Targeted treatment of vascular anomalies.
Ontology highlight
ABSTRACT:
SUBMITTER: Ng AT
PROVIDER: S-EPMC8721128 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Complicated vascular anomalies have limited therapeutic options and cause significant morbidity and mortality. This Phase II trial enrolled patients with complicated vascular anomalies to determine the efficacy and safety of treatment with sirolimus for 12 courses; each course was defined as 28 days.Treatment consisted of a continuous dosing schedule of oral sirolimus starting at 0.8 mg/m(2) per dose twice daily, with pharmacokinetic-guided target serum trough levels of 10 to 15 ng/mL. The primary outcomes were responsiveness to sirolimus by the end of course 6 (evaluated according to functional impairment score, quality of life, and radiologic assessment) and the incidence of toxicities and/or infection-related deaths.Sixty-one patients were enrolled; 57 patients were evaluable for efficacy at the end of course 6, and 53 were evaluable at the end of course 12. No patient had a complete response at the end of course 6 or 12 as anticipated. At the end of course 6, a total of 47 patients had a partial response, 3 patients had stable disease, and 7 patients had progressive disease. Two patients were taken off of study medicine secondary to persistent adverse effects. Grade 3 and higher toxicities attributable to sirolimus included blood/bone marrow toxicity in 27% of patients, gastrointestinal toxicity in 3%, and metabolic/laboratory toxicity in 3%. No toxicity-related deaths occurred.Sirolimus was efficacious and well tolerated in these study patients with complicated vascular anomalies. Clinical activity was reported in the majority of the disorders.
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Project description:Vascular anomalies, both tumors and malformations, can occur anywhere in the body, including the airway, often without any external manifestations. However, vascular anomalies involving the airway deserve special consideration as proper recognition and management can be lifesaving. In this article, the authors discuss vascular anomalies as they pertains to the airway, focusing on proper diagnosis, diagnostic modalities, and therapeutic options.
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Project description:Imaging of patients with vascular tumors and malformations has been sufficiently refined to answer pertinent questions when making treatment decisions in this challenging subgroup of pediatric patients. The imaging modalities at hand include conventional radiography, Doppler ultrasound, and magnetic resonance imaging with time-resolved, contrast-material enhanced magnetic resonance angiography. This review article will focus on the characteristic imaging features of some focal and diffuse vascular lesions, which have been classified by their clinical history and physical exam, and further labeled as a vascular tumor or slow-flow versus high-flow vascular malformation based on the updated classification system proposed by the International Society for the Study of Vascular Anomalies. The recent advances in knowledge regarding the biology of these vascular anomalies have led to increased awareness of the current nomenclature. Moreover, with better understanding of the imaging features, the radiologist has become a key player in the multidisciplinary approach offered at various institutions where appropriate treatment algorithms and interventional strategies are put together. This is crucial in avoiding misdiagnosis and improper management.
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Project description:Vascular anomalies (VAs) comprise a large variety of individual diagnoses that in different phases of treatment require a diverse number of medical specialists to provide optimal care. Medical therapies include agents usually associated with cancer chemotherapy, such as vincristine, as well more immunomodulatory types of drugs, such as glucocorticoids and sirolimus. These immunomodulating drugs are being successfully applied in cases that are typically categorized as vascular tumors, including kaposiform hemangioendothelioma (KHE) and tufted angioma (TA), as well as some of the more invasive types of vascular malformations (i.e., microcystic lymphatic malformations and blue rubber bleb nevus syndrome (BRBNS). These therapies need to be combined with good supportive care, which often involves anticoagulation, antimicrobial prophylaxis, and comprehensive pain and symptom-relief strategies, as well as appropriate drug monitoring and management of side effects of medical treatment. The optimal care of these patients frequently involves close collaboration between surgeons, interventional and conventional radiologists, medical subspecialists, and nurses.
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Project description:The presence of a vascular anomaly suggests that capillaries, veins, arteries, and/or lymphatic vessels have demonstrated abnormal development and growth. Often dilated and misshaped, these vessels augment normal flow of blood and lymphatic fluids that increases the overall risk to develop intralesional thrombosis. Abnormal endothelial and lymphoendothelial cells activate hemostasis and hyperfibrinolytic pathways through poorly understood mechanisms, which contribute to the development of localized intravascular coagulopathy. Vascular malformations, tumors, and complex combined syndromes demonstrate varying degrees of prothrombotic activity and consumptive coagulopathy depending on the vessels involved and the pattern and extent of abnormal growth. The clinical impact of venous thromboembolism in pediatric vascular anomalies varies from painful syndromes that disrupt quality of life to life-threatening embolic disease. There remains little literature on the study, evaluation, and treatment of thrombosis in pediatric vascular anomalies. However, there have been great advances in our ability to image complex lesions, to surgically and interventionally augment disease, and to provide enhanced supportive care including patient education, compression therapy, and strategic use of anticoagulation.
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Project description:Glioblastoma is characterized by an aggressive and aberrant vascular network that promotes tumor progression and hinders effective treatment; the median survival is 16 mo despite standard-of-care therapies. There is a need to improve therapeutic options for this disease. We hypothesized that antibody targeting of the vascular endothelium of glioblastoma with cytotoxic short-range, high-energy α-particles would be an effective therapeutic approach.MethodsE4G10, an antibody directed at an epitope of monomeric vascular endothelium cadherin that is expressed in tumor neovasculature and on endothelial progenitor cells in the bone marrow, was labeled with α-particle-emitting 225Ac. Pharmacokinetic studies investigated the tissue distribution and blood clearance of the 225Ac-E4G10 radioimmunoconstruct in a transgenic Nestin-tumor virus A (Ntva) mouse model of high-grade glioblastoma. Histologic analysis was used to demonstrate local therapeutic effects in treated brain tumor sections. Radioimmunotherapy with 225Ac-E4G10 was performed in Ntva mice to assess overall survival alone and in combination with temozolomide, the standard-of-care chemotherapeutic agent.Results225Ac-E4G10 was found to accumulate in tissues expressing the target antigen. Antivascular α-particle therapy of glioblastoma in the transgenic Ntva model resulted in significantly improved survival compared with controls and potent control of tumor growth. Adding the chemotherapeutic temozolomide to the treatment increased survival to 30 d (vs. 9 d for vehicle-treated animals). Histologic analyses showed a remodeled glioblastoma vascular microenvironment.ConclusionTargeted α-particle antivascular therapy is shown for the first time to be effective in increasing overall survival in a solid tumor in a clinically relevant transgenic glioblastoma mouse model.
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Project description:Vascular morphogenesis is a vital process for embryonic development, normal physiologic conditions (e.g. wound healing) and pathological processes (e.g. atherosclerosis, cancer). Genetic studies of vascular anomalies have led to identification of critical genes involved in vascular morphogenesis. A susceptibility gene, VG5Q (formally named AGGF1), was cloned for Klippel-Trenaunay syndrome (KTS). AGGF1 encodes a potent angiogenic factor, and KTS-associated mutations enhance angiogenic activity of AGGF1, defining 'increased angiogenesis' as one molecular mechanism for the pathogenesis of KTS. Similar studies have identified other genes involved in vascular anomalies as important genes for vascular morphogenesis, including TIE2, VEGFR-3, RASA1, KRIT1, MGC4607, PDCD10, glomulin, FOXC2, NEMO, SOX18, ENG, ACVRLK1, MADH4, NDP, TIMP3, Notch3, COL3A1 and PTEN. Future studies of vascular anomaly genes will provide insights into the molecular mechanisms for vascular morphogenesis, and may lead to the development of therapeutic strategies for treating these and other angiogenesis-related diseases, including coronary artery disease and cancer.
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Project description:Chronobiology is the study of biological rhythms. Chronomics investigates interactions with environmental cycles in a genetically coded autoresonance of the biosphere with wrangling space and terrestrial weather. Analytical global and local methods applied to human blood pressure records of around-the-clock measurements covering decades detect physiological-physical interactions, a small yet measurable response to solar and terrestrial magnetism. The chronobiological and chronomic interpretation of ambulatory blood pressure monitoring (C-ABPM) records in the light of time-specified reference values derived from healthy peers matched by sex and age identify vascular variability anomalies (VVAs) for an assessment of cardio-, cerebro-, and renovascular disease risk. Even within the conventionally accepted normal range, VVAs have been associated with a statistically significant increase in risk. Long-term C-ABPM records help to "know ourselves," serving for relief of psychological and other strain once transient VVAs are linked to the source of a load, prompting adjustment of one's lifestyle for strain reduction. Persistent circadian VVAs can be treated, sometimes by no more than a change in timing of the daily administration of antihypertensive medication. Circadian VVA assessment is an emergency worldwide, prompted in the United States by 1,000 deaths per day every day from problems related to blood pressure. While some heads of state met under United Nation and World Health Organization sponsorship to declare that noncommunicable diseases are a slow-motion disaster, a resolution has been drafted to propose C-ABPM as an added tool complementing purely physical environmental monitoring to contribute also to the understanding of social and natural as well as personal cataclysms.
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Project description:Genetic factors play a critical role in the pathogenesis of vascular anomalies. Significant advances have been made in recent years in identifying the genetic and molecular determinants of a variety of vascular anomalies using a molecular genetic approach. Several genes for vascular anomalies have been identified. These genes include AGGF1 for Klippel-Trenaunay syndrome, RASA1 for capillary malformations, KRIT1, MGC4607, PDCD10 for cerebral cavernous malformations, glomulin for glomuvenous malformations, TIE2 for multiple cutaneous and mucosal venous malformations, VEGFR-3, FOXC2, NEMO, SOX18 for lymphedema or related syndromes, ENG, ACVRLK1, MADH4 for HHT or related syndromes, NDP for Coats' disease, Notch3 for CADASIL, and PTEN for Proteus Syndrome. These findings have made genetic testing possible in some clinical cases, and may lead to the development of therapeutic strategies for vascular anomalies. Furthermore, these studies have identified critical genes involved in vascular morphogenesis, and provided fundamental understanding of the molecular mechanisms underlying vasculogenesis and angiogenesis.
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