Pediatric Myocarditis.

Myocarditis is a condition caused by acute or chronic inflammation of the cardiac myocytes, resulting in associated myocardial edema and myocardial injury or necrosis. The exact incidence is unknown, but is likely underestimated, with more mild cases going unreported. Diagnosis and appropriate management are paramount in pediatric myocarditis, as it remains a recognized cause of sudden cardiac death in children and athletes. Myocarditis in children is most often caused by a viral or infectious etiology. In addition, there are now two highly recognized etiologies related to Coronavirus disease of 2019 (COVID-19) infection and the COVID-19 mRNA vaccine. The clinic presentation of children with myocarditis can range from asymptomatic to critically ill. Related to severe acute respiratory syndrome-Coronavirus 2 (SARs-CoV-2), children are at greater risk of developing myocarditis secondary to COVID-19 compared to the mRNA COVID-19 vaccine. Diagnosis of myocarditis typically includes laboratory testing, electrocardiography (ECG), chest X-ray, and additional non-invasive imaging studies with echocardiogram typically being the first-line imaging modality. While the reference standard for diagnosing myocarditis was previously endomyocardial biopsy, with the new revised Lake Louise Criteria, cardiac magnetic resonance (CMR) has emerged as an integral non-invasive imaging tool to assist in the diagnosis. CMR remains critical, as it allows for assessment of ventricular function and tissue characterization, with newer techniques, such as myocardial strain, to help guide management both acutely and long term.

Complications after transesophageal echocardiogram in pediatric patients with gastrostomy tube and/or Nissen fundoplication.

INTRODUCTION: Transesophageal echocardiography (TEE) is frequently used in children with and without congenital heart disease when transthoracic echocardiography is inadequate for visualizing cardiac structures. Recent guidelines state relative contraindications of TEE include post-gastrostomy tube (GT) or Nissen fundoplication surgery. No data exist documenting the incidence of complications in this population after a TEE. Aim of this study was to document the incidence of abdominal complications after TEE in pediatric patients who previously had a GT or Nissen fundoplication. METHODS: Single institution retrospective study was performed evaluating patients from 2013 through 2020. Patients were included if they had previously undergone a GT or Nissen procedure and subsequently underwent a TEE procedure. Baseline demographics were obtained. Major (esophageal/gastric perforation, oropharyngeal dysphagia, GT displacement, and Nissen breakdown) and minor (abdominal pain, feeding intolerance, and GT leakage) complications were recorded. RESULTS: Total of 34 patients underwent 48 TEE procedures. Age was 6.2 ± 6.6 years (median 3.0 years, .4 - 23.0 years) and weight was 18.5 ± 14.8 kgs (median 12.4 kgs, 4.2 - 57.5 kg) at time of TEE. Twenty-nine patients had congenital heart disease. Five patients had a Nissen fundoplication, 14 patients had a GT, and 15 patients had both procedures prior to the TEE. No patient had a major abdominal complication after the TEE. One patient had abdominal pain (2.1%), one patient had feeding intolerance and leakage around the GT site (2.1%), and two patients had leakage around the GT site (4.2%) after the TEE. Patients that experienced complications were significantly younger (1.7 ± 1.1 years vs. 6.6 ± 6.7 years, P < .01) and weighed less (8.7 ± 3.5 kg vs. 20.1 ± 15.5 kg, P < .01) than those that had no complications. All minor complications resolved with minimal interventions required. CONCLUSION: In this study, major abdominal complications did not occur after a TEE procedure in pediatric patients that had previous abdominal surgeries. The incidence of minor complications was relatively low and was easily remedied in this patient population. Though a relative contraindication by guidelines, TEE imaging, including transgastric views, can be performed relatively safely in pediatric patients with prior abdominal surgeries if needed.

Molecular and cellular effects of NEDD8-activating enzyme inhibition in myeloma.

The NEDD8-activating enzyme is upstream of the 20S proteasome in the ubiquitin/proteasome pathway and catalyzes the first step in the neddylation pathway. NEDD8 modification of cullins is required for ubiquitination of cullin-ring ligases that regulate degradation of a distinct subset of proteins. The more targeted impact of NEDD8-activating enzyme on protein degradation prompted us to study MLN4924, an investigational NEDD8-activating enzyme inhibitor, in preclinical multiple myeloma models. In vitro treatment with MLN4924 led to dose-dependent decrease of viability (EC(50) = 25-150 nmol/L) in a panel of human multiple myeloma cell lines. MLN4924 was similarly active against a bortezomib-resistant ANBL-6 subline and its bortezomib-sensitive parental cells. MLN4924 had submicromolar activity (EC(50) values <500 nmol/L) against primary CD138(+) multiple myeloma patient cells and exhibited at least additive effect when combined with dexamethasone, doxorubicin, and bortezomib against MM.1S cells. The bortezomib-induced compensatory upregulation of transcripts for ubiquitin/proteasome was not observed with MLN4924 treatment, suggesting distinct functional roles of NEDD8-activating enzyme versus 20S proteasome. MLN4924 was well tolerated at doses up to 60 mg/kg 2× daily and significantly reduced tumor burden in both a subcutaneous and an orthotopic mouse model of multiple myeloma. These studies provide the framework for the clinical investigation of MLN4924 in multiple myeloma.

BET bromodomain inhibition as a therapeutic strategy to target c-Myc.

MYC contributes to the pathogenesis of a majority of human cancers, yet strategies to modulate the function of the c-Myc oncoprotein do not exist. Toward this objective, we have targeted MYC transcription by interfering with chromatin-dependent signal transduction to RNA polymerase, specifically by inhibiting the acetyl-lysine recognition domains (bromodomains) of putative coactivator proteins implicated in transcriptional initiation and elongation. Using a selective small-molecule bromodomain inhibitor, JQ1, we identify BET bromodomain proteins as regulatory factors for c-Myc. BET inhibition by JQ1 downregulates MYC transcription, followed by genome-wide downregulation of Myc-dependent target genes. In experimental models of multiple myeloma, a Myc-dependent hematologic malignancy, JQ1 produces a potent antiproliferative effect associated with cell-cycle arrest and cellular senescence. Efficacy of JQ1 in three murine models of multiple myeloma establishes the therapeutic rationale for BET bromodomain inhibition in this disease and other malignancies characterized by pathologic activation of c-Myc.

Molecular and cellular effects of multi-targeted cyclin-dependent kinase inhibition in myeloma: biological and clinical implications.

Cell cycle regulators, such as cyclin-dependent kinases (CDKs), are appealing targets for multiple myeloma (MM) therapy given the increased proliferative rates of tumour cells in advanced versus early stages of MM. We hypothesized that a multi-targeted CDK inhibitor with a different spectrum of activity compared to existing CDK inhibitors could trigger distinct molecular sequelae with therapeutic implications for MM. We therefore studied the small molecule heterocyclic compound NVP-LCQ195/AT9311 (LCQ195), which inhibits CDK1, CDK2 and CDK5, as well as CDK3 and CDK9. LCQ195 induced cell cycle arrest and eventual apoptotic cell death of MM cells, even at sub-µmol/l concentrations, spared non-malignant cells, and overcame the protection conferred to MM cells by stroma or cytokines of the bone marrow milieu. In MM cells, LCQ195 triggered decreased amplitude of transcriptional signatures associated with oncogenesis, drug resistance and stem cell renewal, including signatures of activation of key transcription factors for MM cells e.g. myc, HIF-1α, IRF4. Bortezomib-treated MM patients whose tumours had high baseline expression of genes suppressed by LCQ195 had significantly shorter progression-free and overall survival than those with low levels of these transcripts in their MM cells. These observations provide insight into the biological relevance of multi-targeted CDK inhibition in MM.