Summary
Langerhans cell histiocytosis (LCH) is a rare disease, affecting subjects of any age, with extremely variable clinical manifestations. Although most patients with LCH have localized disease, ...requiring local or even no therapy, those patients with disseminated, ‘multi‐system’ disease require specific therapy because they may be at risk for morbidity or even mortality. The current standard of care has developed empirically, based mainly on the experience of treating children with leukaemia and other haemo‐proliferative disorders. At the time of writing, the combined use of vinblastine and prednisone remains the standard of care for children with multi‐system LCH. The combination of cytarabine and cladribine is the current standard for second‐line therapy of refractory cases with vital organ dysfunction. Recent advances in the knowledge of the pathogenesis of LCH may support a change in treatment strategy. Evidence of mutations that aberrantly activate RAF/MEK/ERK signalling in over two thirds of patients with LCH may direct a target therapy strategy. Vemurafenib, a small molecule widely used in the treatment of melanoma, is the main candidate for testing in prospective trials for patients with evidence of BRAFV600E mutation on lesional tissue. Additional molecules, including the recently approved trametinib, could follow. Identification of mutations in other genes in the remaining multisystem LCH cases could contribute to define a scenario in which target therapy becomes the main therapeutic choice in this intriguing disorder. However, because the long‐term risks and benefits of these agents in children are unknown, and other effective treatments exist for many LCH patients, the optimal indications for administering a tyrosine kinase inhibitor to children is an open question.
Langerhans cell histiocytosis (LCH) is a rare disease affecting people of any age, with widely variable clinical manifestations and different outcomes. The precise chain of events driving lesional ...granuloma formation has remained elusive for many years. There is evidence for inherited predisposition to and derangement of apoptosis and inflammation in lesional dendritic cells. Recently somatic BRAFV600E mutation in myeloid precursor dendritic cells was associated with the more aggressive form of the disease, although the same mutation in a more differentiated dendritic cell might drive a less aggressive disease. Whether this picture convincingly put LCH in the field of myeloid neoplasm remains to be determined. Altogether, these findings suggest that future therapeutic strategy might incorporate a screening of this genetic mutation for high-risk patients potentially suitable for target therapy.
Hemophagocytic lymphohistiocytosis (HLH) used to have a dismal prognosis. We report the final results of HLH-94, the largest prospective diagnostic/therapeutic HLH study so far. The treatment ...includes immunosuppressive and cytotoxic therapy aiming at clinical remission, followed by HSCT in patients with familial, persistent, or recurrent disease. Altogether, 249 patients fulfilled inclusion criteria and started HLH-94 therapy (July 1994-December 2003); 227 (91%) were followed-up for ≥ 5 years. At 6.2 years median follow-up, estimated 5-year probability of survival was 54% ± 6%. Seventy-two patients (29%) died before HSCT, 64 within 1 year, 97% of whom had active disease. In 124 patients who underwent HSCT, 5-year survival was 66 ± 8%; tendency to increased survival (P = .064) in patients with nonactive disease at HSCT. Patients with familial disease had a 5-year survival of 50% ± 13%; none survived without HSCT. Patients deceased during the first 2 months more often had jaundice, edema, and elevated creatinine. Forty-nine patients (20%) were alive without signs of HLH activity and off-therapy > 1-year without HSCT; they presented at older age (P < .001), were more often female (P = .011), and less often had CNS disease (P < .001) or hepatomegaly (P = .007). To conclude, HLH-94 chemoimmunotherapy has considerably improved outcome in HLH. Collaborative efforts are needed to further reduce early mortality, HSCT-related mortality, and neurologic late effects.
Familial haemophagocytic lymphohistiocytosis (FHL) is an inherited immune deficiency with defective cytotoxicity of natural killer cells and cytotoxic T lymphocytes. A highly stimulated, but ...ineffective immune response leads to severe hyperinflammation. Clinical and laboratory features are characteristic, but unspecific; thus awareness of FHL is important for early diagnosis. FHL is rapidly fatal without treatment. Standard‐of‐care therapy is etoposide and corticosteroids, followed by haematopoietic stem cell transplantation (HSCT).
Conclusion
FHL has become a curable disease with present treatment. Additional cytokine‐directed therapy still has to prove its value. Earlier HSCT and less toxic conditioning regimens will lead to improved cure rates.
2019-nCoV: Polite with children Caselli, Désirée; Aricò, Maurizio
Pediatric reports,
02/2020, Letnik:
12, Številka:
1
Journal Article
Recenzirano
Odprti dostop
A novel epidemic is challenging the global health care system. Starting from probably November to December 2019, another Coronavirus entered the arena of human pathogens, to be then defined ...2019-nCoV....
Natural killer (NK) cells were recently shown to play a relevant role in the process of dendritic cell (DC) maturation. This function is exerted either by direct DC stimulation or through killing ...those DCs that did not properly acquire a mature phenotype. While killing of immature DCs is dependent on the function of the NKp30 triggering receptor, the mechanism by which NK cells induce DC maturation is still unclear. In this study, we show that also the NK-mediated induction of DC maturation is dependent on NKp30. Upon NK/DC interaction, resulting in NKp30 engagement, NK cells produced tumor necrosis factor α (TNFα) (and interferon γ IFNγ) that, in turn, promoted DC maturation. Masking of NKp30 with specific monoclonal antibodies (mAbs) strongly reduced maturation of DCs cocultured with NK cells. In addition, supernatant from NK cells stimulated via NKp30 induced DC maturation, and this effect was neutralized by anti-TNFα antibodies (Abs). This NKp30 function is controlled by the HLA-specific inhibitory NK receptors. Accordingly, the ability to promote maturation was essentially confined to NK cells expressing the killer immunoglobulin-like receptor–negative (KIR–) NKG2Adull phenotype. Finally, the analysis of perforin-deficient NK cells allowed the dissection of the 2 NKp30-mediated NK-cell functions, since NKp30 could induce cytokine-dependent DC maturation in the absence of NK-mediated DC killing.
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