Langerhans cell histiocytosis (LCH) is a clonal disorder with elusive etiology, characterized by the accumulation of CD207(+) dendritic cells (DCs) in inflammatory lesions. Recurrent BRAF-V600E ...mutations have been reported in LCH. In this study, lesions from 100 patients were genotyped, and 64% carried the BRAF-V600E mutation within infiltrating CD207(+) DCs. BRAF-V600E expression in tissue DCs did not define specific clinical risk groups but was associated with increased risk of recurrence. Strikingly, we found that patients with active, high-risk LCH also carried BRAF-V600E in circulating CD11c(+) and CD14(+) fractions and in bone marrow (BM) CD34(+) hematopoietic cell progenitors, whereas the mutation was restricted to lesional CD207(+) DC in low-risk LCH patients. Importantly, BRAF-V600E expression in DCs was sufficient to drive LCH-like disease in mice. Consistent with our findings in humans, expression of BRAF-V600E in BM DC progenitors recapitulated many features of the human high-risk LCH, whereas BRAF-V600E expression in differentiated DCs more closely resembled low-risk LCH. We therefore propose classification of LCH as a myeloid neoplasia and hypothesize that high-risk LCH arises from somatic mutation of a hematopoietic progenitor, whereas low-risk disease arises from somatic mutation of tissue-restricted precursor DCs.
To assess the toxicity, pharmacokinetics, and pharmacodynamics of multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in children with relapsed/refractory leukemia.
Twelve ...patients with acute leukemia (11 with acute myeloid leukemia AML) received sorafenib on days 1 to 7 and then concurrently with cytarabine (1 g/m(2)) and clofarabine (stratum one: 40 mg/m(2), n = 10; stratum two recent transplantation or fungal infection: 20 mg/m(2), n = 2) on days 8 to 12. Sorafenib was continued until day 28 if tolerated. Two sorafenib dose levels (200 mg/m(2) and 150 mg/m(2) twice daily) were planned. Sorafenib pharmacokinetic and pharmacodynamic studies were performed on days 7 and 8.
At sorafenib 200 mg/m(2), two of four patients in stratum one and one of two patients in stratum two had grade 3 hand-foot skin reaction and/or rash as dose-limiting toxicities (DLTs). No DLTs were observed in six patients in stratum one at sorafenib 150 mg/m(2). Sorafenib inhibited the phosphorylation of AKT, S6 ribosomal protein, and 4E-BP1 in leukemia cells. The rate of sorafenib conversion to its metabolite sorafenib N-oxide was high (mean, 33%; range, 17% to 69%). In vitro, the N-oxide potently inhibited FLT3-internal tandem duplication (ITD; binding constant, 70 nmol/L) and the viability of five AML cell lines. On day 8, sorafenib decreased blast percentages in 10 of 12 patients (median, 66%; range, 9% to 95%). After combination chemotherapy, six patients (three FLT3-ITD and three FLT3 wild-type AML) achieved complete remission, two (both FLT3-ITD AML) had complete remission with incomplete blood count recovery, and one (FLT3 wild-type AML) had partial remission.
Sorafenib in combination with clofarabine and cytarabine is tolerable and shows activity in relapsed/refractory pediatric AML.
Mixing of complementary tree species may increase stand productivity, mitigate the effects of drought and other risks, and pave the way to forest production systems which may be more resource-use ...efficient and stable in the face of climate change. However, systematic empirical studies on mixing effects are still missing for many commercially important and widespread species combinations. Here we studied the growth of Scots pine (Pinus sylvestris L.) and European beech (Fagus sylvatica L.) in mixed versus pure stands on 32 triplets located along a productivity gradient through Europe, reaching from Sweden to Bulgaria and from Spain to the Ukraine. Stand inventory and taking increment cores on the mainly 60–80 year-old trees and 0.02–1.55 ha sized, fully stocked plots provided insight how species mixing modifies the structure, dynamics and productivity compared with neighbouring pure stands. In mixture standing volume (+12 %), stand density (+20 %), basal area growth (+12 %), and stand volume growth (+8 %) were higher than the weighted mean of the neighbouring pure stands. Scots pine and European beech contributed rather equally to the overyielding and overdensity. In mixed stands mean diameter (+20 %) and height (+6 %) of Scots pine was ahead, while both diameter and height growth of European beech were behind (−8 %). The overyielding and overdensity were independent of the site index, the stand growth and yield, and climatic variables despite the wide variation in precipitation (520–1175 mm year⁻¹), mean annual temperature (6–10.5 °C), and the drought index by de Martonne (28–61 mm °C⁻¹) on the sites. Therefore, this species combination is potentially useful for increasing productivity across a wide range of site and climatic conditions. Given the significant overyielding of stand basal area growth but the absence of any relationship with site index and climatic variables, we hypothesize that the overyielding and overdensity results from several different types of interactions (light-, water-, and nutrient-related) that are all important in different circumstances. We discuss the relevance of the results for ecological theory and for the ongoing silvicultural transition from pure to mixed stands and their adaptation to climate change.
Past failures of monocultures, caused by wind-throw or insect damages, and ongoing climate change currently strongly stimulate research into mixed-species stands. So far, the focus has mainly been on ...combinations of species with obvious complementary functional traits. However, for any generalization, a broad overview of the mixing reactions of functionally different tree species in different mixing proportions, patterns and under different site conditions is needed, including assemblages of species with rather similar demands on resources such as light. Here, we studied the growth of Scots pine and oak in mixed versus monospecific stands on 36 triplets located along a productivity gradient across Europe, reaching from Sweden to Spain and from France to Georgia. The set-up represents a wide variation in precipitation (456–1250 mm year
−1
), mean annual temperature (6.7–11.5 °C) and drought index by de Martonne (21–63 mm °C
−1
). Stand inventories and increment cores of trees stemming from 40- to 132-year-old, fully stocked stands on 0.04–0.94-ha-sized plots provided insight into how species mixing modifies stand growth and structure compared with neighbouring monospecific stands. On average, the standing stem volume was 436 and 360 m
3
ha
−1
in the monocultures of Scots pine and oak, respectively, and 418 m
3
ha
−1
in the mixed stands. The corresponding periodical annual volume increment amounted to 10.5 and 9.1 m
3
ha
−1
year
−1
in the monocultures and 10.5 m
3
ha
−1
year
−1
in the mixed stands. Scots pine showed a 10% larger quadratic mean diameter (
p
< 0.05), a 7% larger dominant diameter (
p
< 0.01) and a 9% higher growth of basal area and volume in mixed stands compared with neighbouring monocultures. For Scots pine, the productivity advantages of growing in mixture increased with site index (
p
< 0.01) and water supply (
p
< 0.01), while for oak they decreased with site index (
p
< 0.01). In total, the superior productivity of mixed stands compared to monocultures increased with water supply (
p
< 0.10). Based on 7843 measured crowns, we found that in mixture both species, but especially oak, had significantly wider crowns (
p
< 0.001) than in monocultures. On average, we found relatively small effects of species mixing on stand growth and structure. Scots pine benefiting on rich, and oak on poor sites, allows for a mixture that is productive and most likely climate resistant all along a wide ecological gradient. We discuss the potential of this mixture in view of climate change.
Vascular anomalies represent a diverse group of complex disorders that can cause significant complications, including coagulopathies, pain, and decreased function. The diagnosis of vascular anomalies ...is often challenging due to heterogeneity of presenting phenotypes and overlapping clinical features with other pediatric conditions. Pediatric hematologists/oncologists (PHO) are uniquely positioned for an essential role in diagnosing, managing, and coordinating the multidisciplinary care required to maximize the quality of life of these patients. Here, we review the diagnostic approach involved in patients with vascular anomalies and utilize cases to highlight the challenges involved, and how PHOs can play a vital part in the care of these patients.
Treatment failure from drug resistance is the primary reason for relapse in acute lymphoblastic leukemia (ALL). Improving outcomes by targeting mechanisms of drug resistance is a potential solution.
...We report results investigating the epigenetic modulators decitabine and vorinostat with vincristine, dexamethasone, mitoxantrone, and PEG-asparaginase for pediatric patients with relapsed or refractory B-cell ALL (B-ALL). Twenty-three patients, median age 12 years (range, 1-21) were treated in this trial.
The most common grade 3-4 toxicities included hypokalemia (65%), anemia (78%), febrile neutropenia (57%), hypophosphatemia (43%), leukopenia (61%), hyperbilirubinemia (39%), thrombocytopenia (87%), neutropenia (91%), and hypocalcemia (39%). Three subjects experienced dose-limiting toxicities, which included cholestasis, steatosis, and hyperbilirubinemia (
= 1); seizure, somnolence, and delirium (
= 1); and pneumonitis, hypoxia, and hyperbilirubinemia (
= 1). Infectious complications were common with 17 of 23 (74%) subjects experiencing grade ≥3 infections including invasive fungal infections in 35% (8/23). Nine subjects (39%) achieved a complete response (CR + CR without platelet recovery + CR without neutrophil recovery) and five had stable disease (22%). Nine (39%) subjects were not evaluable for response, primarily due to treatment-related toxicities. Correlative pharmacodynamics demonstrated potent
modulation of epigenetic marks, and modulation of biologic pathways associated with functional antileukemic effects.
Despite encouraging response rates and pharmacodynamics, the combination of decitabine and vorinostat on this intensive chemotherapy backbone was determined not feasible in B-ALL due to the high incidence of significant infectious toxicities. This study is registered at http://www.clinicaltrials.gov as NCT01483690.
Establishing mixed-species stands is frequently proposed as a strategy to adapt forests to the increasing risk of water scarcity, yet contrasted results have been reported regarding mixing effects on ...tree drought exposure. To investigate the drivers behind the spatial and temporal variation in water-related mixing effects, we analysed the δ
13
C variation in 22-year tree ring chronologies for beech and pine trees sampled from 17 pure and mixed pine–beech stands across a large gradient of environmental conditions throughout Europe. In the pure stands, average δ
13
C values were lower for beech (−27.9‰ to −22.2‰) than for pine (−26.0‰ to −21.1‰), irrespective of site conditions. Decreasing SPEI values (calculated over June to September) were associated with an increase in δ
13
C for both species, but their effect was influenced by stand basal area for pine and site water availability for beech. Mixing did not change the temporal constancy of δ
13
C nor the tree reaction to a drought event, for any of the species. While the mixing effect (Δ δ
13
C = δ
13
C pure stands − δ
13
C mixed stands) was on average positive for beech and non-significant for pine across the whole gradient, this effect strongly differed between sites. For both species, mixing was not significant at extremely dry sites and positive at dry sites; on moderately wet sites, mixing was positive for beech and negative for pine; at sites with permanent water supply, no general patterns emerge for any of the species. The pattern of mixing effect along the gradient of water availability was not linear but showed threshold points, highlighting the need to investigate such relation for other combinations of tree species.
Therapy with the tyrosine kinase inhibitor imatinib mesylate has become standard initial treatment for adult and pediatric patients with chronic myelogenous leukemia. Long-term follow-up data are now ...available in the adult population, and the toxicity profile of imatinib mesylate among adults has been extensively studied and reported. Despite its increasing use in the pediatric population, there are limited data regarding adverse event profiles of imatinib mesylate in children, and few reports exist in the literature focusing on nonhematologic toxicity in this population. We reviewed our institutional experience with imatinib therapy for chronic myelogenous leukemia over an 8-year period of time. Nine pediatric patients began therapy with imatinib mesylate and were included in this review. We reviewed the occurrence of nonhematologic toxicity in this cohort and the impact of that toxicity on continuation of therapy. Eight patients experienced nonhematologic toxicity, including nausea/vomiting (44.4%) and musculoskeletal pain (88.9%). Three patients (33.3%) required discontinuation of imatinib therapy due to grade 3/4 musculoskeletal pain, a rate that is significantly higher than that seen in the adult population. As imatinib therapy becomes increasingly widespread in the treatment of pediatric malignancies, there may be different patterns of clinically significant nonhematologic toxicity, including higher grade musculoskeletal pain.
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