State of the Art: Contrast Enhanced 4D Ultrasound to Monitor or Assess Locoregional Therapies

Locoregional therapies (LRTs) are an essential management tool in the treatment of primary liver cancers or metastatic liver disease. LRTs include curative and palliative modalities. Monitoring treatment response of LRTs is crucial for maximizing benefit and improving clinical outcomes. Clinical use of contrast-enhanced ultrasound (CEUS) was introduced more than two decades ago. Its portability, cost effectiveness, lack of contraindications and safety make it an ideal tool for treatment monitoring in numerous situations. Two-dimensional dynamic CEUS has been proved to be equivalent to the current imaging standard in the guidance of LRTs, assessment of their adequacy, and detection of early tumor recurrence. Recent technical advances in ultrasound transducers and image processing have made 3D CEUS scanning widely available on most commercial ultrasound systems. 3D scanning offers a broad multiplanar view of anatomic structures, overcoming many limitations of two-dimensional scanning. Furthermore, many ultrasound systems provide real-time dynamic 3D CEUS, also known as 4D CEUS. Volumetric CEUS has shown to perform better than 2D CEUS in the assessment and monitoring of some LRTs. CEUS presents a valid alternative to the current imaging standards with reduced cost and decreased risk of complications. Future efforts will be directed toward refining the utility of 4D CEUS through approaches such as multi-parametric quantitative analysis and machine learning algorithms.

Interventional Radiology Image-Guided Locoregional Therapies (LRTs) and Immunotherapy for the Treatment of HCC

Image-guided locoregional therapies (LRTs) are a crucial asset in the treatment of hepatocellular carcinoma (HCC), which has proven to be characterized by an impaired antitumor immune status. LRTs not only directly destroy tumor cells but also have an immunomodulating role, altering the tumor microenvironment with potential systemic effects. Nevertheless, the immune activation against HCC induced by LRTs is not strong enough on its own to generate a systemic significant antitumor response, and it is incapable of preventing tumor recurrence. Currently, there is great interest in the possibility of combining LRTs with immunotherapy for HCC, as this combination may result in a mutually beneficial and synergistic relationship. On the one hand, immunotherapy could amplify and prolong the antitumoral immune response of LRTs, reducing recurrence cases and improving outcome. On the other hand, LTRs counteract the typical immunosuppressive HCC microenvironment and status and could therefore enhance the efficacy of immunotherapy. Here, after reviewing the current therapeutic options for HCC, we focus on LRTs, describing for each of them the technique and data on its effect on the immune system. Then, we describe the current status of immunotherapy and finally report the recently published and ongoing clinical studies testing this combination.

Locoregional Therapies for Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis

Hepatocellular carcinoma is the fourth leading cause of cancer worldwide, and the fastest increasing cause of cancer mortality in the United States. Its propensity for vascular invasion leads to the presence of portal vein tumor thrombus in up to half of patients. PVTT results in a classification of advanced disease, given the risk recurrence secondary to intravascular spread, and formal guidelines recommend systemic therapy in these patients. However, recent advances in locoregional therapies including TACE, TARE, and ablation have demonstrated the potential to drastically improve overall survival in patients with HCC complicated by PVTT.

Liver transplantation for hepatocellular carcinoma with portal vein tumor thrombosis

Traditionally, liver transplantation for hepatocellular carcinoma with portal vein tumor thrombosis is not recommended. However, with recent developments in locoregional therapies for hepatocellular carcinoma, more aggressive treatments have been attempted for advanced hepatocellular carcinoma. Recently, various studies on locoregional therapies for downstaging followed by living donor liver transplantation reported inspiring overall survival and recurrence-free survival of patients. These downstaging procedures included three-dimensional conformal radiation therapy, trans-arterial chemoembolization, stereotactic body radiation therapy, trans-arterial radioembolization, hepatic arterial infusion chemotherapy and combinations of these therapies. Selection of the optimal downstaging protocol should depend on tumor location, biology and background liver status. The risk factors affecting outcome include pre-downstaging alpha-fetoprotein values, delta alpha-fetoprotein values, disappearance of portal vein tumor thrombosis on imaging and meeting the Milan criteria or not after downstaging. For hepatocellular carcinoma with portal vein tumor thrombosis, downstaging procedure with liver transplantation in mind would be helpful. If the reaction of the downstaged tumor is good, liver transplantation may be performed.

Transjugular Intrahepatic Portosystemic Shunt and Locoregional Therapies in Patients Undergoing Orthotopic Liver Transplantation: A Protocol for a Retrospective, Linked United Network for Organ Sharing Cohort

ABSTRACTIntroductionOrthotopic Liver Transplantation (OLT) is the potential curative treatment option for patients with end-stage liver disease (ESLD) or hepatocellular carcinoma (HCC) within organ procurement and transplantation network (OPTN) criteria. However, these groups of patients may require bridging interventions, including Transjugular Intrahepatic Portosystemic Shunt (TIPS) or Locoregional Therapies (LRTs), given the nationwide organ shortage and increasing waitlist time. The perioperative and long-term post-OLT survival and clinical outcomes require further investigation to evaluate the clinical utility and therapeutic advantages of these bridging interventions, if any. We propose a large retrospective database analysis that will evaluate both perioperative and long-term effects of these OLT-related interventions.Methods and analysisThree datasets from the United Network for Organ Sharing (UNOS) database will be included and linked to estimate the causal effect of 1) Transjugular Intrahepatic Portosystemic Shunts and 2) Locoregional therapies in patients undergoing OLT, the latter among patients with HCC. Only therapy naïve adult patients, without multivisceral transplants, and without living donor transplants will be included. The primary outcome will be overall survival. Secondary outcomes will include perioperative clinical outcomes, post-operative survival, and postoperative clinical outcomes. The inverse probability of treatment weighted models with Cox regression will be utilized to analyze survival outcomes, logistic regression for categorical outcomes, and ordinary least squares regression for continuous outcomes. A sensitivity analysis will be conducted to assess the appropriateness of a complete-case analysis for the primary outcome and ensure the robustness of the findings.Ethics and DisseminationThis study protocol was reviewed by the Emory University School of Medicine Institutional Review Board (IRB), and ethical approval was waived due to the retrospective analysis of the originally anonymized database. The results will be disseminated in peer-reviewed journals and presented at relevant conferences. It was not appropriate or possible to involve patients or the public in the design, or conduct, or reporting, or dissemination plans of our research.STRENGTHS AND LIMITATIONS OF THIS STUDYStrengthsThe proposed study:Will be the first study evaluating the causal effect of TIPS in OLT candidates and of locoregional therapies in OLT candidates with HCCWill be the first study to link UNOS datasets to investigate the estimands, thereby providing insight into the clinical impact of TIPS and LRTs at various stages in the clinical pathway.LimitationsThe proposed study:Will be a retrospective study and thus subject to poor or inadequate reporting in the registry, though propensity score matching will be doneMay be subject to unmeasured confounding and sensitive to model misspecificationMay lack the necessary sample size and subsequently be underpowered to estimate the target estimands