Publications by authors named "Andreas Beilken"

13 Publications

  • Page 1 of 1

ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition.

Blood 2022 Jan;139(2):256-280

Pathology Unit, Laboratories Department, Bambino Gesù Children's Hospital IRCCS, Rome, Italy.

ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.
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http://dx.doi.org/10.1182/blood.2021013338DOI Listing
January 2022

Newly Diagnosed Metastatic Intracranial Ependymoma in Children: Frequency, Molecular Characteristics, Treatment, and Outcome in the Prospective HIT Series.

Oncologist 2019 09 8;24(9):e921-e929. Epub 2019 Mar 8.

Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Background: Data on frequency, clinical presentation, and outcome of primary metastatic intracranial ependymoma in children are scarce.

Patients And Methods: Prospective data on patients younger than 21 years with metastatic intracranial ependymoma at first diagnosis, registered from 2001 to 2014 in the HIT-2000 trial and the HIT-2000 Interim Registry, were analyzed.

Results: Of 453 registered patients with intracranial ependymoma and central neuropathology review, initial staging included spinal magnetic resonance imaging in all patients and lumbar cerebrospinal fluid (CSF) analysis in 402 patients. Ten patients (2.2%) had metastatic disease, including three with microscopic CSF positivity only (M1 metastasis stage, 0.7% of patients with CSF staging). Location of the primary tumor was supratentorial in four patients (all supratentorial -fused ependymoma [ST-EPN-RELA]) and within the posterior fossa in five patients (posterior fossa ependymoma type A [PF-EPN-A],  = 4; posterior fossa ependymoma not further classifiable,  = 1), and multifocal in one patient.All four patients with ST-EPN-RELA were alive in first or second complete remission (CR) 7.5-12.3 years after diagnosis. All four patients with macroscopic metastases of posterior fossa or multifocal ependymoma died. Three patients with initial M1 stage (ST-EPN-RELA,  = 1; PF-EPN-A,  = 2) received chemotherapy and local irradiation and were alive in second or third CR 3.0-9.7 years after diagnosis. Progression-free and overall survival of the entire cohort at 5 years was 13% (±6%), and 58% (±16%), respectively.

Conclusion: Primary metastatic disease is rare in children with intracranial ependymoma. Prognosis may depend on molecular subgroup and extent of dissemination, and relevance of CSF analysis for initial staging remains to be clarified.

Implications For Practice: Childhood ependymoma presenting with metastasis at first diagnosis is very rare with a frequency of 2.4% in this population-based, well-characterized cohort. Detection of microscopic metastases in the cerebrospinal fluid was extremely rare, and impact on prognosis and respective treatment decision on irradiation field remains unclear. Initial metastatic presentation occurs in both supratentorial -fused ependymoma and posterior fossa ependymoma. Prognosis may differ according to extent of metastasis and biological subgroup, with poor prognosis in diffusely spread metastatic posterior fossa ependymoma even after combination therapy with both intensive chemotherapy and craniospinal irradiation, which may help to guide individual therapeutic decisions for future patients.
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http://dx.doi.org/10.1634/theoncologist.2018-0489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738295PMC
September 2019

Influenza and respiratory syncytial virus screening for the detection of asymptomatically infected patients in hematology and oncology.

GMS Hyg Infect Control 2018 24;13:Doc08. Epub 2018 Sep 24.

Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School (MHH), Hannover, Germany.

Respiratory syncytial virus (RSV) and influenza virus infections are a significant healthcare risk for immunocompromised patients. In addition to community onset, nosocomial acquisition and transmission may also occur. Detection of asymptomatic shedders (e.g., patients in the incubation period or immunosuppressed long term shedders) facilitates control of nosocomial transmission. To strengthen the existing infection control concept, a PCR-based screening for RSV and influenza virus was implemented for all patients lacking respiratory symptoms (asymptomatic patients) who were hospitalized on an adult and a pediatric hemato-oncological ward. Laboratory results of this screening were analyzed retrospectively. 665 respiratory specimens were obtained for screening from 251 patients (26% were 18 years and younger) from December 2016 to April 2017. In 23 patients without respiratory symptoms, either influenza virus or RSV infection was found, resulting in a detection rate of about 9%. In 6 patients, the infection was presumably detected during the incubation period, because an increase of viral load was observed in subsequent specimens. Positive screening results facilitated timely implementation of adequate infection control precautions. Nosocomial clusters of RSV or influenza were not detected during the screening period on the two wards. The seasonal screening program expanded our existing infection control concept in terms of patients lacking respiratory symptoms who shed influenza virus or RSV. It enabled us to identify 23 RSV or influenza infections in patients lacking respiratory symptoms in a 4-month period and thus to rapidly take isolation precautions.
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http://dx.doi.org/10.3205/dgkh000314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234716PMC
September 2018

THROMBOTECT - a randomized study comparing low molecular weight heparin, antithrombin and unfractionated heparin for thromboprophylaxis during induction therapy of acute lymphoblastic leukemia in children and adolescents.

Haematologica 2019 04 27;104(4):756-765. Epub 2018 Sep 27.

Department of Pediatrics, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.

Thromboembolism is a serious complication of induction therapy for childhood acute lymphoblastic leukemia. We prospectively compared the efficacy and safety of antithrombotic interventions in the consecutive leukemia trials ALL-BFM 2000 and AIEOP-BFM ALL 2009. Patients with newly diagnosed acute lymphoblastic leukemia (n=949, age 1 to 18 years) were randomized to receive low-dose unfractionated heparin, prophylactic low molecular weight heparin (enoxaparin) or activity-adapted antithrombin throughout induction therapy. The primary objective of the study was to determine whether enoxaparin or antithrombin reduces the incidence of thromboembolism as compared to unfractionated heparin. The principal safety outcome was hemorrhage; leukemia outcome was a secondary endpoint. Thromboembolism occurred in 42 patients (4.4%). Patients assigned to unfractionated heparin had a higher risk of thromboembolism (8.0%) compared with those randomized to enoxaparin (3.5%; =0.011) or antithrombin (1.9%; <0.001). The proportion of patients who refused antithrombotic treatment as allocated was 3% in the unfractionated heparin or antithrombin arms, and 33% in the enoxaparin arm. Major hemorrhage occurred in eight patients (no differences between the groups). The 5-year event-free survival was 80.9±2.2% among patients assigned to antithrombin compared to 85.9±2.0% in the unfractionated heparin group (=0.06), and 86.2±2.0% in the enoxaparin group (=0.10). In conclusion, prophylactic use of antithrombin or enoxaparin significantly reduced thromboembolism. Despite the considerable number of patients rejecting the assigned treatment with subcutaneous injections, the result remains unambiguous. Thromboprophylaxis - for the present time primarily with enoxaparin - can be recommended for children and adolescents with acute lymphoblastic leukemia during induction therapy. Whether and how antithrombin may affect leukemia outcome remains to be determined.
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http://dx.doi.org/10.3324/haematol.2018.194175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442986PMC
April 2019

Molecular characteristics and successful management of a respiratory syncytial virus outbreak among pediatric patients with hemato-oncological disease.

Antimicrob Resist Infect Control 2018 13;7:21. Epub 2018 Feb 13.

1Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.

Background: Respiratory syncytial virus (RSV) is responsible for upper and lower respiratory tract infection in adults and children. Especially immunocompromised patients are at high risk for a severe course of infection, and mortality is increased. Moreover RSV can spread in healthcare settings and can cause outbreaks. Herein we demonstrate the successful control and characteristics of a RSV outbreak that included 8 patients in our Department of Pediatric Hematology and Oncology.

Methods: We performed an epidemiologic investigation and a molecular analysis of the outbreak strains. Moreover we present the outbreak control bundle and our concept for RSV screening in the winter season.

Results: RSV A and B strains caused the outbreak. RSV B strains affected 3 patients, 2 of whom were co-infected with RSV A. Exactly this RSV A strain was detected in another 5 patients. Our multimodal infection control bundle including prophylactic RSV screening was able to rapidly stop the outbreak.

Conclusion: An infection control bundle in RSV outbreaks should address all potential transmission pathways. In pediatric settings the restriction of social activities might have a temporal negative impact on quality of life but helps to limit transmission opportunities. Molecular analysis allows better understanding of RSV outbreaks and, if done in a timely manner, might be helpful for guidance of infection control measures.
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http://dx.doi.org/10.1186/s13756-018-0316-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812225PMC
July 2019

Haematological malignancies following temozolomide treatment for paediatric high-grade glioma.

Eur J Cancer 2017 08 3;81:1-8. Epub 2017 Jun 3.

Division of Pediatric Hematology and Oncology, Department of Child and Adolescent Health, University Medical Center Göttingen, Göttingen, Germany.

Background: Temozolomide (TMZ) is widely used in high-grade glioma (HGG). There is a major concern of treatment-induced secondary haematological malignancies (SHMs). Due to the poor overall survival of HGG patients, the true incidence is yet elusive. Thus, the aim of this study was to determine the risk of SHMs following TMZ in paediatric HGG.

Methods: We analysed 487 patients from the HIT-HGG database of the German-speaking Society of Pediatric Oncology and Hematology with follow up beyond 1 year.

Results: The incidence of SHM was 7.7 ± 3.2% at 10 years. No SHM occurred in 194 patients after first-line TMZ therapy, but four out of 131 patients treated with TMZ for relapse following first-line multiagent chemotherapy experienced SHM (20% at 10 years; p = 0.041). SHMs occurred in two out of 162 patients who underwent multiagent chemotherapy without TMZ (4.1% at 10 years). Gender, patient age and acute haematological toxicity during treatment did not affect the incidence of SHMs.

Conclusion: Data of our cohort do not indicate an increased risk of SHM following TMZ treatment when compared to previous chemotherapy regimen. However, if TMZ is administered as a second-line treatment following conventional chemotherapy regimen, the risk might be disproportionately increasing.
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http://dx.doi.org/10.1016/j.ejca.2017.04.023DOI Listing
August 2017

A novel germline POLE mutation causes an early onset cancer prone syndrome mimicking constitutional mismatch repair deficiency.

Fam Cancer 2017 01;16(1):67-71

Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.

In a 14-year-old boy with polyposis and rectosigmoid carcinoma, we identified a novel POLE germline mutation, p.(Val411Leu), previously found as recurrent somatic mutation in 'ultramutated' sporadic cancers. This is the youngest reported cancer patient with polymerase proofreading-associated polyposis indicating that POLE mutation p.(Val411Leu) may confer a more severe phenotype than previously reported POLE and POLD1 germline mutations. The patient had multiple café-au-lait macules and a pilomatricoma mimicking the clinical phenotype of constitutional mismatch repair deficiency. We hypothesize that these skin features may be common to different types of constitutional DNA repair defects associated with polyposis and early-onset cancer.
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http://dx.doi.org/10.1007/s10689-016-9925-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5243902PMC
January 2017

Proof of principle for bevacizumab activity in desmoid-type fibromatosis.

Clin Sarcoma Res 2016 4;6. Epub 2016 Apr 4.

Department of Pediatric Hematology and Oncology, Medical School Hannover, Hannover, Germany.

Background: Desmoid-type fibromatosis (DF) is a rare disease, which often occurs in young adults. Medical treatment is an important option in the treatment algorithm of DF. Different chemotherapeutic regimens showed clinical activity in DF, but overall treatment tolerability remains poor for this patient cohort. Novel approaches investigated tyrosine kinase inhibitors in DF, but tolerability remained an issue.

Case Presentation: We treated a patient with progressive DF after failure of chemotherapy for 1 year with singe agent bevacizumab. He achieved a symptomatic and radiologic response while attainning excellent tolerability.

Conclusions: This is the first report on single agent bevacizumab in DF, which showed both, good tolerability and efficacy in our patient, thereby warranting future trials in DF.
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http://dx.doi.org/10.1186/s13569-016-0045-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819267PMC
April 2016

Variable disease progression after successful stem cell transplantation: prospective follow-up investigations in eight patients with Hurler syndrome.

Pediatr Transplant 2011 Dec;15(8):861-9

Department of Paediatric IV Haematology and Oncology, Anna Stift, Berufs-Bildungswerk, Medical University Hannover, Hannover, Germany.

We report the results of a prospective, standardized follow-up programme of eight children (median age at SCT 1.2 yr) with mucopolysaccharidosis (MPS1H, M. Hurler) transplanted using a fludarabine-based SCT. SCT resulted in stable engraftment without transplant-related mortality. All patients are alive, engrafted and in ambulatory care. During follow-up (median five yr, 1.9-8 yr), six of eight showed developmental delay (two severe, two mild/no), all eight had spinal deformities and one received hip surgery for acetabular dysplasia. Hand surgery for carpal tunnel release and trigger digits was required in five of the patients. The cranio-cervical junction was narrowed in four patients, one child having already received surgery. CC was present in all patients prior to SCT. It remained unchanged in seven and regressed in one child. Severe cardiac dysfunction was present in two of the eight children before SCT. Cardiac pump function was normal in six patients and ameliorated in two, while valve abnormalities could be detected in six patients. Currently, transplantation seems no longer the major obstacle for MPS1H patients, but the variable musculoskeletal disease progression after successful SCT remains a challenge. Patients with Hurler syndrome need specialized follow-up care because of their manifold health problems. The standardized follow-up presented here is a step to optimize care for MPS children and their families after SCT.
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http://dx.doi.org/10.1111/j.1399-3046.2011.01595.xDOI Listing
December 2011

G-CSF mobilised granulocyte transfusions in 32 paediatric patients with neutropenic sepsis.

Support Care Cancer 2006 Sep 19;14(9):910-6. Epub 2006 Apr 19.

Department of Paediatric Haematology and Oncology, OE 6780 Medizinische Hochschule Hannover, Hannover, Germany.

Introduction: In this retrospective, uncontrolled, observational study, the effect of granulocyte colony-stimulating factor (G-CSF)-stimulated granulocyte transfusions (GTX) in neutropenic paediatric patients with sepsis was evaluated.

Patients And Methods: Granulocytes were collected from unrelated, ABO group-matched and cytomegalic-antibody compatible donors. For neutrophil mobilization, donors received a single subcutaneous dose of glycosylated G-CSF (Lenograstim, Chugai Pharma, Japan) plus oral dexamethasone (8 mg). In total, 168 (range 1-19 per patient) GTX were transfused in 32 children with a median age of 7.4 (0.25 to 16) years.

Results: The underlying diseases comprised predominantly haematooncological malignancies (31 children). In 15 of 32 patients, neutropenia was related to allogeneic stem cell transplantation. All children suffered from sepsis based on international criteria (fever, tachycardia, respiratory rate >2 SD above normal in the context of a suspected or proven infection). In ten children bacteria were isolated, in six children a fungal infection was diagnosed and four sepsis episodes were caused by viral infections. GTX contained a median neutrophil number of 6.3 (range 1.9-13.9)x10(10) per transfusion and obtained a sustained haematological response after GTX. Nineteen out of 32 children survived the neutropenic sepsis, particularly nine out of 11 patients with bacterial sepsis.

Discussion: In contrast to the non-survivors, we observed a significant decrease in the C-reactive protein levels shortly after initiation of the GTX treatment in the surviving patients. A clear-cut benefit of GTX for children with neutropenic sepsis cannot be concluded from these data, but in children with (severe) bacterial sepsis refractory to antibiotic treatment, GTX were feasible, safe and could reduce mortality rates in this subgroup of patients.
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http://dx.doi.org/10.1007/s00520-006-0041-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102011PMC
September 2006

Secondary prophylaxis of invasive fungal infections with combination antifungal therapy and G-CSF-mobilized granulocyte transfusions in three children with hematological malignancies.

Support Care Cancer 2006 Jul 16;14(7):783-6. Epub 2006 Feb 16.

Department of Paediatric Haematology and Oncology, Medizinische Hochschule Hannover, OE 6780, Carl-Neuberg Str. 1, D-30625 Hannover, Germany.

Fungal infections represent a life-threatening complication for patients receiving chemotherapy or undergoing hematopoietic stem cell transplantation. Historically, antifungal monotherapy is associated with a poor outcome. We treated three children with hematological malignancies and proven fungal infections (one cerebral mold infection, one disseminated Candida infection, one naso-pharyngeal mucor infection) with combination antifungal therapy plus granulocyte-colony-stimulation-factor-mobilized granulocyte transfusions as secondary prophylaxis during subsequent neutropenic episodes. With this approach, the fungal infection was effectively treated, and the anticancer therapy was completed without major delay. All children survived the fungal infection and the underlying malignancy. These experiences illustrate the feasibility of this approach using more than one antifungal agent together with immune-therapy in high-risk patients.
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http://dx.doi.org/10.1007/s00520-005-0910-8DOI Listing
July 2006

Multiple spleen and liver abscesses due to Yersinia enterocolitica septicemia in a child with congenital sideroblastic anemia.

J Pediatr Hematol Oncol 2005 Nov;27(11):624-6

Medizinische Hochschule Hannover, Department of Paediatric Haematology and Oncology, Hannover, Germany.

In patients with iron overload, opportunistic infections are an underestimated risk. Yersinia enterocolitica is a rare organism to be isolated in this setting. The authors report a case of disseminated Y. enterocolitica sepsis in a 5-year-old boy with sideroblastic anemia. Ultrasound examination revealed massive ascites, a pseudo-appendicitis, and hypoechogenic lesions corresponding to abscess formations in the liver and spleen. The initial antibiotic therapy consisted of cefotaxime, gentamicin, and metronidazole, but only treatment with ciprofloxacin and meropenem led to defervescence and clinical stabilization. The risk of developing uncommon infections in patients with iron overload should be acknowledged by all physicians, and the relevance of ultrasound examination is emphasized. In this case, only a detailed history revealed that several days before the onset of diarrhea, the child was feeding a deer; this is how infection was probably acquired.
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http://dx.doi.org/10.1097/01.mph.0000188630.03392.12DOI Listing
November 2005

Monitoring of adenovirus infection in pediatric transplant recipients by quantitative PCR: report of six cases and review of the literature.

Am J Transplant 2004 Dec;4(12):2102-8

Department of Pediatric Cardiology and Intensive Care, Hannover Medical School, Germany.

Adenoviral (AdV) infections after transplantation remain a challenge in pediatric patients. Qualitative and quantitative PCR offer new approaches to early diagnosis and monitoring. However, their role in the management of AdV infections in pediatric transplant recipients remains to be determined. We report six children with positive qualitative serum-PCR for AdV on routine follow-up after transplantation (liver n = 4, hematopoetic stem cells (HSCT) n = 1, combined liver and HSCT n = 1). None of these children were symptomatic at the time of first detection of AdV. Two patients remained asymptomatic, one developed hemorrhagic cystitis and enteritis. Three children with positive PCR developed high viral load on quantitative PCR, all developed clinical AdV sepsis with further rising virus load. Despite antiviral therapy with cidofovir, these three patients died of septic multiorgan failure. Positive qualitative AdV-PCR from blood after pediatric transplantation is not necessarily followed by clinical disease. In case of positive AdV-PCR, monitoring by serial quantitative PCR is useful regarding treatment decision and prevention of fatal disease.
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http://dx.doi.org/10.1111/j.1600-6143.2004.00631.xDOI Listing
December 2004
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