University Childrens Hospital of Muenster

Münster, Germany

University Childrens Hospital of Muenster

Münster, Germany
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Lanvers-Kaminsky C.,University Childrens Hospital Of Muenster
Cancer Chemotherapy and Pharmacology | Year: 2017

Purpose: The benefits of asparaginase (ASNASE) in the treatment of ALL and NHL are indisputable and new ASNASE preparations are under clinical development to overcome limitations of the actual ASNASE therapy, especially immunogenicity. Apart from ALL and NHL further indications of ASNASE are preclinically and clinically evaluated. Methods: We reviewed ASNASE literature and especially focused on the mechanism of action, on biomarker, which determine ASNASE sensitivity and resistance, and on ASNASE pharmacodynamics in vivo. Results: More than 40 years after the clinical introduction of ASNASE its mechanism of action is yet not fully understood. Studies on asparagine synthetase (ASNS) as biomarker for ASNASE resistance are contradictory and complicated by methodological obstacles. The role of glutamine hydrolysis for ASNASE efficacy is still debated, other mechanisms are possibly not yet identified. In addition, individual pharmacokinetic/-dynamic relationships cannot be properly addressed because of methodological limitations. Conclusion: More sophisticated preclinical models and suitable methods for monitoring of ASNASE pharmacodynamics are urgently needed (1) to understand the mechanism of action, (2) to establish valid biomarkers for ASNASE sensitivity and resistance, (3) to evaluate the pharmacokinetics/-dynamics of ASNASEs in individual patients, and (4) to compare the bioequivalence of clinically established, as well as new ASNASE preparations. © 2017 Springer-Verlag Berlin Heidelberg


Gerss J.,University of Munster | Gerss J.,The Interdisciplinary Center | Roth J.,University of Munster | Holzinger D.,The Interdisciplinary Center | And 33 more authors.
Annals of the Rheumatic Diseases | Year: 2012

Objectives: Juvenile idiopathic arthritis (JIA) is a chronic inflammatory joint disease affecting children. Even if remission is successfully induced, about half of the patients experience a relapse after stopping antiinflammatory therapy. The present study investigated whether patients with JIA at risk of relapse can be identified by biomarkers even if clinical signs of disease activity are absent. Methods: Patients fulfilling the criteria of inactive disease on medication were included at the time when all medication was withdrawn. The phagocyte activation markers S100A12 and myeloid-related proteins 8/14 (MRP8/14) were compared as well as the acute phase reactant high-sensitivity C reactive protein (hsCRP) as predictive biomarkers for the risk of a flare within a time frame of 6 months. Results: 35 of 188 enrolled patients experienced a flare within 6 months. Clinical or standard laboratory parameters could not differentiate between patients at risk of relapse and those not at risk. S100A12 and MRP8/14 levels were significantly higher in patients who subsequently developed flares than in patients with stable remission. The best single biomarker for the prediction of flare was S100A12 (HR 2.81). The predictive performance may be improved if a combination with hsCRP is used. Conclusions: Subclinical disease activity may result in unstable remission (ie, a status of clinical but not immunological remission). Biomarkers such as S100A12 and MRP8/14 inform about the activation status of innate immunity at the molecular level and thereby identify patients with unstable remission and an increased risk of relapse.


Willer A.,University Childrens Hospital of Muenster | Gerss J.,University of Munster | Konig T.,medac GmbH | Franke D.,medac GmbH | And 7 more authors.
Blood | Year: 2011

Hypersensitivity reactions limit the use of the antileukemic enzyme asparaginase (ASE). We evaluated Ab levels against Escherichia coli ASE and ASE activity in 1221 serum samples from 329 patients with acute lymphoblastic leukemia who had received ASE treatment according to the ALL-BFM 2000 or the ALL-REZ BFM 2002 protocol for primary or relapsed disease. ASE activity during first-line treatment with native E coli ASE and second- line treatment with pegylated E coli ASE was inversely related to anti-E coli ASE Ab levels (P < .0001; Spearman rank order correlation). An effect on ASE activity during second-line treatment with pegylated E coli ASE was, however, only observed when anti-E coli ASE Ab levels were high (> 200 AU/mL). In the presence of moderate or intermediate Ab levels (6.25-200 AU/mL) the switch from native to pegylated E coli ASE resulted in a significant increase of ASE activity above the threshold of 100 U/L (P < .05). Erwinia chrysanthemi ASE activity was not correlated with anti-E coli ASE Ab levels. Erwinia ASE was found to be the best ASE alternative if Ab levels against E coli ASE exceed 200 AU/mL. This retrospective analysis is the first to describe the relationship between the level of anti-E coli ASE Abs and serum activity of pegylated E coli ASE used second-line after native E coli ASE. These studies are registered at http://clinicaltrials.org as NTC00430118 and NCT00114348. © 2011 by The American Society of Hematology.


Lanvers-Kaminsky C.,University Childrens Hospital of Muenster | Westhoff P.S.,University Childrens Hospital of Muenster | D'Incalci M.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | Zucchetti M.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | Boos J.,University Childrens Hospital of Muenster
Therapeutic Drug Monitoring | Year: 2014

Background: Monitoring of asparagine (ASN) during asparaginase (ASE) treatment directly links to the antileukemic effect of ASE but is challenging because of ASE-induced ex vivo hydrolysis of ASN. Assuming that ASE is not active at 4°C, immediate cooling of blood samples became the accepted method for ASN determination during ASE therapy. Methods: To evaluate the effect of immediate sample cooling on the ex vivo hydrolysis of ASN by ASE the degradation of 13C4-ASN in whole blood, spiked with different ASE concentrations were analyzed HPLC-MS. 13C4-ASN and ASE were added either to blood at 4°C or to blood at 37°C, which was instantly cooled down to 4°C. Results: Immediate cooling did not prevent the ex vivo hydrolysis of ASN by ASE. The rate of ASN degradation to aspartic acid depended on the amount of ASE, ASE preparation, and time. Spiked into blood at 4°C 100 U/L native E. coli ASE already immediately degraded 100% of 13C4-ASN, whereas 10 U/L reduced the amount of 13C4-ASN by 30%. Spiked into blood at 37°C, which was immediately cooled thereafter, 10 U/L native E. coli ASE hydrolyzed 60% of C4-ASN and 1 U/L between 5% and 10% of C4-ASN. Concentrations of aspartic acid increased in parallel with ASN degradation. In addition, the ex vivo hydrolysis also affected concentrations of glutamine and glutamic acid. Conclusions: Cooling of blood samples did not inactivate ASE. Thus, to evaluate the precise pharmacodynamics of ASE, alternative methods for effective ASE inactivation at the time of blood withdrawal are needed. Copyright © 2013 by Lippincott Williams & Wilkins.


Rieger-Fackeldey E.,Nationwide Childrens Hospital Research Institute | Rieger-Fackeldey E.,University Childrens Hospital of Muenster | Park M.S.,Nationwide Childrens Hospital Research Institute | Park M.S.,Yonsei University | And 9 more authors.
American Journal of Pathology | Year: 2014

Exposure of newborn mice to hyperoxia arrests lung development, with resultant pathological characteristics similar to bronchopulmonary dysplasia in infants born prematurely. We tested the hypothesis that aberrations in lung development caused by 14 days of sublethal hyperoxia would be reversed during 14 days of recovery to room air (RA) when the concentration of oxygen exposure was weaned gradually. Newborn FVB mice were exposed to 85% oxygen or RA for 14 days. Weaning from hyperoxia was by either transfer directly into RA or a decrease in the concentration of oxygen by 10% per days. At 28 days, pups were euthanized, and the lungs were inflation fixed and assessed. At postnatal day 28, lungs of mice weaned abruptly from hyperoxia had fewer (6 ± 0.6 versus 10 ± 0.7; P < 0.001) alveoli per high-powered field and larger alveoli (4050 ± 207 versus 2305 ± 182 μm2) than animals weaned gradually; both hyperoxia-exposed groups were different from lungs obtained from air-breathing controls (20 ± 0.5 alveoli per high-powered field; P < 0.001). The results are consistent with the absence of catch-up alveolarization in this model and indicate that the long-term consequences of early exposures to hyperoxia merit closer examination. The effects of abrupt weaning to RA observed further suggest that weaning should be considered in experimental models of newborn exposure to hyperoxia.


Lanvers-Kaminsky C.,University Childrens Hospital of Muenster | Sprowl J.A.,St Jude Childrens Research Hospital | Malath I.,University Childrens Hospital of Muenster | Deuster D.,University Hospital of Muenster | And 12 more authors.
Pharmacogenomics | Year: 2015

Aim: Assuming that genetic variants of the SLC22A2 and SLC31A1 transporter affect patients' susceptibility to cisplatin-induced ototoxicity, we compared the distribution of 11 SLC22A2 variants and the SLC31A1 variant rs10981694 between patients with and without cisplatin-induced ototoxicity. Patients & methods: Genotyping was performed in 64 pediatric patients and significant findings were re-evaluated in 66 adults. Results: The SLC22A2 polymorphism rs316019 (c.808G>T; Ser270Ala) was significantly associated with protection from cisplatin-induced ototoxicity in the pediatric (p = 0.022) and the adult cohort (p = 0.048; both: Fisher's exact test). This result was confirmed by multiple logistic regression analysis accounting for age which was identified as a relevant factor for ototoxicity as well (rs316019: OR [G/T vs G/G] = 0.12, p = 0.009; age: OR [per year]: 0.84, p = 0.02). Conclusion: These results identified rs316019 as potential pharmacogenomic marker for cisplatin-induced ototoxicity and point to a critical role of SLC22A2 for cisplatin transport in humans and its contribution to the organ specific side effects of this drug. Original submitted 17 September 2014; Revision submitted 19 December 201. © 2015 Future Medicine Ltd.


PubMed | University Childrens Hospital of Muenster and University Hospital of Muenster
Type: | Journal: Clinical pharmacology and therapeutics | Year: 2016

Drug ototoxicity limits quality of life of patients after treatment, having serious consequences especially for psychosocial development of children. While the ototoxicity of many drugs resolves after treatment discontinuation, the use of platinum derivatives and aminoglycosides is associated with permanent hearing loss. In this review, we have listed ototoxic drugs and the mechanisms by which they damage the ears. Moreover, possible protective strategies and important methods for early detection of ototoxic effects are discussed. This article is protected by copyright. All rights reserved.


Bauer J.,University Childrens Hospital of Muenster | Gerss J.,University of Munster
Clinical Nutrition | Year: 2011

Background & aims: The primary objective of this study was to investigate the composition of breast milk of mothers with extremely preterm infants (<28 weeks) for their nutrient content over the first 8 weeks of lactation, and to compare premature to term milk. Methods: Breast milk from 102 mothers who had delivered preterm infants and from 10 mothers who had delivered term infants were collected longitudinally. Fat, protein, carbohydrate, minerals and energy content were estimated weekly in each participant. Milk samples were representative of complete 24-h cycles. Results: Carbohydrate, fat and energy concentrations were significantly higher in preterm than in term milk (p < 0.05). Protein content of both preterm and term milk decreased with the progress of lactation demonstrating significantly higher values in extremely preterm milk (<28 weeks) than in moderately preterm and term milk (p < 0.0001). The sodium levels of preterm milk were significantly elevated (p < 0.05) only in the first week. Other changes in mineral content were detected neither in preterm nor term milk. Conclusions: Our data provide new information on the macronutrient content of milk in mothers of extremely preterm infants with possible implications for the nutrition of this population. © 2010 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism.


Hypersensitivity reactions limit the use of the antileukemic enzyme asparaginase (ASE). We evaluated Ab levels against Escherichia coli ASE and ASE activity in 1221 serum samples from 329 patients with acute lymphoblastic leukemia who had received ASE treatment according to the ALL-BFM 2000 or the ALL-REZ BFM 2002 protocol for primary or relapsed disease. ASE activity during first-line treatment with native E coli ASE and second-line treatment with pegylated E coli ASE was inversely related to anti-E coli ASE Ab levels (P < .0001; Spearman rank order correlation). An effect on ASE activity during second-line treatment with pegylated E coli ASE was, however, only observed when anti-E coli ASE Ab levels were high (> 200 AU/mL). In the presence of moderate or intermediate Ab levels (6.25-200 AU/mL) the switch from native to pegylated E coli ASE resulted in a significant increase of ASE activity above the threshold of 100 U/L (P < .05). Erwinia chrysanthemi ASE activity was not correlated with anti-E coli ASE Ab levels. Erwinia ASE was found to be the best ASE alternative if Ab levels against E coli ASE exceed 200 AU/mL. This retrospective analysis is the first to describe the relationship between the level of anti-E coli ASE Abs and serum activity of pegylated E coli ASE used second-line after native E coli ASE.


PubMed | University Childrens Hospital of Muenster
Type: Journal Article | Journal: Pharmacogenomics | Year: 2015

Assuming that genetic variants of the SLC22A2 and SLC31A1 transporter affect patients susceptibility to cisplatin-induced ototoxicity, we compared the distribution of 11 SLC22A2 variants and the SLC31A1 variant rs10981694 between patients with and without cisplatin-induced ototoxicity.Genotyping was performed in 64 pediatric patients and significant findings were re-evaluated in 66 adults.The SLC22A2 polymorphism rs316019 (c.808G>T; Ser270Ala) was significantly associated with protection from cisplatin-induced ototoxicity in the pediatric (p = 0.022) and the adult cohort (p = 0.048; both: Fishers exact test). This result was confirmed by multiple logistic regression analysis accounting for age which was identified as a relevant factor for ototoxicity as well (rs316019: OR [G/T vs G/G] = 0.12, p = 0.009; age: OR [per year]: 0.84, p = 0.02).These results identified rs316019 as potential pharmacogenomic marker for cisplatin-induced ototoxicity and point to a critical role of SLC22A2 for cisplatin transport in humans and its contribution to the organ specific side effects of this drug. Original submitted 17 September 2014; Revision submitted 19 December 2014.

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