Gliomatosis cerebri (GC) is a universally fatal extensive and diffuse infiltration of brain parenchyma by a glial tumor. Many aspects of this phenomenon remain unknown. The First International Gliomatosis cerebri Group Meeting had the following goals: refine the clinical and radiologic diagnostic criteria for GC, suggest appropriate diagnostic procedures, standardize tissue manipulation for histologic and molecular characterization, and prioritize relevant preclinical projects. Also, general treatment recommendations were outlined for the pediatric population. Importantly, this meeting was the starting point for meaningful collaborative international research projects. This review is a consensus summary of discussions shared and conclusions derived from this meeting.
BackgroundNeck lymphangioma is the most common lymphatic malformation of the newborn, representing about 5% of benign tumours of infancy and childhood. Due to its action on angiogenesis and cellular growth, the use of sirolimus (m-Tor inhibitor) has been proposed for treatment, as it has produced satisfactory results in some studies in children and in a few cases in neonatology.PurposeTo describe the use of sirolimus as treatment for a left laterocervical lymphangioma in a newborn.Material and methodsWe report the case of a term male newborn (3.3 kg, 51 cm, 0.22 m2) with a left laterocervical mass (13 cm) diagnosed on a prenatal ultrasound. According to the neonatal cases in the literature, an oral solution of sirolimus 1 mg/mL was started at 0.8 mg/m2/day (divided into 12 hourly doses) for 10 days of life. Sirolimus plasma levels were monitored (LC/MS/MS), with a desired target of 4–8 µg/L, as well as adverse effects and the evolution of the mass.Results
Day
Dose
Levels (ng/mL)
Triglycerides (mg/dL)
Cholesterol-LDL (mg/dL)
10.08 mg bid672860.08 mg bid2389941018.531999128.7382140.1 mg qd190.1 mg qd8103123400.1 mg qd4.1167470.15 mg qd550.15 mg qd7.418096The first 2 months of treatment are described. On day 6, treatment was interrupted owing to high plasma levels. On day 14, sirolimus was reintroduced at a lower dose and once daily schedule (estimated elimination half-life of 33 hours, concordant with the neonatal literature). Posterior levels were correct and the dose was titrated according to them and the weight gain of the child. Regarding side effects, the patient experienced hypertriglyceridaemia and hypercholesterolaemia, with unaltered hepatic and renal functions associated with high sirolimus levels. He also had occasional nausea and vomiting that were appropriately managed. Posterior controls showed normalisation of triglycerides and cholesterol levels. From the beginning of treatment, the cervical mass showed a progressive reduction in size and a marked reduction in consistency.ConclusionSirolimus can be a useful option for the treatment of lymphatic malformations with few short term side effects. More data are needed to characterise the pharmacokinetics of sirolimus in the neonatal population, in order to define optimal dosing.No conflict of interest
Background: The aim of this study was to test the feasibility and utility of developing patient-derived orthotopic xenograft (PDOX) models for patients with malignant peripheral nerve sheath tumors (MPNSTs) to aid therapeutic interventions in real time. Patient & Methods: A sporadic relapsed MPNST developed in a 14-year-old boy was engrafted in mice, generating a PDOX model for use in co-clinical trials after informed consent. SNP-array and exome sequencing was performed on the relapsed tumor. Genomics, drug availability, and published literature guided PDOX treatments. Results: A MPNST PDOX model was generated and expanded. Analysis of the patient’s relapsed tumor revealed mutations in the MAPK1, EED, and CDK2NA/B genes. First, the PDOX model was treated with the same therapeutic regimen as received by the patient (everolimus and trametinib); after observing partial response, tumors were left to regrow. Regrown tumors were treated based on mutations (palbociclib and JQ1), drug availability, and published literature (nab-paclitaxel; bevacizumab; sorafenib plus doxorubicin; and gemcitabine plus docetaxel). The patient had a lung metastatic relapse and was treated according to PDOX results, first with nab-paclitaxel, second with sorafenib plus doxorubicin after progression, although a complete response was not achieved and multiple metastasectomies were performed. The patient is currently disease free 46 months after first relapse. Conclusion: Our results indicate the feasibility of generating MPNST-PDOX and genomic characterization to guide treatment in real time. Although the treatment responses observed in our model did not fully recapitulate the patient’s response, this pilot study identify key aspects to improve our co-clinical testing approach in real time.
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