Dabrafenib and trametinib in Langerhans cell histiocytosis and other histiocytic disorders.

The standard treatment for Langerhans cell histiocytosis (LCH) is chemotherapy, although the failure rates are high. Since MAP-kinase activating mutations are found in most cases, BRAF- and MEK-inhibitors have been used successfully to treat patients with refractory or relapsed disease. However, data on long-term responses in children are limited and there are no data on the use of these inhibitors as first-line therapy. We treated 34 patients (26 with LCH, 2 with juvenile xanthogranuloma, 2 with Rosai-Dorfman disease, and 4 with presumed single site-central nervous system histiocytosis) with dabrafenib and/or trametinib, either as first line or after relapse or failure of chemotherapy. Sixteen patients, aged 1.3-21 years, had disease that was recurrent or refractory to chemotherapy, nine of whom had multisystem LCH with risk-organ involvement. With a median treatment duration of 4.3 years, 15 (94%) patients have sustained favorable responses. Eighteen patients, aged 0.2-45 years, received an inhibitor as first-line treatment. All of these have had sustained favorable responses, with a median treatment duration of 2.5 years. Three patients with presumed isolated central nervous system/pituitary stalk histiocytosis had stabilization or improvement of their disease. Overall, inhibitors were well tolerated. Five patients with single-system LCH discontinued therapy and remain off therapy without recurrence. In contrast, all four patients with multisystem disease who discontinued therapy had to restart treatment. Our data suggest that children suffering from histiocytoses can be treated safely and effectively with dabrafenib or trametinib. Additional studies are, however, needed to determine the long-term safety and optimal duration of therapy.

Inflamed-HLH, MAS, or something else?

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive and maladaptive inflammation. Primary HLH is most frequently encountered in young children, and, without timely recognition and therapy, can lead to multiorgan failure and death. It is most often diagnosed using the HLH-2004 criteria and by identifying pathological mutations. However, the HLH-2004 criteria are not specific for HLH, and patients can easily fulfill these diagnostic criteria in other proinflammatory states in which HLH-therapy would not be indicated, including hematologic malignancies, infections, and rheumatologic disease. Therefore, great care must be taken to ensure that the specific disease associated with features of HLH is accurately recognized, as consequences of improper treatment can be catastrophic. We propose a diagnostic pathway for patients for whom HLH is on the differential (visual abstract). Importantly, in situations in which the initial diagnostic workup is equivocal or unrevealing, reevaluation for occult malignancy, infection, or rheumatologic disease would be prudent, as occult presentations may be missed on primary evaluation. Temporizing medications can be used in critically ill patients while awaiting secondary evaluation. By using this framework, clinicians will be able to more reliably discern primary HLH from other pro-inflammatory states and thus provide timely, appropriate disease-specific therapy.

A Retrospective Review of the Use of Sirolimus for Pediatric Patients With Epithelioid Hemangioendothelioma.

Epithelioid hemangioendothelioma (EHE) is a rare malignant vascular tumor with no standardized treatment. The mammalian target of rapamycin inhibitor, sirolimus, has been used successfully in adult EHE and other vascular tumors in children but has not been studied in pediatric EHE. The aim of this retrospective case series is to discuss the results of sirolimus for treatment in 6 pediatric patients with EHE. Four of 6 patients demonstrated partial response or disease stabilization with sirolimus treatment. No treatment dosing, trough goals, or duration of treatment recommendations can be made. Prospective studies are warranted to further investigate the use of sirolimus in treatment of EHE.

Clinical characterization and long-term outcomes in pediatric epithelioid hemangioendothelioma.

There is a paucity of information about the clinical characteristics and long-term outcomes of pediatric epithelioid hemangioendothelioma (EHE), a rare vascular neoplasm commonly presenting in adulthood. In our case series of 24 patients with EHE aged 2-26 years, the majority presented with multi-organ disease. Progression was seen in 63% of patients with a mean time to progression of 18.4 months (range: 0-72). Three patients treated with sirolimus achieved stable disease or partial response for >2.5 years. Longitudinal prospective pediatric studies are needed to develop standardized approaches to surgical and medical management.

Tumor- and cytokine-primed human natural killer cells exhibit distinct phenotypic and transcriptional signatures.

An emerging cellular immunotherapy for cancer is based on the cytolytic activity of natural killer (NK) cells against a wide range of tumors. Although in vitro activation, or "priming," of NK cells by exposure to pro-inflammatory cytokines, such as interleukin (IL)-2, has been extensively studied, the biological consequences of NK cell activation in response to target cell interactions have not been thoroughly characterized. We investigated the consequences of co-incubation with K562, CTV-1, Daudi RPMI-8226, and MCF-7 tumor cell lines on the phenotype, cytokine expression profile, and transcriptome of human NK cells. We observe the downregulation of several activation receptors including CD16, CD62L, C-X-C chemokine receptor (CXCR)-4, natural killer group 2 member D (NKG2D), DNAX accessory molecule (DNAM)-1, and NKp46 following tumor-priming. Although this NK cell phenotype is typically associated with NK cell dysfunction in cancer, we reveal the upregulation of NK cell activation markers, such as CD69 and CD25; secretion of pro-inflammatory cytokines, including macrophage inflammatory proteins (MIP-1) α /ß and IL-1ß/6/8; and overexpression of numerous genes associated with enhanced NK cell cytotoxicity and immunomodulatory functions, such as FAS, TNFSF10, MAPK11, TNF, and IFNG. Thus, it appears that tumor-mediated ligation of receptors on NK cells may induce a primed state which may or may not lead to full triggering of the lytic or cytokine secreting machinery. Key signaling molecules exclusively affected by tumor-priming include MAP2K3, MARCKSL1, STAT5A, and TNFAIP3, which are specifically associated with NK cell cytotoxicity against tumor targets. Collectively, these findings help define the phenotypic and transcriptional signature of NK cells following their encounters with tumor cells, independent of cytokine stimulation, and provide insight into tumor-specific NK cell responses to inform the transition toward harnessing the therapeutic potential of NK cells in cancer.

Tuning the Multifunctionality of Iron Oxide Nanoparticles Using Self-Assembled Mixed Lipid Layers.

We present an approach to tuning the multifunctionality of iron oxide nanoparticles (IONs) using mixed self-assembled monolayers of cationic lipid and anionic polyethylene glycol (PEG) lipid. By forming stable, monodispersed lipid-coated IONs (L-IONs) through a solvent-exchange technique, we were able to demonstrate the relationship between surface charge, the magnetic transverse relaxivity (r2 from T2-weighted images), and the binding capacity of small interfering ribonucleic acids (siRNAs) as a function of the cationic-to-anionic (PEG) lipid ratio. These properties were controlled by the cationic charge and the PEG conformation; relaxivity and siRNA binding could be varied in the mushroom and brush regimes but not at high brush densities. In vitro results combining cell viability, uptake, and transfection efficiency using HeLa cells suggest that the functional physicochemical and biological properties of L-IONs may be best achieved using catanionic lipid coatings near equimolar ratios of cationic to anionic PEG-lipids.