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BACKGROUND AND OBJECTIVE: Embolotherapy has been increasingly used to disrupt tumor growth. Despite its success in the occlusion of microvessels, it has drawbacks such as limited access to the target location, limited control of the blocker size, and inattention to the tumor characteristics, especially high interstitial fluid pressure. The present work introduces a novel numerical method of gas embolotherapy for cancer treatment through tumor vessel occlusion. METHODS: The gas microbubbles are generated from Levovist bolus injection into the tumor microvessel. The microbubble movement in the blood flow is innovatively controlled by an electric field applied to the tumor-feeding vessel. The interaction between the Levovist microbubbles and the electric field is resolved by developing a fully coupled model using the phase-field model, Carreau model for non-Newtonian blood, Navier-Stokes equations and Maxwell stress tensor. Additionally, the critical effect of high interstitial fluid pressure as a characteristic of solid tumors is included. RESULTS: The findings of this study indicate that the rates of microbubble deformation and displacement increase with the applied potential intensity to the microvessel wall. Accordingly, the required time for a microbubble to join the upper microvessel wall reduces from 1.97ms to 22 µs with an increase of the electric potential from 3.5V to 12.5V. Additionally, an electric potential of 12.5V causes the microbubbles coalescence and formation of a gas column against the bloodstream. CONCLUSIONS: Clinically, our novel embolization procedure can be considered a non-invasive targeted therapy, and under a controlled electric field, the blocker size can be precisely controlled. Also, the proposed method has the potential to be used as a gradual treatment in advanced cancers as tumors develop resistance and relapse.

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Primary aortic sarcoma is a very rare disease, and most primary aortic tumors are malignant mesenchymal tumors. We present the case of a 62-year-old man with sudden epigastric and back pain. Contrast-enhanced computed tomography (CT) revealed a mass lesion about 33.8 mm in diameter, in contact with the left side of the abdominal aorta. Impending rupture of an abdominal aortic aneurysm was suspected, so cardiovascular surgery for stent graft placement was performed the same day. Symptoms immediately improved and CT at 3 months postoperatively showed a marked decrease in lesion size, but the lesion subsequently grew again. Fluorodeoxyglucose (FDG)-positron emission tomography/CT was performed due to the possibility of malignant solid tumor, revealing markedly increased FDG accumulation (maximum standardized uptake value, 36.95) in the mass lesion. Primary aortic sarcoma was diagnosed from thoracoscopic biopsy. Here, we report a primary aortic sarcoma that shrank due to tumor infarction after stent graft placement, followed by tumor regrowth.

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Selective occlusion of tumor vasculature has proven to be an effective strategy for cancer therapy. Among vascular coagulation agents, the extracellular domain of coagulation-inducing protein tissue factor, truncated tissue factor (tTF), is the most widely used. Since the truncated protein exhibits no coagulation activity and is rapidly cleared in the circulation, free tTF cannot be used for cancer treatment on its own but must be combined with other moieties. We here developed a novel, tumor-specific tTF delivery system through coupling tTF with the DNA aptamer, AS1411, which selectively binds to nucleolin receptors overexpressing on the surface of tumor vascular endothelial cells and is specifically cytotoxic to target cells. Systemic administration of the tTF-AS1411 conjugates into tumor-bearing animals induced intravascular thrombosis solely in tumors, thus reducing tumor blood supply and inducing tumor necrosis without apparent side effects. This conjugate represents a uniquely attractive candidate for the clinical translation of vessel occlusion agent for cancer therapy.

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Besides its central functional role in coagulation, TF has been described as being operational in the development of malignancies and is currently being studied as a possible therapeutic tool against cancer. One of the avenues being explored is retargeting TF or its truncated extracellular part (tTF) to the tumor vasculature to induce tumor vessel occlusion and tumor infarction. To this end, multiple structures on tumor vascular wall cells have been studied at which tTF has been aimed via antibodies, derivatives, or as bifunctional fusion protein through targeting peptides. Among these targets were vascular adhesion molecules, oncofetal variants of fibronectin, prostate-specific membrane antigens, vascular endothelial growth factor receptors and co-receptors, integrins, fibroblast activation proteins, NG2 proteoglycan, microthrombus-associated fibrin-fibronectin, and aminopeptidase N. Targeting was also attempted toward cellular membranes within an acidic milieu or toward necrotic tumor areas. tTF-NGR, targeting tTF primarily at aminopeptidase N on angiogenic endothelial cells, was the first drug candidate from this emerging class of coaguligands translated to clinical studies in cancer patients. Upon completion of a phase I study, tTF-NGR entered randomized studies in oncology to test the therapeutic impact of this novel therapeutic modality.

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Tumor vasculature has long been considered as an extremely valuable therapeutic target for cancer therapy, but how to realize controlled and site-specific drug release in tumor blood vessels remains a huge challenge. Despite the widespread use of nanomaterials in constructing drug delivery systems, they are suboptimal in principle for meeting this demand due to their easy blood cell adsorption/internalization and short lifetime in the systemic circulation. Here, natural red blood cells (RBCs) are repurposed as a remote-controllable drug vehicle, which retains RBC's morphology and vessel-specific biodistribution pattern, by installing photoactivatable molecular triggers on the RBC membrane via covalent conjugation with a finely tuned modification density. The molecular triggers can burst the RBC vehicle under short and mild laser irradiation, leading to a complete and site-specific release of its payloads. This cell-based vehicle is generalized by loading different therapeutic agents including macromolecular thrombin, a blood clotting-inducing enzyme, and a small-molecule hypoxia-activatable chemodrug, tirapazamine. In vivo results demonstrate that the repurposed "anticancer RBCs" exhibit long-term stability in systemic circulation but, when tumors receive laser irradiation, precisely releases their cargoes in tumor vessels for thrombosis-induced starvation therapy and local deoxygenation-enhanced chemotherapy. This study proposes a general strategy for blood vessel-specific drug delivery.

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Selective occlusion of tumor vasculature has proven to be an effective strategy for cancer therapy. Among vascular coagulation agents, the extracellular domain of coagulation-inducing protein tissue factor, truncated tissue factor (tTF), is the most widely used. Since the truncated protein exhibits no coagulation activity and is rapidly cleared in the circulation, free tTF cannot be used for cancer treatment on its own but must be combined with other moieties. We here developed a novel, tumor-specific tTF delivery system through coupling tTF with the DNA aptamer, AS1411, which selectively binds to nucleolin receptors overexpressing on the surface of tumor vascular endothelial cells and is specifically cytotoxic to target cells. Systemic administration of the tTF-AS1411 conjugates into tumor-bearing animals induced intravascular thrombosis solely in tumors, thus reducing tumor blood supply and inducing tumor necrosis without apparent side effects. This conjugate represents a uniquely attractive candidate for the clinical translation of vessel occlusion agent for cancer therapy.

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Sclerosing mucoepidermoid carcinoma (SMEC) is extremely rare variant of the mucoepidermoid carcinoma, which is the most common primary malignancy of the salivary glands. As its name suggests, SMEC is characterized by an intense central sclerosis that occupies the entirety of an otherwise typical tumor, frequently with an inflammatory infiltrate of plasma cells, eosinophils, and/or lymphocytes at its peripheral regions, but its uncompanionship with inflammatory cell infiltration might explain its progressive stage of the sclerosis. The sclerosis associated with these tumors may obscure their typical morphologic features and result in diagnostic difficulties. Tumor infarction and extravasation of mucin eventuating in reactive fibrosis are two mechanisms of formation that have been suggested as underlying this morphologic variant. Morphologic evidence in support of the mucin extravasation hypothesis was identified, as small pools of mucin were present throughout the tumor.