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Sonstige beteiligte Institutionen
- Department of Medicinal Chemistry, University of Vienna, Althanstraße 14, 1090 Vienna, Austria (1)
- Department of Paediatric Radiology, Institute of Diagnostic and Interventional Radiology, Josef-Schneider-Straße 2, Wuerzburg 97080, Germany (1)
- Department of Pediatrics, Pediatrics I, Innsbruck Medical University, Anichstr. 35, 6020, Innsbruck, Austria (1)
- Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Althanstraße 14, 1090 Vienna, Austria (1)
- Interdisciplinary Center for Clinical Research (IZKF), Würzburg, Germany (1)
- Interdisziplinäres Zentrum für Klinische Forschung (IZKF) (1)
EU-Project number / Contract (GA) number
- 229289 (1)
- 241778 (1)
- 609,020 (1)
- HEALTH-F2-2009-241778 (1)
Background:
Although caffeine and glucocorticoids are frequently used to treat chronic lung disease in preterm neonates, potential interactions are largely unknown. While anti-inflammatory effects of glucocorticoids are well defined, their impact on airway remodeling is less characterized. Caffeine has been ascribed to positive effects on airway inflammation as well as remodeling. Connective tissue growth factor (CTGF, CCN2) plays a key role in airway remodeling and has been implicated in the pathogenesis of chronic lung diseases such as bronchopulmonary dysplasia (BPD) in preterm infants. The current study addressed the impact of glucocorticoids on the regulation of CTGF in the presence of caffeine using human lung epithelial and fibroblast cells.
Methods:
The human airway epithelial cell line H441 and the fetal lung fibroblast strain IMR-90 were exposed to different glucocorticoids (dexamethasone, budesonide, betamethasone, prednisolone, hydrocortisone) and caffeine. mRNA and protein expression of CTGF, TGF-β1-3, and TNF-α were determined by means of quantitative real-time PCR and immunoblotting. H441 cells were additionally treated with cAMP, the adenylyl cyclase activator forskolin, and the selective phosphodiesterase (PDE)-4 inhibitor cilomilast to mimic caffeine-mediated PDE inhibition.
Results:
Treatment with different glucocorticoids (1 μM) significantly increased CTGF mRNA levels in H441 (p < 0.0001) and IMR-90 cells (p < 0.01). Upon simultaneous exposure to caffeine (10 mM), both glucocorticoid-induced mRNA and protein expression were significantly reduced in IMR-90 cells (p < 0.0001). Of note, 24 h exposure to caffeine alone significantly suppressed basal expression of CTGF mRNA and protein in IMR-90 cells. Caffeine-induced reduction of CTGF mRNA expression seemed to be independent of cAMP levels, adenylyl cyclase activation, or PDE-4 inhibition. While dexamethasone or caffeine treatment did not affect TGF-β1 mRNA in H441 cells, increased expression of TGF-β2 and TGF-β3 mRNA was detected upon exposure to dexamethasone or dexamethasone and caffeine, respectively. Moreover, caffeine increased TNF-α mRNA in H441 cells (6.5 ± 2.2-fold, p < 0.05) which has been described as potent inhibitor of CTGF expression.
Conclusions:
In addition to well-known anti-inflammatory features, glucocorticoids may have adverse effects on long-term remodeling by TGF-β1-independent induction of CTGF in lung cells. Simultaneous treatment with caffeine may attenuate glucocorticoid-induced expression of CTGF, thereby promoting restoration of lung homeostasis.
Stimulating the immune system to attack cancer is a promising approach, even for the control of advanced cancers. Several cytokines that promote interferon-γ-dominated immune responses show antitumor activity, with interleukin 12 (IL-12) being of major importance. Here, we used an antibody-IL-12 fusion protein (NHS-IL12) that binds histones of necrotic cells to treat human sarcoma in humanized mice. Following sarcoma engraftment, NHS-IL12 therapy was combined with either engineered IL-7 (FcIL-7) or IL-2 (IL-2MAB602) for continuous cytokine bioavailability. NHS-IL12 strongly induced innate and adaptive antitumor immunity when combined with IL-7 or IL-2. NHS-IL12 therapy significantly improved survival of sarcoma-bearing mice and caused long-term remissions when combined with IL-2. NHS-IL12 induced pronounced cancer cell senescence, as documented by strong expression of senescence-associated p16\(^{INK4a}\) and nuclear translocation of p-HP1γ, and permanent arrest of cancer cell proliferation. In addition, this cancer immunotherapy initiated the induction of myogenic differentiation, further promoting the hypothesis that efficient antitumor immunity includes mechanisms different from cytotoxicity for efficient cancer control in vivo.
Extracellular vesicles (EVs) are a heterogenous population of plasma membrane-surrounded particles that are released in the extracellular milieu by almost all types of living cells. EVs are key players in intercellular crosstalk, both locally and systemically, given that they deliver their cargoes (consisting of proteins, lipids, mRNAs, miRNAs, and DNA fragments) to target cells, crossing biological barriers. Those mechanisms further trigger a wide range of biological responses. Interestingly, EV phenotypes and cargoes and, therefore, their functions, stem from their specific parental cells. For these reasons, EVs have been proposed as promising candidates for EV-based, cell-free therapies. One of the new frontiers of cell-based immunotherapy for the fight against refractory neoplastic diseases is represented by genetically engineered chimeric antigen receptor T (CAR-T) lymphocytes, which in recent years have demonstrated their effectiveness by reaching commercialization and clinical application for some neoplastic diseases. CAR-T-derived EVs represent a recent promising development of CAR-T immunotherapy approaches. This crosscutting innovative strategy is designed to exploit the advantages of genetically engineered cell-based immunotherapy together with those of cell-free EVs, which in principle might be safer and more efficient in crossing biological and tumor-associated barriers. In this review, we underlined the potential of CAR-T-derived EVs as therapeutic agents in tumors.
Juvenile idiopathic arthritis (JIA) encompasses a heterogeneous group of diseases. The appearance of antinuclear antibodies (ANAs) in almost half of the patients suggests B cell dysregulation as a distinct pathomechanism in these patients. Additionally, ANAs were considered potential biomarkers encompassing a clinically homogenous subgroup of JIA patients. However, in ANA+ JIA patients, the site of dysregulated B cell activation as well as the B cell subsets involved in this process is still unknown. Hence, in this cross-sectional study, we aimed in an explorative approach at characterizing potential divergences in B cell differentiation in ANA+ JIA patients by assessing the distribution of peripheral blood (PB) and synovial fluid (SF) B cell subpopulations using flow cytometry. The frequency of transitional as well as switched-memory B cells was higher in PB of JIA patients than in healthy controls. There were no differences in the distribution of B cell subsets between ANA- and ANA+ patients in PB. However, the composition of SF B cells was different between ANA- and ANA+ patients with increased frequencies of CD21\(^{lo/−}\)CD27\(^−\)IgM\(^−\) “double negative” (DN) B cells in the latter. DN B cells might be a characteristic subset expanding in the joints of ANA+ JIA patients and are potentially involved in the antinuclear immune response in these patients. The results of our explorative study might foster further research dissecting the pathogenesis of ANA+ JIA patients.
(1) Background: Refractory acute graft-versus-host disease (R-aGvHD) remains a leading cause of death after allogeneic stem cell transplantation. Survival rates of 15% after four years are currently achieved; deaths are only in part due to aGvHD itself, but mostly due to adverse effects of R-aGvHD treatment with immunosuppressive agents as these predispose patients to opportunistic infections and loss of graft-versus-leukemia surveillance resulting in relapse. Mesenchymal stromal cells (MSC) from different tissues and those generated by various protocols have been proposed as a remedy for R-aGvHD but the enthusiasm raised by initial reports has not been ubiquitously reproduced. (2) Methods: We previously reported on a unique MSC product, which was generated from pooled bone marrow mononuclear cells of multiple third-party donors. The products showed dose-to-dose equipotency and greater immunosuppressive capacity than individually expanded MSCs from the same donors. This product, MSC-FFM, has entered clinical routine in Germany where it is licensed with a national hospital exemption authorization. We previously reported satisfying initial clinical outcomes, which we are now updating. The data were collected in our post-approval pharmacovigilance program, i.e., this is not a clinical study and the data is high-level and non-monitored. (3) Results: Follow-up for 92 recipients of MSC-FFM was reported, 88 with GvHD ≥°III, one-third only steroid-refractory and two-thirds therapy resistant (refractory to steroids plus ≥2 additional lines of treatment). A median of three doses of MSC-FFM was administered without apparent toxicity. Overall response rates were 82% and 81% at the first and last evaluation, respectively. At six months, the estimated overall survival was 64%, while the cumulative incidence of death from underlying disease was 3%. (4) Conclusions: MSC-FFM promises to be a safe and efficient treatment for severe R-aGvHD.
Circulating MACC1 transcripts in glioblastoma patients predict prognosis and treatment response
(2019)
Glioblastoma multiforme is the most aggressive primary brain tumor of adults, but lacksreliable and liquid biomarkers. We evaluated circulating plasma transcripts of metastasis-associatedin colon cancer-1 (MACC1), a prognostic biomarker for solid cancer entities, for prediction of clinicaloutcome and therapy response in glioblastomas. MACC1 transcripts were significantly higher inpatients compared to controls. Low MACC1 levels clustered together with other prognosticallyfavorable markers. It was associated with patients’ prognosis in conjunction with the isocitratedehydrogenase (IDH) mutation status: IDH1 R132H mutation and low MACC1 was most favorable(median overall survival (OS) not yet reached), IDH1 wildtype and high MACC1 was worst (medianOS 8.1 months), while IDH1 wildtype and low MACC1 was intermediate (median OS 9.1 months).No patients displayed IDH1 R132H mutation and high MACC1. Patients with low MACC1 levelsreceiving standard therapy survived longer (median OS 22.6 months) than patients with high MACC1levels (median OS 8.1 months). Patients not receiving the standard regimen showed the worstprognosis, independent of MACC1 levels (low: 6.8 months, high: 4.4 months). Addition of circulatingMACC1 transcript levels to the existing prognostic workup may improve the accuracy of outcomeprediction and help define more precise risk categories of glioblastoma patients.
Background: The 2009 pandemic influenza A (H1N1) (PIA) virus infected large parts of the pediatric population with a wide clinical spectrum and an initially unknown complication rate. The aims of our study were to define clinical characteristics and outcome of pandemic influenza A (H1N1) 2009-associated hospitalizations (PIAH) in children <18 years of age. All hospitalized cases of children <18 years of age with laboratory-confirmed pandemic influenza A (H1N1) 2009 in the region of Wuerzburg (Northern Bavaria, Germany) between July 2009 and March 2010 were identified. For these children a medical chart review was performed to determine their clinical characteristics and complications. Results: Between July 2009 and March 2010, 94 PIAH (62% males) occurred in children <18 years of age, with a median age of 7 years (IQR: 3–12 years). Underlying diseases and predisposing factors were documented in 40 (43%) children; obesity (n = 12, 30%), asthma (n = 10, 25%) and neurologic disorders (n = 8, 20%) were most frequently reported. Sixteen (17%) children received oxygen supplementation; three (3%) children required mechanical ventilation. Six (6%) children were admitted to an intensive care unit, four of them with underlying chronic diseases. Conclusions: Most PIAH demonstrated a benign course of disease. However, six children (6%) needed treatment at an intensive care unit for severe complications.
Background
Previous influenza surveillance at paediatric intensive care units (PICUs) in Germany indicated increased incidence of PICU admissions for the pandemic influenza subtype A(H1N1)pdm09. We investigated incidence and clinical characteristics of influenza in children admitted to PICUs during the first three post-pandemic influenza seasons, using active screening.
Methods
We conducted a prospective surveillance study in 24 PICUs in Bavaria (Germany) from October 2010 to September 2013. Influenza cases among children between 1 month and 16 years of age admitted to these PICUs with acute respiratory infection were confirmed by PCR analysis of respiratory secretions.
Results
A total of 24/7/20 influenza-associated PICU admissions were recorded in the post-pandemic seasons 1/2/3; incidence estimates per 100,000 children were 1.72/0.76/1.80, respectively. Of all 51 patients, 80 % had influenza A, including 65 % with A(H1N1)pdm09. Influenza A(H1N1)pdm09 was almost absent in season 2 (incidence 0.11), but dominated PICU admissions in seasons 1 (incidence 1.35) and 3 (incidence 1.17). Clinical data was available for 47 influenza patients; median age was 4.8 years (IQR 1.6–11.0). The most frequent diagnoses were influenza-associated pneumonia (62 %), bronchitis/bronchiolitis (32 %), secondary bacterial pneumonia (26 %), and ARDS (21 %). Thirty-six patients (77 %) had underlying medical conditions. Median duration of PICU stay was 3 days (IQR 1–11). Forty-seven per cent of patients received mechanical ventilation, and one patient (2 %) extracorporeal membrane oxygenation; 19 % were treated with oseltamivir. Five children (11 %) had pulmonary sequelae. Five children (11 %) died; all had underlying chronic conditions and were infected with A(H1N1)pdm09. In season 3, patients with A(H1N1)pdm09 were younger than in season 1 (p = 0.020), were diagnosed more often with bronchitis/bronchiolitis (p = 0.004), and were admitted to a PICU later after the onset of influenza symptoms (p = 0.041).
Conclusions
Active screening showed a continued high incidence of A(H1N1)pdm09-associated PICU admissions in the post-pandemic seasons 1 and 3, and indicated possible underestimation of incidence in previous German studies. The age shift of severe A(H1N1)pdm09 towards younger children may be explained by increasing immunity in the older paediatric population. The high proportion of patients with underlying chronic conditions indicates the importance of consistent implementation of the current influenza vaccination recommendations for risk groups in Germany.
Medulloblastoma is the most common high-grade brain tumor in childhood. Medulloblastomas with c-myc amplification, classified as group 3, are the most aggressive among the four disease subtypes resulting in a 5-year overall survival of just above 50%. Despite current intensive therapy regimens, patients suffering from group 3 medulloblastoma urgently require new therapeutic options. Using a recently established c-myc amplified human medulloblastoma cell line, we performed an in-vitro-drug screen with single and combinatorial drugs that are either already clinically approved or agents in the advanced stage of clinical development. Candidate drugs were identified in vitro and then evaluated in vivo. Tumor growth was closely monitored by BLI. Vessel development was assessed by 3D light-sheet-fluorescence-microscopy. We identified the combination of gemcitabine and axitinib to be highly cytotoxic, requiring only low picomolar concentrations when used in combination. In the orthotopic model, gemcitabine and axitinib showed efficacy in terms of tumor control and survival. In both models, gemcitabine and axitinib were better tolerated than the standard regimen comprising of cisplatin and etoposide phosphate. 3D light-sheet-fluorescence-microscopy of intact tumors revealed thinning and rarefication of tumor vessels, providing one explanation for reduced tumor growth. Thus, the combination of the two drugs gemcitabine and axitinib has favorable effects on preventing tumor progression in an orthotopic group 3 medulloblastoma xenograft model while exhibiting a favorable toxicity profile. The combination merits further exploration as a new approach to treat high-risk group 3 medulloblastoma.
Immunotherapy of malignant gliomas with autologous dendritic cells (DCs) in addition to surgery and radiochemotherapy has been a focus of intense research during the past decade. Since both children and adults are affected by this highly aggressive brain tumor, 10–15% of the several hundred vaccinated patients represent children, making pediatric glioma patients the largest uniform pediatric vaccination cohort so far. In general, DC vaccination in malignant gliomas has been shown to be safe and several studies with a non-vaccinated control group could clearly demonstrate a survival benefit for the vaccinated patients. Interestingly, children and adolescents below 21 years of age seem to benefit even more than adult patients. This review summarizes the findings of the 25 clinical trials published so far and gives a perspective how DC vaccination could be implemented as part of multimodal therapeutic strategies in the near future.
Background
To evaluate optimal therapy and potential risk factors.
Methods
Data of DSRCT patients <40 years treated in prospective CWS trials 1997-2015 were analyzed.
Results
Median age of 60 patients was 14.5 years. Male:female ratio was 4:1. Tumors were abdominal/retroperitoneal in 56/60 (93%). 6/60 (10%) presented with a localized mass, 16/60 (27%) regionally disseminated nodes, and 38/60 (63%) with extraperitoneal metastases. At diagnosis, 23/60 (38%) patients had effusions, 4/60 (7%) a thrombosis, and 37/54 (69%) elevated CRP. 40/60 (67%) patients underwent tumor resection, 21/60 (35%) macroscopically complete. 37/60 (62%) received chemotherapy according to CEVAIE (ifosfamide, vincristine, actinomycin D, carboplatin, epirubicin, etoposide), 15/60 (25%) VAIA (ifosfamide, vincristine, adriamycin, actinomycin D) and, 5/60 (8%) P6 (cyclophosphamide, doxorubicin, vincristine, ifosfamide, etoposide). Nine received high-dose chemotherapy, 6 received regional hyperthermia, and 20 received radiotherapy. Among 25 patients achieving complete remission, 18 (72%) received metronomic therapies. Three-year event-free (EFS) and overall survival (OS) were 11% (±8 confidence interval [CI] 95%) and 30% (±12 CI 95%), respectively, for all patients and 26.7% (±18.0 CI 95%) and 56.9% (±20.4 CI 95%) for 25 patients achieving remission. Extra-abdominal site, localized disease, no effusion or ascites only, absence of thrombosis, normal CRP, complete tumor resection, and chemotherapy with VAIA correlated with EFS in univariate analysis. In multivariate analysis, significant factors were no thrombosis and chemotherapy with VAIA. In patients achieving complete remission, metronomic therapy with cyclophosphamide/vinblastine correlated with prolonged time to relapse.
Conclusion
Pleural effusions, venous thrombosis, and CRP elevation were identified as potential risk factors. The VAIA scheme showed best outcome. Maintenance therapy should be investigated further.
Data on biomarker-assisted diagnosis of invasive aspergillosis (IA) in pediatric patients is scarce. Therefore, we conducted a cohort study over two years including 404 serum specimens of 26 pediatric patients after allogeneic hematopoietic stem cell transplantation (alloSCT). Sera were tested prospectively twice weekly for Aspergillus-specific DNA, galactomannan (GM), and retrospectively for (1→3)-β-D-glucan (BDG). Three probable IA and two possible invasive fungal disease (IFD) cases were identified using the European Organization for Research and Treatment of Cancer and the Mycoses Study Group (EORTC/MSGERC) 2019 consensus definitions. Sensitivity and specificity for diagnosis of probable IA and possible IFD was 80% (95% confidential interval (CI): 28–99%) and 55% (95% CI: 32–77%) for BDG, 40% (95% CI: 5–85%) and 100% (95% CI: 83–100%) for GM, and 60% (95% CI: 15–95%) and 95% (95% CI: 75–100%) for Aspergillus-specific real-time PCR. However, sensitivities have to be interpreted with great caution due to the limited number of IA cases. Interestingly, the low specificity of BDG was largely caused by false-positive BDG results that clustered around the date of alloSCT. The following strategies were able to increase BDG specificity: two consecutive positive BDG tests for diagnosis (specificity 80% (95% CI: 56–94%)); using an optimized cutoff value of 306 pg/mL (specificity 90% (95% CI: 68–99%)) and testing BDG only after the acute posttransplant phase. In summary, BDG can help to diagnose IA in pediatric alloSCT recipients. However, due to the poor specificity either an increased cutoff value should be utilized or BDG results should be confirmed by an alternative Aspergillus assay.
Purpose
In selected cases of severe Cushing’s syndrome due to uncontrolled ACTH secretion, bilateral adrenalectomy appears unavoidable. Compared with unilateral adrenalectomy (for adrenal Cushing’s syndrome), bilateral adrenalectomy has a perceived higher perioperative morbidity. The aim of the current study was to compare both interventions in endogenous Cushing’s syndrome regarding postoperative outcomes.
Methods
We report a single-center, retrospective cohort study comparing patients with hypercortisolism undergoing bilateral vs. unilateral adrenalectomy during 2008–2021. Patients with adrenal Cushing’s syndrome due to adenoma were compared with patients with ACTH-dependent Cushing’s syndrome (Cushing’s disease and ectopic ACTH production) focusing on postoperative morbidity and mortality as well as long-term survival.
Results
Of 83 patients with adrenalectomy for hypercortisolism (65.1% female, median age 53 years), the indication for adrenalectomy was due to adrenal Cushing’s syndrome in 60 patients (72.2%; 59 unilateral and one bilateral), and due to hypercortisolism caused by Cushing’s disease (n = 16) or non-pituitary uncontrolled ACTH secretion of unknown origin (n = 7) (27.7% of all adrenalectomies). Compared with unilateral adrenalectomy (n = 59), patients with bilateral adrenalectomy (n = 24) had a higher rate of severe complications (0% vs. 33%; p < 0.001) and delayed recovery (median: 10.2% vs. 79.2%; p < 0.001). Using the MTL30 marker, patients with bilateral adrenalectomy fared worse than patients after unilateral surgery (MTL30 positive: 7.2% vs. 25.0% p < 0.001). Postoperative mortality was increased in patients with bilateral adrenalectomy (0% vs. 8.3%; p = 0.081).
Conclusion
While unilateral adrenalectomy for adrenal Cushing’s syndrome represents a safe and definitive therapeutic option, bilateral adrenalectomy to control ACTH-dependent extra-adrenal Cushing’s syndrome or Cushing’s disease is a more complicated intervention with a mortality of nearly 10%.
Primary prevention strategies, such as vaccinations at the age extremes, in neonates and elderly individuals, demonstrate a challenge to health professionals and public health specialists. The aspects of the differentiation and maturation of the adaptive immune system, the functional implications of immunological immaturity or immunosenescence and its impact on vaccine immunogenicity and efficacy will be highlighted in this review. Several approaches have been undertaken to promote Th1 responses in neonates and to enhance immune functions in elderly, such as conjugation to carrier proteins, addition of adjuvants, concomitant vaccination with other vaccines, change in antigen concentrations or dose intervals or use of different administration routes. Also, early protection by maternal vaccination seems to be beneficial in neonates. However, it also appears necessary to think of other end points than antibody concentrations to assess vaccine efficacy in neonates or elderly, as also the cellular immune response may be impaired by the mechanisms of immaturity, underlying health conditions, immunosuppressive treatments or immunosenescence. Thus, lifespan vaccine programs should be implemented to all individuals on a population level not only to improve herd protection and to maintain protective antibody levels and immune memory, but also to cover all age groups, to protect unvaccinated elderly persons and to provide indirect protection for neonates and small infants.
Background: There is much evidence that T cells are strongly involved in the pathogenesis of localized and systemic forms of scleroderma (SSc). A dysbalance between FoxP3+ regulatory CD4+ T cells (Tregs) and inflammatory T-helper (Th) 17 cells has been suggested. Methods: The study aimed (1) to investigate the phenotypical and functional characteristics of Th17 and Tregs in SSc patients depending on disease manifestation (limited vs. diffuse cutaneous SSc, dcSSc) and activity, and (2) the transcriptional level and methylation status of Th17- and Treg-specific transcription factors. Results: There was a concurrent accumulation of circulating peripheral IL-17-producing CCR6+ Th cells and FoxP3+ Tregs in patients with dcSSc. At the transcriptional level, Th17- and Treg-associated transcription factors were elevated in SSc. A strong association with high circulating Th17 and Tregs was seen with early, active, and severe disease presentation. However, a diminished suppressive function on autologous lymphocytes was found in SSc-derived Tregs. Significant relative hypermethylation was seen at the gene level for RORC1 and RORC2 in SSc, particularly in patients with high inflammatory activity. Conclusions: Besides the high transcriptional activity of T cells, attributed to Treg or Th17 phenotype, in active SSc disease, Tregs may be insufficient to produce high amounts of IL-10 or to control proliferative activity of effector T cells in SSc. Our results suggest a high plasticity of Tregs strongly associated with the Th17 phenotype. Future directions may focus on enhancing Treg functions and stabilization of the Treg phenotype.
B cells and DCs are suspected to play an important role in the pathogenesis of cGvHD, which is a serious complication of HSCT with high morbidity. It is characterized by immune responses of donor immune cells against recipient-derived antigens. athogenesis is not yet fully understood, however reconstitution of B cells after HSCT has similarities to physiologic ontogeny. Immunophenotyping and co-cultivation-experiments of B cells and DCs from pediatric patients with cGvHD as well as healthy donors were conducted. Significant differences between patients and healthy donors were observed with increased memory, transitional, CD69+ and CD86+ phenotype and lower levels of naïve B cells due to apoptosis. Co-cultivation revealed this to be primarily B cell-dependent without major effects of and with DCs. There was a decreased CD11c- phenotype in patients and less apoptosis of DCs. Our data suggest a disturbed homeostasis in B cells with increased memory phenotype in patients, whereas DCs could not influence these differences, therefore DCs are not imposing as promising targets. B cell-dependent approaches should be further investigated.
Background
Extreme prematurity has been associated with exercise intolerance and reduced physical activity. We hypothesized that children with bronchopulmonary dysplasia (BPD) would be especially affected based on long-term lung function impairments. Therefore, the objective of this study was to compare exercise capacity and habitual physical activity between children born very and extremely preterm with and without BPD and term-born children.
Methods
Twenty-two school-aged children (aged 8 to 12 years) born with a gestational age < 32 weeks and a birthweight < 1500 g (9 with moderate or severe BPD (=BPD), 13 without BPD (=No-BPD)) and 15 healthy term-born children (=CONTROL) were included in the study. Physical activity was measured by accelerometry, lung function by spirometry and exercise capacity by an incremental cardiopulmonary exercise test.
Results
Peak oxygen uptake was reduced in the BPD-group (83 ± 11%predicted) compared to the No-BPD group (91 ± 8%predicted) and the CONTROL group (94 ± 9%predicted). In a general linear model, variance of peak oxygen uptake was significantly explained by BPD status and height but not by prematurity (p < 0.001).
Compared to CONTROL, all children born preterm spent significantly more time in sedentary behaviour (BPD 478 ± 50 min, No-BPD 450 ± 52 min, CONTROL 398 ± 56 min, p < 0.05) and less time in moderate-to-vigorous-physical activity (BPD 13 ± 8 min, No-BPD 16 ± 8 min, CONTROL 33 ± 16 min, p < 0.001). Prematurity but not BPD contributed significantly to explained variance in a general linear model of sedentary behaviour and likewise moderate-to-vigorous-physical activity (p < 0.05 and p < 0.001 respectively).
Conclusion
In our cohort, BPD but not prematurity was associated with a reduced exercise capacity at school-age. However, prematurity regardless of BPD was related to less engagement in physical activity and more time spent in sedentary behaviour. Thus, our findings suggest diverging effects of prematurity and BPD on exercise capacity and physical activity."
Background
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved survival in high-risk childhood leukemia but is associated with long-term sequelae such as impaired pulmonary function and reduced exercise capacity impacting quality of life.
Methods
A convenience sample of 17 patients after allo-HSCT (HSCT—12 male, age 15.7±6.7 years, time after HSCT 5.3±2.8 years) underwent pulmonary function testing, echocardiography, and an incremental exercise test on a bike. Physical activity and health-related quality of life were assessed by questionnaires (7-day physical activity recall, PEDS-QL). Seventeen healthy age- and gender-matched controls served as control group (CG) for results of pulmonary function and exercise testing.
Results
HSCT showed reduced pulmonary function (HSCT vs. CG: FEV1 90.5±14.0 vs. 108.0±8.7%pred; FVC 88.4±19.3 vs. 107.6±6.9%pred, DLCO 75.3±23.6 vs. 104.9±12.8%pred) and exercise capacity (VO2peak 89±30.8%pred, CG 98±17.5%pred; Wmax 84±21.7%pred, CG 115±22.8%pred), but no relevant cardiac dysfunction and a good quality of life (PEDS-QL mean overall score 83.3±10.7). Differences in peak oxygen uptake between groups were mostly explained by 5 adolescent patients who underwent total body irradiation for conditioning. They showed significantly reduced diffusion capacity and reduced peak oxygen uptake.
Patients reported a mean time of inactivity of 777±159min/day, moderate activity of 110±107 min/day, hard activity of 35±36 min/day, and very hard activity of 23±22 min/day. A higher amount of inactivity was associated with a lower peak oxygen uptake (correlation coefficient tau −0.48, p=0.023).
Conclusions
This pilot study shows that although patients after allo-HSCT reported a good quality of life, regular physical activity and exercise capacity are reduced in survivors of stem cell transplantation, especially in adolescents who are treated with total body irradiation for conditioning. Factors hindering regular physical activity need to be identified and exercise counseling should be part of follow-up visits in these patients.
Background:
The use of venoarterial extracorporeal membrane oxygenation (va-ECMO) via peripheral cannulation for septic shock is limited by blood flow and increased afterload for the left ventricle.
Case Report:
A 15-year-old girl with acute myelogenous leukemia, suffering from severe septic and cardiogenic shock, was treated by venoarterial extracorporeal membrane oxygenation (va-ECMO). Sufficient extracorporeal blood flow matching the required oxygen demand could only be achieved by peripheral cannulation of both femoral arteries. Venous drainage was performed with a bicaval cannula inserted via the left V. femoralis. To accomplish left ventricular unloading, an additional drainage cannula was placed in the left atrium via percutaneous atrioseptostomy (va-va-ECMO). Cardiac function recovered and the girl was weaned from the ECMO on day 6. Successful allogenic stem cell transplantation took place 2 months later.
Conclusions:
In patients with vasoplegic septic shock and impaired cardiac contractility, double peripheral venoarterial extracorporeal membrane oxygenation (va-va-ECMO) with transseptal left atrial venting can by a lifesaving option.
Background
In individuals suffering from a rare disease the diagnostic process and the confirmation of a final diagnosis often extends over many years. Factors contributing to delayed diagnosis include health care professionals' limited knowledge of rare diseases and frequent (co-)occurrence of mental disorders that may complicate and delay the diagnostic process. The ZSE-DUO study aims to assess the benefits of a combination of a physician focusing on somatic aspects with a mental health expert working side by side as a tandem in the diagnostic process.
Study design
This multi-center, prospective controlled study has a two-phase cohort design.
Methods
Two cohorts of 682 patients each are sequentially recruited from 11 university-based German Centers for Rare Diseases (CRD): the standard care cohort (control, somatic expertise only) and the innovative care cohort (experimental, combined somatic and mental health expertise). Individuals aged 12 years and older presenting with symptoms and signs which are not explained by current diagnoses will be included. Data will be collected prior to the first visit to the CRD’s outpatient clinic (T0), at the first visit (T1) and 12 months thereafter (T2).
Outcomes
Primary outcome is the percentage of patients with one or more confirmed diagnoses covering the symptomatic spectrum presented. Sample size is calculated to detect a 10 percent increase from 30% in standard care to 40% in the innovative dual expert cohort. Secondary outcomes are (a) time to diagnosis/diagnoses explaining the symptomatology; (b) proportion of patients successfully referred from CRD to standard care; (c) costs of diagnosis including incremental cost effectiveness ratios; (d) predictive value of screening instruments administered at T0 to identify patients with mental disorders; (e) patients’ quality of life and evaluation of care; and f) physicians’ satisfaction with the innovative care approach.
Conclusions
This is the first multi-center study to investigate the effects of a mental health specialist working in tandem with a somatic expert physician in CRDs. If this innovative approach proves successful, it will be made available on a larger scale nationally and promoted internationally. In the best case, ZSE-DUO can significantly shorten the time to diagnosis for a suspected rare disease.