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1.
Clin Chim Acta ; 499: 108-114, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31513787

RESUMO

BACKGROUND: Appropriate reference intervals are essential when evaluating laboratory test results. However, establishment of reference intervals is challenging, especially for coagulation screening tests, and uncertainty exists regarding age- and sex-dependency of test results. Data mining of laboratory information systems is an emerging approach to reference interval determination, and we evaluated its applicability to coagulation tests. METHODS: We analyzed measurements of activated partial thromboplastin time (aPTT), prothrombin time (PT), international normalized ratio (INR), thrombin time (TT), and fibrinogen performed during clinical care in the University Hospital Erlangen, Germany (1,778,738 samples from 116,754 adult patients, 45,577-509,859 samples per analyte). We identified the proportion of samples from healthy individuals using an established statistical approach (Reference Limit Estimator), in which the distribution of physiological test results is approximated using a parametrical function, and used for the calculation of reference intervals. RESULTS: We established age- and sex specific reference intervals for aPTT, PT, INR, TT, and fibrinogen, and created batch- and reagent-specific aPTT-reference intervals. Additionally, we evaluated the sensitivity of the established aPTT reference intervals for the detection of factor VIII, IX, XI, XII deficiencies. CONCLUSION: Data mining of laboratory test results allows the creation of age- and sex-reference intervals for coagulation tests that are specific to the examined population, analytical framework, and reagent. This approach can complement conventional methods when establishing reference intervals and improve clinical decision-making based on coagulation tests. The reference intervals established in this study show only minor variation with sex and age, supporting the practice of providing a common reference interval for adult women and men.

2.
Leukemia ; 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31431735

RESUMO

We used hybrid capture-targeted next-generation sequencing of circulating cell-free DNA (ccfDNA) of pediatric Hodgkin lymphoma (PHL) patients to determine pathogenic mechanisms and assess the clinical utility of this method. Hodgkin-Reed/Sternberg (HRS) cell-derived single nucleotide variants, insertions/deletions, translocations and VH-DH-JH rearrangements were detected in pretherapy ccfDNA of 72 of 96 patients. Number of variants per patient ranged from 1 to 21 with allele frequencies from 0.6 to 42%. Nine translocation breakpoints were detected. Genes involved in JAK/STAT, NFkB and PI3K signaling and antigen presentation were most frequently affected. SOCS1 variants, mainly deletions, were found in most circulating tumor (ct) DNAs, and seven of the nine translocation breakpoints involved SOCS1. Analysis of VH-DH-JH rearrangements revealed an origin of PHL HRS cells from partially selected germinal center B cells. Amounts of pretherapy ctDNA were correlated with metabolic tumor volumes. Furthermore, in all ccfDNA samples of 43 patients with early response assessment quantitative qPET < 3, indicative of a favorable clinical course, ctDNA was not detectable. In contrast, in five of six patients with qPET > 3, indicative of an unfavorable clinical course, ctDNA remained detectable. ccfDNA analysis of PHL is thus a suitable approach to determine pathogenic mechanisms and monitor therapy response.

4.
J Cell Mol Med ; 23(8): 4955-4961, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31199062

RESUMO

Quantification of tumour-specific molecular markers at the RNA and DNA level for treatment response monitoring is crucial for risk-adapted stratification and guidance of individualized therapy in leukaemia and other malignancies. Most pediatric leukaemias and solid tumours of mesenchymal origin are characterized by a relatively low mutation burden at the single nucleotide level and the presence of recurrent chromosomal translocations. The genomic fusion sites resulting from translocations are stable molecular tumour markers; however, repeat-rich DNA sequences flanking intronic breakpoints limit the design of high sensitivity PCR assays for minimal residual disease (MRD) monitoring. Here, we quantitatively evaluated the impact of repeat elements on assay selection and the feasibility of using extended amplicons (≤1330 bp) amplified by droplet digital PCR to monitor pediatric chronic myeloid leukaemia (CML). Molecular characterization of 178 genomic BCR-ABL1 fusion sites showed that 64% were located within sequence repeat elements, impeding optimal primer/probe design. Comparative quantification of DNA and RNA BCR-ABL1 copy numbers in 687 specimens from 55 pediatric patients revealed that their levels were highly correlated. The combination of droplet digital PCR, double quenched probes and extended amplicons represents a valuable tool for sensitive MRD assessment in CML and may be adapted to other translocation-positive tumours.

5.
Eur J Cancer ; 114: 27-35, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31022591

RESUMO

PURPOSE: Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive paediatric brain tumour with fatal outcome. The Individualised Therapy For Relapsed Malignancies In Childhood (INFORM) registry study offers comprehensive molecular profiling of high-risk tumours to identify target alterations for potential precision therapy. We analysed molecular characteristics and clinical data after brainstem biopsy of all enrolled newly diagnosed DIPGs. PATIENTS AND METHODS: From -February 2015 to February 2018, 21 subsequent primary DIPG cases were enrolled in the nation-wide multicentre INFORM registry study after brainstem biopsy. Whole-genome, whole-exome sequencing and DNA methylation analysis were performed, and RNA-sequencing was added in case of sufficient material. Clinical data were obtained from standardised questionnaires and the INFORM clinical data bank. RESULTS: Tumour material obtained from brainstem biopsy was sufficient for DNA analysis in all cases and RNA analysis in 16 of 21 cases. In 16 of 21 cases (76%), potential targetable alterations were identified including highly relevant MET and NTRK1 fusions as well as an EZH2 alteration not previously described in DIPG. In 5 of 21 cases, molecular information was used for initiation of targeted treatment. The majority of patients (19/21) presented with neurological deficits at diagnosis. Newly arising or worsening of neurological deficits post-biopsy occurred in nine patients. Symptoms were reversible or improved notably in eight cases. CONCLUSION: In this multicentre study setting, brainstem biopsy of DIPG was feasible and yielded sufficient material for comprehensive molecular profiling. Relevant molecular targets were identified impacting clinical management in a substantial subset. Death or severe bleeding occurred in none of the cases. One of 20 patients experienced unilateral paraesthesia possibly related to biopsy.

6.
J Laparoendosc Adv Surg Tech A ; 29(5): 688-693, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30946003

RESUMO

Introduction: In pediatric patients, thoracoscopic wedge-resection of pulmonary nodules is an established therapy. However, intraoperative localization of small lesions is still challenging. Purpose of this study was to evaluate the efficacy of preoperative computed tomography (CT)-guided wire-marking of small lung nodules. Materials and Methods: Between 2012 and 2017 a total of six cases receiving thoracoscopic resection of CT-marked lung nodules were analyzed. The nodules were preoperatively tagged by a wire, which was attached to the thoracic wall by sterile dressing. Characteristics of interest were stability of wire, complete resection, and prevention of open thoracotomy. Results: Six procedures were performed on five patients, including four men and one woman. Median age at intervention was 16 years (range 11-19 years). All patients had a history of primary malignancies, including osteosarcoma (n = 4) and synovial sarcoma (n = 1). A total of 10 nodules were visualized in CT of which 9 were marked by wire. The median expected size of nodules was 6 mm (range 2-23 mm). Two patients had bilateral, two left-sided and two right-sided lung lesions. There was no wire slippage. In five procedures wedge resection was possible; one case needed a near total lobe resection. In one case a mini-thoracotomy at port insertion site was performed to extract the specimen. There was no conversion to thoracotomy. Histopathology showed R0 resection in all patients. Malignancy was found in all specimens. In one patient postoperative hemorrhagic anemia necessitated transfusion. Conclusions: Preoperative wire-localization of small lung nodules is a safe and effective tool to enable thoracoscopic resection in children and to avoid thoracotomic interventions.


Assuntos
Neoplasias Pulmonares/cirurgia , Pulmão/cirurgia , Nódulo Pulmonar Solitário/cirurgia , Cirurgia Torácica Vídeoassistida/métodos , Tomografia Computadorizada por Raios X , Adolescente , Criança , Feminino , Seguimentos , Humanos , Masculino , Osteossarcoma/complicações , Osteossarcoma/cirurgia , Pediatria , Período Pós-Operatório , Anormalidades do Sistema Respiratório/cirurgia , Estudos Retrospectivos , Sarcoma Sinovial/complicações , Sarcoma Sinovial/cirurgia , Toracotomia/métodos , Adulto Jovem
7.
Pediatr Blood Cancer ; 66(8): e27780, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31034759

RESUMO

BACKGROUND: Assessment of minimal residual disease (MRD) is an integral component for response monitoring and treatment stratification in acute lymphoblastic leukemia (ALL). We aimed to evaluate the genomic ETV6-RUNX1 fusion sites as a single marker for MRD quantification. PROCEDURE: In a representative, uniformly treated cohort of pediatric relapsed ALL patients (n = 52), ETV6-RUNX1 fusion sites were compared to the current gold standard, immunoglobulin/T-cell receptor (Ig/TCR) gene rearrangements. RESULTS: Primer/probe sets designed to ETV6-RUNX1 fusions achieved significantly more frequent a sensitivity and a quantitative range of at least 10-4 compared to the gold standard with 100% and 73% versus 76% and 47%, respectively. The breakpoint sequence was identical at diagnosis and relapse in all tested cases. There was a high degree of concordance between quantitative MRD results assessed using ETV6-RUNX1 and the highest Ig/TCR marker (Spearman's 0.899, P < .01) with differences >½ log-step in only 6% of patients. A high proportion of ETV6-RUNX1-positive ALL relapses (40%) in our cohort showed a poor response to induction treatment at relapse, and therefore had an indication for hematopoietic stem cell transplantation, demonstrating the need of accurate identification of this subgroup. CONCLUSIONS: ETV6-RUNX1 fusion sites are highly sensitive and reliable MRD markers. Our data confirm that they are unaffected by clonal evolution and selection during front-line and second-line chemotherapy in contrast to Ig/TCR rearrangements, which require several markers per patient to compensate for the observed loss of target clones. In future studies, the genomic ETV6-RUNX1 fusion can be used as single MRD marker.

8.
Clin Chem Lab Med ; 57(10): 1595-1607, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31005947

RESUMO

Background Interpreting hematology analytes in children is challenging due to the extensive changes in hematopoiesis that accompany physiological development and lead to pronounced sex- and age-specific dynamics. Continuous percentile charts from birth to adulthood allow accurate consideration of these dynamics. However, the ethical and practical challenges unique to pediatric reference intervals have restricted the creation of such percentile charts, and limitations in current approaches to laboratory test result displays restrict their use when guiding clinical decisions. Methods We employed an improved data-driven approach to create percentile charts from laboratory data collected during patient care in 10 German centers (9,576,910 samples from 358,292 patients, 412,905-1,278,987 samples per analyte). We demonstrate visualization of hematology test results using percentile charts and z-scores (www.pedref.org/hematology) and assess the potential of percentiles and z-scores to support diagnosis of different hematological diseases. Results We created percentile charts for hemoglobin, hematocrit, red cell indices, red cell count, red cell distribution width, white cell count and platelet count in girls and boys from birth to 18 years of age. Comparison of pediatricians evaluating complex clinical scenarios using percentile charts versus conventional/tabular representations shows that percentile charts can enhance physician assessment in selected example cases. Age-specific percentiles and z-scores, compared with absolute test results, improve the identification of children with blood count abnormalities and the discrimination between different hematological diseases. Conclusions The provided reference intervals enable precise assessment of pediatric hematology test results. Representation of test results using percentiles and z-scores facilitates their interpretation and demonstrates the potential of digital approaches to improve clinical decision-making.

9.
Int J Cancer ; 145(4): 941-951, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30694527

RESUMO

Two percent of patients with Wilms tumors have a positive family history. In many of these cases the genetic cause remains unresolved. By applying germline exome sequencing in two families with two affected individuals with Wilms tumors, we identified truncating mutations in TRIM28. Subsequent mutational screening of germline and tumor DNA of 269 children affected by Wilms tumor was performed, and revealed seven additional individuals with germline truncating mutations, and one individual with a somatic truncating mutation in TRIM28. TRIM28 encodes a complex scaffold protein involved in many different processes, including gene silencing, DNA repair and maintenance of genomic integrity. Expression studies on mRNA and protein level showed reduction of TRIM28, confirming a loss-of-function effect of the mutations identified. The tumors showed an epithelial-type histology that stained negative for TRIM28 by immunohistochemistry. The tumors were bilateral in six patients, and 10/11 tumors are accompanied by perilobar nephrogenic rests. Exome sequencing on eight tumor DNA samples from six individuals showed loss-of-heterozygosity (LOH) of the TRIM28-locus by mitotic recombination in seven tumors, suggesting that TRIM28 functions as a tumor suppressor gene in Wilms tumor development. Additionally, the tumors showed very few mutations in known Wilms tumor driver genes, suggesting that loss of TRIM28 is the main driver of tumorigenesis. In conclusion, we identified heterozygous germline truncating mutations in TRIM28 in 11 children with mainly epithelial-type Wilms tumors, which become homozygous in tumor tissue. These data establish TRIM28 as a novel Wilms tumor predisposition gene, acting as a tumor suppressor gene by LOH.

10.
Clin Chem Lab Med ; 2018 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-30367783

RESUMO

Background Conventional establishment of reference intervals for hematological analytes is challenging due to the need to recruit healthy persons. Indirect methods address this by deriving reference intervals from clinical laboratory databases which contain large datasets of both physiological and pathological test results. Methods We used the "Reference Limit Estimator" (RLE) to establish reference intervals for common hematology analytes in adults aged 18-60 years. One hundred and ninety-five samples from 44,519 patients, measured on two different devices in a tertiary care center were analyzed. We examined the influence of patient cohorts with an increasing proportion of abnormal test results, compared sample selection strategies, explored inter-device differences, and analyzed the stability of reference intervals in simulated datasets with varying overlap of pathological and physiological test results. Results Reference intervals for hemoglobin, hematocrit, red cell count and platelet count remained stable, even if large numbers of pathological samples were included. Reference intervals for red cell indices, red cell distribution width and leukocyte count were sufficiently stable, if patient cohorts with the highest fraction of pathological samples were excluded. In simulated datasets, estimated reference limits shifted, if the pathological dataset contributed more than 15%-20% of total samples and approximated the physiological distribution. Advanced sample selection techniques did not improve the algorithm's performance. Inter-device differences were small except for red cell distribution width. Conclusions The RLE is well-suited to create reference intervals from clinical laboratory databases even in the challenging setting of a adult tertiary care center. The procedure can be used as a complement for reference interval determination where conventional approaches are limited.

11.
Math Med Biol ; 2018 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-30357334

RESUMO

Acute lymphoblastic leukemia is the most common malignancy in childhood and requires prolonged oral maintenance chemotherapy to prevent disease relapse after remission induction with intensive intravenous chemotherapy. In maintenance therapy, drug doses of 6-mercaptopurine (6-MP) and methotrexate (MTX) are adjusted to achieve sustained antileukemic activity without excessive myelosuppression. However, uncertainty exists regarding timing and extent of drug dose responses and optimal dose adaptation strategies. We propose a novel comprehensive mathematical model for 6-MP and MTX pharmacokinetics, pharmacodynamics and myelosuppression in acute lymphoblastic maintenance therapy. We personalize and cross-validate the mathematical model using clinical data and propose a real-time algorithm to predict chemotherapy responses with a clinical decision support system as a potential future application.

12.
Science ; 361(6405)2018 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-30166462

RESUMO

Sarcomas are cancers of the bone and soft tissue often defined by gene fusions. Ewing sarcoma involves fusions between EWSR1, a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) transcription factors. We explored how and when EWSR1-ETS fusions arise by studying the whole genomes of Ewing sarcomas. In 52 of 124 (42%) of tumors, the fusion gene arises by a sudden burst of complex, loop-like rearrangements, a process called chromoplexy, rather than by simple reciprocal translocations. These loops always contained the disease-defining fusion at the center, but they disrupted multiple additional genes. The loops occurred preferentially in early replicating and transcriptionally active genomic regions. Similar loops forming canonical fusions were found in three other sarcoma types. Chromoplexy-generated fusions appear to be associated with an aggressive form of Ewing sarcoma. These loops arise early, giving rise to both primary and relapse Ewing sarcoma tumors, which can continue to evolve in parallel.


Assuntos
Neoplasias Ósseas/genética , Rearranjo Gênico , Proteínas de Fusão Oncogênica/genética , Sarcoma de Ewing/genética , Neoplasias de Tecidos Moles/genética , Adolescente , Neoplasias Ósseas/patologia , Criança , Replicação do DNA , Evolução Molecular , Feminino , Genoma Humano , Humanos , Masculino , Mutação , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Neoplasias de Tecidos Moles/patologia
13.
Nat Commun ; 9(1): 3184, 2018 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-30093639

RESUMO

Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk.

14.
Pediatr Blood Cancer ; 65(12): e27431, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30160364

RESUMO

Since the patent for imatinib has expired, the role of generic imatinib (GI) in the management of Philadelphia chromosome-positive (Ph+) leukemia in pediatric patients has had ongoing discussion. Some studies in adults demonstrated that equivalent doses of GI and branded imatinib (BI) result in comparable plasma concentrations and clinical efficacy. However, other studies found that GI users are more likely to stop imatinib, with intolerance and decreased persistence as the main causes. Economic factors also heavily influence GI selection. This article aims to review the present knowledge to support further discussion on the role of GI in the management of pediatric Ph+ leukemia.

15.
Br J Haematol ; 183(1): 104-109, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30028016

RESUMO

Osteonecrosis (ON) was prospectively assessed in 557 children and adolescents in the Berlin-Frankfurt-Münster Stem Cell Transplantation in children with acute lymphoblastic leukaemia 2003 trial. Median age at haematopoietic stem cell transplantation (HSCT) was 10·3 years (range 0·5-26). Cumulative incidence of symptomatic ON (sON) was 9% at 5 years (standard deviation 1%), median time from HSCT to diagnosis of sON was 12·4 months (range 1-126). Multivariate analysis identified age at HSCT [10-15 years vs. <10 years: hazard ratio (HR) 3·73, P = 0·009; >15 years vs. <10 years: HR 5·46, P = 0·001], diagnosis of sON prior to HSCT and chronic graft-versus-host disease (yes versus no: HR 2·696, P = 0·015) as significant independent risk factors for the development of sON.

16.
Leukemia ; 32(7): 1657-1669, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29925908

RESUMO

A total of 156 patients (age range 1.3-18.0 years, median 13.2 years; 91 (58.3%) male) with newly diagnosed CML (N = 146 chronic phase (CML-CP), N = 3 accelerated phase (CML-AP), N = 7 blastic phase (CML-BP)) received imatinib up-front (300, 400, 500 mg/m2, respectively) within a prospective phase III trial. Therapy response, progression-free survival, causes of treatment failure, and side effects were analyzed in 148 children and adolescents with complete data. Event-free survival rate by 18 months for patients in CML-CP (median follow-up time 25 months, range: 1-120) was 97% (95% CI, 94.2-99.9%). According to the 2006 ELN-criteria complete hematologic response by month 3, complete cytogenetic response (CCyR) by month 12, and major molecular response (MMR) by month 18 were achieved in 98, 63, and 59% of the patients, respectively. By month 36, 86% of the patients achieved CCyR and 74% achieved MMR. Thirty-eight patients (27%) experienced imatinib failure because of unsatisfactory response or intolerance (N = 9). In all, 28/148 patients (19%) underwent stem cell transplantation (SCT). In the SCT sub-cohort 2/23 patients diagnosed in CML-CP, 0/1 in CML-AP, and 2/4 in CML-BP, respectively, died of relapse (N = 3) or SCT-related complications (N = 2). This large pediatric trial extends and confirms data from smaller series that first-line imatinib in children is highly effective.

17.
Oncotarget ; 9(41): 26543-26555, 2018 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-29899875

RESUMO

Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion genes resulting from the translocation t(2;5)(p23;q35) are present in almost 90% of childhood ALK-positive anaplastic large-cell lymphomas (ALCL). Detection and quantification of minimal disseminated disease (MDD) by measuring NPM-ALK fusion transcript levels in the blood provide independent prognostic parameters. Characterization of the genomic breakpoints provides insights into the pathogenesis of the translocation and allows for DNA-based minimal disease monitoring. We designed a nested multiplex PCR assay for identification and characterization of genomic NPM-ALK fusion sequences in 45 pediatric ALCL-patients, and used the sequences for quantitative MDD monitoring. Breakpoint analysis indicates the involvement of inaccurate non-homologous end joining repair mechanisms in the formation of NPM-ALK fusions. Parallel quantification of RNA and DNA levels in the cellular fraction of 45 blood samples from eight patients with NPM-ALK-positive ALCL correlated, as did cell-free circulating NPM-ALK DNA copies in the plasma fraction of 37 blood samples. With genomic NPM-ALK fusion sequence quantification, plasma samples of ALCL patients become an additional source for MRD-assessment. Parallel quantification of NPM-ALK transcripts and fusion genes in ALCL cell lines treated with the ALK kinase inhibitor crizotinib illustrates the potential value of supplementary DNA-based quantification in particular clinical settings.

18.
Artigo em Inglês | MEDLINE | ID: mdl-29899990

RESUMO

We report on a boy of Albanian descent with the history of juvenile myelomonocytic leukemia (JMML). JMML was diagnosed at the age of 17 months and treated by hematopoietic stem cell transplantation (HSCT). At the age of 14.3 years, about 12 years after HSCT, he was hospitalized with an adrenal crisis. Hormone findings were consistent with primary adrenal insufficiency. Autoimmune adrenalitis was confirmed by positive autoantibodies against 21-hydroxylase and adrenal tissue. Since autoimmune Hashimoto thyroiditis was already known from the age of 9 years, we assume that both diseases are part of the spectrum of autoimmune polyglandular syndrome (APS) type 2. APS type 2 is a rare endocrine disease characterized by Addison's disease along with autoimmune thyroid disease and/or type 1 diabetes. Learning points: Endocrine sequelae after hematopoietic stem cell transplantation (HSCT) are common and can develop over a long period.Primary adrenal insufficiency after HSCT is absolutely rare.The combination of adrenal autoimmune disease and Hashimoto thyroiditis is consistent with autoimmune polyglandular syndrome type 2.

19.
Oncol Res Treat ; 41(7-8): 430-436, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29902787

RESUMO

BACKGROUND: Childhood cancer survivors are at risk for therapy-related sequelae and, therefore, require long-term follow-up. At 2 university hospitals in Germany collaborative multidisciplinary late effects clinics were installed to provide specialized care and to evaluate the current health status of these patients in a clinical setting. Patients andMethods: Every patient who visited the late effects clinics at the university hospital in Lübeck and Erlangen over a period of 3 years and met the inclusion criteria was included in the study. Patients' characteristics as well as cancer diagnosis, treatment related factors and the prevalence of chronic health conditions were assessed. RESULTS: 220 patients attended the late effects clinics during the observation period. The median follow-up period was 16 years (range 5-45 years). In total over 64% of the patients were affected by at least 1 chronic health condition, including endocrine disruptions in 19.1% of the patients. Moreover, secondary neoplasms occurred in 9.1% of the study participants. CONCLUSION: German childhood cancer survivors are affected by multiple therapy-related sequelae. A comprehensive network of late effects clinics should be established to ensure specialized and risk-adapted care for every childhood cancer survivor in Germany.

20.
Klin Padiatr ; 230(3): 142-150, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29631306

RESUMO

BACKGROUND: Application of potentially nephrotoxic chemotherapy requires continuous monitoring of renal function for toxicity and dosing. Novel pediatric glomerular filtration rate (GFR) estimating equations including cystatin C have been proposed to enhance the reliability of GFR calculation. MATERIALS AND METHODS: We examined a pediatric oncologic data set with a total of 363 GFR measurements. An analysis of distribution characteristics and comparison of medians was performed to compare creatinine and cystatin C-based GFR estimating formulae. Furthermore, we investigated the clinical impact of different equations in regard to therapeutic consequences. RESULTS: Significant differences in estimated GFR values were calculated depending on the applied formula (range of median GFR from 94.8 to 180.9 mL/min per 1.73 m2) which may result in different therapeutic consequences for the use of potentially nephrotoxic chemotherapeutic agents. Significant correlation for all examined formulae was identified, however there were large fluctuations among the correlation coefficients ranging from 0.254 to 1.0. CONCLUSION: This study compares proposed pediatric GFR estimating equations in a clinical setting. It underlines the current limitations and difficulties of GFR estimation including potential dosing errors. Cystitis C-based equations can be used as alternatives to creatinine-based estimations when the appropriate laboratory method has been applied. A comparative calculator for pediatric GFR estimating equations along with background information is provided at http://gfr.pedz.de and may support clinical decision-making.

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