Distinct metabolic phenotype renders β-catenin mutant hepatocellular carcinoma susceptible to treatment-induced ischemia

medRxiv · 2023-09-29 · 2 citations

ABSTRACT Background & Aims Transarterial chemoembolization (TACE) is the most common treatment for hepatocellular carcinoma (HCC) worldwide; however, response rates and durability vary widely. With the growing armamentarium of therapies for HCC patients, identifying predictors of response to TACE has become increasingly important for a patient population with limited hepatic reserve. We hypothesized that a distinct metabolic phenotype associated with β-catenin pathway mutations render HCC tumors more susceptible to TACE-induced ischemia. Material and Methods HCC patients referred for TACE were enrolled in a prospective cohort study at two academic medical centers from April 2016 to October 2021. Liver biopsies were acquired at the time of TACE, and mutational profiles were determined using next generation sequencing. Tumor response was determined by MRI using modified Response Evaluation Criteria in Solid Tumors. HCC cell lines with and without B-catenin mutations were grown in standard and ischemic cell culture conditions (1% O 2 , low nutrient media). Cell viability was measured by WST-1 reagent and Annexin-V PI assay. ATP concentration and metabolites were measured using CellTiter Glo and a YSI biochemical analyzer, respectively. Mitochondrial function was assessed through Seahorse XF Mito Stress Test. Results 53 HCC tumors from 50 HCC patients were biopsied prior to TACE, including 22/53 (41.5%) tumors with β-catenin pathway mutations. Despite larger tumor size (4.9 cm vs 3.0 cm p=0.01), tumors with these mutations demonstrated increased rates of complete response after TACE at first imaging (9/22, 40.9% vs 6/31, 19.4%, p=0.06) and best response (12/22, 54.5% vs 7/31, 22.6%, p=0.02), as well as a longer time to tumor progression (median not yet reached vs 8.3 months, p=0.02). In vitro modeling confirmed that β-catenin mutant HCC cells have reduced viability (21.4% vs 59.9%, p<0.01) and ATP levels (8.47 vs 4.26 pM/cell, p<0.001) under ischemic conditions compared to β-catenin wild type HCC cells. β-catenin mutant HCC cells had a dramatic increase in their susceptibility to glycolysis inhibition that was not seen in wild type HCC cells (0.09 vs 0.79 IC50 ration for ischemic vs standard conditions, p=0.004), suggesting a change from predominantly aerobic to anaerobic metabolism under ischemia specific to β-catenin mutant. This was further supported by increased sensitivity of β-catenin mutant cells to inhibition of the electron transport chain (43.9% vs 59.5%, p=0.02,) as well as significantly higher basal oxygen consumption rates (0.74 vs 0.39 pmoles/min, p=0.04), maximal respiratory capacity (1.46 vs 0.51 pmoles/min, p=0.01) and ATP-linked respiration (0.58 vs 0.29 pmoles/min, p=0.04). Conclusions HCC tumors with activating B-catenin pathway mutations demonstrate a superior response to TACE, driven by enhanced susceptibility to ischemia due to a greater dependence on oxidative phosphorylation for bioenergetic homeostasis. These findings hold the potential to provide a molecular basis for treatment selection in patients with HCC. IMPACT AND IMPLICATIONS With the growing armamentarium of locoregional and systemic therapies for patients with HCC, identifying predictors of response to individual therapies has become increasingly important for a patient population with limited hepatic reserve. Current treatment guidelines fail to incorporate molecular biomarkers to inform therapy. In a prospective clinical study of HCC patients undergoing transarterial chemoembolization (TACE), we demonstrated that tumors with activating mutations in the Wnt/B-catenin pathway have increased rates of complete response and longer time to local progression. We further characterized this finding in vitro by modeling the post-TACE ischemic environment and demonstrated that B-catenin mutant HCC cells have a distinct metabolic phenotype that renders this subtype more susceptible to ischemia. These findings provide the rationale for genotype-based strategies to enable precision medicine for patients with HCC patients.

Editor's Choice – Management of Lower Extremity Venous Outflow Obstruction: Results of an International Delphi Consensus

European Journal of Vascular and Endovascular Surgery · 2023-10-04 · 7 citations

Abstract No. 173 Driver mutations predict response to transarterial chemoembolization in unresectable hepatocellular carcinoma

Journal of Vascular and Interventional Radiology · 2022-05-27

A Framework for Developing a Comprehensive Venous Practice

Vascular and Endovascular Review · 2022-12-21

Chronic venous disease (CVD) of the lower extremities is a complex process encompassing abnormalities related to venous drainage secondary to thrombotic and non-thrombotic pathologies. CVD can have an untold economic impact due to lost productivity and the costs of treating its sequela and underlying aetiologies. Building a comprehensive venous service for the treatment of CVD requires a multifaceted approach with longitudinal care, similar to those that have been developed for peripheral arterial disease and oncology.

Variability in biopsy quality informs translational research applications in hepatocellular carcinoma

Scientific Reports · 2021 · 11 citations

• Medicine
• Internal medicine
• Radiology

In the era of precision medicine, biopsies are playing an increasingly central role in cancer research and treatment paradigms; however, patient outcomes and analyses of biopsy quality, as well as impact on downstream clinical and research applications, remain underreported. Herein, we report biopsy safety and quality outcomes for percutaneous core biopsies of hepatocellular carcinoma (HCC) performed as part of a prospective clinical trial. Patients with a clinical diagnosis of HCC were enrolled in a prospective cohort study for the genetic, proteomic, and metabolomic profiling of HCC at two academic medical centers from April 2016 to July 2020. Under image guidance, 18G core biopsies were obtained using coaxial technique at the time of locoregional therapy. The primary outcome was biopsy quality, defined as tumor fraction in the core biopsy. 56 HCC lesions from 50 patients underwent 60 biopsy events with a median of 8 core biopsies per procedure (interquartile range, IQR, 7-10). Malignancy was identified in 45/56 (80.4%, 4 without pathology) biopsy events, including HCC (40/56, 71.4%) and cholangiocarcinoma (CCA) or combined HCC-CCA (5/56, 8.9%). Biopsy quality was highly variable with a median of 40% tumor in each biopsy core (IQR 10-75). Only 43/56 (76.8%) and 23/56 (41.1%) samples met quality thresholds for genomic or metabolomic/proteomic profiling, respectively, requiring expansion of the clinical trial. Overall and major complication rates were 5/60 (8.3%) and 3/60 (5.0%), respectively. Despite uniform biopsy protocol, biopsy quality varied widely with up to 59% of samples to be inadequate for intended purpose. This finding has important consequences for clinical trial design and highlights the need for quality control prior to applications in which the presence of benign cell types may substantially alter findings.

Management of Patients when Superficial Venous Disease Arises from Pelvic Escape Points

Seminars in Interventional Radiology · 2021-06-01 · 8 citations

Chronic pelvic pain (CPP) is a common condition in women that carries with it significant morbidity. It is commonly seen in patients presenting to obstetrics and gynecology outpatient clinic visits. CPP is a presenting symptom of various pathologies including pelvic varicocele, pelvic adhesions, spastic colon syndrome, uterine fibroids, endometriosis, and psychosomatic disorders. Pelvic congestion syndrome has more recently been termed "pelvic venous insufficiency (PVI)" due to the underlying retrograde flow through incompetent ovarian and pelvic veins that are thought to cause the symptoms of CPP. Pelvic varices can commonly present alongside vulvar, perineal, and lower extremity varices. There are some predictable "escape pathways" for these varices that may present for interventional treatment. This article introduces the reader to current terminology, clinical presentation, diagnosis, and treatment of patients with pelvic varices due to PVI.

Abstract No. 560 Quality of large-volume percutaneous core biopsies of hepatocellular carcinoma for research applications

Journal of Vascular and Interventional Radiology · 2021-04-28

Infection Rates Following Hepatic Embolotherapy in Patients with Prior Biliary Interventions: Comparison of Single-Drug Moxifloxacin and Multidrug Antibiotic Prophylaxis

Journal of Vascular and Interventional Radiology · 2021-02-27 · 6 citations

Endovascular IVC Reconstruction in an 18 Year Old Patient with Subtotal IVC Atresia

EJVES Vascular Forum · 2021-01-01 · 9 citations

INTRODUCTION: Inferior vena cava (IVC) atresia is an uncommon venous anomaly that is an under recognised cause of unprovoked acute deep venous thrombosis (DVT) in young adults. The purpose of this case report is to highlight endovascular IVC reconstruction as a feasible treatment option, particularly in challenging cases when other therapeutic modalities have failed. REPORT: This is the report of an 18 year old patient with near complete IVC atresia and a longstanding history of exertional nausea of unknown aetiology, who presented with extensive acute DVT. He was treated successfully by endovascular IVC reconstruction after failing initial anticoagulation and thrombolysis. Symptom resolution and venous patency were maintained at 2.5 year follow up. DISCUSSION: IVC atresia is an important aetiology to consider in a young patient presenting with unprovoked DVT. Endovascular stenting can restore venous patency and is feasible even when there is near complete IVC atresia. This case was uniquely challenging in the length of atretic IVC that was reconstructed and also highlights an atypical clinical presentation of IVC atresia.

Cancer-Associated Venous Thromboembolic Disease, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

PubMed · 2021-10-15 · 153 citations

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Associated Venous Thromboembolic Disease focus on the prevention, diagnosis, and treatment of patients with cancer who have developed or who are at risk for developing venous thromboembolism (VTE). VTE is a significant concern among cancer patients, who are at heightened risks for developing as well as dying from the disease. The management of patients with cancer with VTE often requires multidisciplinary efforts at treating institutions. The NCCN panel comprises specialists from various fields: cardiology, hematology/hematologic oncology, internal medicine, interventional radiology, medical oncology, pharmacology/pharmacy, and surgery/surgical oncology. This article focuses on VTE prophylaxis for medical and surgical oncology inpatients and outpatients, and discusses risk factors for VTE development, risk assessment tools, as well as management methods, including pharmacological and mechanical prophylactics. Contraindications to therapeutic interventions and special dosing, when required, are also discussed.