Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition.

Arteriovenous malformations (AVM) are benign vascular anomalies prone to pain, bleeding, and progressive growth. AVM are mainly caused by mosaic pathogenic variants of the RAS-MAPK pathway. However, a causative variant is not identified in all patients. Using ultra-deep sequencing, we identified novel somatic RIT1 delins variants in lesional tissue of three AVM patients. RIT1 encodes a RAS-like protein that can modulate RAS-MAPK signaling. We expressed RIT1 variants in HEK293T cells, which led to a strong increase in ERK1/2 phosphorylation. Endothelial-specific mosaic overexpression of RIT1 delins in zebrafish embryos induced AVM formation, highlighting their functional importance in vascular development. Both ERK1/2 hyperactivation in vitro and AVM formation in vivo could be suppressed by pharmacological MEK inhibition. Treatment with the MEK inhibitor trametinib led to a significant decrease in bleeding episodes and AVM size in one patient. Our findings implicate RIT1 in AVM formation and provide a rationale for clinical trials with targeted treatments.

Treatment practices and response in kaposiform hemangioendothelioma: A multicenter cohort study.

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.

Next generation sequencing aids diagnosis and management in a case of encephalocraniocutaneous lipomatosis.

Encephalocraniocutaneous lipomatosis (ECCL) is a rare neurocutaneous disorder caused by somatic FGFR1 and KRAS variants. It shares significant phenotypic overlap with several closely related disorders caused by mutations in the RAS-MAPK pathway (mosaic RASopathies). We report a diagnostically challenging case of ECCL in which next-generation sequencing of affected tissue identified a pathologic FGFR1 p.K656E variant, thereby establishing a molecular diagnosis. Patients with FGFR1-associated ECCL carry a risk of developing malignant brain tumors; thus, genetic testing of patients with suspected ECCL has important management implications.

How we approach the use of sirolimus and new agents: Medical therapy to treat vascular anomalies.

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.

Splenic Lymphatic Malformation With Papillary Endothelial Proliferation: A Rare Histologic Variant or a Unique Entity?

Lymphatic malformations (LMs) are congenital anomalies of the lymphatic system due to abnormalities that occur during the development of the lymphovascular system. Also known as lymphangiomas, they are usually multifocal, affect multiple organ systems, and are seen in a variety of developmental or overgrowth syndromes. Splenic lymphangiomas are uncommon and usually occur in the context of multiorgan lymphangiomatosis. Within the spleen, 7 prior cases have been reported of LMs with unusual papillary endothelial proliferations (PEPs), which can mimic more aggressive splenic lymphovascular tumors. It is not currently known if splenic LM-PEP represents a unique entity, or is simply an unusual, site-specific, morphologic variant of LM. To address this question, we conducted a retrospective, single-institutional review of this rare entity and systematically evaluated its clinical, histologic, radiologic, electron microscopical, and molecular features. In all 3 splenic LM-PEPs, the clinical course was benign, imaging demonstrated subcapsular lesions with characteristic "spoke-and-wheel" appearance, histology showed distinctive PEPs within lymphatic microcysts, immunohistochemistry confirmed a lymphatic endothelial phenotype and electron microscopy demonstrated lesional endothelial cells, rich in mitochondria and intermediate filaments with prominent cytoplasmic lumina and vacuoles and lacking Weibel-Palade granules. Occasional lymphothelial cells were situated within the cytoplasm of another lesional cell, appearing to be engulfed. Next-generation sequencing identified a PIK3CA mutation in 1 patient, while in 2 others no molecular alterations were identified. We conclude with a summary of all prior published cases and discuss key diagnostic elements that distinguish this benign entity from its more aggressive mimickers.

African American patient experiences with a rapid HIV testing program in an urban public clinic.

BACKGROUND: Of 1174 new human immunodeficiency virus (HIV) cases diagnosed in Philadelphia, Pennsylvania, in 2008, a total of 771 (66%) were among African Americans. Philadelphia recently introduced a citywide rapid HIV testing program in public clinics. METHODS: We conducted a qualitative study among 60 African Americans undergoing rapid HIV testing in one of Philadelphia's public clinics located in a zip code with high HIV incidence. Employing grounded theory, we used semistructured interviews to assess patients' motivations, perceptions, and clinical experiences with rapid HIV testing. Interviews were transcribed and coded; 20% were double coded to enhance reliability. RESULTS: Primary motivations for undergoing rapid HIV testing included: testing during routine clinical care, presenting for care with symptomatic sexually transmitted infections or opportunistic infections, knowing someone living with HIV/ AIDS, and perceiving oneself at risk for HIV. Most patients reported positive experiences with rapid testing and preferred it to conventional testing because it eliminated the need for return visits and decreased anxiety; however, many expressed concerns about accuracy of rapid HIV testing. Barriers to HIV testing among this population included low self-perceived risk, HIV stigma, and reported homophobia in respondents' communities. CONCLUSION: This rapid testing program was acceptable, convenient, and preferred over conventional HIV testing. Providing educational information about rapid and confirmatory HIV testing may further enhance acceptability of rapid HIV testing in this population. Nationwide expansion of rapid HIV testing in public health centers is an important and acceptable means of achieving President Obama's National AIDS Strategy goals of reducing racial disparities in HIV infection and improving linkage to HIV/AIDS treatment and care services.

A precision medicine approach to hereditary hemorrhagic telangiectasia and complex vascular anomalies.

Vascular anomalies represent a diverse group of disorders classified broadly as malformations or tumors and include the second most common hereditary bleeding disorder worldwide, hereditary hemorrhagic telangiectasia (HHT). Patients with HHT and other vascular anomalies suffer morbid consequences of these diseases, including bleeding, thrombosis, anemia, localized intravascular coagulation, tissue overgrowth, infections, and other complications. 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, and the treatments for vascular anomalies are rapidly evolving. Recent discoveries have elucidated the molecular basis of a number of common and uncommon vascular anomalies. HHT occurs due to mutations in the transforming growth factor beta (TGF-ß) pathway, resulting in vascular endothelial growth factor excess. Complex vascular anomalies including Klippel-Trénaunay syndrome (KTS) and arteriovenous malformation (AVM) may occur due to mutations in the PI3K/AKT/mTOR and RAS/MAPK/MEK pathways. The discovery of the pathophysiologic mechanisms driving these diseases has led to improved phenotype-genotype correlation and the opportunity to target molecular pathways with medical therapies. Therefore, targeted agents have quickly become a standard of care in the treatment of vascular disorders (particularly HHT). Herein, we provide a case-based approach to the use of antiangiogenic therapies including bevacizumab and pazopanib for the treatment of bleeding in HHT and the use of mammalian target of rapamycin (sirolimus), PIK3CA (alpelisib), and MEK (trametinib) inhibitors in the treatment of complex vascular anomalies.

Cerebrospinal fluid leak in epidural venous malformations and blue rubber bleb nevus syndrome.

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.

Kaposiform Lymphangiomatosis: Pathologic Aspects in 43 Patients.

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%.