Risk factors for mixed chimerism in children with hemophagocytic lymphohistiocytosis after reduced toxicity conditioning.

BACKGROUND: Reduced toxicity conditioning for hematopoietic stem cell transplantation of patients with hemophagocyticlymphohistiocytosis (HLH) results in favorable survival, however at the expense of relevant rates of mixed chimerism. Factors predisposing to mixed chimerism remain to be determined. PROCEDURE: Patients with primary HLH transplanted 2009-2016 after treosulfan- or melphalan-based conditioning regimens were analyzed in a retrospective multicenter study for survival, engraftment, chimerism, and adverse events. Mixed chimerism was considered substantial if < 25% donor chimerism occurred and/or if secondary cell therapy was administered. Donor type, graft source, type of alkylating agent, type of serotherapy, and remission status were analyzed as potential risk factors in a multivariable logistic regression model. RESULTS: Among 60 patients, engraftment was achieved in 95%, and the five-year estimated overall survival rate was 75%. Prevalence of any recipient chimerism was 48%. Substantial recipient chimerism was recorded in 32% of patients. Secondary post-HSCT cell therapy was administered in 30% of patients. A human leukocyte antigen (HLA)-mismatched donor (< 10/10) was the only significant risk factor for the occurrence of substantial recipient chimerism (P = 0.01; odds ratio, 5.8; CI 95%, 1.5-26.3). CONCLUSION: The use of an HLA-matched donor is the most important factor to avoid substantial recipient chimerism following treosulfan -or melphalan-based conditioning in primary HLH.

Chronic recurrent multifocal osteomyelitis in association with pyoderma gangraenosum.

BACKGROUND: Chronic recurrent multifocal osteomyelitis (CRMO) is a rare acquired inflammatory skeletal disorder of unknown origin. CRMO was first described by Gideon in 1972 and mainly affects children and young adults of female gender. The CRMO is part of the clinical picture of non-bacterial Osteomyelitis (NBO) and typically presents a relapsing recurring course with both remission and spontaneous exacerbation. CRMO is typically encountered in the limbs and the metaphysis of long bones in particular. Usually the clinical symptoms include painful swellings of the affected regions. This case report describes the rare case of a CRMO of the mandible in association with pyoderma gangraenosum. CASE PRESENTATION: A 14-year old female caucasian patient, residing in the south of Germany, presented in the oncological outpatient clinic of our Department of Paediatrics and Adolescent Medicine in June 2014 complaining of increasing neck pain and progressive swelling at her left cheek ongoing for about 6 weeks. These symptoms had been occurring quarterly for 4 years, but had never been as pronounced. Blood biochemistry showed a moderately elevated CRP (35 mg/l) and a significantly increased blood sedimentation rate (BSR 48/120 mm). The panoramic radiograph, however, revealed a bone alteration in the left mandibular region. Further investigations confirmed the diagnosis of CRMO. CONCLUSION: The present case underlines the fact that rare diseases might occasionally present with even more rare symptoms. These occasions can obviously be considered to present a considerable diagnostic challenge.

Infants and Newborns with Atypical Teratoid Rhabdoid Tumors (ATRT) and Extracranial Malignant Rhabdoid Tumors (eMRT) in the EU-RHAB Registry: A Unique and Challenging Population.

Introduction: Malignant rhabdoid tumors (MRT) predominantly affect infants and young children. Patients below six months of age represent a particularly therapeutically challenging group. Toxicity to developing organ sites limits intensity of treatment. Information on prognostic factors, genetics, toxicity of treatment and long-term outcomes is sparse. Methods: Clinical, genetic, and treatment data of 100 patients (aged below 6 months at diagnosis) from 13 European countries were analyzed (2005-2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using 450 k / 850 k-profiling. Results: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Metastases (M+) were present in 27% (26/97) at diagnosis. A germline mutation (GLM) was detected in 55% (47/86). DNA methylation subgrouping was available in 50% (31 / 62) with ATRT or SYN; for eMRT, methylation-based subgrouping was not performed. The 5-year overall (OS) and event free survival (EFS) rates were 23.5 ± 4.6% and 19 ± 4.1%, respectively. Male sex (11 ± 5% vs. 35.8 ± 7.4%), M+ stage (6.1 ± 5.4% vs. 36.2 ± 7.4%), presence of SYN (7.1 ± 6.9% vs. 26.6 ± 5.3%) and GLM (7.7 ± 4.2% vs. 45.7 ± 8.6%) were significant prognostic factors for 5-year OS. Molecular subgrouping and survival analyses confirm a previously described survival advantage for ATRT-TYR. In an adjusted multivariate model, clinical factors that favorably influence the prognosis were female sex, localized stage, absence of a GLM and maintenance therapy. Conclusions: In this cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M-stage, GLM and maintenance therapy. We confirm the need to stratify which patient groups benefit from multimodal treatment, and which need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option.

Changes of orexin A plasma levels in girls with anorexia nervosa during eight weeks of realimentation.

OBJECTIVE: Orexin A (OXA) is a hypothalamic neuropeptide involved in regulation of food intake and nutritional status. There are multiple disturbances of neuropeptide signaling described in girls with anorexia nervosa (AN), but OXA levels have not been addressed in this population to date. Therefore, we analyzed OXA levels of AN girls in this study. METHOD: OXA (radioimmunoassay/RIA/method), leptin, insulinlike growth factor-1 (IGF-1), and insulinlike growth factor-1 binding protein-3 (IGFBP-3) levels were measured before and after 8 weeks of realimentation in 36 girls with AN and in 14 healthy controls (control group: CG). RESULTS: Average weight increased significantly in AN during the study (p < .0001), while plasma levels of OXA decreased (before realimentation: 56.2 ± 2.4 pg/ml; after realimentation: 47.5 ± 1.4 pg/ml; p = .0025). OXA levels before realimentation differed from levels in the CG (47.15 ± 2.6 pg/ml, p = .034), but not afterward. We did not find any correlation between OXA and age, height, weight, BMI; or IGF-1, IGFBP-3, and leptin levels. DISCUSSION: OXA levels in untreated AN patients differ significantly from healthy subjects and decrease during realimentation. These findings indicate that OXA may be involved in the nutritional regulation of malnourished children and adolescents.

Parecoxib does not suppress thromboxane synthesis in newborn piglets with group B streptococcal sepsis.

Group B streptococci (GBS) cause fatal sepsis in newborns. Strong activation of thromboxane synthesis is assumed to correlate with severe pulmonary hypertension. In this study we compared the impact of indomethacin versus parecoxib on hemodynamics and outcome and investigated the pharmacological effects on thromboxane synthesis and EP-3 receptor gene expression. Whereas both parecoxib and indometacin reduced expression of thromboxane synthase and EP-3 receptor in infected lung tissue, parecoxib did not suppress urine levels of thromboxane like indometacin. We presume that COX-2 inhibition in GBS sepsis is associated with enhanced thrombogenicity.

Diffuse Encephalopathy Associated with Isolated Cerebral Langerhans Cell Histiocytosis.

BACKGROUND: Langerhans cell histiocytosis is a rare disease of the monocyte-macrophage system. Abnormalities of the hypothalamic-pituitary region are common in individuals with central nervous system involvement. PATIENT DESCRIPTION: This six-year-old boy developed rapidly progressive aggressive behavior, central diabetes insipidus, and repeated complex partial seizures. Magnetic resonance imaging revealed a diffuse leukoencephalopathy-like pattern and numerous infratentorial and supratentorial granulomatous nodules in the brain parenchyma along with infundibular and hypothalamic mass lesions. Stereotactic serial biopsies enabled histopathologic and immunohistochemical diagnosis of Langerhans cell histiocytosis. CONCLUSIONS: Similar MRI findings have rarely been described in the literature. These findings represent part of the broad neuroradiological spectrum of Langerhans cell histiocytosis of the nervous system in children.

Aerosolized adrenomedullin suppresses pulmonary transforming growth factor-beta1 and interleukin-1 beta gene expression in vivo.

The effect of aerosolized adrenomedullin on interleukin-1 beta and transforming growth factor (TGF)-beta1 mRNA and protein expression was studied in surfactant depleted piglets, receiving aerosolized adrenomedullin (adrenomedullin, n=6), aerosolized adrenomedullin plus i.v. N(G)-nitro-L-arginine-methylester (adrenomedullin+L-NAME, n=5), or aerosolized saline solution (control, n=6). After 8 h of aerosol interval therapy, mRNA expression of interleukin-1 beta and TGF-beta1 in lung tissue was quantified normalized to beta-actin and hypoxanthine-guanine-phosphoribosyl-transferase by real-time polymerase chain reaction (PCR). Interleukin-1 beta and TGF-beta1 protein concentration in lung tissue was quantified by enzyme-linked immunosorbent assay (ELISA). In the adrenomedullin group, interleukin-1 beta and TGF-beta1 mRNA expression was lower than in controls. Reduction for interleukin-1 beta/beta-actin was 56% (p<0.001), for interleukin-1 beta/hypoxanthine-guanine-phosphoribosyl-transferase 60% (p<0.001), for TGF-beta1/beta-actin 65.5% (p<0.001), and for TGF-beta1/hypoxanthine-guanine-phosphoribosyl-transferase 56.2% (p<0.001). Mean interleukin-1 beta protein expression was different between the groups, p<0.05 (adrenomedullin 601+/-61, Control 836+/-88 pg/mg protein). L-NAME did not antagonize adrenomedullin effect on TGF-beta1 mRNA. In conclusion, aerosolized adrenomedullin reduced pulmonary inflammatory and pro-fibrotic response.

Anakinra (IL-1R antagonist) lowers pulmonary artery pressure in a neonatal surfactant depleted piglet model.

In acute respiratory distress syndrome (ARDS) with pulmonary hypertension, interleukin-1 beta (IL-1 beta) and interleukin-8 (IL-8) are involved in the pulmonary inflammatory reaction. The purpose of this study was to determine whether systemic and aerosolized administered IL-1 receptor antagonist (IL-1Ra) Anakinra (Kineret) improves lung mechanics and pulmonary artery pressure in surfactant depleted newborn piglets. After induction of acute lung injury by lung lavage, neonatal piglets received repetitive treatment of either aerosolized IL-1Ra (IL-1Ra-Aerosol) or intravenous IL-1Ra (IL-1Ra-i.v.), or saline solution as control. IL-1Ra given as aerosol or intravenously significantly reduced mean pulmonary artery pressure (MPAP) but did not influence mean systemic arterial pressure (MAP) compared with the control group. IL-1 beta and IL-8 mRNA expressions normalized to beta-actin and hypoxanthine-guanine-phosphoribosyl transferase were significantly reduced in the IL-1Ra-Aerosol group but not in IL-1Ra-i.v. group compared to the control group. The lung injury score was not significantly different between IL-1Ra groups and the control group. Application of aerosolized IL-1Ra reduced MPAP without affecting MAP in a piglet model of surfactant depletion with pulmonary hypertension. Furthermore, there is evidence for reduction of early pro-inflammatory pulmonary reaction.

Dose response to aerosolized perflubron in a neonatal swine model of lung injury.

Aerosolized perfluorocarbon (PFC) improves gas exchange, lung mechanics, and pulmonary artery pressure. The objective of this intervention was to study the dose-response effect to aerosolized perfluorooctylbromide (PFOB; perflubron, LiquiVent, Alliance Pharmaceutical Corp.) in surfactant-depleted piglets. After induction of lung injury by saline lavage, 25 newborn piglets were randomly assigned to receive 0, 1.25, 2.5, 5.0, or 7.5 mL/kg aerosolized PFOB per hour. A 2-h therapy period was followed by a 3-h observation period. In all animals, respiratory support was performed with intermittent mandatory ventilation. After aerosol treatment and 3 h of observation, arterial oxygen pressure was similarly improved in the 2.5-, 5.0-, and 7.5-mL. kg(-1). h(-1) aerosol-PFOB groups and higher compared with the 1.25-mL. kg(-1). h(-1) aerosol-PFOB (P < 0.01) and the control groups (P < 0.001). Compared with the control group, arterial carbon dioxide pressure was significantly reduced with 2.5-, 5.0-, and 7.5-mL. kg(-1). h(-1) aerosol-PFOB (P < 0.001). Treatment with 1.25 mL. kg(-1). h(-1) aerosol-PFOB did not significantly affect arterial carbon dioxide pressure. The 20% terminal dynamic compliance/dynamic compliance was significantly improved in the groups that received 2.5, 5.0, and 7.5 mL. kg(-1). h(-1) aerosol-PFOB compared with control animals. Mean pulmonary artery pressure was lower after therapy with 5.0 and 7.5 mL. kg(-1). h(-1) aerosol-PFOB (P < 0.01) than in the control group. IL-1beta gene expression in lung tissue was significantly reduced with PFOB 1.25 mL. kg(-1). h(-1). In summary, aerosolized PFOB improved terminal dynamic compliance, pulmonary gas exchange, and pulmonary artery pressure in a dose-dependent manner. In terms of oxygenation and lung mechanics, the optimum dose was between 2.5 and 5 mL. kg(-1). h(-1).

Pilot intervention: aerosolized adrenomedullin reduces pulmonary hypertension.

In pulmonary hypertension, systemic infusion of adrenomedullin (ADM), a potent vasodilator peptide, leads to pulmonary vasodilatation. However, systemic blood pressure declines alike. The present study investigated the effect of aerosolized ADM on pulmonary arterial pressure in surfactant-depleted newborn piglets with pulmonary hypertension. Animals randomly received aerosolized ADM (ADM, n = 6), aerosolized ADM combined with intravenous application of NG-nitro-l-arginine methylester to inhibit nitric-oxide (NO) synthases (ADM + l-NAME, n = 5), or aerosolized normal saline solution (control, n = 6). Aerosol therapy was performed in 30-min intervals for 5 h. After a total experimental period of 8 h, mRNA expression of endothelial and inducible NO synthase and endothelin-1 (ET-1) in lung tissue was quantified using TaqMan real-time polymerase chain reaction. Aerosolized ADM reduced mean pulmonary artery pressure (MPAP) compared with control (p < 0.001; at the end of the study, Delta-MPAP -13.5 +/- 1.4 versus -6.2 +/- 2.4 mm Hg). PaO2 significantly increased in the ADM (DeltaPaO2 243.3 mm Hg) and the ADM + l-NAME group (DeltaPaO2 217.4 mm Hg) compared with the control group (DeltaPaO2 82.9 mm Hg; p < 0.001). Aerosolized ADM did not influence mean systemic arterial pressure (baseline 63.2 +/- 2.7 versus end of the study 66.3 +/- 6.5 mm Hg; not significant). NO synthases gene expressions were 20 to 30% lower with ADM compared with control. ET-1 gene expression was significantly reduced (>50%) after ADM aerosol therapy (p < 0.001). Aerosolized adrenomedullin significantly reduced MPAP without lowering the systemic arterial pressure and improved profoundly the arterial oxygen tension. This effect seems to be mediated at least in part by the reduction of ET-1.