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Introduction: Venous malformations (VMs) are a prevalent type of congenital vascular disorder, affecting nearly 1% of the population. These low-flow vascular anomalies often lead to chronic swelling, pain, and mobility challenges, often interfering with a child’s daily life. Their development is mostly caused by genetic abnormalities in the TIE2/TEK and PIK3CA pathways, which cause poor venous remodeling and vascular proliferation. This study aims to assess the clinical manifestations, diagnostic methods, and therapeutic alternatives for pediatric venous malformations, emphasizing the effectiveness of different treatment modalities. Recognizing clinical presentations and understanding treatment outcomes are essential for improving early diagnosis and optimizing patient-centered care strategies. Materials and methods: Between 2019 and 2023, the Clinic for Pediatric Surgery in Skopje treated 38 pediatric patients with venous abnormalities. Patient demographics, lesion characteristics, and treatment options (including conservative management, sclerotherapy, and surgical intervention) were examined. Results: The majority of patients (39.5%) received conservative treatment, whereas 23.7% underwent sclerotherapy and 34.2% needed surgical intervention. Sclerotherapy results were evaluated according to lesion size. Treatment was effective for smaller lesions (<5 cm), while bigger or recurring cases required multiple treatment sessions. Conclusion: The results highlight the importance of early identification and individualized treatment strategies for pediatric venous malformations. Sclerotherapy is the primary therapeutic option for minor to moderate lesions, whereas surgical intervention is designated for symptomatic or refractory patients. A multidisciplinary approach is crucial for enhancing patient outcomes, and future research should focus on the advancement of minimally invasive therapeutic techniques and the exploration of targeted genetic medicines.

Alagille syndrome (ALGS) is an autosomal dominant disorder characterized by involvement of various organ systems. It predominantly affects the liver, skeleton, heart, kidneys, eyes and major blood vessels. With myriads of presentations across different age groups, ALGS is usually suspected in infants presenting with high gamma glutamyl transpeptidase cholestasis and/or congenital heart disease. In children it may present with decompensated cirrhosis, intellectual disability or short stature, and in adults vascular events like stroke or ruptured berry aneurysm are more commonly noted. Liver transplantation (LT) is indicated in children with cholestasis progressing to cirrhosis with decompensation. Other indications for LT include intractable pruritus, recurrent fractures, hepatocellular carcinoma and disfiguring xanthomas. Due to an increased risk of renal impairment noted in ALGS, these patients would require optimized renal sparing immunosuppression in the post-transplant period. As the systemic manifestations of ALGS are protean and a wider spectrum is being increasingly elucidated, a multidisciplinary team needs to be involved in managing these patients. Moreover, many basic-science and clinical questions especially with regard to its presentation and management remain unanswered. The aim of this review is to provide updated insights into the management of the multi-system involvement of ALGS.

Background Fibro-adipose vascular anomaly (FAVA) is a new entity of vascular anomalies with somatic and mosaic gain-of-function mutations of the phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA ). PIK3CA mutation excessively activates mammalian target of rapamycin (mTOR) pathway, which promotes angiogenesis and lymphangiogenesis. Histologically, FAVA is composed of intramuscular fibrous and adipose tissues with venous malformation (VM). Although sirolimus known as a mTOR inhibitor has good response to FAVA, expression pattern of the mTOR pathway was still unclear. Herein, we immunohistochemically investigated three novel FAVA patients with an emphasis on the mTOR pathway (p-S6K1, p-4EBP1 and p-AKT). Case presentation Case 1: A 10-year-old female had complained of pain in the left thigh since she was 6-year-old. Under the clinical diagnosis of VM, she underwent surgical resection for the lesion. Case 2: A 29-year-old female patient had complained of discomfort and mild pain in the left shoulder since she was 18-year-old. After childbirth, she had severe ongoing pain and contracture of the shoulder. Under clinical diagnosis of VM, surgical resection was performed. Case 3: A 53-year-old female had complained of pain and knee restriction after surgical treatment of a knee tumor at the age of 31. Under the clinical diagnosis of atypical lipomatous tumor or high grade liposarcoma, surgical resection was performed. Histologically, all three patients presented with characteristic features of fibrous and adipose tissues with abnormal vessels within the skeletal muscle, leading to diagnosis of FAVA. Although VM has been reported as an important finding in FAVA, immunohistological findings demonstrated that abnormal vessels comprised complex of VM and lymphatic malformation (LM) in all cases. Furthermore, besides vascular malformation, abnormal fibrous and adipose tissues of FAVA expressed mTOR pathway components. Conclusions We presented three new cases of FAVA. Histological and immunohistochemical analyses revealed that VM and LM complex was an important finding in FAVA, and that the mTOR pathway components were expressed in abnormal fibrous tissue, adipose tissue and vascular malformation. These findings suggested that FAVA might be a mesenchymal malformation caused by PI3K/AKT/mTOR pathway.

Fibro-adipose vascular anomaly (FAVA) is a rare and new entity of vascular anomaly. Activating mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene were identified at a frequency of 62.5% in FAVA cases. The PIK3CA mutations excessively activate mammalian target of rapamycin (mTOR) pathway, which promotes angiogenesis and lymphangiogenesis, implying that PIK3CA mutations may act as drivers of FAVAs. This study investigated the correlations between PIK3CA mutational status, clinicopathological features and immunohistochemical expression of the mTOR pathway in a series of FAVA. We retrospectively evaluated the clinical and pathological findings of four FAVA cases. We performed next-generation sequencing (NGS) with a custom panel of genes associated with the mTOR pathway and genes responsible for other vascular anomalies; followed by direct sequencing and immunohistochemical analysis of the mTOR pathway. Two PIK3CA-mutation cases and two PIK3CA-wild-type (wt) cases exhibited similar typical clinical features of FAVA. Histological analysis revealed venous malformation, lymphatic malformation, nerves containing enlarged abnormal vessels and fibrofatty tissue were observed regardless of PIK3CA mutational status. In contrast to clinical and histological findings, the immunohistochemical expression of activated AKT and mTOR that are upstream of the mTOR pathway was detected in abnormal vessels of PIK3CA-mutation cases but not in those of PIK3CA-wt cases. However, activated eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) and ribosomal protein S6 kinase 1 (S6K1), both of which are downstream effectors of the mTOR pathway, were expressed in abnormal vessels of both PIK3CA-mutation and PIK3CA-wt cases. Furthermore, targeting NGS did not find any common genetic mutations involved in the mTOR pathway among PIK3CA-wt cases. There was no significant association between the presence of PIK3CA mutations and the clinicopathological features of FAVA, suggesting that the PIK3CA gene is not necessarily involved in the onset of FAVA. FAVAs lacking PIK3CA mutations may be caused by other gene mutations that activate 4EBP1 and S6K1.

Objective: Vascular anomalies are a diverse group of lesions, ranging from simple to complex, disfiguring anomalies. Our objective was to diagnose and provide comprehensive treatment to patients presenting with vascular anomalies, using a multi-disciplinary approach involving dermatologists, plastic surgeons, radiologists and pediatric surgeons. Methods: Patients presenting with vascular anomalies to The Indus Hospital, Karachi, from January 2017 to March 2019 were enrolled, using a pre-defined questionnaire. Assessment, diagnostic work up, management and clinical and photographic follow up was maintained to monitor outcomes. Results: One hundred eighty seven patients with a mean age of 4.6 years, (females 62%) were enrolled. Diagnoses included vascular tumors (n=89, 47.6%), lymphatic malformations (n=38, 20.3%), capillary malformations (n=19, 10%), venous malformations (n=16, 8.5%), arterio-venous malformations (n=14, 7.5%) and mixed anomalies (n=11, 5.9%). Treatment modalities, in isolation or combination, included oral propranolol, topical timolol, pulsed dye laser and intra-lesional sclerotherapy. Mean follow up was in 7.1 months, with 27 patients achieving treatment completion. 26 children were lost to follow-up. Conclusions: Vascular anomalies have mostly been managed successfully at VAC using single or multimodal treatment. Increasingly complex anomalies can be handled using a multi-disciplinary approach. Establishment of VAC has facilitated many patients who were earlier considered as diagnostic and therapeutic challenges. doi: https://doi.org/10.12669/pjms.36.ICON-Suppl.1710 How to cite this:Mazhar A, Moosa S, Abbas A, Mallick Y, Samad L. A multi-disciplinary, multimodal approach for the management of vascular anomalies. Pak J Med Sci. Special Supplement ICON 2020. 2020;36(1):S14-S19. doi: https://doi.org/10.12669/pjms.36.ICON-Suppl.1710 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Ya-Hui Hu,1,* Wan-Xia Li,2,3,* Lin Fan,1,* Zhou Zhou,3,* Hong-Li Guo,1 Feng Chen,1 Jian-Jun Zou,3 Yi Ji,4 Jin Xu,1 Wei-Min Shen4 1Pharmaceutical Sciences Research Center, Department of Pharmacy, Children’s Hospital of Nanjing Medical University, Nanjing, 210008, China; 2School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China; 3Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China; 4Department of Burns and Plastic Surgery, Children’s Hospital of Nanjing Medical University, Nanjing, 210008, China*These authors contributed equally to this workCorrespondence: Yi Ji, Children’s Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, People’s Republic of China, Email summer035@hotmail.com Wei-Min Shen, Children’s Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, People’s Republic of China, Email swmswmswm@sina.comIntroduction: Sirolimus, also known as rapamycin, is an mTOR receptor inhibitor that suppresses cell proliferation and angiogenesis, demonstrating efficacy against multiple types of vascular anomalies. However, sub-therapeutic concentrations (below effective levels) and supra-therapeutic concentrations (leading to adverse reactions) of sirolimus may both negatively impact patient treatment outcomes. This study aimed to establish optimal models to predict the risk of sirolimus exposure using machine learning, ensure that sirolimus blood concentrations remain within the therapeutic range, and thus enhance the efficacy and safety of sirolimus therapy for children with vascular anomalies.Methods: We retrospectively analyzed 134 sirolimus therapeutic drug monitoring (TDM) measurements from 49 patients. Data were randomly split into training (80%) and testing (20%) sets, with an additional temporal cohort for external validation. Six machine learning models were developed to predict sub-therapeutic and supra-therapeutic risks, and evaluated primarily by the area under the receiver operating characteristic curve (AUROC) and Brier score. The optimal model was interpreted using SHapley Additive exPlanations (SHAP) analysis.Results: The sub-therapeutic risk model included body mass index (BMI), white blood cells (WBC), mean corpuscular hemoglobin (MCH), triglycerides (TG), and total bilirubin (TBIL); while the supra-therapeutic model comprised height, platelet count (PLT), alanine aminotransferase (ALT), high-density lipoprotein cholesterol (HDL), and total cholesterol (TC). The multilayer perceptron (MLP) and extreme gradient boosting (XGB) models showed optimal performance for sub-therapeutic (AUROC = 0.646, Brier = 0.190) and supra-therapeutic (AUROC = 0.825, Brier = 0.143) risk prediction, respectively, with consistent results in temporal validation (AUROC: 0.678, Brier = 0.190 and AUROC: 0.767, Brier = 0.190).Conclusion: This study is the first to use machine learning models to predict the risk of sub- or supra-therapeutic sirolimus concentrations in vascular anomalies children. By enabling personalized exposure risk prediction, the dosing accuracy of sirolimus for the treatment of children with vascular anomalies can be optimized, thereby enhancing effectiveness and safety.Keywords: sirolimus, vascular anomalies, machine learning, concentration risk prediction, children

Background Congenital anomalies of the aortic arch are important as they may be associated with vascular ring anomalies. The most common vascular ring anomaly in dogs is a persistent right aortic arch. However, published data of the distribution of the different types of vascular ring anomalies and other aortic arch anomalies are lacking. The objective of this retrospective descriptive study was to evaluate both the prevalence and the different types of aortic arch anomalies that can be detected using thoracic computed tomography (CT) examination. Archived thoracic CT examinations acquired between 2008 and 2020 at a single institution were retrospectively evaluated by 2 evaluators for the prevalence and type of aortic arch anomaly. Breed, age, and presenting complaint were obtained from the medical record system. Results A total of 213 CT studies were evaluated; 21 dogs (21/213, 9.9%) showed a right aortic arch and a left ligamentum arteriosum with compression of the esophagus. The following incidental additional findings were detected: aberrant left subclavian artery (17/21, 76.2%), branching from the persistent ductus arteriosus (PDA) (1/21, 4.8%), left-sided brachiocephalic trunk (3/21, 14.3%), bicarotid trunk (17/21, 81.0%), double aortic arch (1/21, 4.8%). One hundred ninety two dogs (192/213, 90.1%) showed a left aortic arch without esophageal compression. The following additional abnormalities were obtained in those dogs with left aortic arch: aberrant right subclavian artery (3/192, 1.6%) without clinical signs of esophageal compression, aberrant vessel branching from the aorta into the left caudal lung lobe (2/192, 1.0%), focal dilatation of the left or right subclavian artery (2/192, 1.0%), bicarotid trunk (1/192, 0.5%). Conclusion Similar to previous studies an aberrant left subclavian artery is the most common additional finding in dogs with persistent right aortic arch. Newly, a left-sided brachiocephalic trunk was identified in 14.3% of the dogs with a persistent right aortic arch; no additional compression was caused by the left sided brachiocephalic trunk. Similarly, aberrant right subclavian artery can be an incidental CT finding without causing compression of the esophagus.

Arteriovenous malformations are a vascular anomaly typically present at birth, characterized by an abnormal connection between an artery and a vein (bypassing the capillaries). These high flow lesions can vary in size and location. Therapeutic approaches are limited, and AVMs can cause significant morbidity and mortality. Here, we describe our current understanding of the pathogenesis of arteriovenous malformations based on preclinical and clinical findings. We discuss past and present accomplishments and challenges in the field and identify research gaps that need to be filled for the successful development of therapeutic strategies in the future.

Vascular anomalies include a heterogeneous group of disorders that are categorized as vascular tumors or vascular malformations. Treatment options include resection, embolization, laser therapy, and sclerotherapy or medical treatment such as propranolol, steroids, interferon, and cytostatic chemotherapy. Mammalian target of rapamycin seems to play a key role in the signal pathway of angiogenesis and subsequently in the development of vascular anomalies. Recently, the successful use of sirolimus has been reported in children with lymphatic malformations and kaposiform hemangioendotheliomas. We report on six patients with different vascular anomalies (kaposiform hemangioendothelioma n  = 2, combined lymphatico-venous malformation n  = 2, pulmonary lymphangiectasia n  = 1, and orbital lymphatic malformation n  = 1) who were treated with peroral sirolimus. Three of the children initially presented with a Kasabach-Merrit phenomenon. Median duration of treatment was 10 months; two children are still on treatment. Three children each achieved complete and partial remission. Kasabach-Merrit phenomenon resolved within 1 month in all patients. Treatment with sirolimus was tolerated well; only mild reversible leukopenia was observed. Conclusion : Sirolimus proved to be effective in children with complicated lymphatic or lymphatico-venous malformations and kaposiform hemangioendotheliomas. Treatment was tolerated well with acceptable side effects. The optimum length of treatment and possible long-term side effects have to be evaluated. What is Known: • Vascular anomalies including vascular tumors and vascular malformations may lead to life-threatening conditions . • Some patients are refractory to established treatment and/or are not available for local invasive procedures . What is New: • We reviewed the literature focusing treatment of vascular anomalies in children and adolescents . • Our data support recent studies that sirolimus is an effective treatment option in patients with complicated vascular tumors and malformations .