Alpelisib for the treatment of PIK3CA-related head and neck lymphatic malformations and overgrowth.

Purpose: PIK3CA-related overgrowth spectrum (PROS) conditions of the head and neck are treatment challenges. Traditionally, these conditions require multiple invasive interventions, with incomplete malformation removal, disfigurement, and possible dysfunction. Use of the PI3K inhibitor alpelisib, previously shown to be effective in PROS, has not been reported in PIK3CA-associated head and neck lymphatic malformations (HNLMs) or facial infiltrating lipomatosis (FIL).

Delaying Invasive Treatment in Unilateral Head and Neck Lymphatic Malformation Improves Outcomes.

Objectives: Large (De Serres stage [IV-V]) head and neck lymphatic malformations (HNLMs) often have multiple, high-risk, invasive treatments (ITs) to address functional compromise. Logically reducing HNLM ITs should reduce treatment risk. We tested whether delaying HNLM ITs reduces total IT number.

Somatic activating variants cause isolated lymphatic malformations.

Somatic activating variants in , the gene that encodes the p110 catalytic subunit of phosphatidylinositol 3-kinase (PI3K), have been previously detected in ∼80% of lymphatic malformations (LMs). We report the presence of somatic activating variants in in individuals with LMs that do not possess pathogenic variants. The BRAF substitution p.

Extra-axial haemorrhages in young children with skull fractures: abuse or accident?

Objective: Infant and toddler subdural haemorrhages (SDH) are often considered indicative of abuse or major trauma. However, accidental impact events, such as falls, cause contact extra-axial haemorrhages (EAHs). The current study sought to determine frequency and clinical behaviour of EAHs with infant and toddler accidental and abusive skull fractures.

Acetylsalicylic acid suppression of the PI3K pathway as a novel medical therapy for head and neck lymphatic malformations.

Objectives: Head and neck lymphatic malformations (HNLM) are caused by gain-of-function somatic mutations in PIK3CA. Acetylsalicylic acid (ASA/aspirin) is thought to limit growth in PIK3CA-mutated neoplasms through PI3K pathway suppression. We sought to determine if ASA could be beneficial for HNLM.

Delays in care seeking for young children with accidental skull fractures are common.

Aim: We sought to determine the frequency and patterns of delayed medical care seeking for young children with skull fractures.

Methods: We identified accidental skull fractures <4 years old, 2011-2012. Child abuse paediatricians abstracted retrospective data and paediatric radiologists re-reviewed images.

Active Observation as an Alternative to Invasive Treatments for Pediatric Head and Neck Lymphatic Malformations.

Objectives: An increasing number of treatment modalities for lymphatic malformations are being described, complicating therapeutic decisions. Understanding lymphatic malformation natural history is essential. We describe management of head and neck lymphatic malformations where decisions primarily addressed lesion-induced functional compromise (ie, breathing, swallowing) to identify factors associated with invasive treatment and active observation.

Airway Hemangiomas in PHACE Syndrome: A Multicenter Experience.

Objective: To describe the prevalence and clinical characteristics of airway findings in a multi-institutional cohort of PHACE patients.

Study Design: Multicenter retrospective case series.

Setting: Multidisciplinary vascular anomalies clinics at 2 institutions.

Cell-free DNA as a diagnostic analyte for molecular diagnosis of vascular malformations.

Purpose: Vascular malformations (VM) are primarily caused by somatic activating pathogenic variants in oncogenes. Targeted pharmacotherapies are emerging but require molecular diagnosis. Since variants are currently only detected in malformation tissue, patients may be ineligible for clinical trials prior to surgery.

Are Complex Skull Fractures Indicative of Either Child Abuse or Major Trauma in the Era of 3-Dimensional Computed Tomography Imaging?

Objective: The aim of the study was to determine whether complex skull fractures are more indicative of child abuse or major trauma than simple skull fractures.

Design: This is a retrospective chart and imaging review of children diagnosed with a skull fracture. Subjects were from 2 pediatric tertiary care centers.

Fracture-Associated Bruising and Soft Tissue Swelling in Young Children With Skull Fractures: How Sensitive Are They to Fracture Presence?

Objectives: The aim of this study was to determine how reliable scalp bruising and soft tissue swelling/cephalohematomas (STS) are for underlying young child skull fractures.

Methods: This was a retrospective clinical and imaging review from 2011 to 2012 of children younger than 4 years with skull fractures from 2 tertiary care hospitals. Imaging was reread by 3 pediatric radiologists.

Retinal and visual function in infants with non-accidental trauma and retinal hemorrhages.

Purpose: To investigate retinal function and visual outcomes in infants with retinal hemorrhages due to non-accidental trauma (NAT).

Methods: This is a retrospective review of full-field or multifocal electroretinogram (ERG) recordings, visual acuity in log minimum angle of resolution (logMAR), clinical status, and neuroimaging. Multifocal ERGs from the central 40° were compared to corresponding fundus imaging.

Genotype correlates with clinical severity in PIK3CA-associated lymphatic malformations.

Lymphatic malformations (LMs) are congenital, nonneoplastic vascular malformations associated with postzygotic activating PIK3CA mutations. The mutation spectrum within LMs is narrow, with the majority having 1 of 3 hotspot mutations. Despite this relative genetic homogeneity, clinical presentations differ dramatically.

Regulatory B cells preferentially accumulate in tumor-draining lymph nodes and promote tumor growth.

Our previous studies found that B16-F10 melanoma growth in the rear footpad of immunocompetent mice induces marked B cell accumulation within tumor-draining popliteal lymph nodes (TDLN). This B cell accumulation drives TDLN remodeling that precedes and promotes metastasis, indicating a tumor-promoting role for TDLN B cells. Here we show that phenotypic characterization of lymphocytes in mice bearing B16-F10 melanomas identifies preferential accumulation of T2-MZP B cells in the TDLN.

Tumor-induced alterations in lymph node lymph drainage identified by contrast-enhanced MRI.

Background: To use high resolution MRI lymphography to characterize altered tumor-draining lymph node (TDLN) lymph drainage in response to growth of aggressive tumors.

Methods: Six mice bearing B16-F10 melanomas in one rear footpad were imaged by 3.0 Tesla (T) MRI before and after subcutaneous injection of Gadofosveset trisodium (Gd-FVT) contrast agent into both rear feet.

Metabolomic profiling of tumor-bearing mice.

Metabolomics is one of the newcomers among the "omics" techniques, perhaps also constituting the most relevant for the study of pathophysiological conditions. Metabolomics may indeed yield not only disease-specific biomarkers but also profound insights into the etiology and progression of a variety of human disorders. Various metabolomic approaches are currently available to study oncogenesis and tumor progression in vivo, in murine tumor models.

Kidney tumor biomarkers revealed by simultaneous multiple matrix metabolomics analysis.

Metabolomics is increasingly being used in cancer biology for biomarker discovery and identification of potential novel therapeutic targets. However, a systematic metabolomics study of multiple biofluids to determine their interrelationships and to describe their use as tumor proxies is lacking. Using a mouse xenograft model of kidney cancer, characterized by subcapsular implantation of Caki-1 clear cell human kidney cancer cells, we examined tissue, serum, and urine all obtained simultaneously at baseline (urine) and at, or close to, animal sacrifice (urine, tissue, and plasma).

Urine metabolomics for kidney cancer detection and biomarker discovery.

Renal cell carcinoma (RCC) is one of the few human cancers whose incidence is increasing. The disease regularly progresses asymptomatically and is frequently metastatic upon presentation, thereby necessitating the development of an early method of detection. A metabolomic approach for biomarker detection using urine as a biofluid is appropriate since the tumor is located in close proximity to the urinary space.

Urinary acylcarnitines are altered in human kidney cancer.

Kidney cancer often diagnosed at late stages when treatment options are severely limited. Thus, greater understanding of tumor metabolism leading ultimately to novel approaches to diagnosis is needed. Our laboratory has been utilizing metabolomics to evaluate compounds appearing in kidney cancer patients' biofluids at concentrations different from control patients.

Urine metabolomic analysis identifies potential biomarkers and pathogenic pathways in kidney cancer.

Kidney cancer is the seventh most common cancer in the Western world, its incidence is increasing, and it is frequently metastatic at presentation, at which stage patient survival statistics are grim. In addition, there are no useful biofluid markers for this disease, such that diagnosis is dependent on imaging techniques that are not generally used for screening. In the present study, we use metabolomics techniques to identify metabolites in kidney cancer patients' urine, which appear at different levels (when normalized to account for urine volume and concentration) from the same metabolites in nonkidney cancer patients.

A metabolomics approach using juvenile cystic mice to identify urinary biomarkers and altered pathways in polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and affects 1 in 1,000 individuals. Ultrasound is most often used to diagnose ADPKD; such a modality is only useful late in the disease after macroscopic cysts are present. There is accumulating evidence suggesting that there are common cellular and molecular mechanisms responsible for cystogenesis in human and murine PKD regardless of the genes mutated, and, in the case of complex metabolomic analysis, the use of a mouse model has distinct advantages for proof of principle over a human study.