RESUMEN
The lymphatic system is one of the most essential and complex systems in the human body. Disorders that affect the development or function of the lymphatic system can lead to multi-system complications and life-long morbidity. The past two decades have seen remarkable progress in our knowledge of the basic biology and function of the lymphatic system, the molecular regulators of lymphatic development, and description of disorders associated with disrupted lymphangiogensis. In this chapter we will touch on the clinical features of complex lymphatic anomalies, new molecular knowledge of the drivers of these disorders, and novel developmental therapeutics for lymphatic disease.
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Anomalías Linfáticas , Humanos , Anomalías Linfáticas/terapia , Anomalías Linfáticas/genética , Anomalías Linfáticas/diagnóstico , Linfangiogénesis/genéticaRESUMEN
Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK, an endothelial transmembrane receptor signaling through PIK3CA. Venous malformations are associated with pain, bleedings, thrombosis, pulmonary embolism, esthetic deformities and, in severe cases, life-threatening situations. No authorized medical treatment exists for patients with venous malformations. Here, we created a genetic mouse model of PIK3CA-related capillary venous malformations that replicates patient phenotypes. We showed that these malformations only partially signal through AKT proteins. We compared the efficacy of different drugs, including rapamycin, a mTORC1 inhibitor, miransertib, an AKT inhibitor and alpelisib, a PI3Kα inhibitor at improving the lesions seen in the mouse model. We demonstrated the effectiveness of alpelisib in preventing vascular malformations' occurrence, improving the already established ones, and prolonging survival. Considering these findings, we were authorized to treat 25 patients with alpelisib, including 7 children displaying PIK3CA (n = 16) or TEK (n = 9)-related capillary venous malformations resistant to usual therapies including sirolimus, debulking surgical procedures or percutaneous sclerotherapies. We assessed the volume of vascular malformations using magnetic resonance imaging (MRI) for each patient. Alpelisib demonstrated improvement in all 25 patients. Vascular malformations previously considered intractable were reduced and clinical symptoms were attenuated. MRI showed a decrease of 33.4% and 27.8% in the median volume of PIK3CA and TEK malformations respectively, over 6 months on alpelisib. In conclusion, this study supports PI3Kα inhibition as a promising therapeutic strategy in patients with PIK3CA or TEK-related capillary venous malformations.
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Capilares , Fosfatidilinositol 3-Quinasa Clase I , Malformaciones Vasculares , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Animales , Ratones , Humanos , Malformaciones Vasculares/genética , Malformaciones Vasculares/tratamiento farmacológico , Malformaciones Vasculares/patología , Capilares/efectos de los fármacos , Capilares/patología , Femenino , Masculino , Sirolimus/farmacología , Sirolimus/uso terapéutico , Niño , Modelos Animales de Enfermedad , Terapia Molecular Dirigida , TiazolesRESUMEN
BACKGROUND: Angiopoietin-2 (Ang-2) is increased in the blood of patients with kaposiform lymphangiomatosis (KLA) and kaposiform hemangioendothelioma (KHE). While the genetic causes of KHE are not clear, a somatic activating NRASQ61R mutation has been found in the lesions of KLA patients. PROCEDURE: Our study tested the hypothesis that the NRASQ61R mutation drives elevated Ang-2 expression in endothelial cells. Ang-2 was measured in human endothelial progenitor cells (EPC) expressing NRASQ61R and a genetic mouse model with endothelial targeted NRASQ61R. To determine the signaling pathways driving Ang-2, NRASQ61R EPC were treated with signaling pathway inhibitors. RESULTS: Ang-2 levels were increased in EPC expressing NRASQ61R compared to NRASWT by Western blot analysis of cell lysates and ELISA of the cell culture media. Ang-2 levels were elevated in the blood of NRASQ61R mutant mice. NRASQ61R mutant mice also had reduced platelet counts and splenomegaly with hypervascular lesions, like some KLA patients. mTOR inhibitor rapamycin attenuated Ang-2 expression by NRASQ61R EPC. However, MEK1/2 inhibitor trametinib was more effective blocking increases in Ang-2. CONCLUSIONS: Our studies show that the NRASQ61R mutation in endothelial cells induces Ang-2 expression in vitro and in vivo. In cultured human endothelial cells, NRASQ61R drives elevated Ang-2 through MAP kinase and mTOR-dependent signaling pathways.
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Angiopoyetina 2 , Proteínas de la Membrana , Animales , Humanos , Angiopoyetina 2/genética , Angiopoyetina 2/metabolismo , Ratones , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Mutación , Transducción de Señal , Ratones TransgénicosRESUMEN
Turner syndrome (45,X) is caused by a complete or partial absence of a single X chromosome. Vascular malformations occur due to abnormal development of blood and/or lymphatic vessels. They arise from either somatic or germline pathogenic variants in the genes regulating growth and apoptosis of vascular channels. Aortic abnormalities are a common, known vascular anomaly of Turner syndrome. However, previous studies have described other vascular malformations as a rare feature of Turner syndrome and suggested that vascular abnormalities in individuals with Turner syndrome may be more generalized. In this study, we describe two individuals with co-occurrence of Turner syndrome and vascular malformations with a lymphatic component. In these individuals, genetic testing of the lesional tissue revealed a somatic pathogenic variant in PIK3CA-a known and common cause of lymphatic malformations. Based on this finding, we conclude that the vascular malformations presented here and likely those previously in the literature are not a rare part of the clinical spectrum of Turner syndrome, but rather a separate clinical entity that may or may not co-occur in individuals with Turner syndrome.
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Anomalías Cardiovasculares , Anomalías Linfáticas , Síndrome de Turner , Malformaciones Vasculares , Humanos , Síndrome de Turner/complicaciones , Síndrome de Turner/genética , Mosaicismo , Anomalías Linfáticas/genética , Malformaciones Vasculares/complicaciones , Malformaciones Vasculares/genética , Fosfatidilinositol 3-Quinasa Clase I/genéticaRESUMEN
BACKGROUND AND OBJECTIVES: Kaposiform hemangioendothelioma (KHE) and tufted angioma (TA) are rare vascular tumors in children historically associated with significant morbidity and mortality. This study was conducted to determine first-line therapy in the absence of available prospective clinical trials. METHODS: Patients from 17 institutions diagnosed with KHE/TA between 2005 and 2020 with more than 6 months of follow-up were included. Response rates to sirolimus and vincristine were compared at 3 and 6 months. Durability of response and response to other treatment modalities were also evaluated. RESULTS: Of 159 unique KHE/TA subjects, Kasabach-Merritt phenomenon (KMP) was present in 64 (40.3%), and only two patients were deceased (1.3%). Over 60% (n = 96) demonstrated treatment response at 3 months, and more than 70% (n = 114) by 6 months (no significant difference across groups). The vincristine group had higher radiologic response at 3 months compared to sirolimus (72.7% vs. 20%, p = .03), but there were no differences between these groups at 6 months. There were no differences in rates of recurrent or progressive disease between vincristine and sirolimus. CONCLUSIONS: In this large, multicenter cohort of 159 patients with KHE/TA, rates of KMP were consistent with historical literature, but the mortality rate (1.3%) was much lower. Overall treatment response rates were high (>70%), and there was no significant difference in treatment response or durability of disease comparing sirolimus to vincristine. Our results support individualized treatment decision plans depending on clinical scenario and patient/physician preferences. Response criteria and response rates reported here will be useful for guiding future treatment protocols for vascular tumors.
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Hemangioendotelioma , Hemangioma , Síndrome de Kasabach-Merritt , Sarcoma de Kaposi , Neoplasias Cutáneas , Neoplasias Vasculares , Niño , Humanos , Síndrome de Kasabach-Merritt/tratamiento farmacológico , Síndrome de Kasabach-Merritt/patología , Vincristina , Estudios Prospectivos , Hemangioendotelioma/tratamiento farmacológico , Hemangioendotelioma/patología , Sarcoma de Kaposi/patología , Sirolimus/uso terapéuticoRESUMEN
PURPOSE: PIK3CA-related overgrowth spectrum (PROS) encompasses several rare conditions resulting from activating variants in PIK3CA. Alpelisib, a PI3Kα-selective inhibitor, targets the underlying etiology of PROS, offering a novel therapeutic approach to current management strategies. This study evaluated the safety and efficacy of alpelisib in pediatric and adult patients with PROS. METHODS: EPIK-P1 (NCT04285723) was a non-interventional, retrospective chart review of 57 patients with PROS (≥2 years) treated with alpelisib through compassionate use. Patients had severe/life-threatening PROS-related conditions and confirmed PIK3CA pathogenic variant. The primary end point assessed patient response to treatment at Week 24 (6 months). RESULTS: Twenty-four weeks (6 months) after treatment initiation, 12 of 32 (37.5%) patients with complete case records included in the analysis of the primary end point experienced a ≥20% reduction in target lesion(s) volume. Additional clinical benefit independent from lesion volume reduction was observed across the full study population. Adverse events (AEs) and treatment-related AEs were experienced by 82.5% (47/57) and 38.6% (22/57) of patients, respectively; the most common treatment-related AEs were hyperglycemia (12.3%) and aphthous ulcer (10.5%). No deaths occurred. CONCLUSION: EPIK-P1 provides real-world evidence of alpelisib effectiveness and safety in patients with PROS and confirms PI3Kα as a valid therapeutic target for PROS symptom management.
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Tiazoles , Adulto , Humanos , Niño , Estudios Retrospectivos , Mutación , Tiazoles/efectos adversos , Fosfatidilinositol 3-Quinasa Clase I/genéticaRESUMEN
Vascular anomalies are malformations or tumors of the blood or lymphatic vasculature and can be life-threatening. Although molecularly targeted therapies can be life-saving, identification of the molecular etiology is often impeded by lack of accessibility to affected tissue samples, mosaicism or insufficient sequencing depth. In a cohort of 356 participants with vascular anomalies, including 104 with primary complex lymphatic anomalies (pCLAs), DNA from CD31+ cells isolated from lymphatic fluid or cell-free DNA from lymphatic fluid or plasma underwent ultra-deep sequencing thereby uncovering pathogenic somatic variants down to a variant allele fraction of 0.15%. A molecular diagnosis, including previously undescribed genetic causes, was obtained in 41% of participants with pCLAs and 72% of participants with other vascular malformations, leading to a new medical therapy for 63% (43/69) of participants and resulting in improvement in 63% (35/55) of participants on therapy. Taken together, these data support the development of liquid biopsy-based diagnostic techniques to identify previously undescribed genotype-phenotype associations and guide medical therapy in individuals with vascular anomalies.
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Anomalías Linfáticas , Malformaciones Vasculares , Humanos , Mutación , Pruebas Genéticas/métodos , Malformaciones Vasculares/diagnóstico , Malformaciones Vasculares/genética , Malformaciones Vasculares/terapia , Alelos , Anomalías Linfáticas/genética , GenómicaRESUMEN
Complex lymphatic anomalies are debilitating conditions characterized by aberrant development of the lymphatic vasculature (lymphangiogenesis). Diagnosis is typically made by history, examination, radiology, and histologic findings. However, there is significant overlap between conditions, making accurate diagnosis difficult. Recently, genetic analysis has been offered as an additional diagnostic modality. Here, we describe four cases of complex lymphatic anomalies, all with PIK3CA variants but with varying clinical phenotypes. Identification of PIK3CA resulted in transition to a targeted inhibitor, alpelisib. These cases highlight the genetic overlap between phenotypically diverse lymphatic anomalies.
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Kaposiform lymphangiomatosis (KLA) is a life-threatening rare disease that can cause substantial morbidity, mortality, and social burdens for patients and their families. Diagnosis often occurs long after initial symptoms, and there are few centers in the world with the expertise to diagnose and care for patients with the disease. KLA is a lymphatic anomaly and significant advancements have been made in understanding its pathogenesis and etiology since its first description in 2014. This review provides multidisciplinary, comprehensive, and state-of-the-art information on KLA patient presentation, diagnostic imaging, pathology, organ involvement, genetics, and pathogenesis. Finally, we describe current therapeutic approaches, important areas for research, and challenges faced by patients and their families. Further insights into the pathogenesis of KLA may advance our understanding of other vascular anomalies given that similar signaling pathways may be involved.
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Anomalías Linfáticas , Humanos , Transducción de SeñalRESUMEN
Background: To describe the dynamic contrast magnetic resonance lymphangiography (DCMRL) findings of three patients with complicated lymphatic anomaly (CLA) and protein losing enteropathy. We further discuss the importance of a multicompartment (intrahepatic [IH], intramesenteric [IM], and intranodal [IN]) DCMRL in delineating central lymphatic flow pathologies. Methods and Results: This is a retrospective study of three patients-one adult and two children who individually underwent the three-compartment DCMRL, namely IN-DCMRL, IH-DCMRL, and IM-DCMCRL. Findings from the results of the DCMRL for these three patients were obtained from the medical records and compared. Using the multicompartment imaging modalities, chylous fluid leakage into the peritoneum was observed using IM-DCMRL and IH-DCMRL but not IN-DCMRL for one of the patients in the case series. In contrast, leakage of chyle into the mediastinum was noted using IN-DCMRL but not IH-DCMRL and IM-DCMRL on another patient in this case series. Conclusion: Owing to the variability in outlining lymphatic flow pathologies, multicompartment imaging gives a more global picture of individual conduction disorders, has the potential to improve clinical assessment, and in some cases leads to a diagnosis of the abnormality and thus provides a better understanding of lymphatic flow anomalies in patients with CLAs.
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Anomalías Linfáticas , Linfografía , Niño , Adulto , Humanos , Linfografía/métodos , Estudios Retrospectivos , Medios de Contraste , Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia MagnéticaRESUMEN
The lymphatic system plays an integral part in fluid homeostasis. Disturbances in lymphatic pathways are congenital, posttraumatic, or posttreatment related, such as after Fontan palliation. Lymphatic pathway evaluation is challenging because of the difficulty in introducing contrast material into the lymphatics. Intranodal, intramesenteric, and intrahepatic dynamic contrast-enhanced MR lymphangiography (DCMRL) offer better visualization of major lymphatic pathways. However, these techniques exclude pathways outside the central conduction system, preventing the visualization of abnormalities and, thus, administration of treatment. The authors describe alternative imaging of an axillary pathway via DCMRL in a patient with a symptomatic chylous effusion not previously assessed with current techniques. Keywords: Lymphatic, MR-Dynamic Contrast Enhanced, Pediatrics, Thorax, Pleura Supplemental material is available for this article. © RSNA, 2022.
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Kaposiform hemangioendothelioma is classified as a locally aggressive vascular tumor of childhood resulting from abnormal angiogenesis and lymphangiogenesis. Most commonly, KHE presents as a single tissue mass, ranging from an erythematous papule to a violaceous indurated tumor. Definitive diagnosis requires tissue sampling with the demonstration of ill-defined nodules and fascicles of spindle-shaped D2-40 positive endothelial cells, forming slit-like vascular channels. This newborn presented with multifocal cutaneous Kaposiform hemangioendothelioma associated with Kasabach-Merritt phenomenon confirmed on histopathology with immunostaining.
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Hemangioendotelioma , Síndrome de Kasabach-Merritt , Sarcoma de Kaposi , Recién Nacido , Humanos , Síndrome de Kasabach-Merritt/diagnóstico , Síndrome de Kasabach-Merritt/complicaciones , Células Endoteliales , Hemangioendotelioma/diagnóstico , Hemangioendotelioma/complicaciones , Sarcoma de Kaposi/diagnóstico , Sarcoma de Kaposi/complicacionesRESUMEN
OBJECTIVE: Clinical manifestations of blue rubber bleb nevus syndrome (BRBNS) and multifocal venous malformation (MVM) vary depending on the location of the lesions. The aim of this study was to assess the risk of developing CSF leaks in patients with epidural venous malformations (VMs). METHODS: The authors retrospectively investigated the relationship between the development of a CSF leak and the presence of epidural VMs. RESULTS: Nine patients (5 females) had epidural VMs and presentation that was confirmatory or suggestive of a CSF leak: 4 had BRBNS, 4 had MVMs, and 1 had a solitary VM. Of 66 patients with BRBNS, clinical and imaging features of CSF leak were noted in 3 (4.5%) with epidural VMs at the age of 11-44 years. A fourth patient had suggestive symptoms without imaging confirmation. An epidural blood patch was ineffective in 2 patients, both with more than one source of leakage, requiring surgical repair or decompression. Symptomatic downward displacement of the cerebellar tonsils was noted in 3 patients with MVM and 1 with a solitary VM; 3 required surgical decompression. CONCLUSIONS: These findings suggest an increased risk of CSF leak in patients with epidural VM, including BRBNS, MVMs, and solitary VMs. Awareness of the association between epidural VM and CSF leakage may facilitate earlier diagnosis and therapeutic intervention.
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Kaposiform lymphangiomatosis is an uncommon generalized lymphatic anomaly with distinctive clinical, radiologic, histopathologic, and molecular findings. Herein, we document the pathology in 43 patients evaluated by the Boston Children's Hospital Vascular Anomalies Center from 1999 to 2020. The most frequent presentations were respiratory difficulty, hemostatic abnormalities, and a soft tissue mass. Imaging commonly revealed involvement of some combination of mediastinal, pulmonary, pleural, and pericardial compartments and most often included spleen and skeleton. Histopathology was characterized by dilated, redundant, and abnormally configured lymphatic channels typically accompanied by dispersed clusters of variably canalized, and often hemosiderotic, spindled lymphatic endothelial cells that were immunopositive for D2-40, PROX1, and CD31. An activating lesional NRAS variant was documented in 9 of 10 patients. The clinical course was typically aggressive, marked by hemorrhage, thrombocytopenia, diminished fibrinogen levels, and a mortality rate of 21%.
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Células Endoteliales , Pulmón , Boston , Niño , HumanosRESUMEN
Vascular anomalies (VAs) are a heterogeneous group of primarily congenital tumors and malformations. The International Society for the Study of Vascular Anomalies (ISSVA) has developed a standard classification of these disorders, creating a uniform approach to their diagnosis. Recent discoveries evaluating the genetic causes of VAs have revealed that they are due to mutations in cancer pathways, including the PI3K/AKT/mTOR and RAS/MAPK/MEK pathways. These discoveries have led to improved phenotype-genotype correlation and have expanded medical therapy for this group of unique disorders.
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Sirolimus , Malformaciones Vasculares , Humanos , Mutación , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sirolimus/uso terapéutico , Malformaciones Vasculares/tratamiento farmacológico , Malformaciones Vasculares/genética , Malformaciones Vasculares/patologíaRESUMEN
Central conducting lymphatic anomaly (CCLA), characterized by the dysfunction of core collecting lymphatic vessels including the thoracic duct and cisterna chyli, and presenting as chylothorax, pleural effusions, chylous ascites, and lymphedema, is a severe disorder often resulting in fetal or perinatal demise. Although pathogenic variants in RAS/mitogen activated protein kinase (MAPK) signaling pathway components have been documented in some patients with CCLA, the genetic etiology of the disorder remains uncharacterized in most cases. Here, we identified biallelic pathogenic variants in MDFIC, encoding the MyoD family inhibitor domain containing protein, in seven individuals with CCLA from six independent families. Clinical manifestations of affected fetuses and children included nonimmune hydrops fetalis (NIHF), pleural and pericardial effusions, and lymphedema. Generation of a mouse model of human MDFIC truncation variants revealed that homozygous mutant mice died perinatally exhibiting chylothorax. The lymphatic vasculature of homozygous Mdfic mutant mice was profoundly mispatterned and exhibited major defects in lymphatic vessel valve development. Mechanistically, we determined that MDFIC controls collective cell migration, an important early event during the formation of lymphatic vessel valves, by regulating integrin ß1 activation and the interaction between lymphatic endothelial cells and their surrounding extracellular matrix. Our work identifies MDFIC variants underlying human lymphatic disease and reveals a crucial, previously unrecognized role for MDFIC in the lymphatic vasculature. Ultimately, understanding the genetic and mechanistic basis of CCLA will facilitate the development and implementation of new therapeutic approaches to effectively treat this complex disease.
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Quilotórax , Vasos Linfáticos , Linfedema , Factores Reguladores Miogénicos , Animales , Quilotórax/genética , Quilotórax/metabolismo , Células Endoteliales , Femenino , Humanos , Hidropesía Fetal/genética , Hidropesía Fetal/metabolismo , Vasos Linfáticos/patología , Linfedema/genética , Linfedema/metabolismo , Ratones , Factores Reguladores Miogénicos/genética , EmbarazoRESUMEN
Noonan syndrome is a disorder characterized by central and peripheral lymphatic conducting anomalies, leading to chylothorax, chylous ascites, and metabolic derangement. Novel imaging methods, including dynamic contrast magnetic resonance lymphangiography and intranodal lymphangiography, have allowed for increased visualization of lymphatic pathology. Severe pulmonary insufficiency and chylothoraces developed in a 61-year-old man with Noonan syndrome. Dynamic contrast magnetic resonance lymphangiography and intranodal lymphangiography demonstrated central thoracic duct (TD) occlusion. The patient's condition significantly improved after a microsurgical TD-venous anastomosis assisted by TD catheterization for imaging guidance, resulting in decompression of the lymphatic system and resolution of the pulmonary symptoms.
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Quilotórax , Anomalías Linfáticas , Síndrome de Noonan , Insuficiencia Respiratoria , Anastomosis Quirúrgica , Quilotórax/diagnóstico , Quilotórax/etiología , Quilotórax/cirugía , Humanos , Anomalías Linfáticas/complicaciones , Anomalías Linfáticas/diagnóstico , Anomalías Linfáticas/cirugía , Linfografía/métodos , Masculino , Persona de Mediana Edad , Síndrome de Noonan/complicaciones , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/cirugía , Insuficiencia Respiratoria/diagnóstico , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/cirugía , Conducto Torácico/patología , Conducto Torácico/cirugíaRESUMEN
Parkes Weber syndrome is a vascular malformation overgrowth condition typically involving the legs. Its main features are diffuse arteriovenous fistulas and enlargement of the limb. The condition has been associated with pathogenic germline variants in RASA1 and EPHB4 We report two individuals with Parkes Weber syndrome of the leg and primary lymphedema containing a somatic KRAS variant (NM_004985.5:c.35G > A; p.Gly12Asp). KRAS variants, which cause somatic intracranial and extracranial arteriovenous malformations, also result in Parkes Weber syndrome with lymphatic malformations.
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Fístula Arteriovenosa , Malformaciones Arteriovenosas , Linfedema , Síndrome de Sturge-Weber , Humanos , Proteínas Proto-Oncogénicas p21(ras) , Proteína Activadora de GTPasa p120RESUMEN
BACKGROUND: Nonmalignant vascular anomalies (VA) comprise a heterogeneous spectrum of conditions characterized by aberrant growth or development of blood and/or lymphatic vessels and can cause significant morbidity. Little is known about outcomes after radiotherapy in pediatric and young adult patients with nonmalignant VA. METHODS: Thirty patients who were diagnosed with nonmalignant VA and treated with radiotherapy prior to 2017 and before the age of 30 were identified. Clinical and treatment characteristics and outcomes were recorded. RESULTS: Median age at first radiotherapy was 15 years (range 0.02-27). Median follow-up from completion of first radiotherapy was 9.8 years (range 0.02-67.4). Lymphatic malformations (33%), kaposiform hemangioendothelioma (17%), and venous malformations (17%) were the most common diagnoses. The most common indication for first radiotherapy was progression despite standard therapy and/or urgent palliation for symptoms (57%). After first radiotherapy, 14 patients (47%) had a complete response or partial response, defined as decrease in size of treated lesion or symptomatic improvement. After first radiotherapy, 27 (90%) required additional treatment for progression or recurrence. Long-term complications included telangiectasias, fibrosis, xerophthalmia, radiation pneumonitis, ovarian failure, and central hypothyroidism. No patient developed secondary malignancies. At last follow-up, three patients (10%) were without evidence of disease, 26 (87%) with disease, and one died of complications (3.3%). CONCLUSIONS: A small group of pediatric and young adult patients with nonmalignant, high-risk VA experienced clinical benefit from radiotherapy with expected toxicity; however, most experienced progression. Prospective studies are needed to characterize indications for radiotherapy in VA refractory to medical therapy, including targeted inhibitors.