Summary
The population‐based Nordic/Baltic acute lymphoblastic leukaemia (ALL) Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol combined minimal residual disease ...(MRD)‐driven treatment stratification with very intense first line chemotherapy for patients with high risk ALL. Patients with MRD ≥5% at end of induction or ≥10−3 at end of consolidation or following two high risk blocks were eligible for haematopoietic cell transplantation (HCT) in first remission. After at least three high risk blocks a total of 71 children received HCT, of which 46 had MRD ≥5% at end of induction. Ten patients stratified to HCT were not transplanted; 12 received HCT without protocol indication. Among 69 patients with evaluable pre‐HCT MRD results, 22 were MRD‐positive, one with MRD ≥10−3. After a median follow‐up of 5·5 years, the cumulative incidence of relapse was 23·5% (95% confidence interval CI: 10·5–47·7) for MRD‐positive versus 5·1% (95% CI: 1·3–19·2), P = 0·02) for MRD‐negative patients. MRD was the only variable significantly associated with relapse (hazard ratio 9·1, 95% CI: 1·6–51·0, P = 0·012). Non‐relapse mortality did not differ between the two groups, resulting in disease‐free survival of 85·6% (95% CI: 75·4–97·2) and 67·4% (95% CI: 50·2–90·5), respectively. In conclusion, NOPHO block treatment efficiently reduced residual leukaemia which, combined with modern transplant procedures, provided high survival rates, also among pre‐HCT MRD‐positive patients.
There are many known endocrine complications after allogeneic hematopoietic stem cell transplantation (HSCT) in childhood including increased risk of biochemical hypogonadism. However, little is ...known about sexuality in adulthood following childhood HSCT. In this multicenter study, sexual functions and possible risk factors were assessed comprehensively in two national cohorts (Finland and Denmark) of male adult survivors of childhood HSCT. Compared to a healthy control group (n = 56), HSCT survivors (n = 97) reported less sexual fantasies, poorer orgasms, lower sexual activity with a partner and reduced satisfaction with their sex life, even in the presence of normal erectile functions and a similar frequency of autoerotic acts. Of the HSCT survivors, 35% were cohabitating/married and 66% were sexually active. Risk factors for poorer self-reported sexual functions were partner status (not cohabitating with a partner), depressive symptoms, CNS and testicular irradiation. Sexual dysfunction increased by age in the HSCT group with a pace comparable to that of the control group. However, because of the lower baseline level of sexual functions in the HSCT group, they will reach the level of clinically significant dysfunction at a younger age. Hence, male survivors of childhood HSCT should be interviewed in detail about their sexual health beyond erectile functions.
...of the 8 patients with normal WASP expression, 3 mutations were intronic and 3 located at the C-terminus. Because the WASP antibody recognizes an epitope in the region between aa.146-265, it may ...still bind proteins bearing missense or C-terminal–truncating mutations.4 Six patients with missense mutations displayed staining ratios between 0.3 and 0.5. Future efforts to improve the accuracy of WAS screening diagnostics could include the development of a functional assay demonstrating defective actin remodeling during lymphocyte polarization.9 Such an assay might potentially also be useful in diagnosing X-linked thrombocytopenia and X-linked neutropenia, and would be especially useful for the evaluation of potential patients with WAS with novel mutations of unknown significance with unperturbed WASP staining. The only female sample was a heterozygous carrier with normal levels of WASP staining and therefore included in the control group for analysis.WASP staining Whole-blood samples from patients and healthy controls were surface stained for CD45 (BD Biosciences, La Jolla, Calif), fixed, and then permeabilized before being incubated with anti-WASP antibody (BD Biosciences, clone 5A5).E1 Cells were acquired on a FACS Canto II (BD Biosciences) and analyzed with FCS Express (v4, De Novo Software, Glendale, Calif). WASP stain index Presentation age Variant reported PMID dbSNP frequency (%) genomAD SIFT Mutation Taster score PolyPhen-2 WAS score Lowest platelet count ± 6 mo of WASP sampling Eczema Infections Autoimmune disease Missense/intronic 1 0.28 10 mo c.134C>T p.(Thr45Met) 7753869, 19817875, 23160469 25525159 rs132630273 NA 0.01 Disease causing 1 2 8 K/mcL Mild Minor None 2 0.28 NA c.167C>T p.(Ala56Val) 7795648, 19817875, 25091438 rs132630269 NA 0.24 Disease causing 1 NA 3 0.38 9 y c.167C>T p.(Ala56Val) 2 86 K/mcL Mild None None 4 0.24 NA c.167C>T p.(Ala56Val) NA 5 0.38 6 y c.167C>T p.(Ala56Val) 3 30 K/mcL Persistent but manageable Minor None 6 0.16 NA c.193A>C p.(Thr65Pro) NA NA NA 0.14 Polymorphism 0.990 NA 7 0.33 NA c.229G>A p.(Asp77Asn) NA NA NA 0 Disease causing 0.994 NA 8 0.40 NA c.229G>A p.(Asp77Asn) NA 9 0.32 NA c.231T>A p.(Asp77Glu) NA NA NA 0 Disease causing 0.999 NA 10 0.13 1 wk c.245C>A p.(Ser82Tyr) NA NA NA 0 Disease causing 1 1 37 K/mcL None None None 11 0.19 2 y c.257G>A p.(Arg86His) 8069912, 19817875, 23160469, rs132630268 NA 0.01 Disease causing 1 1 9 K/mcL Persistent but manageable None HSP 12 0.13 NA c.319T>A p.(Tyr107Asn) NA NA NA 0.1 Polymorphism 1 NA 13 0.18 3 mo c.356G>A p.(Gly119Glu) 8931701, 19817875 NA NA 0.34 Disease causing 1 5 33 K/mcL Mild Recurring ITP 14 0.19 1 mo c.356G>A p.(Gly119Glu) 5 25 K/mcL Mild Recurring ITP 15 0.17 1 mo c.356G>A p.(Gly119Glu) 5 32 K/mcL Mild Recurring ITP 16 0.18 1 wk c.383T>C p.(Phe128Ser) 8931701 NA NA 0.01 Disease causing 1 3 51 K/mcL Persistent but manageable Recurring None 17 0.19 NA c.397G>A p.(Glu133Lys) 7753869, 19817875 NA NA 0.04 Disease causing 1 NA 18 0.83 NA c.463+3G>C p.? NA NA 0.0019 Predicted loss at donor site 3bp upstream (34.8%) NA 19 0.17 6 mo c.506-1G>C p.? Skip of exon 6 is likely, MaxEnt, NNSPLICE, and HSF algorithms predict loss of acceptor site (100%) 2 80 K/mcL Mild Recurring None 20 0.98 NA c.538C>A p.(His180Asn) 20173115, 24728327 NA 0.095 NA NA NA 2 180 K/mcL None Minor None 21 0.17 5 mo c.559+5G>C p.? NA ClinVar -Likely pathogenic NA NA NA 2 21 K/mcL Mild None None 22 0.20 4 mo c.559+5G>C p.? 2 12 K/mcL Persistent but manageable Recurring None 23 0.26 1 mo c.559+5G>A p.? 9326235, 25525159 ClinVar -Likely pathogenic NA NA NA 5 45 K/mcL Mild Minor ITP 24 0.18 NA c.559+5G>A p.? NA 25 0.14 10 mo c.559+5G>A p.? 5 34 K/mcL Mild Minor ITP 26 0.20 NA c.778-2A>G p.? 8595430 NA NA NA NA NA NA 27 0.84 NA c.995T>C p.(Val332Ala) 17400488, 22995991, 24728327, 24369837, rs2737799 0.47 0.4 Polymorphism 0 NA 28 1.18 NA c.1315C>T p.(Arg439Trp) NA NA NA 0.01 Disease causing 1 NA 29 0.50 NA c.1339-2A>G p.? Skip of exon 11 is likely.
Hemophagocytic lymphohistiocytosis (HLH) is an often-fatal hyperinflammatory syndrome characterized by fever, hepatosplenomegaly, cytopenia, and in some cases hemophagocytosis. Here, we describe the ...mutation analysis, clinical presentation, and functional analysis of natural killer (NK) cells in patients with mutations in STXBP2 encoding Munc18-2, recently associated with familial HLH type 5. The disease severity among 11 persons studied here was highly variable and, accordingly, age at diagnosis ranged from 2 months to 17 years. Remarkably, in addition to typical manifestations of familial HLH (FHL), the clinical findings included colitis, bleeding disorders, and hypogammaglobulinemia in approximately one-third of the patients. Laboratory analysis revealed impairment of NK-cell degranulation and cytotoxic capacity. Interleukin-2 stimulation of lymphocytes in vitro rescued the NK cell–associated functional defects. In conclusion, familial HLH type 5 is associated with a spectrum of clinical symptoms, which may be a reflection of impaired expression and function of Munc18-2 also in cells other than cytotoxic lymphocytes. Mutations in STXBP2 should thus also be considered in patients with clinical manifestations other than those typically associated with HLH.
The output and size distribution of aerosols from dry powder inhalers are dependent on the flow rate through the device. Therefore, in an in vivo study, we examined the flow-dependency of the effect ...of formoterol when delivered from a dry powder inhaler, the Aerolizer, in a flow range relevant to schoolchildren. In a preliminary study comprising 126 asthmatic children aged 3-10 yrs, the relationship between age and peak inspiratory flow (PIF) rate through the Aerolizer was determined. Mean PIF was 104 L.min-1 and all children aged > 5 yrs performed a PIF > 60 L.min-1. Sixteen children aged 8-15 yrs with exercise-induced asthma (EIA) took part in the main trial comparing the protective effect of 12 micrograms formoterol inhaled at 60 and 120 L.min-1. The effect from high and low inspiratory flow was judged from the protective effect against EIA 12 h after drug administration. The decrease in forced expiratory volume in one second (FEV1) after exercise was 34% on the placebo day, but only 15% when formoterol was inhaled at the high flow rate. This difference was statistically significant. The decrease in FEV1 was 23% after treatment with formoterol inhaled at the low flow rate, that was not significantly different from placebo or from high-flow formoterol treatment. These clinical findings correspond with the in vitro findings of flow-dependent fine particle mass from the Aerolizer, and corroborate the relationship between fine particle mass of aerosol and clinical effect. The results indicate a flow-dependent effect of formoterol dry powder inhaled from the Aerolizer, within the range of inspiratory flow rate obtainable by school-children. This questions its applicability in children with asthma.
Background: The majority of children undergoing allogenic hematopoietic stem cell transplantation (HSCT) experience severe pain due to chemotherapy-induced gastrointestinal toxicity. Inter-individual ...differences in pain perceived and opioid consumption remain unexplained, limiting the possibility for individualized pain control. The aim of this study was to investigate the associations between opioid consumption and markers of gastrointestinal toxicity (plasma citrulline) and systemic inflammation (plasma CRP and IL-6) in these patients.
Methods: We retrospectively included 38 children undergoing HSCT in Denmark in 2010-2012. Opioids doses on days 0-21 post-HSCT were registered as intravenous morphine equivalents (MEs). CRP was measured daily on days 0-21. IL-6 was measured on day 7. Citrulline was measured before conditioning, on days 7 and 21.
Results: Out of 38 children, 37 (97%) received opioids during days 0-21. CRP level and ME dose peaked on days 9-10 while citrulline level reached a nadir on day 7 indicating maximum enterocyte loss. CRP was associated with ME dose, with an estimated increase of 0.030 mg/kg (95% CI 0.024-0.035) in ME for a 50% increase in CRP level on the same day (p < .001). IL-6 was correlated with ME on day 7 (rho = 0.55, p = .002). Citrulline did not correlate with ME.
Conclusions: Opioid consumption in the early post-HSCT period is associated with the degree of chemotherapy-induced systemic inflammation and not with the extent of enterocyte loss. These findings contribute to our understanding of mucositis-related pain and may be of interest for future studies on therapeutic strategies.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Male gonadal dysfunction is a frequent late effect after pediatric hematopoietic stem cell transplantation (HSCT) that can lead to disturbances in pubertal development, sexual dysfunction, and ...infertility. However, no systematic review exists regarding prevalence and risk factors in relation to different treatment regimens. To systematically evaluate the current evidence regarding the prevalence of male gonadal dysfunction after pediatric HSCT, related risk factors, and the diagnostic value of surrogate markers of spermatogenesis in this patient group. We searched PubMed and Embase using a combination of text words and subject terms. The eligibility screening was conducted using predefined criteria. Data were extracted corresponding to the Leydig cell compartment involved in testosterone production and the germ cell compartment involved in spermatogenesis, respectively. Subsequently, data synthesis was performed. Of 2369 identified records, 25 studies were eligible. The studies were heterogeneous in terms of included diagnoses, gonadotoxic therapy, follow-up time, and definitions of gonadal dysfunction. The data synthesis revealed a preserved Leydig cell function in patients treated with non-total body irradiation (TBI) regimens, whereas the evidence regarding the impact of TBI conditioning on Leydig cell function was conflicting. Based on surrogate markers of spermatogenesis and only limited data on semen quality, the germ cell compartment was affected in half of the patients treated with non-TBI regimens and in nearly all patients treated with TBI conditioning. Testicular irradiation as part of front-line therapy before referral to HSCT led to complete Leydig cell failure and germ cell failure. Evidence regarding the impact of diagnosis, pubertal stage at HSCT, and chronic graft-versus-host disease is limited, as is the evidence of the diagnostic value of surrogate markers of spermatogenesis. Testicular irradiation as part of front-line therapy and TBI conditioning are the main risk factors associated with male gonadal dysfunction after pediatric HSCT; however, impaired spermatogenesis is also observed in half of the patients treated with non-TBI regimens. Methodological shortcomings limit existing evidence, and future studies should include semen quality analyses, follow-up into late adulthood, and evaluation of the cumulative exposure to gonadotoxic therapy.
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