4.0 cm, p = 0.049) subgroups. The mOS was longer with TACE (37 vs. 22 months; hazard ratio [HR] 1.65, 95% CI: 1.19–2.29, p = 0.002). In BCLC 0/A patients, TACE yielded longer mOS (60 vs. 25 months; HR 2.35, 95% CI: 1.17–4.69; p = 0.016). In BCLC B, mOS was longer with TACE (32 vs. 20 months), but was not statistically significant (HR 1.39, 95% CI: 0.96–2.03, p = 0.080). In BCLC 0/A, complete response rates were higher with TACE (43.2% vs. 34.3%, p = 0.012). Hepatic decompensation was more frequent with TARE- (26.0%) than with TACE-treated patients (13.7%, p = 0.010). Conclusions: TACE demonstrated superior survival outcomes over TARE, particularly in early-stage disease. These results advocate for a more nuanced selection of embolization therapies in these patients. Full article

Hepatocellular carcinoma (HCC) remains a major clinical challenge due to its high recurrence rate and limited response to monotherapies, such as sorafenib—the standard first-line therapy for advanced HCC. This is partly attributed to its cellular heterogeneity. Increasing evidence implies SRC family kinase (SFK) activation in HCC progression, highlighting the potential of SRC-targeted therapies. In this study, we observed that SRC and YES1 were significantly upregulated in clinical HCC specimens compared to its adjacent non-tumoral tissues (p < 0.001), suggesting relevance as therapeutic targets. High SRC expression was noticed in patients with poor prognosis, as confirmed in TCGA cohort. To evaluate the efficacy of dual targeting, we assessed the combination between SRC inhibitors, saracatinib and dasatinib, with sorafenib in six hepatic cell models, representing both S1 and S2 subtypes. Cytotoxicity assays demonstrated reduced cell viability with the combination therapies compared to either monotherapy, irrespective of the HCC subtype. Wound healing and Transwell migration assays revealed inhibition of cell migration and invasion following combination treatment, underscoring its potential to suppress metastatic behavior. RT-qPCR analysis further confirmed downregulation of the expression of MMP2 and MMP9, genes associated with HCC cell invasion. Additionally, combined therapies decreased VEGFA and HIF1A expression compared to sorafenib alone, suggesting a potential to counteract the adaptive resistance mechanisms of cells to sorafenib. In summary, the combination of SFK inhibitors with sorafenib significantly enhances anti-tumor activity, offering a promising strategy to address HCC cellular heterogeneity and improve treatment efficacy. Full article

Hepatocellular carcinoma is the most common primary liver tumor and is strongly related to underlying liver cirrhosis. Common etiologies include viral hepatitis, elevated alcohol consumption and metabolic diseases, all of which result in liver inflammation and scarring. Previously, systemic therapies for locally advanced or metastatic disease were limited to tyrosine kinase inhibitors with poor efficacy and rare cures. Recent advances have harnessed the power of the immune system to combat disease, resulting in improved outcomes and occasional cures. Here, we describe the recent clinical trials in immunotherapies for the treatment of hepatocellular carcinoma as first- and second-line therapies and in combination with other drug classes. Full article

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with metastasis representing a pivotal factor in poor prognosis and high fatality rates. This review offers a comprehensive examination of the key molecular events and regulatory mechanisms driving HCC metastasis, with a particular focus on genetic mutations, epigenetic alterations, and dysregulated signaling pathways. Special emphasis is placed on the role of three-dimensional genome structural remodeling in HCC initiation and metastatic progression. Additionally, the latest advances in targeted therapies for advanced HCC are summarized, including both first-line and second-line treatments, highlighting their impact on controlling metastatic disease. The review also examines a variety of potential biomarkers linked to HCC metastasis, including circulating tumor cells, circulating tumor DNA, and exosomal contents, all of which demonstrate significant promise for the early detection, diagnosis, and therapeutic monitoring of HCC metastasis. By bridging molecular insights with clinical applications, this review provides valuable perspectives to guide future research in the diagnosis and treatment of HCC metastasis. Full article

Liver malignancies, both primary and metastatic tumors, are a major cause of cancer-related mortality. Colorectal cancer alone results in liver metastases in nearly 50% of patients, with approximately 85% presenting with unresectable disease. Similarly, hepatocellular carcinoma and intrahepatic cholangiocarcinoma frequently present at advanced stages, limiting curative options. Systemic therapies provide modest survival benefits, underscoring the need for alternative treatments. Locoregional approaches, such as thermal ablation and chemoembolization, while effective, have notable limitations, including invasiveness, peri-procedural risks, and the requirement to interrupt systemic treatments. Histotripsy is a novel, non-invasive method that uses focused ultrasound-induced cavitation to enable precise tumor ablation without heat or radiation. Our institution utilizes a multidisciplinary tumor board approach to evaluate patients for histotripsy, particularly in cases involving unresectable disease, complex surgical candidacy, palliative intent related to disease control and symptom management, or as bridging therapy for transplantation. Early results, including preclinical data and the THERESA and #HOPE4LIVER trials, highlight its efficacy in treating liver tumors with minimal complications. This review outlines institutional protocols for histotripsy, covering pre- and post-procedural management, along with ethical considerations of current treatment paradigms. As a patient-centered approach, histotripsy offers a novel treatment option with a favorable safety profile and compatibility with systemic therapies. Full article

Transplant oncology integrates a wide variety of fields, such as surgery, oncology, and transplant medicine, intending to increase the range of studies and treatments for hepatobiliary cancers and other liver-related malignant lesions. Liver transplantation (LT) has proven to be an effective treatment for hepatocellular carcinoma. While the Milan criteria are still the gold standard, several new, more inclusive criteria have been proposed, and hepatocellular carcinoma has become a major indication for liver transplantation. The continuous evolution of diagnostic technologies supported this with higher image quality and more accurate staging. This review describes the current applications of transplant oncology in hepatocellular carcinoma, cholangiocarcinoma, neuroendocrine tumors, and liver metastatic disease from colorectal cancer and discusses the path that led to the development of transplant oncology as an organized approach to managing gastrointestinal malignancies through transplantation. More importantly, the significance of a multidisciplinary approach and criteria in the selection of suitable candidates are discussed. In addition, newer aspects of transplant oncology, such as immunotherapy, circulating tumor DNA (ctDNA), novel surgical techniques, and the utilization of artificial intelligence, are presented. Finally, the opportunities and challenges involved in the field’s future, as well as the evolution of the criteria used over the years and insightful thoughts for the future of the criteria, are discussed. Full article

Transforming growth factor-beta (TGF-β) plays a dual role in hepatocellular carcinoma (HCC), acting as a tumor suppressor in early stages by inducing cell cycle arrest and apoptosis, and as a promoter in advanced stages by fostering tumor progression, epithelial–mesenchymal transition (EMT), and metastasis. Understanding TGF-β’s role in HCC progression, particularly its impact on tumor–stroma interactions, is crucial for developing personalized therapies. This study aims to clarify TGF-β function in HCC using patient-derived cell lines and advanced 2D and 3D culture models. Three new cell lines (HLC21, HLC19 tumoral, and HLC19 metastatic) were isolated from HCC patient biopsies, characterizing their phenotypic markers and responses to TGF-β and its inhibitor, galunisertib. HLC21 cells displayed a mixed epithelial–mesenchymal phenotype, responding to TGF-β suppressing growth and undergoing EMT, which were inhibited by galunisertib. Conversely, HLC19 tumoral and metastatic cells exhibited mesenchymal phenotypes and were resistant to both TGF-β suppression and galunisertib effects. In 3D co-cultures with hepatic fibroblasts, TGF-β inhibitory effects were diminished for responsive cell lines, while resistant lines maintained their non-responsiveness. These findings highlight TGF-β’s dual role in HCC and its influence on tumor–stroma crosstalk, offering valuable models for exploring personalized anti-TGF-β therapies based on tumor characteristics. Full article

Background/Objective: Hepatocellular carcinoma (HCC) is an aggressive disease that is known to be resistant to conventional chemotherapy and radiotherapy. While surgical resection and transarterial therapy can improve overall survival, the biological aspects of HCC contribute to the complexity of its management and limit the effectiveness of current treatment options. The purpose of this scoping review is to identify the limitations of the currently available therapies for HCC and explore the emerging role that histotripsy could play in addressing these limitations, with the intent of informing the direction of future research and clinical management. Methods: The PRISMA checklist for scoping reviews was followed to structure this review, and a systematic search was conducted in the following online databases: PubMed/MEDLINE (National Library of Medicine), Embase (Elsevier), and Scopus (Elsevier). Results: The current evidence supports that histotripsy offers several key advantages that address the limitations of the current treatment strategies for HCC. Clinical trials have highlighted the ability of this technology to destroy solid tumors and induce remission with minimal side effects. In addition, current preclinical studies point to the potent immunostimulatory effects of histotripsy, including the induction of abscopal effects. This poses significant promise in treating tumor metastasis as well as improving clinical regimens by combining histotripsy with immunotherapy. Future research should aim to overcome the current limitations of histotripsy and enhance clinical outcomes for patients. This review examines existing treatments for HCC, emphasizing the promising potential of combining histotripsy with immunotherapy to target the metastatic and advanced stages of the disease. Full article

Cancer remains a significant global public health challenge, with hepatocellular carcinoma (HCC) ranking among the top five malignancies in terms of mortality. Faberidilactone A, a sesquiterpenoid dimer isolated from Inula japonica, exhibits potent cytotoxicity against various human tumor cell lines and demonstrates remarkable antitumor potential. In vitro studies using HepG2 cells revealed that faberidilactone A induces apoptosis and ferroptosis, causes cell cycle arrest, enhances the production of intracellular reactive oxygen species (ROS), and disrupts mitochondrial function. Mechanistic investigations via Western blot analysis indicated that faberidilactone A impedes HepG2 cell proliferation by modulating the signal transducer and activator of the transcription 3 (STAT3) signaling pathway and inhibits metastasis by affecting the focal adhesion kinase (FAK) pathway. In vivo experiments using a zebrafish model demonstrated that faberidilactone A effectively suppresses the dissemination and metastasis of HepG2 cells and exhibits anti-angiogenic properties. When the concentration of faberidilactone A reached 10 µM, the inhibition rates of tumor proliferation, migration, and intersegmental vessels (ISVs) length were 76.9%, 72.6%, and 46.2%, respectively. These findings underscore the therapeutic potential of faberidilactone A as a promising agent for HCC treatment. Full article

Over the past several years, the therapeutic landscape for patients with advanced, unresectable, or metastatic hepatocellular carcinoma has been transformed by the incorporation of checkpoint inhibitor immunotherapy into the treatment paradigm. Frontline systemic treatment options have expanded beyond anti-angiogenic tyrosine kinase inhibitors, such as sorafenib, to a combination of immunotherapy approaches, including atezolizumab plus bevacizumab and durvalumab plus tremelimumab, both of which have demonstrated superior response and survival to sorafenib. Additionally, combination treatments with checkpoint inhibitors and tyrosine kinase inhibitors have been investigated with variable success. In this review, we discuss these advances in systemic treatment with immunotherapy, with a focus on understanding both the underlying biology and mechanism of these strategies and their efficacy outcomes in clinical trials. We also review challenges in identifying predictive biomarkers of treatments and discuss future directions with novel immunotherapy targets. Full article

Background/Objectives: Transarterial chemoembolization (TACE) is a widely accepted and minimally invasive treatment for primary and metastatic liver cancer. Performing TACE with drug-eluting beads helps obtain a greater drug concentration in the target lesion, significantly reducing systemic drug leakage, liver toxicity, and adverse events. The aim of this study is to describe the safety and feasibility of TACE performed with BioPearl^TM, the first biodegradable drug-eluting microspheres. Methods: This was a retrospective observational study on 13 consecutive patients affected by hepatocellular carcinoma (HCC) treated with doxorubicin-loaded-BioPearl^TM-TACE. Data on safety, feasibility, and tumor response were collected. Results: One intra-procedural catheter blockage was registered, as well as two post-treatment bilomas that required additional treatment. No severe general drug-related side effects were detected at the follow-up. The 1-month overall disease control was 90.9%, with six complete responses. Conclusions: Data suggest that chemoembolization with BioPearl^TM is feasible and safe for the treatment of HCC as indicated by good tolerability. Full article

Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers and typically arises in the context of chronic liver disease. With the increasing prevalence of metabolic disorders, metabolic dysfunction-associated steatotic liver disease (MASLD) has become the leading cause of chronic liver disease and the most rapidly increasing cause of HCC. The role of dysfunctional innate and adaptive immune responses in the development and progression of HCC is well-established, prompting numerous trials to evaluate the efficacy of immune checkpoint inhibitors (ICIs) in targeting tumor cells. These trials have yielded promising results, and ICIs, in combination with anti-vascular endothelial growth factor (VEGF) monoclonal antibodies, are now approved as first-line therapy for patients with metastatic or unresectable HCC, irrespective of the underlying liver disease. Notably, MASLD itself is characterized by immune system dysfunction, as metabolic inflammation plays a central role in its onset and progression. However, clinical studies and post-hoc analyses suggest that immunotherapy may be less effective in MASLD-associated HCC compared to viral-related HCC. This emerging evidence raises the question of whether the underlying liver disease influences the therapeutic response to ICIs in HCC. It may be time to consider tailoring therapeutic strategies for HCC based on the specific etiological, histological, and genotypical subgroups. Full article

Canopy FGF signaling regulator 2 (CNPY2) has emerged as a crucial player in cancer development by promoting cell proliferation, tissue repair, and angiogenesis. This review synthesizes the current understanding of CNPY2’s role in solid tumors, particularly renal cell carcinoma, prostate cancer, hepatocellular carcinoma, and non-small-cell lung cancer. CNPY2 modulates key pathways such as p53, MYLIP, NF-κB, and AKT/GSK3β, thereby driving tumor growth and progression. In renal cell carcinoma, CNPY2 paradoxically promotes tumor growth through p53 upregulation, while in hepatocellular carcinoma, CNPY2 drives cell cycle progression via p53 destabilization. In prostate cancer, it enhances tumor progression by stabilizing androgen receptors through MYLIP interaction, and in non-small-cell lung cancer, it contributes to chemoresistance and metastasis through NF-κB and AKT/GSK3β signaling. Additionally, CNPY2 influences the tumor microenvironment, impacting immune function and metastatic potential. As a potential biomarker, CNPY2 shows promise for cancer detection and prognosis, particularly when used in combination with other markers. Early therapeutic strategies, including siRNA and miRNA approaches, are under exploration, though challenges remain due to CNPY2’s expression in normal tissues and potential off-target effects. This review underscores the need for further research to fully elucidate CNPY2’s oncogenic mechanisms and develop targeted therapies. Improved understanding of CNPY2’s diverse roles may lead to novel diagnostic and therapeutic approaches in solid tumors. Full article