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1.
Cancers (Basel) ; 16(11)2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38893276

RESUMO

GCTs are developmental tumors and are likely to reflect ontogenetic and teratogenetic determinants. The objective of this study was to identify syndromes with or without congenital anomalies and non-syndromic defects as potential risk factors. Patients with extracranial GCTs (eGCTs) registered in MAKEI 96/MAHO 98 between 1996 and 2017 were included. According to Teilum's holistic concept, malignant and benign teratomas were registered. We used a case-control study design with Orphanet as a reference group for syndromic defects and the Mainz birth registry (EUROCAT) for congenital anomalies at birth. Co-occurring genetic syndromes and/or congenital anomalies were assessed accordingly. Odds ratios and 95% confidence intervals were calculated and p-values for Fisher's exact test with Bonferroni correction if needed. A strong association was confirmed for Swyer (OR 338.6, 95% CI 43.7-2623.6) and Currarino syndrome (OR 34.2, 95% CI 13.2-88.6). We additionally found 16 isolated cases of eGCT with a wide range of syndromes. However, these were not found to be significantly associated following Bonferroni correction. Most of these cases pertained to girls. Regarding non-syndromic defects, no association with eGCTs could be identified. In our study, we confirmed a strong association for Swyer and Currarino syndromes with additional congenital anomalies.

2.
Br J Anaesth ; 131(3): 472-481, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37380568

RESUMO

BACKGROUND: Patient Blood Management (PBM) is a patient-centred, systematic, evidence-based approach to improve patient outcomes by managing and preserving a patient's own blood whilst promoting patient safety and empowerment. The effectiveness and safety of PBM over a longer period have not yet been investigated. METHODS: We performed a prospectively designed, multicentre follow-up study with non-inferiority design. Data were retrospectively extracted case-based from electronic hospital information systems. All in-hospital patients (≥18 yr) undergoing surgery and discharged between January 1, 2010 and December 31, 2019 were included in the analysis. The PBM programme focused on three domains: preoperative optimisation of haemoglobin concentrations, blood-sparing techniques, and guideline adherence/standardisation of allogeneic blood product transfusions. The outcomes were utilisation of blood products, composite endpoint of in-hospital mortality and postoperative complications (myocardial infarction/ischaemic stroke/acute renal failure with renal replacement therapy/sepsis/pneumonia), anaemia rate at admission and discharge, and hospital length of stay. RESULTS: A total of 1 201 817 (pre-PBM: n=441 082 vs PBM: n=760 735) patients from 14 (five university/nine non-university) hospitals were analysed. Implementation of PBM resulted in a substantial reduction of red blood cell utilisation. The mean number of red blood cell units transfused per 1000 patients was 547 in the PBM cohort vs 635 in the pre-PBM cohort (relative reduction of 13.9%). The red blood cell transfusion rate was significantly lower (P<0.001) with odds ratio 0.86 (0.85-0.87). The composite endpoint was 5.8% in the PBM vs 5.6% in the pre-PBM cohort. The non-inferiority aim (safety of PBM) was achieved (P<0.001). CONCLUSIONS: Analysis of >1 million surgical patients showed that the non-inferiority condition (safety of Patient Blood Management) was fulfilled, and PBM was superior with respect to red blood cell transfusion. CLINICAL TRIAL REGISTRATION: NCT02147795.


Assuntos
Isquemia Encefálica , Acidente Vascular Cerebral , Humanos , Transfusão de Sangue , Seguimentos , Estudos Retrospectivos , Adolescente , Adulto
3.
Mol Genet Genomic Med ; 9(9): e1746, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34382369

RESUMO

BACKGROUND: Isolated myelosarcoma of infancy is a rare presentation of acute myelogenous leukaemia (AML). Because of its rarity and early onset in infancy underlying genetic predisposition is potentially relevant in disease initiation. METHODS AND RESULTS: We report an oncologic emergency in an infant with thoracic and intraspinal aleukaemic myeloid sarcoma causing acute myelon compression and lower leg palsy. Whole-exome sequencing of the patient's germline DNA identified a rare PALB2 (OMIM 610355) variant (p.A1079S), which is located in a domain critical for the gene's proper function within the homology-directed repair pathway. In line with potential DNA damage repair defects mediated by the PALB2 deregulation, the patient's fibroblasts showed increased sensitivity towards radiation and DNA intercalating agents. CONCLUSION: Therefore, we suggest PALB2 p.A1079S as a pathogenic variant potentially contributing to the here observed patient phenotype.


Assuntos
Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Sarcoma Mieloide/genética , Neoplasias da Coluna Vertebral/genética , Células Cultivadas , Proteína do Grupo de Complementação N da Anemia de Fanconi/metabolismo , Fibroblastos/metabolismo , Fibroblastos/fisiologia , Pontos de Checagem da Fase G2 do Ciclo Celular , Mutação em Linhagem Germinativa , Humanos , Lactente , Masculino , Sarcoma Mieloide/patologia , Neoplasias da Coluna Vertebral/patologia
4.
Sci Rep ; 10(1): 9058, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32493972

RESUMO

Acute lymphoblastic leukaemia (ALL) is the most common form of paediatric cancer and epigenetic aberrations are determinants of leukaemogenesis. The aim of this study was to investigate the methylation degree of a distinct phospholipase A2 receptor 1 (PLA2R1) promoter region in paediatric ALL patients and to evaluate its relevance as new biomarker for monitoring treatment response and burden of residual disease. The impact of PLA2R1 re-expression on proliferative parameters was assessed in vitro in Jurkat cells with PLA2R1 naturally silenced by DNA methylation. Genomic DNA was isolated from bone marrow (BM) and peripheral blood (PB) of 44 paediatric ALL patients. PLA2R1 methylation was analysed using digital PCR and compared to 20 healthy controls. Transfected Jurkat cells were investigated using cell growth curve analysis and flow cytometry. PLA2R1 was found hypermethylated in BM and PB from pre-B and common ALL patients, and in patients with the disease relapse. PLA2R1 methylation decreased along with leukaemic blast cell reduction during ALL induction treatment. In vitro analysis revealed an anti-proliferative phenotype associated with PLA2R1 re-expression, suggesting a tumour-suppressive function of PLA2R1. Collected data indicates that PLA2R1 promoter methylation quantitation can be used as biomarker for ALL induction treatment control, risk stratification, and early detection of ALL relapse.


Assuntos
Metilação de DNA/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Regiões Promotoras Genéticas/genética , Receptores da Fosfolipase A2/genética , Adolescente , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Criança , Pré-Escolar , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Lactente , Células Jurkat , Masculino , Recidiva Local de Neoplasia/genética
5.
Br J Haematol ; 188(5): 701-706, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31617211

RESUMO

A considerable proportion of patients with chronic myeloid leukaemia (CML) may present at diagnosis with high platelet counts. This may result in thrombosis or bleeding complications due to binding of von Willebrand factor (VWF) multimers to platelets. Paediatric CML is very rare and no systematic investigation on clinical complications of elevated platelets has been reported. Data on platelet count and associated haemostaseological complications were retrospectively analysed in a cohort of 156 children with CML. Fifty-one percent (81/156) patients presented with thrombocytosis (platelet count> 500 × 109 /l), and were extreme (>1 000 × 109 /l) in 23/156 (16%). There were no cases of thrombosis but mild bleeding signs were present in 12% (n = 9) children with thrombocytosis. Bleeding occurred without correlation to elevated platelet counts and was associated with reduced large VWF multimers, indicating a diagnosis of acquired von Willebrand syndrome (AVWS), which resolved after initiation of CML treatment. Patients with paediatric CML frequently exhibit high platelet counts not resulting in thrombosis. In patients with thrombocytosis mild bleeding signs due to a low percentage of large VWF multimers can be demonstrated. AVWS may be underdiagnosed in paediatric CML (Clinical-Trials.gov NCT00445822, 9 March 2007).


Assuntos
Hemorragia , Leucemia Mielogênica Crônica BCR-ABL Positiva , Doenças de von Willebrand , Adolescente , Criança , Pré-Escolar , Feminino , Hemorragia/sangue , Hemorragia/diagnóstico , Humanos , Lactente , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Masculino , Contagem de Plaquetas , Síndrome , Trombocitose/sangue , Trombocitose/diagnóstico , Doenças de von Willebrand/sangue , Doenças de von Willebrand/diagnóstico , Fator de von Willebrand/metabolismo
6.
Breast Care (Basel) ; 13(4): 264-271, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30319328

RESUMO

BACKGROUND: Advances in oncological therapy have significantly improved breast cancer survival; therefore comorbid conditions are becoming more relevant. We investigated the prevalence of prior cardiovascular diseases and risk factors in patients with breast cancer compared to those in the general female population in Germany. METHODS: The PASSOS heart study is a retrospective multicenter cohort study on cardiac late effects in breast cancer patients treated between 1998 and 2008. We analyzed the frequencies of cardiac diseases and cardiovascular risk factors in patients from this cohort as documented in anesthesia protocols compared to self-reported frequencies in the general female population in Germany. RESULTS: 3,496 patients aged between 40 and 79 years who underwent breast surgery were considered for analysis. The age-standardized prevalence of cardiac diseases or cardiovascular risk factors was 6.75 versus 7.52% and 69 versus 80.92%, respectively. Coronary heart disease (3.96 vs. 5.18%) and angina pectoris (0.37 vs. 1.03%) prevalence was lower in breast cancer patients, while non-fatal myocardial infarction (2.06 vs. 1.81%) and stroke (2.64 vs. 2.34%) were more frequent (not statistically significant). CONCLUSION: Pre-existing cardiac diseases and cardiovascular risk factors are common in both study populations, being slightly less frequent in the PASSOS cohort. When making therapy decisions, the cardiac risk profile should be carefully monitored and taken into account.

7.
Cancer Genomics Proteomics ; 15(4): 299-312, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29976635

RESUMO

BACKGROUND/AIM: DNA methylation plays an important role in the initiation and propagation of carcinogenesis; however, the role of heterogeneously methylated epialleles is currently not well studied, also due to the lack of sensitive, unbiased and high throughput methods. Here, a newly developed droplet digital PCR (ddPCR)-based method was evaluated regarding its ability to quantify such heterogeneously methylated epialleles with sufficient analytical sensitivity and specificity. MATERIALS AND METHODS: Genomic DNA from blood leukocytes and bone marrow aspirate of an 8-year old male with B-cell acute lymphoblastic leukemia (B-ALL) and from normal and malignant prostate cell lines were analysed using ddPCR. RESULTS: By using these DNA samples, the specificity of an applied set of fluorescence-labeled probes was demonstrated as a proof of concept. CONCLUSION: All individual heterogeneously-methylated epialleles were quantifiable by a set of fluorescence-labeled probes with complementary sequences to epialleles in a closed-tube and high-throughput manner. The new method named epiallele-sensitive droplet digital PCR (EAST-ddPCR) may give new insights in the generation and regulation of epialleles and may help in finding new biomarkers for the diagnosis of benign und malignant diseases.


Assuntos
Alelos , Metilação de DNA , DNA/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Próstata/metabolismo , Biomarcadores Tumorais/genética , Células Cultivadas , Criança , DNA/análise , Heterogeneidade Genética , Humanos , Masculino , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , Receptores da Fosfolipase A2/genética
8.
Klin Padiatr ; 230(3): 138-141, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29618138

RESUMO

BACKGROUND: Burkitt lymphoma (BL) in children often presents with abdominal localization. Intestinal perforations have been described mainly during treatment. We report on a three-year-old patient with abdominal BL who was diagnosed with a duodenocolonic fistula. CASE REPORT: A three-year-old boy presented with diarrhea, crampy abdominal pain, and a four-week history of loss of appetite and weight. Ultrasound and MRI detected a colonic tumor forming a duodenocolonic fistula which was verified by gastroduodenoscopy. A surgical biopsy revealed BL. The stage III BL with low LDH was treated with four courses of BFM-type short-pulse chemotherapy. After two courses of chemotherapy the patient developed a mechanic ileus. A segmental resection of a short segment of the colon at the right flexure carrying the residual tumor mass with cicatricial stenosis and fistula followed by colonic end to end anastomosis and covering of the fistula by omentum major were carried out without complication. 15 days after surgery, two additional courses of chemotherapy could be administrated and the boy is in ongoing remission and free of any symptoms with a follow-up interval of 18 months. CONCLUSIONS: Duodeonocolonic fistula at presentation in a child with abdominal BL is extremely rare. Delayed surgery after size of the tumor bulk has been reduced by chemotherapy might represent a risk adapted approach. However, due to limited experience with duodenocolonic fistulas even in larger pediatric lymphoma trials any decision has to be based on the problems to be faced in individual cases.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/patologia , Colo/diagnóstico por imagem , Diarreia/etiologia , Fístula Intestinal/diagnóstico por imagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biópsia , Linfoma de Burkitt/cirurgia , Pré-Escolar , Duodenoscopia , Gastroscopia , Humanos , Fístula Intestinal/etiologia , Fístula Intestinal/cirurgia , Imageamento por Ressonância Magnética , Masculino , Estadiamento de Neoplasias , Resultado do Tratamento , Ultrassonografia
9.
Mol Clin Oncol ; 7(1): 148-150, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28685094

RESUMO

Antineoplastic treatment of osteoblastic osteosarcoma in a patient with cystic fibrosis (CF) may harbor a high risk of neutropenia-associated complications, and, to the best of our knowledge, has not been previously reported. Diagnosis of CF was confirmed in a 6-week-old boy following pathological newborn screening. The patient had a stable course of CF under standardized continuous therapy. At the age of 5 years, osteosarcoma of the left proximal humerus was diagnosed without evidence of metastases. Neoadjuvant chemotherapy, including doxorubicin, cisplatin and methotrexate, was administered for 10 weeks. The patient tolerated this therapy relatively well, with a continuous antibiotic prophylaxis of cefuroxime without experiencing major complications; in particular, no pulmonary exacerbations were observed as a consequence of immunosuppression or mucosal toxicity. The tumor responded well, and amputation of the limb was avoided via the use of 'clavicle per humerus' osteosynthesis. Postoperatively, compartmental syndrome occurred, requiring management by fasciotomy. Adjuvant chemotherapy was applied thereafter again, without major toxicity that would have required dose reduction. Under intensive physiotherapy, the mobility of the left arm and hand was deemed to be satisfactory. The coincidence of CF with osteosarcoma is extremely rare, and, to the best of our knowledge, has not been previously described. Under antibiotic prophylaxis, antineoplastic treatment was possible without major complications during neutropenia.

11.
Afr J Paediatr Surg ; 9(1): 71-3, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22382110

RESUMO

Gastric teratomas are very rare embryonal neoplasms, accounting for 2.6% of all perinatal diagnosed germ cell tumours. About 85% are well-differentiated mature lesions and about 15% are immature tumours with the potential of malignant transformation. The recommended therapy for gastric teratomas is surgical excision. We present the case of a 6-month-old boy with an incidentally detected epigastric mass. The histological examination revealed a mature gastric teratoma. The diagnostic imaging, therapy and postoperative follow-up are discussed.


Assuntos
Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/cirurgia , Teratoma/diagnóstico , Teratoma/cirurgia , Humanos , Achados Incidentais , Lactente , Masculino
12.
Blood ; 102(1): 246-53, 2003 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-12623853

RESUMO

Effective therapy of high-risk leukemia with established cytotoxic drugs may be limited by poor antitumor efficacy, systemic toxicity, and the induction of drug resistance. Here, we provide the first evidence that hydrolytically activated prodrugs may overcome these problems. For this purpose, VP16 was functionally blocked by hydrolytically cleavable carbonate linkers with unique characteristics to generate 2 novel prodrugs of VP16. First, we established a more than 3-log higher efficacy of the 2 prodrugs compared with VP16 on a panel of naturally drug-resistant tumor cell lines. Second, the prodrugs did overcome VP16-induced multidrug resistance-1 gene (MDR-1)-mediated multidrug resistance in vitro in a newly established VP16-resistant T-cell leukemia cell line MOVP-3 by functionally blocking MDR-1-mediated efflux. Third, in vivo studies showed a maximum tolerated dose of ProVP16-II (> 45mg/kg), which was at least 3-fold higher than that of VP16 (15 mg/kg). Finally, tests of ProVP16-II in a multidrug-resistant xenograft model of T-cell leukemia expressing MDR-1 indicated that only the mice treated with this prodrug revealed a complete and long-lasting regression of established, drug-resistant leukemia. In summary, the hydrolytically activated etoposide prodrugs proved effective against multidrug-resistant T-cell leukemia in vitro and in vivo and provide proof of concept for a highly promising new strategy for the treatment of MDR-1 drug-resistant malignancies.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Etoposídeo/farmacologia , Leucemia de Células T/patologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Etoposídeo/química , Feminino , Humanos , Hidrólise , Concentração Inibidora 50 , Leucemia de Células T/tratamento farmacológico , Camundongos , Camundongos Endogâmicos , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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