Uwe Kordes

University Medical Center Hamburg - Eppendorf · Department of Paediatrics

Infantile myofibromatosis (IM), which is typically diagnosed in young children, comprises a wide clinical spectrum ranging from inconspicuous solitary soft tissue nodules to multiple disseminated tumors resulting in life-threatening complications. Familial IM follows an autosomal dominant mode of inheritance and is linked to PDGFRB germline variant...

Loss of nuclear SMARCB1 (INI1/hSNF5/BAF47) protein expression due to biallelic mutations of the SMARCB1 tumor suppressor gene is a hallmark of atypical teratoid/rhabdoid tumors (ATRT), but the presence of cytoplasmic SMARCB1 protein in these tumors has not yet been described. In a series of 102 primary ATRT, distinct cytoplasmic SMARCB1 staining on...

Extracranial rhabdoid tumours (ECRT) are an aggressive malignancy of infancy and early childhood. The vast majority of cases demonstrate inactivation of SMARCB1 (ECRTSMARCB1) on a background of a remarkably stable genome, a low mutational burden, and no other recurrent mutations. Rarely, ECRT can harbour the alternative inactivation of SMARCA4 (ECR...

Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant brain tumor predominantly occurring in infants. Biallelic SMARCB1 mutations causing loss of nuclear SMARCB1/INI1 protein expression represent the characteristic genetic lesion. Pathogenic SMARCB1 mutations comprise single nucleotide variants, small insertions/deletions, large deletions, which...

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant central nervous system tumor predominantly occurring in infants that may also arise in older children and adults. Rare secondary AT/RT developing from other tumors such as pleomorphic xanthoastrocytoma (PXA) are on record, but AT/RT presenting with molecular features of PXA have not bee...

We report on a long-term survivor of an atypical teratoid/rhabdoid tumor (ATRT-TYR) as an index patient, who carries a SMARCB1 exon 6 gain inherited from his father. The father was diagnosed with an unusual sequence of a myxopapillary INI1-negative ependymoma and a relapsing BRAF V600 wild type hairy-cell leukemia. He has two yet healthy sisters ag...

The rhabdoid tumor (RT) predisposition syndromes 1 and 2 (RTPS1 and 2) are rare genetic conditions rendering young children vulnerable to an increased risk of RT, malignant neoplasms affecting the kidney, miscellaneous soft-part tissues, the liver and the central nervous system (Atypical Teratoid Rhabdoid Tumors, ATRT). Both, RTPS1&2 are due to pat...

Atypical teratoid/rhabdoid tumors (ATRTs) are very aggressive childhood malignancies of the central nervous system. The underlying genetic cause are inactivating bi-allelic mutations in SMARCB1 or (rarely) in SMARCA4. ATRT-SMARCA4 have been associated with a higher frequency of germline mutations, younger age, and an inferior prognosis in compariso...

Introduction Extracranial rhabdoid tumours are rare, highly aggressive malignancies primarily affecting young children. The EU-RHAB registry was initiated in 2009 to prospectively collect data of rhabdoid tumour patients treated according to the EU-RHAB therapeutic framework. Methods We evaluated 100 patients recruited within EU-RHAB (2009–2018)....

Background Choroid plexus tumors (CPTs) are intraventricular brain tumors predominantly arising in children but also affecting adults. In most cases, driver mutations have not been identified, although there are reports of frequent chromosome-wide copy-number alterations and TP53 mutations, especially in choroid plexus carcinomas (CPCs). Methods D...

PurposeChoroid plexus tumors comprise of choroid plexus papilloma (CPP, WHO grade I), atypical choroid plexus papilloma (aCPP, WHO grade II) and choroid plexus carcinoma (CPC, WHO grade III). Molecular events driving the majority of choroid plexus tumors remain poorly understood. Recently, DNA methylation profiling has revealed different epigenetic...

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. Aft...

Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly occurring in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. SMARCB1-mutant tumors in adolescents and adults are rare and may show uncommon histopathological and clinical features. Here we report seven SMARCB1-deficient intracranial...

Background: Controversy exists as to what may be defined as standard of care (including markers for stratification) for patients with Atypical Teratoid Rhabdoid Tumors (ATRT). The European Rhabdoid Registry, EU-RHAB, recruits uniformly treated patients and offers standardized genetic and DNA methylation analyses. Methods: Clinical, genetic and t...

Background: Until today, adult and pediatric clinical trials investigating single-agent or combinatorial HDAC inhibitors including vorinostat in solid tumors have largely failed to demonstrate efficacy. These results may in part be explained by data from preclinical models showing significant activity only at higher concentrations compared to thos...

This report describes the diagnosis and treatment of a 27-year-old patient with neurofibromatosis 1 (NF1) and late progression of a pre-existing optic pathway glioma (OPG) that caused significant reduction in vision. OPG is one of the diagnostic criteria for establishing the diagnosis of NF1. Most common findings of NF1 are café-au-lait spots, axil...

Hydroxyurea (HU) is approved in EU and USA for preventing vaso-occlusive crises (VOC) including acute chest syndromes (ACS) in adults, adolescents and children ≥2 years with sickle-cell disease (SCD). Further to the double blinded, randomized controlled Multicenter Study of Hydroxyurea administration (MSH) which provided the first data on clinical...

Paediatric CNS tumours are the most common cause of childhood cancer-related morbidity and mortality, and improvements in their diagnosis and treatment are needed. New genetic and epigenetic information about paediatric CNS tumours is transforming the field dramatically. For most paediatric CNS tumour entities, subgroups with distinct biological ch...

AT/RT is a challenging entity due to a dearth of controlled clinical trials and lack of biological samples. We aimed to identify clinical and molecular risk factors in a carefully characterised series of AT/RT. METHODS We enrolled 142 patients from 13 European countries (06/2009 to 08/2017). Median age at diagnosis was 17,5 months (25th /75th perc...

Choroid plexus tumors (CPT) comprise choroid plexus papilloma (CPP, WHO grade I), atypical choroid plexus papilloma (aCPP, WHO grade II), and choroid plexus carcinoma (CPC, WHO grade III). CPT from 20 nations were prospectively recruited into the CPT-SIOP-2000 study (01/2000–03/2010, n=129, median follow-up 7.4 years) and the CPT-SIOP registry (04/...

Background The clinical phenotype associated with germline SMARCB1 mutations has as yet not been fully documented. It is known that germline SMARCB1 mutations may cause rhabdoid tumor predisposition syndrome (RTPS1) or schwannomatosis. However, the co‐occurrence of rhabdoid tumor and schwannomas in the same patient has not so far been reported. Me...

Germline variants that affect function are found in seven genes of the BAF chromatin-remodeling complex. They are linked to a broad range of diseases that, according to the gene affected, range from non-syndromic or syndromic neurodevelopmental disorders to low-grade tumors and malignancies. In the current meta-analysis, we evaluate genetic and cli...

Objective: The aims of this study were to analyze the maxillomandibular morphology of patients with mucopolysaccharidosis (MPS) type I, II, III, IVa and VI and to evaluate the craniofacial effect of hematopoietic stem cell transplantation (HCST) in MPS I. Materials and methods: One hundred head magnetic resonance images were retrospectively anal...

Glycogen storage disease (GSD) 0a is a rare congenital metabolic disease with symptoms in infancy and childhood caused by biallelic GYS2 germline variants. A predisposition to cancer has not been described yet. We report here a boy with GSD 0a, who developed a malignant brain tumor at the age of 4.5 years. The tumor was classified as a group 3 medu...

Primäre ZNS-Tumoren sind im Kindes- und Jugendalter mit >20 % nach den Leukämien die zweithäufigste Gruppe aller onkologischen Erkrankungen. Neben der frühzeitigen Diagnosestellung stellt die Versorgung dieser Patienten hohe Anforderungen an ein interdisziplinäres Team. Durch den Einsatz multimodaler Therapiekonzepte liegt die 10-Jahres-Überlebensr...

Germline mutations affecting the SWI/SNF chromatin remodeling complex are associated with a broad spectrum of different diseases, including malignant and benign tumors as well as neurodevelopmental disorders. Such mutations are detected in multiple genes of the complex and encompass a variety of mutation types. However, due to the rarity of mutatio...

Background. The TWiTCH multicentre randomised phase III trial showed recently non inferiority of hydroxyurea (HU) with phlebotomy versus transfusions with chelation for primary stroke prevention and management of iron overload in children with sickle cell anemia, having had abnormal transcranial Doppler but no severe vasculopathy and after at least...

ESCORT-HU (European Sickle Cell Disease (SCD) COhoRT - HydroxyUrea) is a multicenter prospective non interventional study implemented in Europe, following the European Medical Agency's request to collect more information focused on long-term safety profile of hydroxycarbamide (HU) in SCD patients treated with HU. Primary endpoint of the study is to...

Some years ago, HLA-typing (rSSO & SBT) of a young Turkish patient with Wiskott-Aldrich syndrome (WAS) revealed a DQB1*03:02:01 in combination with a new HLA-DQB1*06:02 variant, later named as DQB1*06:37. The DQB1*06:37 allele differs from DQB1*06:02:01 in two non-synonymous nucleotide positions in exon 2 (codon 62: AAC->AAG, Asn->Lys and codon 70:...

Some years ago, HLA-typing (rSSO & SBT) of a young Turkish patient with Wiskott-Aldrich syndrome (WAS) revealed a DQB1*03:02:01 in combination with a new HLA-DQB1*06:02 variant, later named as DQB1*06:37. The DQB1*06:37 allele differs from DQB1*06:02:01 in two non-synonymous nucleotide positions in exon 2 (codon 62: AAC->AAG, Asn->Lys and codon 70:...

Background: Choroid plexus tumors are intraventricular neoplasms derived from the choroid plexus epithelium. A better knowledge of molecular factors involved in choroid plexus tumor biology may aid in identifying patients at risk for recurrence. Methods: Methylation profiles were examined in 29 choroid plexus papillomas (CPPs, WHO grade I), 32 a...

Tumours of the central nervous system (CNS) are the most frequent solid tumours and the second most frequent type of cancer in children and adolescents. Overall survival has continuously improved in Germany, since an increasing number of patients have been treated according to standardised, multicentre, multimodal treatment recommendations, trials...

Choroid plexus carcinomas (CPCs) are rare pediatric tumors often associated with Li-Fraumeni Syndrome (LFS), a germline mutation in the TP53 tumor-suppressor gene, predisposing to cancer. We performed a systemic literature review from 1990-2013 to evaluate the hypothesis that radiation therapy should be avoided in patients with CPC and LFS. Overall...

Choroid plexus tumors are rare neoplasms that mainly affect children. They include papillomas, atypical papillomas, and carcinomas. Detailed genetic studies are rare, and information about their molecular pathogenesis is limited. Molecular inversion probe analysis is a hybridization-based method that represents a reliable tool for the analysis of h...

Hydroxycarbamide (HU) is a myelosuppressive drug marketed since 1968 for the treatment of hematological cancer, and authorized since 2007 in Europe as orphan medicinal product for the prevention of recurrent vaso-occlusive crises including acute chest syndrome in adults and children older than 2 years with sickle cell disease (SCD). ESCORT-HU (Euro...

INTRODUCTION: There are only a few reports of brain irradiation during pregnancy. The probable effects of radiation exposure during foetal period include mental retardation, anatomical malformations, carcinogenesis and death of embryo or foetus.We report a method for reducing foetal dose while delivering radiotherapy for brain tumours during pregna...

Rhabdoid tumor predisposition syndrome is usually associated with shorter survival in patients with malignant rhabdoid tumors regardless of anatomical origin. Here we present four children harboring truncating heterozygous SMARCB1/INI1 germline mutations with favorable outcome. All four patients received multi-modality treatment, three according to...

Choroid plexus carcinoma is a malignant brain tumor predominantly occurring in young children. Only limited data are available regarding the underlying molecular genetic alterations. Therefore, molecular inversion probe single nucleotide polymorphism (MIP SNP) arrays were performed on a series of 26 neuropathologically well-characterized choroid pl...

A retrospective analysis of data from the European Rhabdoid Registry (EU-RHAB) was performed to describe the outcome of children with atypical teratoid/rhabdoid tumors (AT/RT) who underwent high-dose chemotherapy (HDCT) with auto-SCT. Nineteen patients (male, n=15; median age at diagnosis 21 months) were identified. Nine patients presented with met...

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare malignant pediatric brain tumor characterized by genetic alterations affecting the SMARCB1 (hSNF5/INI1) locus in chromosome band 22q11.2. To identify potential additional genetic alterations, high-resolution genome-wide analysis was performed using a molecular inversion probe single-nucleotide poly...

Ependymomas comprise 8 % of all intracranial tumors in children <15 years. Recent studies revealed that some supratentorial ependymomas express neuronal antigens and that high expression of neurofilament protein light polypeptide (NEFL) correlates with better clinical outcome. We retrospectively analyzed an expanded panel of proteins in 6 supratent...

BACKGROUND Tumours are responsive to temozolomide (TMZ) if they are deficient in O(6)-methylguanine-DNA methyltransferase (MGMT), and mismatch repair (MMR) proficient. METHODS The effect of TMZ on medulloblastoma (MB) cell killing was analysed with clonogenic survival assays. Expression of DNA repair genes and enzymes was investigated using microar...

Choroid plexus carcinomas are malignant brain tumors predominantly arising in young children. Because a prognostic role of p53 alterations has been demonstrated, further research into potential underlying mechanisms is essential. Our objective was, therefore, to investigate the role of p53 in the growth-inhibitory potential of a variety of anticanc...

BACKGROUND: The diagnosis of atypical teratoid/rhabdoid tumor (AT/RT) may pose difficulties. We therefore aim to share our experiences as reference pathologists within the European Rhabdoid Tumor Registry (EURHAB) and the International Choroid Plexus Tumor Registry CPT-SIOP. METHODS: Evaluation of clinical, histological and molecular genetic featur...

Primary Leptomeningeal Anaplastic Oligodendroglioma (PLAO) is a very rare tumor that grows in the subarachnoid space with no obvious findings of intraparenchymal mass lesion. Here we report an 11-year-old girl who was diagnosed as PLAO with temporal bone invasion. She has a history of shunted hydrocephalus of unknown etiology since the age of 8. Co...

Background: Although prognosis of children with solid tumors is steadily improving, long-term survival is not achievable in all patients, especially in patients with recurrent or refractory disease. Despite the increasing number of targeted therapeutics (TT), only very few TT have been introduced into clinical protocols. Accordingly, clinical exper...

Purpose: The choroid plexus tumor SIOP initiative aims to improve the care of choroid plexus tumors by supporting prospective randomized protocols, international registries and literature monitoring. Method: From 01-2000 to 03-2010 173 patients with choroid plexus tumors were registered from 173 nations. Reference pathology was completed in 138 pat...

Little is known about pediatric spinal cord high grade gliomas (SCHGG) beyond their dismal prognosis. Here, we analyzed the HIT-GBM(®) database for the influence of surgical resection on survival. Between 1991 and 2010 the HIT-GBM group collected data from European children diagnosed with high grade glioma. Patients with the following inclusion cri...

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly aggressive and uncommon neoplasm of the central nervous system that usually occurs in children less than 2 years of age. It is characterized by deletions and/or mutations of the INI1 tumor suppressor gene located in chromosome band 22q11.2. We performed cytogenetic and molecular studies of an AT/...

We report a Caucasian neonate with chronic non-spherocytic hemolytic anemia due to a class I G6PD deficiency. A novel mutation missense mutation in exon eight of the G6PD gene was detected (c.827C>T p.Pro276Leu). Bilirubin peaked on day 5 at 24 mg/dl with a conjugated bilirubin of 17 mg/dl. Jaundice resolved within 4 weeks. A detailed work-up faile...

Rhabdoid tumors of early infancy are highly aggressive with consequent poor prognosis. Most cases show inactivation of the SMARCB1 (also known as INI1 and hSNF5) tumor suppressor, a core member of the ATP-dependent SWI/SNF chromatin-remodeling complex. Familial cases, described as rhabdoid tumor predisposition syndrome (RTPS), have been linked to h...

Brain tumors are the second most frequent malignancies of childhood cancer. Histological entities, pathogenesis, therapeutic concepts, and prognosis differ significantly from adults. According to age, extent of resection, staging, histology, and biological criteria, specific risk-adapted therapeutic concepts (postoperative radiotherapy alone, chemo...

Atypical teratoid/rhabdoid tumors are malignant embryonal tumors characterized by the presence of rhabdoid cells, genetic alterations affecting the SMARCB1 gene (hSNF5/INI1), and a poor prognosis. Whether INI1 plays a role in the pathogenesis of other central nervous system tumors is uncertain. We report on cases of 2 young children with unusual in...

4680 One of the most common human chromosomal abnormalities, Down syndrome, is caused by trisomy 21. Transient myeloproloferative disorders (TMD) occur in 10-20 % of newborns with Down syndrome. About 30 % of those TMD patients develop Acute Megakaryoblastic Leukemia (AMKL) within 4 years. Therefore both disorders have their origin in the fetus. Th...

The SMARCB1 gene status in 50 patients with atypical teratoid rhabdoid tumor and/or malignant rhabdoid tumor recruited to a German registry was prospectively analyzed with FISH and PCR. Altogether we found 40 SMARCB1 mutations in 28 patients. Two patients were positive for SMARCB1 staining at immunochemistry. Germline mutations were identified in 1...

Atypical teratoid/rhabdoid tumors are malignant embryonal tumors characterized by the presence of rhabdoid cells, genetic alterations affecting the SMARCB1 gene (hSNF5/INI1), and a poor prognosis. Whether INI1 plays a role in the pathogenesis of other central nervous system tumors is uncertain. We report on cases of 2 young children with unusual in...

In T-cell prolymphocytic leukemia (T-PLL), chromosomal imbalances affecting the long arm of chromosome 22 are regarded as typical chromosomal aberrations secondary to a TCRAD-TCL1A fusion due to inv(14) or t(14;14). We analyzed recently obtained data from conventional karyotyping, SNP-chip array copy number mapping, genome-wide expression profiling...

Inhibitor development is a rare but serious event in hemophilia B patients. Management is hampered by the frequent occurrence of allergic reactions to factor IX, low success rates of current inhibitor elimination protocols and the risk of development of nephrotic syndrome. Single cases of immune tolerance induction (ITI) including immunosuppressive...

Large gene deletions in male subjects at Xp21.1 may cause contiguous gene syndromes by loss of hemizygosity for genes located in this region. Among them are CYBB and XK causing X-CGD and McLeod syndrome. Absence of the XK-encoded membrane glycoprotein Kx abolishes or weakens expression of the highly polymorphic and antigenic Kell antigens, resultin...

SUMMARY: In patients with pathologically altered erythrocytes, red blood cell exchange is a very efficient therapeutic measure without important side effects. With increasing migration more patients with e.g. severe malaria or sickle cell anemia have to be treated. In minor or bidirectional ABO-mismatched stem cell transplantations after reduced in...

Hemolysis in non- or rarely transfused patients with sickle cell disease may lead to higher iron stores. We prospectively studied their iron stores by using SQUID biomagnetic liver susceptometry. Liver iron concentration (LIC) and liver/spleen volume were measured at the Hamburg low TC-SQUID biosusceptometer facility in a total of 34 pediatric pati...

The SOX group E transcription factors play an integral role in the specification and differentiation of astrocytes and oligodendrocytes. We have examined the pattern of expression for SOX9 and SOX10 in primary brain tumors by immunohistochemistry. Pediatric and adult high grade tumors display strong nuclear staining for both SOX9 and SOX10 (astrocy...

Ovarian small cell carcinoma of the hypercalcemic type is a rare neoplasm that is associated with a poor prognosis. The objective of the current study was to investigate the clinicopathologic features of this tumor and to develop preliminary diagnostic and therapeutic guidelines. Between 1994 and 2005, 11 girls (ages 9–22 years) who were registered...

Rhabdoid tumors represent an independent entity among embryonal neoplasms. These tumors affect the kidney (RTK, rhabdoid tumor of kidney) and central nervous system (AT/RT, atypical teratoid, rhabdoid tumor), but may also be found in peripheral soft tissue. Unifying features include immunohistochemical characteristics and inactivation of the putati...

The SoxE genes, Sox8, Sox9 and Sox10, have been shown to modulate glial specification and differentiation in the peripheral nervous system and spinal cord. However, little is known of their expression during brain development. We have therefore analyzed their expression in developing brain, focused on the cerebellum. In situ hybridization showed a...

We studied a patient with mild beta-thalassaemia major under treatment with the oral chelator deferiprone (DFP or L1) for about 10 yr (L1 veteran). Due to poor compliance with desferrioxamine, the patient started compassionate use of DFP at an age of 23 yr with a serum ferritin of 5200 microg/L. Monitoring iron overload by SQUID biosusceptometry re...

Actinomycosis is a chronic, granulomatous disease of cervicofacial (55%), abdominal (20%), or thoracic (15%) location caused by Actinomyces israelii .1 It is often accompanied by copathogens such as Actinobacillus actinomycetemcomitans , which is also strongly associated with gingivitis.2 We report on a 9 year old boy who presented with a six week...

We investigated the efficacy of an antithymocyte globulin/cyclophosphamide preparative regimen prior to allogeneic stem cell transplantation from HLA-identical siblings in patients with severe aplastic anemia. Since 1990, 21 patients, 6 males and 15 females, with a median age of 25 years (range: 7-43) have been enrolled in the protocol consisting o...

Three patients with myelofibrosis received allogeneic stem cell transplantation after a dose-reduced conditioning regimen of busulphan (8 mg/kg), fludarabine (180 mg/m2) and antithymocyte globulin (4 x 10 mg/kg). The median age at transplantation was 51 years (range 44-58). All patients engrafted with a leucocyte count > 1.0 x 10(9)/l after a media...

For the long-term survival of iron-loaded patients, early and well adjusted treatment with iron chelators is of crucial importance, especially in children. Basis of the adequate treatment are appropriate diagnostic parameters which are capable to monitor the range of the individual iron burden. In the time period between 1989 and 2001, the status o...

The pleiotropic transcription factor NF-kappaB controls cellular apoptotic and growth processes and increasing evidence suggests a role in tumorigenesis. We describe here that constitutively activated NF-kappaB complexes are found in the vast majority (39 out of 42 samples) of childhood acute lymphoblastic leukemia (ALL) without any subtype restric...

A common characteristic of malignant cells derived from patients with Hodgkin's disease (HD) is a high level of constitutive nuclear NF-kappaB/Rel activity, which stimulates proliferation and confers resistance to apoptosis. We have analysed the mechanisms that account for NF-kappaB activation in a panel of Hodgkin/Reed-Sternberg (H-RS) cell lines....

Three studies using multiple modalities in treating germ cell tumors are compared. The evolution of a more prominent role for chemotherapy is demonstrated for a subgroup of this heterogenous group of tumors. This includes nongerminomatous germ cell tumors as well as pure germinomas.