Practice Variations in Managing Infantile Hemangiomas.

Infantile hemangioma (IH) is the most common benign tumor of infancy. For children with IH who require treatment, propranolol and other beta blockers have been shown to be safe and effective. Although consensus guidelines for managing IH have been published, anecdotal experience suggests that there remain variations in management. This study was performed to document these variations amongst providers and to identify areas for future research. We conducted an Internet-based survey of clinicians who treat patients with IH. Hypothetical cases and management scenarios were presented. Twenty-nine respondents participated in the survey. Most respondents use generic propranolol in infants with growing IH of the head and neck, with a goal dose of 2 mg/kg/d, until ~1 year of age. A variety of management strategies were documented including which patients should be treated, optimal dose and duration of therapy, how patients should be monitored, which patients should get additional workup, how propranolol should best be discontinued, and how often to see patients in follow-up. This study demonstrates wide practice variations in managing patients with IH. Further research is indicated to address these variations and develop additional/updated evidence-based guidelines.

Repurposing of antiangiogenic agents for treatment of vascular anomalies.

Vascular anomalies (VA) are developmental anomalies of veins, arteries, lymphatics or capillaries thought to be caused by mutations in genes that drive angiogenesis. Treatments targeting these genes are limited. We review the literature for conventional medications and products from traditional medicine cultures that have been found to have antiangiogenic activity. Fewer than 50 drugs with credible human activity in VA were identified and include ß blockers, monoclonal antibodies, microtubule inhibitors, multi-kinase inhibitors, PIK3CA- and RAS-MAPK pathway inhibitors, and thalidomides. Other drug categories of potential interest are ACE-inhibitors, antifungals, antimalarials, MMP9-inhibitors, and over-the-counter compounds used in Eastern traditional medicine. Low toxicity for some offers the possibility of combined use with known effective agents. In addition to already familiar drugs, others with antiangiogenic capabilities already in use in children or adults may deserve further attention for repurposing for VA.

Vascular Anomalies Care in the United States: A Cross-Sectional National Survey.

OBJECTIVE: To characterize the current distribution, composition, and practice patterns of multidisciplinary vascular anomalies (VAs) teams in the US. STUDY DESIGN: This is a cross-sectional survey of children's hospitals in the US offering VAs care. We approached 142 children's hospitals that provided care for VAs via email. The survey evaluated VA clinic location, medical staffing, research participation, and treatments offered. The survey was administered between October 2021 and July 2022. RESULTS: Participants from 95 eligible hospitals responded to the survey (response rate = 67%). Large areas of the Midwest and Northwest US had no available multidisciplinary VA teams or clinics. Most respondents worked at academic centers (89%), with 66% at a freestanding children's hospital, and 56% reported having a multidisciplinary clinic. Most common physician participants in clinic included hematology-oncology (91%), interventional radiology (87%), dermatology (85%), plastic surgery (81%), and otolaryngology (74%). Only 38% of programs included medical geneticists. Smaller hospitals had fewer medical and ancillary staff and offered fewer therapeutic options. Research was available at most larger institutions (69%) but less commonly at smaller hospitals (34%). CONCLUSIONS: Major portions of the US lack multidisciplinary VA care. Furthermore, VA programs vary in composition and geneticists are absent from the majority of programs. These findings should inform efforts to address disparate access and develop standards of care for multidisciplinary VA care in the US.

Barriers to Genetic Testing in Vascular Malformations.

Importance: Vascular malformations (VMs) are rare disorders of vasculogenesis associated with substantial morbidity. Improved understanding of their genetic basis is increasingly guiding management, but logistical barriers to obtaining genetic testing in patients with VM may constrain treatment options. Objectives: To examine the institutional mechanisms for and obstacles to obtaining genetic testing for VM. Design, Setting, and Participants: This survey study invited members of the Pediatric Hematology-Oncology Vascular Anomalies Interest Group, representing 81 vascular anomaly centers (VACs) serving individuals up to 18 years of age, to complete an electronic survey. Respondents were mostly pediatric hematologists-oncologists (PHOs) but included geneticists, genetic counselors, clinic administrators, and nurse practitioners. Responses that were received between March 1 and September 30, 2022, were analyzed with descriptive methods. Requirements for genetic testing by several genetics laboratories were also reviewed. Results were stratified by size of the VAC. Main Outcomes and Measures: Vascular anomaly center and associated clinician characteristics and practice patterns for ordering and obtaining insurance approval for genetic testing for VMs were collected. Results: Responses were received from 55 of 81 clinicians, for a response rate of 67.9%. Most respondents were PHOs (50 [90.9%]). Most respondents (32 of 55 respondents [58.2%]) replied that they order genetic testing on 5 to 50 patients per year and reported a genetic testing volume increase of 2- to 10-fold over the past 3 years (38 of 53 respondents [71.7%]). Most testing was ordered by PHOs (35 of 53 respondents [66.0%]), followed by geneticists (28 [52.8%]) and genetic counselors (24 [45.3%]). In-house clinical testing was more common at large and medium-sized VACs. Small VACs were more likely to use oncology-based platforms, which potentially miss low-frequency allelic variants in VM. Logistics and barriers varied by size of the VAC. Obtaining prior authorization was the duty shared among PHOs, nurses, and administrative staff, but the burden of insurance denials and appeals were on PHOs (35 of 53 respondents [66.0%]). Lack of administrative support; unclear institutional, insurance, and laboratory requirements; and lack of clinician education were barriers to genetic testing at VACs of all sizes. The effort to obtain genetic testing for patients with VM, compared with patients with cancer, was perceived as excessive, despite genetic testing being considered standard of care for this population. Conclusions and Relevance: Results of this survey study showed the barriers to genetic testing for VM across VACs, described differences between VACs based on size, and proposed multiple interventions to support clinicians ordering genetic testing for VM. The results and recommendations should have broader application to clinicians caring for patients for whom molecular diagnosis is important to medical management.

Microphysiological model of PIK3CA-driven vascular malformations reveals a role of dysregulated Rac1 and mTORC1/2 in lesion formation.

Somatic activating mutations of PIK3CA are associated with development of vascular malformations (VMs). Here, we describe a microfluidic model of PIK3CA-driven VMs consisting of human umbilical vein endothelial cells expressing PIK3CA activating mutations embedded in three-dimensional hydrogels. We observed enlarged, irregular vessel phenotypes and the formation of cyst-like structures consistent with clinical signatures and not previously observed in cell culture models. Pathologic morphologies occurred concomitant with up-regulation of Rac1/p21-activated kinase (PAK), mitogen-activated protein kinase cascades (MEK/ERK), and mammalian target of rapamycin (mTORC1/2) signaling networks. We observed differential effects between alpelisib, a PIK3CA inhibitor, and rapamycin, an mTORC1 inhibitor, in mitigating matrix degradation and network topology. While both were effective in preventing vessel enlargement, rapamycin failed to reduce MEK/ERK and mTORC2 activity and resulted in hyperbranching, while inhibiting PAK, MEK1/2, and mTORC1/2 mitigates abnormal growth and vascular dilation. Collectively, these findings demonstrate an in vitro platform for VMs and establish a role of dysregulated Rac1/PAK and mTORC1/2 signaling in PIK3CA-driven VMs.

Response of Central Giant Cell Granuloma of the Jaw to Imatinib.

Central giant cell granuloma of the jaw (CGCJ) can be locally aggressive and result in facial and dental deformity. A child with CGCJ was treated surgically and with denosumab with a response but life-threatening toxicity. Imatinib, a tyrosine kinase inhibitor, was prescribed based on clinical similarities between CGCJ and cherubism, for which Imatinib has been effective. Within 2 months, a computed tomographic scan showed significant ossification, which increased over the following 8 months. This case suggests that tyrosine kinase inhibitors may be an effective option, and one with limited toxicity, for CGCJ.

How we approach complex vascular anomalies and overgrowth syndromes.

Vascular anomalies, both vascular tumors and vascular malformations, can occur in isolation or as part of syndromes including those which feature phenotypic overgrowth. To update what is known about vascular anomalies associated with overgrowth, PubMed was searched for "overgrowth syndromes and vascular anomalies or malformations." PubMed, OMIM, and the Rare Disease Database also were searched for specific diagnoses. We review individual overgrowth syndromes, provide a case-based approach to the clinical, radiographic, pathologic, and genetic basis for diagnosis, to complications of both the vascular anomalies and the overgrowth, and emphasize the need for a multidisciplinary approach to care.

Repurposing Psychotropic Agents for Viral Disorders: Beyond Covid.

Recent reports have highlighted the possible role of the antipsychotic chlorpromazine and the antidepressant fluvoxamine as anti-coronavirus disease 2019 (COVID-19) agents. The objective of this narrative review is to explore what is known about the activity of psychotropic medications against viruses in addition to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). PubMed was queried for "drug repurposing, antiviral activity," and for "antiviral activity" with "psychotropic drugs" and individual agents, through November 2020. Of more than 100 psychotropic agents, 37 drugs, including 27 with a history of pediatric use were identified, which had been studied in the preclinical setting and found to have activity against viruses which are human pathogens. Effects were evaluated by type of virus and by category of psychotropic agent. Activity was identified both against viruses known to cause epidemics such as SARS-CoV-2 and Ebola and against those that are the cause of rare disorders such as Human Papillomatosis Virus-related respiratory papillomatosis. Individual drugs and classes of psychotropics often had activity against multiple viruses, with promiscuity explained by shared viral or cellular targets. Safety profiles of psychotropics may be more tolerable in this context than when they are used long-term in the setting of psychiatric illness. Nonetheless, translation of in vitro results to the clinical arena has been slow. Psychotropic medications as a class deserve further study, including in clinical trials for repurposing as antiviral drugs for children and adults.

Rosai-Dorfman Disease and Exocrine Pancreatic Insufficiency in a Patient With a Germline SLC29A3 Mutation.

Rosai-Dorfman disease (RDD) typically presents as bulky lymphadenopathy. Somatic mutations in RAS/MAP kinase pathway genes are common but germline mutations are rare. A patient with RDD and exocrine pancreatic insufficiency was found to have a homozygous germline mutation in SLC29A3, which has been associated with the Histiocytosis/Lymphadenopathy Plus Syndrome. His RDD also was positive for a somatic mutation in lymphoid enhancer binding factor 1 (LEF1). The concurrence of RDD and pancreatic insufficiency should raise consideration of SLC29A3 mutations. Other cases will be needed to confirm this observation and a possible contribution of LEF1 to the development of RDD.

Malignant Melanoma Arising From a Giant Congenital Melanocytic Nevus in a 3-Year Old: Review of Diagnosis and Management.

INTRODUCTION: Giant congenital nevi (GCN), defined as abnormal collections of melanocytes with a diameter greater than 20 cm, occur in 1 in 20,000 births. The lifetime risk of malignant transformation in GCN is reported between 5% and 20% and most commonly occurs in the first 3 to 5 years of life. This article reviews the risk factors of malignant transformation and highlights the diagnostic challenges of malignant melanoma in the pediatric population utilizing a clinical report of a patient with GCN. CASE DESCRIPTION: A male patient with giant congenital nevus of the scalp with over 20 satellite nevi was evaluated at the authors' institution at 1 week of life. Beginning at 9 months of age, he underwent serial excision of GCN and satellite lesions. Initial pathology showed compound congenital melanocytic nevus. Subsequent pathology on serial excisions demonstrated compound nevus with clonal expansion of pigmented epithelioid melanocytoma (PEM). He then underwent complete excision of GCN. Pathology demonstrated malignant melanoma that was confirmed by consensus review with outside institutions. The patient was diagnosed with stage III metastatic melanoma after further imaging. He was treated with cervical nodal dissection and interferon alpha-2b. At the time of last visit, the patient had no evidence of melanoma. DISCUSSION: This case highlights the difficulties of clinical and pathologic diagnosis of malignant melanoma in the setting of GCN. Pathology can vary between biopsy sites and initial biopsies can suggest nonmalignant melanocytic lesions, as demonstrated in this patient's case. Correct histologic evaluation often requires input from a relatively few centers that treat a larger volume of childhood melanoma. Analysis of gene expression profiles aids in accurate diagnosis of PEM, proliferative nodule or melanoma. It is important to differentiate PEM, a low-grade, indolent melanoma, from malignant melanoma as the treatment differs significantly. Review of pathology by expert dermatopathologists from multiple institutions is vital for diagnostic accuracy, and patients with malignant transformation of GCN are best served by multidisciplinary teams.

Accelerated aging among childhood, adolescent, and young adult cancer survivors is evidenced by increased expression of p16INK4a and frailty.

BACKGROUND: Cellular senescence, measured by expression of the cell cycle kinase inhibitor p16INK4a , may contribute to accelerated aging in survivors of childhood, adolescent, and young adult cancer. The authors measured peripheral blood T-lymphocyte p16INK4a expression among pediatric and young adult cancer survivors, hypothesizing that p16INK4a expression is higher after chemotherapy and among frail survivors. METHODS: A cross-sectional cohort of young adult survivors and age-matched, cancer-free controls were assessed for p16INK4a expression and frailty. Newly diagnosed pediatric patients underwent prospective measurements of p16INK4a expression before and after cancer therapy. Frailty was measured with a modified Fried frailty phenotype evaluating sarcopenia, weakness, slowness, energy expenditure, and exhaustion. RESULTS: The cross-sectional cohort enrolled 60 survivors and 29 age-matched controls with a median age of 21 years (range, 17-29 years). The prospective cohort enrolled 9 newly diagnosed patients (age range, 1-18 years). Expression of p16INK4a was higher among survivors compared with controls (9.6 vs 8.9 log2 p16 units; 2-sided P = .005, representing a 25-year age acceleration in survivors) and increased among newly diagnosed patients from matched pretreatment to posttreatment samples (7.3-8.9 log2 p16 units; 2-sided P = .002). Nine survivors (16%) were frail and had higher p16INK4a expression compared with robust survivors (10.5 [frail] vs 9.5 [robust] log2 p16 units; 2-sided P = .055), representing a 35-year age acceleration among frail survivors. CONCLUSIONS: Chemotherapy is associated with increased cellular senescence and molecular age in pediatric and young adult cancer survivors. Frail survivors, compared with robust survivors, exhibit higher levels of p16INK4a , suggesting that cellular senescence may be associated with early aging in survivors.

Mila Blooms: A Mobile Phone Application and Behavioral Intervention for Promoting Physical Activity and a Healthy Diet Among Adolescent Survivors of Childhood Cancer.

Objectives: Smartphone applications ("apps") can be used to promote health behavior change and expand the reach of behavioral interventions. To date, only a few existing apps have been developed for health promotion among adolescent survivors of childhood cancer. To address this gap, we developed an app-based intervention, using game design characteristics, theory-based behavioral strategies, and assistance from a health coach to motivate health behavior change for adolescent survivors of childhood cancer. This article describes the development and initial feasibility evaluation of the intervention. Methods: Using a theoretical framework and an extensive formative process, we developed an app-based game ("Mila Blooms") that promotes healthy eating and physical activity among adolescent survivors of childhood cancer. A single-arm 8-week intervention, using this app-based game, with assistance from a health coach, was conducted among a sample of pediatric cancer survivors (n = 15) to evaluate its initial feasibility for promoting health behavior change. Results: Results from the feasibility evaluation were encouraging. The majority of enrolled participants were retained throughout the 8-week intervention (93.8%). Participant satisfaction feedback indicated positive experiences, related to ease of use and enjoyment of the app. Although there was little evidence for behavior change attributable to the app in this first stage of development, there was a solid demonstration of the viability and appeal of the game features, and there were no adverse side effects. Conclusions: Results provide insights into how gamification can be used to promote health behaviors through an app-based intervention. Mila Blooms holds promise for promoting health behavior change. Lessons learned from our experiences could be useful for the future development and implementation of app-based adolescent health interventions.

Author Correction: Notch signaling pathway is a potential therapeutic target for extracranial vascular malformations.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Long-term Efficacy of Single-agent Vemurafenib for Pleomorphic Xanthoastrocytoma.

Pleomorphic xanthoastrocytoma is a malignant brain tumor that has a good prognosis with complete resection but does not respond well to chemotherapy if there is residual tumor. BRAF V600E mutations are common in pleomorphic xanthoastrocytomas and provide an additional means for treatment when excision is not possible. Monotherapy with the BRAF V600E inhibitor vemurafenib has only been reported in a small number of cases and mostly in adults. We present the case of a 16-year-old male who responded to vemurafenib monotherapy initially and had an additional response to vemurafenib following progression after a brief time off the medication.

Cancer Risk in Klippel-Trenaunay Syndrome.

Background: Klippel-Trenaunay syndrome (KTS) is an overgrowth syndrome defined by capillary/venous/lymphatic malformations (CVLM) with soft tissue and/or bone hypertrophy. Whether KTS predisposes to cancer is not clear. Methods and Results: We surveyed members of the K-T Support Group (KTSG) and reviewed PubMed for "Klippel Trenaunay Syndrome" or "CVLM" and "cancer." Individuals with cancer were reviewed for confirmation of KTS, tumor type, location, and age at presentation. Of 223 KTSG respondents, 24 (10.8%) reported 26 malignancies or benign brain tumors (diagnosed from 6 months to 68 years of age, median 41 years), including 3 who were younger than 18 years (2 with Wilms tumor). Nine of twenty-six cancers were basal cell carcinomas (4% of respondents). From 475 articles, we identified 11 cancers or brain tumors in 10 individuals with KTS. Four of these were in children (Wilms tumor n = 2; rhabdomyosarcoma n = 1; serous borderline tumor n = 1). Tumors in adults included basal cell carcinoma (n = 1), squamous cell carcinoma of skin (n = 2), and angiosarcoma, Hodgkin disease, glioblastoma, malignant hemangiopericytoma in one patient each. Ulceration or lymphedema associated with VLM or capillary malformations were associated with some basal cell or squamous cell carcinomas and angiosarcomas. Conclusions: The risk of embryonal cancer other than Wilms tumor in children with KTS does not appear to be higher than in the general population. Wilms tumor incidence is under 5%, and routine surveillance is not indicated. In adults, particular attention should be paid to skin in the area of malformations. These conclusions may not apply to all overgrowth syndromes with vascular malformations.

Efficacy of systemic sirolimus in the treatment of generalized lymphatic anomaly and Gorham-Stout disease.

BACKGROUND: Generalized lymphatic anomaly (GLA) and Gorham-Stout disease (GSD) are rare complicated lymphatic malformations that occur in multiple body sites and are associated with significant morbidity and mortality. Treatment options have been limited, and conventional medical therapies have been generally ineffective. Emerging data suggest a role for sirolimus as a treatment option for complex lymphatic anomalies. PROCEDURE: Disease response was evaluated by radiologic imaging, quality of life (QOL), and clinical status assessments in children and young adults with GLA and GSD from a multicenter systematic retrospective review of patients treated with oral sirolimus and the prospective phase 2 clinical trial assessing the efficacy and safety of sirolimus in complicated vascular anomalies (NCT00975819). Sirolimus dosing regimens and toxicities were also assessed. RESULTS: Eighteen children and young adults with GLA (n = 13) or GSD (n = 5) received oral sirolimus. Fifteen patients (83%) had improvement in one or more aspects of their disease (QOL 78%, clinical status 72%, imaging 28%). No patients with bone involvement had progression of bone disease, and the majority had symptom or functional improvement on sirolimus. Improvement of pleural and pericardial effusion(s) occurred in 72% and 50% of affected patients; no effusions worsened on treatment. CONCLUSIONS: Sirolimus appears effective at stabilizing or reducing signs/symptoms of disease in patients with GLA and GSD. Functional impairment and/or QOL improved in the majority of individuals with GLA and GSD with sirolimus treatment.

Notch signaling pathway is a potential therapeutic target for extracranial vascular malformations.

Notch expression has been shown to be aberrant in brain arteriovenous malformations (AVM), and targeting Notch has been suggested as an approach to their treatment. It is unclear whether extracranial vascular malformations follow the same patterning and Notch pathway defects. In this study, we examined human extracranial venous (VM) (n = 3), lymphatic (LM) (n = 10), and AV (n = 6) malformations, as well as sporadic brain AVMs (n = 3). In addition to showing that extracranial AVMs demonstrate interrupted elastin and that AVMs and LMs demonstrate abnormal α-smooth muscle actin just as brain AVMS do, our results demonstrate that NOTCH1, 2, 3 and 4 proteins are overexpressed to varying degrees in both the endothelial and mural lining of the malformed vessels in all types of malformations. We further show that two gamma secretase inhibitors (GSIs), DAPT (GSI-IX) and RO4929097, cause dose-dependent inhibition of Notch target gene expression (Hey1) and rate of migration of monolayer cultures of lymphatic endothelial cells (hLECs) and blood endothelial cells (HUVEC). GSIs also inhibit HUVEC network formation. hLECs are more sensitive to GSIs compared to HUVEC. GSIs have been found to be safe in clinical trials in patients with Alzheimer's disease or cancer. Our results provide further rationale to support testing of Notch inhibitors in patients with extracranial vascular malformations.

Hepatocellular Carcinoma, Virilization, and Hilus Cell Hyperplasia in a Girl With Turner Syndrome.

Patients with Turner syndrome (TS) are known to be at risk for excess androgen production and virilization associated with gonadoblastoma and Y chromosome mosaicism, and excess androgens are a risk factor for the development of hepatocellular carcinoma. However, virilization and hepatocellular carcinoma have not been described in a patient with TS. A 10-year-old with nonmosaic 45,X TS presented with clitoromegaly, accelerated linear growth velocity, advanced bone age, and elevated testosterone levels as well as a second occurrence of hepatocellular carcinoma. Gonadectomy was performed, and pathology revealed hilus cell hyperplasia. Immunohistochemical staining of both the original and recurrent hepatocellular carcinoma tissues was diffusely positive for androgen receptors. After gonadectomy, testosterone levels were measurable but normal, with no further virilization; however, the liver mass continued to grow. Ovarian hilus cell hyperplasia should be considered a potential etiology for virilization in the TS population. Excess endogenous testosterone exposure in girls and women with TS may be associated with hepatocellular carcinoma expressing the androgen receptor, though normalizing testosterone levels may not lead to tumor regression in these cases.