At the recent 2024 World ISSVA Conference(May 7-10), groundbreaking research on lymphatic malformation models and therapeutic advancements took center stage. This blog post delves into key studies presented at the event, highlighting significant discoveries and potential treatments for complex lymphatic anomalies. From pharmacological inhibition in KRAS-driven zebrafish models to high-throughput drug screening in Kaposiform lymphangiomatosis (KLA), researchers showcased innovative approaches that promise to enhance our understanding and management of these challenging conditions. Explore how these studies are paving the way for more effective, personalized therapies, offering hope to patients affected by lymphatic anomalies.
Assessing pharmacological inhibition and defining pathogenesis in KRAS-driven zebrafish lymphatic malformation models
The research on KRAS-driven zebrafish lymphatic malformation models has identified key genes such as angpt2a and gna14 that are upregulated, enhancing the understanding of KRAS pathogenesis and suggesting these could serve as biomarkers for future clinical trials. The study highlights that targeting alternative pathways, including Notch signaling, may offer new therapeutic avenues, and preliminary findings indicate that allele-specific KRAS inhibitors show greater efficacy compared to MEK inhibitors. This work lays the foundation for developing more effective and personalized treatments for individuals with KRAS-related complex lymphatic anomalies.
A high throughput zebrafish chemical screen identifies Pan-AKT and tyrosine kinase as novel candidate treatment for Kaposiform Lymphangiomatosis (KLA)
The study developed two zebrafish models with NRAS Q61R mutations to mimic Kaposiform Lymphangiomatosis (KLA), successfully replicating the disease's clinical features, including pronounced pericardial edema and severe lymphatic vessel abnormalities. Through high-throughput chemical screening, 130 drugs were tested, resulting in 36 potential therapeutic hits, notably including receptor tyrosine kinase, PI3K, and MEK inhibitors. Trametinib, GSK690693, and Cabozantinib were validated as effective in reversing lymphatic defects and normalizing endothelial cell behavior. This research highlights the efficacy of these models for drug discovery, identifying promising candidates for KLA treatment.
Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function
This study investigates the role of KRAS mutations in complex lymphatic anomalies (CLAs), revealing that hyperactive KRAS/MAPK signaling disrupts lymphatic vessel development and maturation. Using Lyve1-Cre mice and human lymphatic endothelial cells (LECs), the research demonstrates that active KRAS mutations lead to enlarged lymphatic vessels and abnormal cell behaviors. However, inhibiting MAPK signaling with trametinib or expressing a dominant-negative form of MEK1 mitigates these effects, normalizing cell morphology, reducing proliferation, and enhancing vessel maturation. These findings support the potential of MEK inhibitors as a therapeutic option for CLA patients.
Precision Engineering of Patient-Specific Lymphatic Malformation Models Reveals Alpelisib Responsiveness and Unveils Non-Hot Mutations in the PI3K/Akt/mTOR Pathway
This study explores the role of non-hotspot mutations (NHMs) in the progression, recurrence, and drug resistance of lymphatic malformations (LMs). Using patient-matched LM organoids (LMOs) and a precision medicine approach, the research examines the response of these organoids to PI3K/Akt/mTOR inhibitors. While treatments with alpelisib and sirolimus showed limited effects on cell viability, alpelisib significantly regressed sprouts in certain LMO samples. The study identified key NHMs, including the missense I391M mutation in the kinase domain of pik3ca, linked to better responses to alpelisib. This platform highlights the importance of understanding genetic heterogeneity in LMs, suggesting that personalized genomic data can predict treatment responses and outcomes in patients.
Kaposiform Lymphangiomatosis (KLA): Update on clinical features, treatment approach, and use of targeted medical therapy
This study reviewed clinical features and treatment outcomes for 57 patients with Kaposiform lymphangiomatosis (KLA), a rare and aggressive lymphatic anomaly. Historically managed with supportive care, new therapies like mTOR and MEK inhibitors have emerged. The findings indicate that sirolimus treatment significantly improves five-year overall survival (97%) compared to non-treatment (56%). Genetic mutations, particularly in NRAS and KRAS, were identified in some patients. While sirolimus showed significant benefits, some patients experienced disease progression or toxicity, leading to alternative treatments like trametinib and selumetinib. This study underscores the promise of molecular diagnostics and targeted therapies, highlighting the need for further research into their safety and efficacy in treating KLA.
Utility of cfDNA in comprehensive genomic profiling of complex vascular anomalies
This study investigated the use of comprehensive genomic analyses, including cell-free DNA (cfDNA), to enhance molecular diagnosis and guide medical therapies for complex vascular anomalies. Evaluating 358 individuals, researchers employed various genomic techniques on DNA from blood, saliva, tissue, lymph nodes, and cfDNA from plasma and lymphatic fluid. Pathogenic germline and somatic variants were identified in 203 individuals, revealing new genotype-phenotype associations. Notably, cfDNA from peripheral blood detected somatic variants in 24 patients who could not undergo tissue biopsy, thus enabling molecular diagnosis and targeted therapy. The study highlights cfDNA's high diagnostic yield, particularly in patients with extensive disease, and demonstrates that cfDNA sampling post-treatment can improve molecular diagnostic rates. This approach offers a promising and less invasive alternative for genetic testing, expanding the ability to detect somatic variants and inform targeted therapeutic strategies.
MEK inhibition restores dysregulated genes in human endothelial cells expressing the NRAS Q61R mutation identified in kaposiform lymphangiomatosis
This study focuses on Kaposiform lymphangiomatosis (KLA), characterized by malformed lymphatic channels and elevated Angiopoietin-2 (Ang-2) levels. Researchers used human endothelial progenitor cells (EPC) expressing the NRAS Q61R mutation to identify dysregulated genes and pathways via RNA sequencing. The efficacy of three MEK inhibitors—trametinib, selumetinib, and cobimetinib—on abnormal endothelial spindling and Ang-2 expression was also assessed. RNA sequencing revealed significant gene dysregulation in MAPK signaling, angiogenesis, and coagulation pathways in NRAS Q61R EPC. Trametinib corrected a portion of these gene dysregulations, prevented EPC spindling, and significantly reduced Ang-2 production at lower doses than selumetinib and cobimetinib. This study highlights the MAPK pathway's role in KLA pathology and supports the use of trametinib for reducing abnormal cell behavior and Ang-2 levels in KLA treatment.
Clinical features and advances in treatment of Gorham-Stout disease: a systematic review
This study focuses on Gorham-Stout disease (GSD), a subtype of complex lymphatic malformation with limited research, complicating diagnosis and treatment. By systematically reviewing literature from the past decade, the researchers analyzed clinical features of 222 GSD patients. The study established four diagnostic criteria: lymphangiectasia in biopsy without cytotypy, imaging evidence of bone destruction, locally progressive bone resorption with minimal osteogenic reaction, and negative results for genetic, metabolic, tumor, immune, and infection etiologies. The findings show a slightly higher incidence in males, primarily affecting children and adolescents, with common involvement of the vertebrae, ribs, and pelvic bones. Pain is the most frequent symptom. Post-treatment, 96 patients were stable, while 12 died from severe complications. This study provides essential insights into the clinical characteristics and prognosis of GSD, underscoring the need for further research to improve diagnosis and management.
Improvement of histopathological diagnostics of vascular anomalies through spatial deep-phenotyping using non-destructive 3D histopathology
This study presents an innovative 3D histopathology approach using non-destructive volumetric Light-sheet microscopy, addressing the limitations of conventional 2D slide-based histopathological analysis. This new method allows for rapid, slide-free imaging of entire tissue samples, providing detailed volumetric analysis of diagnostic structures such as immune cells and vessels, and improved spatial analysis of cell distribution. The researchers developed a fluorescence-based analogue of the traditional hematoxylin and eosin (H&E) staining suitable for Light-sheet microscopy, combined with advanced staining protocols to detect relevant markers. This technique not only offers cutting-edge diagnostic phenotyping but also preserves samples for downstream molecular diagnostics. The approach has led to the identification of new vascular phenotypes, potentially improving histological classification. In conclusion, this 3D histopathology method enhances the accuracy and detail of tissue diagnoses, with the potential to become the new gold standard in histopathological analysis.
LYVE1-Driven Expression of NRAS Q61R in Mouse Embryos Causes Edema, Hepatic Vascular Defects, and Abnormal Lymphatic Structures Incompatible with Life
This study aims to understand the role of the NRAS Q61R mutation in the pathogenesis of Kaposiform lymphangiomatosis (KLA), a complex lymphatic anomaly with poor prognosis and severe complications like hemorrhagic effusions and coagulopathy. Researchers developed a novel mouse model by targeting NRAS Q61R expression to the lymphatic endothelium using LYVE1-Cre+/+ and Lox-Stop-Lox-NRAS Q61R+/- mice. The resulting NRAS Q61R embryos did not survive birth, showing significant edema, abnormal blood-filled vessels, hemorrhage, and abnormalities in abdominal organs. Histological analysis revealed hepatic vascular anomalies and irregular cell clusters in the jugular lymph sacs. This novel mouse model demonstrates that constitutive LYVE1-driven expression of NRAS Q61R during embryonic development leads to severe vascular anomalies incompatible with postnatal life, providing a valuable tool for further understanding the pathogenesis of KLA during prenatal development.
Expansion of the Phenotype of Lymphatic Anomalies Caused by Somatic Activating BRAF variants
This study aimed to expand the phenotypic understanding of the somatic BRAF p.V600E variant in individuals with vascular anomalies, following recent identifications of this variant in lymphatic malformations. By reviewing the database of individuals with vascular anomalies at the researchers' institution, five patients with the BRAF p.V600E variant were identified. These patients exhibited complex lymphatic anomalies, including mixed macrocystic/microcystic lymphatic malformations predominantly in the abdomen, retroperitoneum, pelvis, and chest. Central conducting lymphatic dysfunction developed in four patients following procedural interventions, raising questions about whether this was a primary anomaly or a secondary result of traumatic lymphatic disruption. This study highlights a new phenotype associated with the BRAF p.V600E variant, featuring extensive lymphatic malformations and central lymphatic conduction abnormalities, necessitating further investigation to improve multidisciplinary treatment approaches.
A Case of Kaposiform Lymphangiomatosis (KLA) Complicated by Kasabach-Merritt Phenomenon (KMP), Recurrent Pericardial Effusions, Multifocal Lytic Bone Lesions, and Pneumococcal Meningitis
This case report discusses the diagnostic and therapeutic challenges in treating Kaposiform lymphangiomatosis (KLA), a complex lymphatic anomaly with poor prognosis. A 6-year-old boy presented with bleeding symptoms, multifocal lytic bone lesions, pulmonary lymphangiectasia, and splenic lesions, and was diagnosed with KLA. Initially treated with sirolimus and zoledronic acid, he later developed recurrent pericardial effusions and was switched to trametinib after genetic testing revealed an NRAS Q61R mutation. Additional complications included Streptococcal pneumoniae meningitis and transient right hemiparesis. Despite these challenges, his most recent skeletal survey showed resolution of lytic lesions. This case highlights the diagnostic complexities, risk of functional asplenia, and the need for targeted therapies in managing KLA-associated complications.
Generalized lymphatic anomaly with pleomorphic bizarre cells
This case report focuses on complex lymphatic anomalies, specifically a 6-month-old male diagnosed with bilateral chylothorax. Imaging revealed multiple lesions in the right pectoral region, spleen, and bone. A biopsy of the pectoral lesion showed irregular thin-walled vessels lined by large, pleomorphic cells with smudgy chromatin, forming clusters inside the lumen. Diagnosed as a lymphatic malformation with degenerative atypia, the case highlights cytological features resembling those in ancient schwannoma or symplastic hemangioma, which can be mistaken for angiosarcoma. This report underscores the importance of comprehensive clinical and histopathological evaluation to avoid misdiagnosis.
Resolution of refractory coagulopathy in two cases of complex lymphatic anomaly following partial splenic embolisation
This report discusses two cases of complex lymphatic anomaly (CLA) with severe chronic thrombocytopenia that were resolved through partial splenic embolization. CLA is characterized by the proliferation of lymphatic vessels, disrupting normal tissue architecture and organ function, often accompanied by refractory coagulopathy. Case 1 involves a 19-year-old boy with CLA affecting multiple regions, including the spleen, who had chronic thrombocytopenia unresponsive to various medical treatments. Partial splenic embolization at age 4 resulted in the resolution of his thrombocytopenia. Case 2 describes a 17-year-old boy with NRAS p.Q61R CLA affecting several body regions, who also had chronic thrombocytopenia unresponsive to treatments like prednisolone and sirolimus. Partial splenic embolization at age 16 normalized his platelet count. These cases highlight partial splenic embolization as an effective intervention for resolving thrombocytopenia in CLA patients with splenic involvement, potentially eliminating the need for lifelong medical therapy.
Successful Management of Complex Lymphatic Malformation with Combination Therapy
This report examines nine cases of complex lymphatic anomalies (CLAs) that exhibited suboptimal responses to mTOR inhibitor therapy alone and required additional medical treatments to enhance therapeutic outcomes. The cases included eight children and one adult with lymphatic malformations (LM) affecting various regions such as the orbit, face and neck, chest wall, and more generalized areas. Initial sirolimus treatment was insufficient in controlling symptoms like pain, recurrent hemorrhage, and respiratory distress. Consequently, additional therapies, including trametinib (MEK inhibitor), sildenafil (PDE5 inhibitor), and propranolol (nonselective anti-angiogenic agent), were administered. The combination therapies resulted in improved clinical outcomes, including reduced swelling, pain, and hospitalization frequency. MRI scans showed a decrease in LM size in six cases and stability in three, with no disease progression reported. The combination therapies were well-tolerated without additional laboratory or clinical abnormalities. This case series highlights the importance of a personalized approach in managing CLAs, suggesting that incorporating medications with different mechanisms of action can synergistically improve clinical outcomes and prevent life-threatening events. Future larger-scale studies are needed to further evaluate the safety and efficacy of these therapeutic strategies.
