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.

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.

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.

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.

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.

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.

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.

Early Post-Therapy Prescription Drug Usage among Childhood and Adolescent Cancer Survivors.

OBJECTIVE: To describe the patterns of prescription drug use among child and adolescent survivors of cancer in the early post-therapy period compared with matched peers without a cancer history. STUDY DESIGN: Using the MarketScan commercial insurance claims database, we performed a retrospective cohort study identifying survivors of pediatric (0-21 years of age at diagnosis) leukemia, lymphoma, central nervous system, bone, or gonadal cancers who completed therapy from 2000 to 2011 and remained insured for 3 years post-therapy. Prescription fills during the first 3 years post-therapy were examined, categorized by drug class, and compared with age-, sex-, and region-matched individuals without cancer. RESULTS: We identified 1414 survivors and 14 007 comparators. Compared with those without cancer, survivors had 1.5-4.5 times greater risk for filling opioids. Survivors of leukemia, lymphoma, central nervous system, and bone cancers had 2-5 times the risk for antidepressant and 3-7 times the risk for anxiolytic use. Survivors of leukemia, lymphoma, and bone tumors had 3-13 times the risk for angiotensin-converting enzyme inhibitors by the third year post-therapy. CONCLUSION: Compared with peers without cancer, survivors of childhood cancer have greater rates of prescription use across many drug classes, suggesting greater medical morbidity. Survivors were more likely to use opioid, psychoactive, hormone, and cardiovascular medications. All general pediatricians and subspecialists should be aware of potentially emerging morbidities during the early post-therapy period to guide risk-based surveillance and survivorship care.

Inconsistency in classifying vascular anomalies: What's in a name?

BACKGROUND: Vascular anomalies are a heterogeneous group of disorders seen in children and adults. A standard nomenclature for classification has been offered by the International Society for the Study of Vascular Anomalies. Its application is important for communication among the multiple specialties involved in the care of patients and for planning treatment, as well as for research and billing. We hypothesized that terminology still is not uniformly applied, and that this could have an impact on treatment. METHODS: We retrospectively reviewed the medical records of patients with nonbrain lesions from our institutional vascular anomalies database seen during 2010-2016 for whom at least one clinic visit, radiologic imaging report, and pathology report were available to compare diagnoses among and within disciplines, and treatment recommendations. Diagnoses and referral patterns by community healthcare providers were also reviewed. RESULTS: Of 400 patients seen during the targeted time interval, 35 had clinical, imaging, and pathology reports. Agreement in terminology from initial clinic notes with imaging and pathology reports was noted in only three cases (9%). "Hemangioma" was often misused; "lymphangioma" and "cystic hygroma" persist as diagnostic labels. Community healthcare providers referred vascular malformations with a diagnosis of "mass" or "hemangioma" in 17 of 18 cases where that information was available. Incomplete or mislabeling of vascular anomalies sometimes delayed referrals to appropriate clinics, though it did not have a major impact on treatment. CONCLUSIONS: An understanding of vascular anomalies as tumors or malformations is not uniform. Ongoing education will be needed to promote consensus terminology and facilitate referrals.

Clinically significant ascites as an indication for resection of rapidly involuting congenital hepatic hemangiomas.

Hepatic hemangiomas are the most common benign liver tumor of infancy and are divided into two main types: rapidly involuting congenital hemangiomas (RICH) and non-involuting congenital hemangiomas. RICH typically involute by 12 months and are often asymptomatic. Surgical resection is rare. Indications for surgical resection include rupture, rapid growth, consumptive coagulopathy, and abdominal pain. We present two patients from different institutions who both developed clinically significant ascites as the RICH involuted, prompting surgical resection. This is a new indication for resection.

Somatic PTPN11 Mutation in a Child With Neuroblastoma and Protein Losing Enteropathy.

Neuroblastoma and protein losing enteropathy (PLE) are diagnoses commonly seen by oncologists and gastroenterologists, respectively. The concurrence of these 2 entities is rare, and not well explained. We describe the sixth case of PLE in a child with neuroblastoma, and the first for which genetic information is available. Tumor DNA had a mutation in the PTPN11 gene, which has been described in neuroblastoma, and in Noonan syndrome-a diagnosis in which neuroblastoma and PLE independently have been reported. Constitutional DNA was normal. Genetic studies in future patients will be needed to support the link between neuroblastoma and PLE.

Early Posttherapy Hospitalizations Among Survivors of Childhood Leukemia and Lymphoma.

Long-term survivors of childhood cancers are at increased risk for hospitalization. To test the hypothesis that many treatment-related morbidities are identifiable in the early posttherapy period, we determined the rates and causes for hospitalization among survivors of leukemia and lymphoma during the first 3 years posttherapy. Using a health plan claims database, we identified patients aged 0 to 21 years old treated for leukemia or lymphoma from 2000 to 2010. Survivors were matched 10:1 with similar children without a history of cancer. Hospitalization rates over 3 years were compared using Cox proportional hazards regression and risks of cause-specific hospitalization were compared using log-binomial models. Nineteen percent of childhood leukemia and lymphoma survivors were hospitalized in the first 3 years off therapy. Leukemia survivors (N=529) experienced over 6 times (hazard ratio=6.3; 95% confidence interval [CI], 4.9-8.0) and lymphoma survivors (N=454) over 3 times the hospitalization rate of controls (hazard ratio=3.2; 95% CI, 2.5-4.2). Compared with children without a cancer history, survivors were at increased risk for hospitalization due to infectious causes (leukemia: relative risk [RR], 60.0; 95% CI, 23.4-154.0; lymphoma: RR, 10.0; 95% CI, 4.4-22.9). In addition, lymphoma survivors were at increased risk for cardiovascular-related (RR, 15.0; 95% CI, 5.4-42.0) and pulmonary-related (RR, 8.1; 95% CI, 3.9-16.8) hospitalizations. These findings highlight the morbidity experienced by survivors and suggest that treatment-associated complications may be emerging soon after therapy completion.

RUNX1 Amplification Increases the Risk for Thrombosis in Children With B-cell Acute Lymphoblastic Leukemia.

BACKGROUND: RUNX1 (AML1) amplification in patients with B-cell acute lymphoblastic leukemia (B-ALL) has been associated with poor survival for unclear reasons. Our anecdotal experience suggests that children with B-ALL and RUNX1 amplification might be predisposed to thrombosis. PROCEDURE: We performed a retrospective cohort study of children with B-ALL treated from 2008 to 2014 at the North Carolina Children's Hospital. Patient demographics, cytogenetics, and diagnosis of thrombosis were extracted by blinded chart review. Analysis was performed examining the relationship between RUNX1 amplification and thrombosis. RESULTS: We identified 119 patients with B-ALL and a median age of 4.9 years (interquartile range, 2.9 to 8.6 y) at diagnosis. Four patients (3%) had RUNX1 amplification. The average number of RUNX1 copies among those with amplification was 5 (SD 0.81 [range, 4 to 6]). Eighteen thromboses were diagnosed within 6 months of starting treatment. These events were more likely among patients with RUNX1 amplification than in patients without amplification (75% vs. 13%; RR 5.75, 95% confidence interval, 2.75-12.01). CONCLUSIONS: RUNX1 amplification may predispose to early thrombotic events in children with B-ALL which could, in part, contribute to their poorer outcomes. Treatment implications, including possible prophylactic anticoagulation of patients with of RUNX1 amplification, justify larger studies to confirm these findings.

Outcome of Pediatric Gastroenterology Outpatients With Fever and Central Line.

OBJECTIVE: Although management algorithms for fever and central venous catheters (CVCs) have been implemented for pediatric oncology (PO) patients, management of pediatric outpatients with noncancer diagnoses and CVCs lacks clear protocols. The aim of the study was to assess outcomes for pediatric outpatients with gastrointestinal disorders presenting with fever and CVC. METHODS: Using a microbiology database and emergency department records, we created a database of pediatric gastroenterology (PGI) and PO outpatients with fever and a CVC who presented to our emergency department or clinics from January 2010 through December 2012. We excluded patients who had severe neutropenia (absolute neutrophil count, <500/mm). We performed chart reviews to assess demographic and clinical characteristics. RESULTS: A total of 334 episodes in 144 patients were evaluated. Fifty-three percent (95% confidence interval, 38%-68%) of PGI patients had a bloodstream infection, whereas only 9% (95% confidence interval, 5%-14%) of PO patients had a bloodstream infection (P < 0.001). Among patients with a bloodstream infection, the PGI patients were more likely than the PO patients to have polymicrobial infections (46% vs 15%), gram-negative infections (57% vs 27%), and/or infection with enteric organisms (61% vs 23%). The PGI patients had higher rates of CVC removal (19% vs 4%) but no statistical difference in intensive care unit needs (11% vs 4%). CONCLUSIONS: Pediatric gastroenterology outpatients with fever and a CVC have a high prevalence of bloodstream infection. Algorithms for management need to be subspecialty specific. Pediatric gastroenterology patients presenting to emergency departments or clinics with fever and CVC require admission for monitoring and management.

Cerebrospinal fluid proteomics in children during induction for acute lymphoblastic leukemia: A pilot study.

BACKGROUND: Thrombosis in patients with acute lymphocytic leukemia (ALL) can develop after treatment with L-asparaginase (asp) and is often localized to the central nervous system (CNS). We hypothesize that changes in the cerebrospinal fluid (CSF) proteome will occur after asp therapy and will anticipate CNS clots. METHODS: Five newly diagnosed patients, ages 1-11 years, with ALL (n = 4) or lymphoblastic lymphoma (LL) (n = 1) underwent serial lumbar punctures during induction. CSF was depleted of abundant plasma proteins and analyzed by gel-free, label-free quantitative proteomics. RESULTS: More than 600 proteins were quantified across all CSF samples. In four subjects, the expression of proteins involved in coagulation such as protein C Inhibitor (SERPINA5) and heparin cofactor II (SERPIND1) changed over the course of asp therapy. Antithrombin III (ATIII) and plasminogen (PLMN) levels were shown to have decreased expression over time in one child who developed a CNS thrombosis, compared to other subjects. CONCLUSIONS: CSF proteomics is feasible and reproducible in ALL and LL. CSF ATIII and PLMN should be further investigated as predictive markers of CNS thrombosis.

Malignant transformation of infantile hemangioma to angiosarcoma: response to chemotherapy with bevacizumab.

We describe a child initially diagnosed with multi-focal infantile hemangioma (cutaneous, hepatic, pulmonary), a benign vascular lesion, which underwent malignant transformation to angiosarcoma. The use of anti-angiogenic agents, such as bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, has been reported in adults with angiosarcoma. Treatment with chemotherapy (gemcitabine and docetaxel) and bevacizumab resulted in disease response with progression free survival of 12 months. This report describes the response to chemotherapy and bevacizumab in a child with angiosarcoma and highlights the potential for malignant transformation of benign vascular lesions and the need for careful monitoring.

Genetics of hemangiomas, vascular malformations, and primary lymphedema.

With improved genetic testing and genomic sequencing, abnormalities are increasingly being identified in affected or germline tissues in DNA of patients with vascular tumors, vascular malformations, and lymphedema. Recognition of the genetics of vascular anomalies should help clinicians make more specific diagnoses, anticipate diagnosis-specific morbidities, provide better genetic counseling, and have a better understanding of the pathogenesis of these anomalies. Growing pharmacologic options, including therapies targeted to specific mutations, with obvious parallels to cancer treatment now allow the pediatric hematologist-oncologist to assume a more prominent role in clinical care and research for patients with these diagnoses. We summarize genes and genetic loci that have been associated with vascular anomalies and offer guidelines for patient evaluations.

Valproic acid reduces the tolerability of temsirolimus in children and adolescents with solid tumors.

A pediatric study has established a maximum tolerated dose (MTD) for temsirolimus (Tem) of more than 150 mg/m intravenously/week. A phase I trial was conducted to establish the MTD for Tem in combination with valproic acid (VPA) in children and adolescents with refractory solid tumors. The secondary aims included expression of mammalian target of rapamycin (mTOR) markers on archival tumor tissue; Tem pharmacokinetics; assessment of histone acetylation (HA); and tumor response. Patients were treated with VPA (5 mg/kg orally three times daily) with a target serum level of 75-100 mcg/ml. Tem was started at an initial dose of 60 mg/m/week. Pharmacokinetics and HA measurements were performed during weeks 1 and 5. Two of the first three patients experienced dose-limiting toxicity (grade 3 mucositis). Tem at 35 mg/m/week was found to be tolerable. Peak Tem concentrations were higher in all patients compared with those in previously published reports of single agent Tem. Increases in HA are correlated with VPA levels. All tumor samples expressed mTORC1 and mTORC2. An objective response was observed in one patient (melanoma), whereas transient stable disease was observed in four other patients (spinal cord ependymoma, alveolar soft part sarcoma, medullary thyroid carcinoma, and hepatocellular carcinoma). The MTD of Tem when administered with VPA is considerably lower than when used as a single agent, with mucositis the major dose-limiting toxicity. The combination merits further study and may have activity in melanoma. Attention to drug-drug interactions will be important in future multiagent trials including Tem.