Vandetanib-eluting radiopaque beads for chemoembolization: physicochemical evaluation and biological activity of vandetanib in hypoxia.

Vandetanib-eluting radiopaque beads (VERB) have been developed for use in transarterial chemoembolization of liver tumours, with the goal of combining embolization with local delivery of antiangiogenic therapy. The objective of this study was to investigate how embolization-induced hypoxia may affect antitumoural activity of vandetanib, an inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR), in the context of hepatocellular carcinoma (HCC) treatment. We studied the effect of vandetanib on proliferation, cell cycle and apoptosis of HCC cells, in hypoxic conditions, as well as the direct effects of the beads on 3D HCC spheroids. Vandetanib suppressed proliferation and induced apoptosis of HCC cells in vitro and was equipotent in hypoxic and normoxic conditions. High degrees of apoptosis were observed among cell lines in which vandetanib suppressed ERK1/2 phosphorylation and upregulated the proapoptotic protein Bim, but this did not appear essential for vandetanib-induced cell death in all cell lines. Vandetanib also suppressed the hypoxia-induced secretion of VEGF from HCC cells and inhibited proliferation of endothelial cells. Incubation of tumour spheroids with VERB led to sustained growth inhibition equivalent to the effect of free drug. We conclude that vandetanib has both antiangiogenic and direct anticancer activity against HCC cells even in hypoxic conditions, warranting the further evaluation of VERB as novel anticancer agents

VEROnA Protocol: A Pilot, Open-Label, Single-Arm, Phase 0, Window-of-Opportunity Study of Vandetanib-Eluting Radiopaque Embolic Beads (BTG-002814) in Patients With Resectable Liver Malignancies

BACKGROUND: Transarterial chemoembolization (TACE) is the current standard of care for patients with intermediate-stage hepatocellular carcinoma (HCC) and is also a treatment option for patients with liver metastases from colorectal cancer. However, TACE is not a curative treatment, and tumor progression occurs in more than half of the patients treated. Despite advances and technical refinements of TACE, including the introduction of drug-eluting beads-TACE, the clinical efficacy of TACE has not been optimized, and improved arterial therapies are required. OBJECTIVE: The primary objectives of the VEROnA study are to evaluate the safety and tolerability of vandetanib-eluting radiopaque embolic beads (BTG-002814) in patients with resectable liver malignancies and to determine concentrations of vandetanib and the N-desmethyl metabolite in plasma and resected liver following treatment with BTG-002814. METHODS: The VEROnA study is a first-in-human, open-label, single-arm, phase 0, window-of-opportunity study of BTG-002814 (containing 100 mg vandetanib) delivered transarterially, 7 to 21 days before surgery in patients with resectable liver malignancies. Eligible patients have a diagnosis of colorectal liver metastases, or HCC (Childs Pugh A), diagnosed histologically or radiologically, and are candidates for liver surgery. All patients are followed up for 28 days following surgery. Secondary objectives of this study are to evaluate the anatomical distribution of BTG-002814 on noncontrast-enhanced imaging, to evaluate histopathological features in the surgical specimen, and to assess changes in blood flow on dynamic contrast-enhanced magnetic resonance imaging following treatment with BTG-002814. Exploratory objectives of this study are to study blood biomarkers with the potential to identify patients likely to respond to treatment and to correlate the distribution of BTG-002814 on imaging with pathology by 3-dimensional modeling. RESULTS: Enrollment for the study was completed in February 2019. Results of a planned interim analysis were reviewed by a safety committee after the first 3 patients completed follow-up. The recommendation of the committee was to continue the study without any changes to the dose or trial design, as there were no significant unexpected toxicities related to BTG-002814. CONCLUSIONS: The VEROnA study is studying the feasibility of administering BTG-002814 to optimize the use of this novel technology as liver-directed therapy for patients with primary and secondary liver cancer. TRIAL REGISTRATION: ClinicalTrial.gov NCT03291379; https://clinicaltrials.gov/ct2/show/NCT03291379. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/13696

Pseudotumoral tracheobronchial amyloidosis mimicking asthma: a case report

<p>Abstract</p> <p>Introduction</p> <p>Tracheobronchial amyloidosis is an uncommon localized form of amyloidosis that can simulate a tracheal tumor. Clinical signs are not specific and the diagnosis is rarely given before performing a bronchoscopy with multiples biopsies.</p> <p>Case presentation</p> <p>We report the case of a 60-year-old Moroccan woman, complaining of dyspnea and wheezing for three years, who was treated at our institution for management of severe asthma. A bronchoscopy revealed a tumor formation of her trachea; multiples biopsies were performed and a diagnosis made of amyloid light-chain amyloidosis. She successfully received an endoscopic resection.</p> <p>Conclusion</p> <p>This case highlights the importance of routinely carrying out an endoscopy in any patient complaining of atypical bronchial symptoms or with uncontrolled asthma. Tracheal amyloidosis is a rare disease, confirmed by histological examination of bronchial biopsies, and the treatment of choice is based on the bronchoscopic resection.</p