Publications by authors named "Christian Urban"

152 Publications

Long-Term Outcome and Role of Biology within Risk-Adapted Treatment Strategies: The Austrian Neuroblastoma Trial A-NB94.

Cancers (Basel) 2021 Feb 2;13(3). Epub 2021 Feb 2.

St. Anna Children's Hospital, 1090 Vienna, Austria.

We evaluated long-term outcome and genomic profiles in the Austrian Neuroblastoma Trial A-NB94 which applied a risk-adapted strategy of treatment (RAST) using stage, age and amplification (MNA) status for stratification. RAST ranged from surgery only to intensity-adjusted chemotherapy, single or multiple courses of high-dose chemotherapy (HDT) followed by autologous stem cell rescue depending on response to induction chemotherapy, and irradiation to the primary tumor site. Segmental chromosomal alterations (SCAs) were investigated retrospectively using multi- and pan-genomic techniques. The A-NB94 trial enrolled 163 patients. Patients with localized disease had an excellent ten-year (10y) event free survival (EFS) and overall survival (OS) of 99 ± 1% and 93 ± 2% whilst it was 80 ± 13% and 90 ± 9% for infants with stage 4S and for infants with stage 4 non-MNA disease both 83 ± 15%. Stage 4 patients either >12 months or ≤12 months but with MNA had a 10y-EFS and OS of 45 ± 8% and 47 ± 8%, respectively. SCAs were present in increasing frequencies according to stage and age: in 29% of localized tumors but in 92% of stage 4 tumors ( < 0.001), and in 39% of patients ≤ 12 months but in 63% of patients > 12 months ( < 0.001). RAST successfully reduced chemotherapy exposure in low- and intermediate-risk patients with excellent long-term results while the outcome of high-risk disease met contemporary trials.
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http://dx.doi.org/10.3390/cancers13030572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867286PMC
February 2021

Bone marrow aspirations in Ewing sarcomas: Are they still necessary? A single-center retrospective analysis and review of the literature.

J Cancer Res Ther 2020 Jul-Sep;16(4):713-717

Department of Orthopaedic Surgery, Medical University of Graz, Graz, Austria.

Background And Objectives: Currently, one of the most useful prognostic indicators in Ewing sarcomas (ES) is the presence of metastatic disease at diagnosis. According to various clinical guidelines, the assessment of bone marrow (BM) metastases, using light microscopy examination of bone marrow aspirates and biopsies (BMAB) is mandatory. However, the prognostic value of BM positivity is discussed controversially. Therefore, the primary aim of this study was to retrospectively review BM samples from patients with ES.

Materials And Methods: This retrospective single centre study included 31 patients that were newly diagnosed with ES between 2000 and 2014. Twenty-seven patients had skeletal ES and in 4 patients the tumour was localized in the soft tissue only. Metastases at diagnosis were present in 5 out of 31 patients. BM samples were morphologically and immunohistochemically searched and screened for the presence or absence of BM metastases. Furthermore, in 15 of the 31 patients BM samples were still available and were reanalysed, using nested-polymerase chain reaction.

Results: All BM samples of our 31 ES patients, including the 5 metastatic patients, were, morphologically and immunohistochemically tested negative for tumour cell appearance. The nested-PCR results were also negative in all of our 15 retested patients, including two patients with metastatic disease.

Conclusions: Based on our results and on the contradictory results reported in the literature we recommend a re-evaluation of the necessity and the prognostic value of BMAB in the initial staging process of newly diagnosed ES patients.
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http://dx.doi.org/10.4103/jcrt.JCRT_941_16DOI Listing
November 2020

2000-year-old pathogen genomes reconstructed from metagenomic analysis of Egyptian mummified individuals.

BMC Biol 2020 08 28;18(1):108. Epub 2020 Aug 28.

Institute of Evolutionary Medicine, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.

Background: Recent advances in sequencing have facilitated large-scale analyses of the metagenomic composition of different samples, including the environmental microbiome of air, water, and soil, as well as the microbiome of living humans and other animals. Analyses of the microbiome of ancient human samples may provide insights into human health and disease, as well as pathogen evolution, but the field is still in its very early stages and considered highly challenging.

Results: The metagenomic and pathogen content of Egyptian mummified individuals from different time periods was investigated via genetic analysis of the microbial composition of various tissues. The analysis of the dental calculus' microbiome identified Red Complex bacteria, which are correlated with periodontal diseases. From bone and soft tissue, genomes of two ancient pathogens, a 2200-year-old Mycobacterium leprae strain and a 2000-year-old human hepatitis B virus, were successfully reconstructed.

Conclusions: The results show the reliability of metagenomic studies on Egyptian mummified individuals and the potential to use them as a source for the extraction of ancient pathogen DNA.
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http://dx.doi.org/10.1186/s12915-020-00839-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456089PMC
August 2020

Persistent Innate Immune Stimulation Results in IRF3-Mediated but Caspase-Independent Cytostasis.

Viruses 2020 06 11;12(6). Epub 2020 Jun 11.

Research Group "Dynamics of Early Viral Infection and the Innate Antiviral Response", Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

Persistent virus infection continuously produces non-self nucleic acids that activate cell-intrinsic immune responses. However, the antiviral defense evolved as a transient, acute phase response and the effects of persistently ongoing stimulation onto cellular homeostasis are not well understood. To study the consequences of long-term innate immune activation, we expressed the NS5B polymerase of Hepatitis C virus (HCV), which in absence of viral genomes continuously produces immune-stimulatory RNAs. Surprisingly, within 3 weeks, NS5B expression declined and the innate immune response ceased. Proteomics and functional analyses indicated a reduced proliferation of those cells most strongly stimulated, which was independent of interferon signaling but required mitochondrial antiviral signaling protein (MAVS) and interferon regulatory factor 3 (IRF3). Depletion of MAVS or IRF3, or overexpression of the MAVS-inactivating HCV NS3/4A protease not only blocked interferon responses but also restored cell growth in NS5B expressing cells. However, pan-caspase inhibition could not rescue the NS5B-induced cytostasis. Our results underline an active counter selection of cells with prolonged innate immune activation, which likely constitutes a cellular strategy to prevent persistent virus infections.
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http://dx.doi.org/10.3390/v12060635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354422PMC
June 2020

Major Capsid Protein Synthesis from the Genomic RNA of Feline Calicivirus.

J Virol 2020 07 16;94(15). Epub 2020 Jul 16.

Institut für Immunologie, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany

Caliciviruses have a positive-strand RNA genome with a length of about 7.5 kb that contains 2, 3, or 4 functional open reading frames (ORFs). A subgenomic mRNA (sg-RNA) is transcribed in the infected cell, and both major capsid protein viral protein 1 (VP1) and minor capsid protein VP2 are translated from the sg-RNA. Translation of proteins from the genomic RNA (g-RNA) and from the sg-RNA is mediated by the RNA-linked viral protein VPg (virus protein, genome linked). Most of the calicivirus genera have translation mechanisms leading to VP1 expression from the g-RNA. VP1 is part of the polyprotein for sapoviruses, lagoviruses, and neboviruses, and a termination/reinitiation mechanism was described for noroviruses. Vesiviruses have no known mechanism for the expression of VP1 from the g-RNA, and the genus is the only genus of the that generates VP1 via a precursor capsid leader protein (LC-VP1). Analyses of feline calicivirus (FCV) g-RNA translation showed a low level of VP1 expression with an initiation downstream of the original start codon of LC-VP1, leading to a smaller, truncated LC-VP1 (tLC-VP1) protein. Deletion and substitution analyses of the region surrounding the LC-VP1 start codon allowed the identification of sequences within the leader protein coding region of FCV that have an impact on VP1 translation frequency from the g-RNA. Introduction of such mutations into the virus showed an impact of strongly reduced tLC-VP1 levels translated from the g-RNA on viral replication. Caliciviruses are a cause of important diseases in humans and animals. It is crucial to understand the prerequisites of efficient replication of these viruses in order to develop strategies for prevention and treatment of these diseases. It was shown before that all caliciviruses except vesiviruses have established mechanisms to achieve major capsid protein (VP1) translation from the genomic RNA. Here, we show for the first time that a member of the genus also has a translation initiation mechanism by which a precursor protein of the VP1 protein is expressed from the genomic RNA. This finding clearly points at a functional role of the calicivirus VP1 capsid protein in early replication, and we provide experimental data supporting this hypothesis.
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http://dx.doi.org/10.1128/JVI.00280-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375370PMC
July 2020

Hydrostatic pressure mapping of barium titanate phase transitions with quenched FeRh.

Sci Rep 2020 Apr 14;10(1):6312. Epub 2020 Apr 14.

Department of Physics and Center for Advanced Nanoscience, University of California, San Diego, La Jolla, California, 92093, USA.

We report a pressure study of the metamagnetic/ferroelectric hybrid heterostructure of a quenched FeRh thin film (25 nm) grown on single crystal barium titanate (BTO). It has been previously reported that when the BTO undergoes a crystal transition a massive magnetization and coercivity change is triggered in the highly strain sensitive quenched FeRh thin film. Therefore quenched FeRh makes for an ideal probe for mapping a materials structural phase transitions. In this work we demonstrate this effect as a function of both temperature and hydrostatic pressure. As a result, we present the pressure dependence of the hybrid material which aligns identically with the BTO substrates pressure dependence reported in literature. The concept of combining a structural phase transitional (SPT) material with a magnetostrictive magnetic metal has been shown with vanadium oxides and our findings here prove that this methodology can be extended to strain sensitive metamagnetic materials systems in thin film, and possibly in bulk, heterostructures.
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http://dx.doi.org/10.1038/s41598-020-63358-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156734PMC
April 2020

Novel phenotypes observed in patients with -linked leukaemia/familial thrombocytopenia syndrome and a biallelic risk allele as leukaemogenic cofactor.

J Med Genet 2020 06 8;57(6):427-433. Epub 2019 Nov 8.

Division of Pediatric Hemato-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria

The phenotypes of patients with the recently discovered, dominant, -linked leukaemia predisposition and familial thrombocytopenia syndrome are variable, and the exact mechanism of leukaemogenesis remains unclear. Here, we present novel clinical and laboratory phenotypes of seven individuals from three families with germline mutations and a refined genetic analysis of one child with additional high-hyperdiploid acute lymphoblastic leukaemia (HD-ALL), aiming to elucidate second oncogenic hits. Four individuals from two pedigrees harboured one novel or one previously described variant in the central domain of (c.592C>T, p.Gln198* or c.641C>T, p.Pro241Leu, respectively). Neutropenia was an accompanying feature in one of these families that also harboured a variant in (c.1098_1103dup, p.Ile366_Gly367dup), while in the other, an autism-spectrum disorder was observed. In the third family, the index patient suffered from HD-ALL and life-threatening pulmonary mucor mycosis, and had a positive family history of 'immune' thrombocytopenia. Genetic analyses revealed a novel heterozygous mutation in the ETS domain of (c.1136T>C, p.Leu379Pro) along with absence of heterozygosity of chromosome (10)(q21.2q21.3), yielding a biallelic leukaemia risk allele in (rs7090445-C). The neutrophil function was normal in all individuals tested, and the platelet immune histochemistry of all three pedigrees showed delta-storage-pool defect-like features and cytoskeletal defects. Our clinical observations and results of high-resolution genetic analyses extend the spectrum of possible phenotypes cosegregating with germline mutations. Further, we propose as potential leukaemogenic cofactor in patients with -linked leukaemia predisposition and familial thrombocytopenia syndrome.
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http://dx.doi.org/10.1136/jmedgenet-2019-106339DOI Listing
June 2020

Large-scale mitogenomic analysis of the phylogeography of the Late Pleistocene cave bear.

Sci Rep 2019 08 15;9(1):10700. Epub 2019 Aug 15.

Institute for Archaeological Sciences, University of Tübingen, Tübingen, Germany.

The cave bear (Ursus spelaeus) is one of the Late Pleistocene megafauna species that faced extinction at the end of the last ice age. Although it is represented by one of the largest fossil records in Europe and has been subject to several interdisciplinary studies including palaeogenetic research, its fate remains highly controversial. Here, we used a combination of hybridisation capture and next generation sequencing to reconstruct 59 new complete cave bear mitochondrial genomes (mtDNA) from 14 sites in Western, Central and Eastern Europe. In a Bayesian phylogenetic analysis, we compared them to 64 published cave bear mtDNA sequences to reconstruct the population dynamics and phylogeography during the Late Pleistocene. We found five major mitochondrial DNA lineages resulting in a noticeably more complex biogeography of the European lineages during the last 50,000 years than previously assumed. Furthermore, our calculated effective female population sizes suggest a drastic cave bear population decline starting around 40,000 years ago at the onset of the Aurignacian, coinciding with the spread of anatomically modern humans in Europe. Thus, our study supports a potential significant human role in the general extinction and local extirpation of the European cave bear and illuminates the fate of this megafauna species.
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http://dx.doi.org/10.1038/s41598-019-47073-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695494PMC
August 2019

A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape.

Nat Immunol 2019 04 4;20(4):493-502. Epub 2019 Mar 4.

Innate Immunity Laboratory, Max-Planck Institute of Biochemistry, Munich, Germany.

Interferon-stimulated genes (ISGs) form the backbone of the innate immune system and are important for limiting intra- and intercellular viral replication and spread. We conducted a mass-spectrometry-based survey to understand the fundamental organization of the innate immune system and to explore the molecular functions of individual ISGs. We identified interactions between 104 ISGs and 1,401 cellular binding partners engaging in 2,734 high-confidence interactions. 90% of these interactions are unreported so far, and our survey therefore illuminates a far wider activity spectrum of ISGs than is currently known. Integration of the resulting ISG-interaction network with published datasets and functional studies allowed us to identify regulators of immunity and processes related to the immune system. Given the extraordinary robustness of the innate immune system, this ISG network may serve as a blueprint for therapeutic targeting of cellular systems to efficiently fight viral infections.
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http://dx.doi.org/10.1038/s41590-019-0323-3DOI Listing
April 2019

Pseudoachalasia as First Manifestation of a Malignancy.

Dig Dis 2019 2;37(5):347-354. Epub 2019 Jan 2.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria,

Pseudoachalasia is a condition in which symptoms, radiologic, endoscopic, and manometric findings mimick idiopathic achalasia. About 4% of patients with a typical constellation for idiopathic achalasia will turn out to have pseudoachalasia, posing a major diagnostic challenge. A large spectrum of underlying causes of pseudoachalasia has been described. However, in about 70% of affected patients, this condition is caused by a malignancy (mostly adenocarcinoma of the esophagogastric junction or cardia). We describe a 16-year-old high school student referred for management of achalasia who turned out to have pseudoachalasia due to adenocarcinoma of the cardia. He was cured with preoperative chemotherapy followed by radical surgery. Therapy of pseudoachalasia secondary to neoplasia is directed against the tumor or may be palliative to keep the lumen open. Other causes of pseudoachalasia include esophageal motility disturbances as a paraneoplastic phenomenon (e.g., with small cell lung cancer), post fundoplication or post bariatric surgery, in association with a thoracic aortic aneurysm, or with sarcoidosis or amyloidosis. Therapy is directed accordingly to eliminate or correct the underlying cause.
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http://dx.doi.org/10.1159/000495758DOI Listing
July 2019

The Phenotype and Treatment of WIP Deficiency: Literature Synopsis and Review of a Patient With Pre-transplant Serial Donor Lymphocyte Infusions to Eliminate CMV.

Front Immunol 2018 2;9:2554. Epub 2018 Nov 2.

Division of Pediatric Hematology-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University Graz, Graz, Austria.

Early diagnosis of primary immunodeficiency disorders (PID) is vital and allows directed treatment, especially in syndromes with severe or profound combined immunodeficiency. In PID patients with perinatal CMV or other opportunistic, invasive infections (e.g., or ), multi-organ morbidity may already arise within the first months of life, before hematopoietic stem cell transplantation (HSCT) or gene therapy can be undertaken, compromising the definitive treatment and outcome. Deficiency of Wiskott-Aldrich syndrome (WAS) protein-interacting protein (WIP deficiency) causes an autosomal recessive, WAS-like syndrome with early-onset combined immunodeficiency that has been described in three pedigrees to date. While WAS typically includes combined immunodeficiency, microthrombocytopenia, and eczema, the clinical and laboratory phenotypes of WIP-deficient patients-including lymphocyte subsets, platelets, lymphocyte proliferation , and IgE-varied widely and did not entirely recapitulate WAS, impeding early diagnosis in the reported patients. To elucidate the phenotype of WIP deficiency, we provide a comprehensive synopsis of clinical and laboratory features of all hitherto-described patients ( = 6) and WIP negative mice. Furthermore, we summarize the treatment modalities and outcomes of these patients and review in detail the course of one of them who was successfully treated with serial, unconditioned, maternal, HLA-identical donor lymphocyte infusions (DLI) against life-threatening, invasive CMV infection, followed by a TCRαβ/CD19-depleted, treosulfan/melphalan-conditioned, peripheral blood HSCT and repetitive, secondary-prophylactic, CMV-specific DLI with 1-year post-HSCT follow-up. This strategy could be useful in other patients with substantial premorbidity, considered "," who have an HLA-identical family donor, to eliminate infections and bridge until definitive treatment.
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http://dx.doi.org/10.3389/fimmu.2018.02554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224452PMC
September 2019

Enterovirus infections in pediatric hematologic/oncologic patients.

Pediatr Blood Cancer 2019 01 30;66(1):e27448. Epub 2018 Sep 30.

Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria.

Background: Enteroviruses (EV) are a large group of Picornaviruses associated with respiratory, gastrointestinal, and neurologic symptoms in the immunocompetent host. Little is known about the epidemiologic and clinical impact in pediatric hematologic/oncologic patients.

Procedure: From 2001 through 2017, different clinical specimens were collected from pediatric hematologic/oncologic patients and were tested for enteroviral RNA.

Results: Of 13 004 specimens collected from 761 patients, 38 (0.3%) obtained from 14 patients (1.8%) tested positive for EV RNA. Viral shedding was observed without viremia and vice versa. None of 80 cerebrospinal fluid specimens obtained from 60 patients with neurologic symptoms were positive for EV RNA. None of 14 patients positive for EV RNA showed EV-specific symptoms. In 11/14 patients, EV RNA was found to be negative in the follow-up specimen. The remaining patient with a severe primary immune deficiency showed repeated positive EV RNA results for >5 years.

Conclusions: In this pediatric hematologic/oncologic cohort, EV infection occurred rarely and without related symptoms. Specimens concurrently obtained from one patient are commonly not in accordance with each other. In the vast majority of patients, EV RNA appears to turn negative in the follow-up specimen. EV infections seem to have a low impact in this patient cohort.
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http://dx.doi.org/10.1002/pbc.27448DOI Listing
January 2019

HHV-6 Specific T-Cell Immunity in Healthy Children and Adolescents.

Front Pediatr 2018 2;6:191. Epub 2018 Jul 2.

Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria.

Primary infection with human herpes virus 6 (mainly HHV-6B) commonly occurs in the first 2 years of life leading to persistence and the possibility of virus reactivation later in life. Consequently, a specific cellular immune response is essential for effective control of virus reactivation. We have studied cell-mediated immune response to HHV-6 (U54) in healthy children and adolescents. By flow cytometry, the amount of cytokine (interferon gamma-IFN- γ, interleukin 2-IL-2, tumor necrosis factor alpha-TNF-α) secreting T-cells were measured after 10 days of pre-sensitization and 6 h of re-stimulation with mixtures of pooled overlapping peptides from U54, staphylococcal enterotoxin B (SEB, positive control), or Actin (negative control) in healthy children and adolescents without any underlying immune disorder or infectious disease. All individuals showed a virus-specific response for at least one cytokine in either CD4+ or CD8+ cells. Percentages of individuals with HHV-6-specific TNF-α response in CD4+ (48% of individuals) as well as CD8+ (56% of individuals) were always the highest. Our data show significantly higher frequencies of HHV-6-specific TNF-α producing CD8+ T-cells in individuals older than 10 years of life ( = 0.033). Additionally, the frequency of HHV-6 specific TNF-α producing CD8+ T-cells positively correlated with the age of the individuals. Linear regression analysis showed a positive relation between age and frequency of HHV-6-specific TNF-α producing CD8+ T-cells. Results indicate that T-cell immune response against HHV-6 is commonly detectable in healthy children and adolescents with higher frequencies of antigen-specific T-cells in older children and adolescents possibly reflecting repeated stimulation by viral persistence and subclinical reactivation.
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http://dx.doi.org/10.3389/fped.2018.00191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036236PMC
July 2018

Ancient genomes reveal a high diversity of Mycobacterium leprae in medieval Europe.

PLoS Pathog 2018 05 10;14(5):e1006997. Epub 2018 May 10.

Institute for Archaeological Sciences, University of Tübingen, Tübingen, Germany.

Studying ancient DNA allows us to retrace the evolutionary history of human pathogens, such as Mycobacterium leprae, the main causative agent of leprosy. Leprosy is one of the oldest recorded and most stigmatizing diseases in human history. The disease was prevalent in Europe until the 16th century and is still endemic in many countries with over 200,000 new cases reported annually. Previous worldwide studies on modern and European medieval M. leprae genomes revealed that they cluster into several distinct branches of which two were present in medieval Northwestern Europe. In this study, we analyzed 10 new medieval M. leprae genomes including the so far oldest M. leprae genome from one of the earliest known cases of leprosy in the United Kingdom-a skeleton from the Great Chesterford cemetery with a calibrated age of 415-545 C.E. This dataset provides a genetic time transect of M. leprae diversity in Europe over the past 1500 years. We find M. leprae strains from four distinct branches to be present in the Early Medieval Period, and strains from three different branches were detected within a single cemetery from the High Medieval Period. Altogether these findings suggest a higher genetic diversity of M. leprae strains in medieval Europe at various time points than previously assumed. The resulting more complex picture of the past phylogeography of leprosy in Europe impacts current phylogeographical models of M. leprae dissemination. It suggests alternative models for the past spread of leprosy such as a wide spread prevalence of strains from different branches in Eurasia already in Antiquity or maybe even an origin in Western Eurasia. Furthermore, these results highlight how studying ancient M. leprae strains improves understanding the history of leprosy worldwide.
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http://dx.doi.org/10.1371/journal.ppat.1006997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944922PMC
May 2018

Malignancy and chemotherapy induced haemophagocytic lymphohistiocytosis in children and adolescents-a single centre experience of 20 years.

Ann Hematol 2018 Jun 6;97(6):989-998. Epub 2018 Feb 6.

Department of Paediatrics and Adolescent Medicine, Medical University of Graz, Auenbruggerplatz 34/2, A-8036, Graz, Austria.

Haemophagocytic lymphohistiocytosis (HLH) is a possibly life-threatening syndrome of immune dysregulation and can be divided into primary (hereditary) and secondary forms (including malignancy-associated HLH (M-HLH)). We retrospectively analysed epidemiological, clinical, virological and laboratory data from patients with M-HLH treated at our department between 1995 and 2014. Out of 1.706 haemato-/oncologic patients treated at our department between 1995 and 2014, we identified 22 (1.29%) patients with secondary HLH (1.3-18.0, median 10.1 years; malignancy induced n = 2; chemotherapy induced n = 20). Patients with acute myeloblastic leukaemia (AML) developed HLH significantly more often than patients with acute lymphoblastic leukaemia (ALL) (10/55, 18.2% vs. 6/148, 4.1%, p = 0.0021). As possible viral triggers, we detected BKV (53.8% of the tested patients), HHV-6 (33.3%), EBV (27.8%), CMV (23.5%), ADV (16.7%) and PVB19 (16.7%) significantly more frequently than in haemato-/oncologic patients without HLH. Despite lacking evidence of concurrent bacterial infection, C-reactive protein (CRP) and procalcitotnin (PCT) were elevated in 94.7 and 77.7% of the patients, respectively. Ferritin and sIL2R were markedly elevated in all patients. HLH-associated mortality significantly (p = 0.0276) decreased from 66.6% (1995-2004) to 6.25% (2005-2014), suggesting improved diagnostic and therapeutic management. Awareness of HLH is important, and fever refractory to antibiotics should prompt to consider this diagnosis. Elevated ferritin and sIL2R seem to be good markers, while inflammatory markers like CRP and PCT are not useful to discriminate viral triggered HLH from severe bacterial infection. Re-/activation of several viruses may play a role as possible trigger.
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http://dx.doi.org/10.1007/s00277-018-3254-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910490PMC
June 2018

Haploidentical Stem Cell Transplantation for Refractory/Relapsed Neuroblastoma.

Biol Blood Marrow Transplant 2018 05 4;24(5):1005-1012. Epub 2018 Jan 4.

Department of Pediatrics, Children's University Hospital, University of Tübingen, Tübingen, Germany. Electronic address:

Pediatric patients with refractory or relapsed metastatic neuroblastoma (NBL) have a poor prognosis despite autologous stem cell transplantation (SCT). Allogeneic SCT from a haploidentical donor has a remarkable alloreactive effect in patients with leukemia; thus, we evaluated this approach in children with very high-risk NBL. We analyzed data from 2 prospective phase I/II trials. A total of 26 patients with refractory (n = 5), metastatic relapsed (n = 20), or locally relapsed MYCN-positive (n = 1) NBL received a median of 17 × 10/kg T/B cell-depleted CD34 stem cells with 68 × 10/kg residual T cells and 107 × 10/kg natural killer cells. The conditioning regimen comprised melphalan, fludarabine, thiotepa, OKT3, and a short course of mycophenolate mofetil post-transplantation. Engraftment occurred in 96% of the patients. Event-free survival and overall survival at 5 years were 19% and 23%, respectively. No transplantation-related mortality was observed, and the single death was due to progression/subsequent relapse. The median duration of follow-up was 8.1 years. Patients in complete remission before SCT had a significantly better prognosis than those with residual tumor load (P < .01). All patients with progressive disease before SCT relapsed within 1 year. Grade II and grade III acute graft-versus-host disease (GVHD) occurred in 31% and 12% of the patients, respectively. Chronic limited and extensive GVHD occurred in 28% and 10%, respectively. Our data indicate that haploidentical SCT is a feasible treatment option that can induce long-term remission in some patients with NBL with tolerable side effects, and may enable the development of further post-transplantation therapeutic strategies based on the donor-derived immune system.
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http://dx.doi.org/10.1016/j.bbmt.2017.12.805DOI Listing
May 2018

PAXgene fixation enables comprehensive metabolomic and proteomic analyses of tissue specimens by MALDI MSI.

Biochim Biophys Acta Gen Subj 2018 Jan 9;1862(1):51-60. Epub 2017 Oct 9.

Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany. Electronic address:

An alcohol-based non-crosslinking tissue fixative, PAXgene Tissue System, has been proposed as alternative fixation method to formalin, providing superior and morphological preservation. To date, metabolites have not been assessed in PAXgene-fixed tissues. The study focuses on a comparison between PAXgene and standard formalin fixation for metabolomic analysis by MALDI mass spectrometry imaging. Therefore, fifty-six samples from seven mice organs were fixed with PAXgene (PFPE) or formalin (FFPE), embedded in paraffin, and processed to a tissue microarray. PAXgene was able to spatially preserve metabolites in organs achieving an overlap of common metabolites ranging from 34 to 78% with FFPE. Highly similar signal intensities and visualization of molecules demonstrated negligible differences for metabolite imaging on PFPE compared to FFPE tissues. In addition, we performed proteomic analysis of intact proteins and peptides derived from enzymatic digestion. An overlap of 33 to 58% was found between FFPE and PFPE tissue samples in peptide analysis with a higher number of PFPE-specific peaks. Analysis of intact proteins achieved an overlap in the range of 0 to 28% owing to the poor detectability of cross-linked proteins in formalin-fixed tissues. Furthermore, metabolite and peptide profiles obtained from PFPE tissues were able to correctly classify organs independent of the fixation method, whereas a distinction of organs by protein profiles was only achieved by PAXgene fixation. Finally, we applied MALDI MSI to human biopsies by sequentially analyzing metabolites and peptides within the same tissue section. Concerning prospective studies, PAXgene can be used as an alternative fixative for multi-omic tissue analysis.
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http://dx.doi.org/10.1016/j.bbagen.2017.10.005DOI Listing
January 2018

WIP deficiency severely affects human lymphocyte architecture during migration and synapse assembly.

Blood 2017 10 13;130(17):1949-1953. Epub 2017 Sep 13.

Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.

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http://dx.doi.org/10.1182/blood-2017-04-777383DOI Listing
October 2017

Klebsiella Oxytoca Bacteremia Induced Septic Shock following Platelet Transfusion.

Klin Padiatr 2017 09 24;229(5):304-305. Epub 2017 Aug 24.

Department of Pediatrics and Adolescent Medicine, Medical University Graz, Austria.

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http://dx.doi.org/10.1055/s-0043-116850DOI Listing
September 2017

Intrinsic and extrinsic causes of malignancies in patients with primary immunodeficiency disorders.

J Allergy Clin Immunol 2018 01 29;141(1):59-68.e4. Epub 2017 Jun 29.

Research Unit Pediatric Hematology and Immunology, Division of Pediatric Hematology-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University Graz, Graz, Austria. Electronic address:

Malignancies occur with a higher incidence rate and manifest earlier in life in patients with primary immunodeficiency disorders (PIDs) than in the general population. However, no universal mechanism of malignancy predisposition in patients with PIDs has been determined. Despite strong support for the physiologic role of tumor immunosurveillance and the increasing success of strategies in immunologic tumor therapy, which include checkpoint inhibition, mAbs, and engineered T-cell antigen receptors, the incidence and pattern of malignancies in patients with PIDs do not reflect an increased tumor immune escape per se. In contrast, malignancies appear to be restricted to either (1) tissue types bearing the same molecular defect that underlies the PID, such as syndromes of DNA repair deficiency or immune cell-specific maturation or functional defects that suggest a cell-intrinsic oncogenic basis, or (2) other tissues when they are infected by transforming viruses or chronically inflamed, pointing toward extrinsic causes for transformation that are potentially facilitated by but not predominantly caused by a lack of immunosurveillance. Based on recent studies of pre-existing conditions in patients with malignancies and on malignancies in large PID cohorts, we conclude that a large part of tumor predisposition in patients with PIDs is derived from the same molecular defect as the immunodeficiency itself. The presented concept elucidates diverse pathomechanisms and risks of malignancies in patients with PIDs in light of current tumor immune therapies.
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http://dx.doi.org/10.1016/j.jaci.2017.06.009DOI Listing
January 2018

Giant Pelvic Cyst in 16-Year-Old Boy With Bloody Diarrhea: Atypical Presentation of Colonic Adenocarcinoma.

J Pediatr Gastroenterol Nutr 2017 07;65(1):e16

*Department of Pediatrics and Adolescent Medicine †Department of Pediatric and Adolescent Surgery ‡Division of Paediatric and Adolescent Radiology, Medical University of Graz, Graz, Austria.

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http://dx.doi.org/10.1097/MPG.0000000000001017DOI Listing
July 2017

Life-threatening sinusoidal obstruction syndrome after high-dose chemotherapy linked to compound heterozygous mutations in ABCB11.

Pediatr Blood Cancer 2017 12 9;64(12). Epub 2017 Jun 9.

Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria.

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http://dx.doi.org/10.1002/pbc.26666DOI Listing
December 2017

Ancient Egyptian mummy genomes suggest an increase of Sub-Saharan African ancestry in post-Roman periods.

Nat Commun 2017 05 30;8:15694. Epub 2017 May 30.

Institute for Archaeological Sciences, University of Tübingen, 72070 Tübingen, Germany.

Egypt, located on the isthmus of Africa, is an ideal region to study historical population dynamics due to its geographic location and documented interactions with ancient civilizations in Africa, Asia and Europe. Particularly, in the first millennium BCE Egypt endured foreign domination leading to growing numbers of foreigners living within its borders possibly contributing genetically to the local population. Here we present 90 mitochondrial genomes as well as genome-wide data sets from three individuals obtained from Egyptian mummies. The samples recovered from Middle Egypt span around 1,300 years of ancient Egyptian history from the New Kingdom to the Roman Period. Our analyses reveal that ancient Egyptians shared more ancestry with Near Easterners than present-day Egyptians, who received additional sub-Saharan admixture in more recent times. This analysis establishes ancient Egyptian mummies as a genetic source to study ancient human history and offers the perspective of deciphering Egypt's past at a genome-wide level.
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http://dx.doi.org/10.1038/ncomms15694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5459999PMC
May 2017

Low penetration of caspofungin into cerebrospinal fluid following intravenous administration of standard doses.

Int J Antimicrob Agents 2017 Aug 17;50(2):272-275. Epub 2017 May 17.

Department of Paediatrics and Adolescent Medicine, Medical University of Graz, Auenbruggerplatz 30, Graz A-8036, Austria.

The kinetics of caspofungin (CAS) in cerebrospinal fluid (CSF) following intravenous (i.v.) administration has been studied exclusively in animal models. Human data are missing so far. In this study, 13 CSF samples were obtained at different time points following i.v. infusion of CAS in ten paediatric haemato-/oncological patients (age range 1.0-14.2 years, median 8.6 years) without signs of central nervous system (CNS) infection (n = 10 samples) or with infectious meningitis (n = 3 samples). Serum samples were obtained concurrently. Liquid chromatography-tandem mass spectrometry was used for CAS quantification. Whilst CAS serum levels were in the expected range, varying between 0.6 and 20.3 µg/mL (median 7.0 µg/mL), 11 of 13 CSF levels were below the limit of detection of 0.084 µg/mL at 3.0-48.0 h (median 23.3 h) following i.v. infusion. Only two (of three) levels in patients with bacterial meningitis were above the limit of detection (0.3 µg/mL and 0.09 µg/mL, respectively). These results indicate the low capacity of CAS to penetrate into the CNS even in inflamed meninges. Monotherapy with standard doses of CAS appears not to be suitable for treatment of fungal CNS infections.
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http://dx.doi.org/10.1016/j.ijantimicag.2017.02.024DOI Listing
August 2017

Central Hyperventilation in a Patient with Recurrent Acute Lymphoblastic Leukemia.

Klin Padiatr 2017 05 4;229(3):180-181. Epub 2017 Apr 4.

Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Division of Pediatric Hematology/Oncology, Graz, Austria.

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http://dx.doi.org/10.1055/s-0042-124666DOI Listing
May 2017

High hyperdiploid acute lymphoblastic leukemia (ALL)-A 25-year population-based survey of the Austrian ALL-BFM (Berlin-Frankfurt-Münster) Study Group.

Pediatr Blood Cancer 2017 06 2;64(6). Epub 2016 Nov 2.

Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, St. Anna Children's Hospital, Medical University of Vienna, Vienna, Austria.

Background: Approximately 30% of childhood acute lymphoblastic leukemia (ALL) cases are high hyperdiploid (HD). Despite their low relative recurrence risk, this group accounts for the overall largest relapse proportion.

Procedure: To evaluate potential risk factors in our population-based cohort of patients with HD ALL enrolled in four Austrian ALL-BFM (Berlin-Frankfurt-Münster) studies from 1986 to 2010 (n = 210), we reviewed the clinical, laboratory, and cytogenetic data of the respective cases in relation to their outcome.

Results: The 5-year event-free (EFS) and overall survival (OS) of the entire group was 83.1 ± 2.7% and 92.0 ± 1.9%, respectively. Univariate analysis revealed that trisomy 17 was significantly associated with a better EFS and OS, whereas trisomy 10 and a modal chromosome number (MCN) > 53 chromosomes were significantly associated with a better OS. Except for the latter, findings remained valid in multivariate analysis.

Conclusions: In line with previous studies, our retrospective analysis shows that MCN and specific trisomies are relevant prognostic indicators in an ALL-BFM cohort of patients with HD ALL. However, considering the current dominant role of minimal residual disease monitoring for prognostic stratification in ALL, including this particular subgroup, it is unlikely that this information is compelling enough to be utilized for refined risk classification in future ALL-BFM treatment protocols.
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http://dx.doi.org/10.1002/pbc.26327DOI Listing
June 2017

Collective concerted motion in a molecular adlayer visualized through the surface diffusion of isolated vacancies.

J Chem Phys 2016 Oct;145(15):154706

Departamento de Física de la Materia Condensada, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.

We have measured STM movies to study the diffusion of individual vacancies in a self-assembled layer of a tetrathiafulvalene derivative (exTTF) on Au(111) at room temperature. The diffusion is anisotropic, being faster along the compact direction of the molecular lattice. A detailed analysis of the anisotropic displacement distribution of the single vacancies shows that the relative abundance of double jumps (that is, the collective motion of molecular dimers) with respect to single jumps is rather large, the number of double jumps being more than 20% of the diffusion events. We conjecture that the relative abundances of long jumps might be related to the strength of the intermolecular bonding and the misfit of the molecular overlayer with the substrate lattice.
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http://dx.doi.org/10.1063/1.4964862DOI Listing
October 2016

Low vibration high numerical aperture automated variable temperature Raman microscope.

Rev Sci Instrum 2016 04;87(4):043105

Department of Physics, Boston College, 140 Commonwealth Ave., Chestnut Hill, Massachusetts 02467, USA.

Raman micro-spectroscopy is well suited for studying a variety of properties and has been applied to a wide range of areas. Combined with tuneable temperature, Raman spectra can offer even more insights into the properties of materials. However, previous designs of variable temperature Raman microscopes have made it extremely challenging to measure samples with low signal levels due to thermal and positional instabilities as well as low collection efficiencies. Thus contemporary Raman microscope has found limited applicability to probing the subtle physics involved in phase transitions and hysteresis. This paper describes a new design of a closed-cycle, Raman microscope with full polarization rotation. High collection efficiency, thermal stability, and mechanical stability are ensured by both deliberate optical, cryogenic, and mechanical design. Measurements on two samples, Bi2Se3 and V2O3, which are challenging due to low thermal conductivities, low signal levels, and/or hysteretic effects, are measured with previously undemonstrated temperature resolution.
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http://dx.doi.org/10.1063/1.4944559DOI Listing
April 2016

Trends in incidence, survival and mortality of childhood and adolescent cancer in Austria, 1994-2011.

Cancer Epidemiol 2016 06 4;42:72-81. Epub 2016 Apr 4.

The Children Cancer Research Institute, St. Anna Children's Hospital, Kinderspitalgasse 6, 1090 Vienna, Austria. Electronic address:

Background: This is the first study on trends in cancer incidence, survival and mortality for children and adolescents in Austria. The aim was to assess to what extent progress against childhood and adolescent cancer has been made in Austria since the 1990s and to complement the childhood and adolescent cancer trends for Central Europe.

Methods: All malignant neoplasms and non-malignant tumours of the Central Nervous System (CNS) in patients aged less than 20 years and diagnosed between 1994 and 2011 (N=5425) were derived from the Austrian National Cancer Registry (ANCR). Incidence and mortality trends were evaluated by the average annual percentage change (AAPC). Observed survival rates were calculated based on follow-up until December 31st 2013.

Results: Childhood cancer remained stable with 182 cases per million in 2011, but rose among girls by 1.4% (95% CI: .1, 3.6) annually due to an increase of non-malignant CNS tumours and Non-Hodgkin lymphoma. Adolescent cancer rose by 1.5% (95% CI: .4, 2.6) annually, from 182 cases per million in 1994-269 in 2011, especially leukaemia, CNS tumours (including non-malignant types) and epithelial tumours. Five-year survival improved by 5-7% reaching 86% for both groups (p<.05). Mortality declined by -2.4% (95% CI: -3.7, -1.2) and -2.0% (95% CI: -4.6, .5), respectively, especially for childhood leukaemia.

Conclusion: Progress is demonstrated by improved survival and declined mortality most likely related to improved diagnostic techniques, more effective therapeutic regimes, supportive care and a central advisory function of experts in the Austrian paediatric oncology.
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http://dx.doi.org/10.1016/j.canep.2016.03.015DOI Listing
June 2016