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1.
Eur J Pediatr ; 178(12): 1893-1902, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31624947

RESUMO

Life-limiting conditions in children in specialized pediatric palliative care (PPC) are manifold. The "Together for Short Lives" (TfSL) association established four disease categories, which represent the most common illness trajectories. Better understanding the palliative care needs and symptoms of children within these TfSL groups will result in improved anticipation of clinical problems and tailored care. During this retrospective single-center cohort study, 198 children, adolescents, and young adults (CAYAs) were in PPC. Mean age at referral was 8.7 years (range 0.0-25.0), mean duration of care 355 days (range 1-2754). One hundred six (53.5%) CAYAs died during the study period. Sixty-five (32.8%) CAYAs were assigned to TfSL-1, 13 (6.6%) to TfSL-2, 49 (24.7%) to TfSL-3, and 71 (35.9%) to TfSL-4. Home visits were conducted on average every 9.6 days in TfSL-1, 18.9 days in TfSL-2, 31.7 days in TfSL-3, and 31.8 days in TfSL-4 (p value < 0.01).Conclusions: Intensity of palliative care significantly differed between the TfSL groups. Neurological and gastrointestinal symptoms were most prominent across all TfSL groups. Symptom cluster analysis showed distinct clusters in TfSL-1 (cluster 1, fatigue/lack of appetite/nausea/somnolence; cluster 2, dyspnea/fear/myoclonus/seizures/spasticity) and TfSL-3/4 (cluster 1, spasticity; cluster 2, all other symptoms).What is Known:• The four TfSL (together for short lives) groups represent the four most common illness trajectories of pediatric palliative care patients.• Better understanding the palliative care needs and symptoms of children within these four TfSL groups will result in improved anticipation of clinical problems and tailored care.What is New:• In our study, TfSL-1 represented the largest individual group of patients, also requiring the most intensive care (defined by the number of visits per days of care).• Symptom cluster analysis revealed distinct symptom clusters in TfSL-1 and TfSL-3/4, which can be used to anticipate clinically common challenges in these patients.

2.
Eur J Cancer ; 122: 61-71, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31629941

RESUMO

BACKGROUND: Adolescents (aged 10-17 years) with acute lymphoblastic leukaemia (ALL) have unfavourable disease features and an inferior outcome when compared with younger children, but it is still unclear if differences in disease biology and prognosis exist between adolescents older or younger than 15 years. METHODS: We retrospectively analysed outcomes of 1094 adolescents with ALL, aged 10-17 years, treated within the AIEOP-BFM ALL 2000 trial, overall and by the age groups 10-14 and 15-17 years. FINDINGS: Compared with younger children (aged 1-9 years, n = 3647), adolescents had a statistically inferior 5-year event-free survival (EFS) [74.6% (1.3) vs. 84.4% (0.6)] and overall survival (OS) [83.4% (1.1) vs. 92.7% (0.4); p < 0.001]. Clinical and biological disease characteristics did not differ between the two subgroups of adolescents, including minimal residual disease (MRD) results during initial therapy, except for ETV6-RUNX1 frequency and gender. With a median follow-up of 8.8 years, the 5-year EFS and OS were 76.2% (1.5) and 84.9% (1.3), respectively, for those aged 10-14 years and 70.0% (2.8) and 78.8% (2.5) for those aged 15-17 years (p = 0.06; 0.05). There was no significant difference in the cumulative incidence of relapses [17.8% (1.4) and 18.3% (2.4); p = 0.98], while the incidence of treatment-related deaths as a first event was 2.6% (0.6) versus 7.4% (1.6) (p < 0.001) with, in particular, a higher incidence in the high-risk arm. INTERPRETATION: Further prospective studies and biological investigations are required to define optimal treatment for adolescents, in particular for those aged 15-17 years. Newer agents (immunotherapy, targeted therapy) in early treatment phases of patients at higher risk of treatment failure could replace most toxic treatment elements, with the aim of reducing both toxicity and the risk of relapses.

3.
Blood Adv ; 3(20): 3143-3156, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31648313

RESUMO

Survival of patients with pediatric acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-SCT) is mainly compromised by leukemia relapse, carrying dismal prognosis. As novel individualized therapeutic approaches are urgently needed, we performed whole-exome sequencing of leukemic blasts of 10 children with post-allo-SCT relapses with the aim of thoroughly characterizing the mutational landscape and identifying druggable mutations. We found that post-allo-SCT ALL relapses display highly diverse and mostly patient-individual genetic lesions. Moreover, mutational cluster analysis showed substantial clonal dynamics during leukemia progression from initial diagnosis to relapse after allo-SCT. Only very few alterations stayed constant over time. This dynamic clonality was exemplified by the detection of thiopurine resistance-mediating mutations in the nucleotidase NT5C2 in 3 patients' first relapses, which disappeared in the post-allo-SCT relapses on relief of selective pressure of maintenance chemotherapy. Moreover, we identified TP53 mutations in 4 of 10 patients after allo-SCT, reflecting acquired chemoresistance associated with selective pressure of prior antineoplastic treatment. Finally, in 9 of 10 children's post-allo-SCT relapse, we found alterations in genes for which targeted therapies with novel agents are readily available. We could show efficient targeting of leukemic blasts by APR-246 in 2 patients carrying TP53 mutations. Our findings shed light on the genetic basis of post-allo-SCT relapse and may pave the way for unraveling novel therapeutic strategies in this challenging situation.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31618689

RESUMO

Allogeneic hematopoietic stem cell transplantation (HSCT) is widely performed in children and adolescents with hematologic diseases, including very high-risk leukemia. With increasing success and survival rates, the long-term sequelae of HSCT have become important. Here, we provide guidance to the prevention and treatment of the most common bone morbidities-osteoporosis and osteonecrosis-emerging in the context of HSCT in children and adolescents. We give an overview on definitions, symptoms, and diagnostics and propose an algorithm for clinical practice based on discussions within the International Berlin Frankfurt Münster (BFM) Stem Cell Transplantation Committee and the Pediatric Disease Working Party of the European Society for Blood and Marrow Transplantation, our expert knowledge, and a literature review.

5.
Pediatr Blood Cancer ; 66(11): e27916, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31342632

RESUMO

Approximately 10% of all children with cancer are affected by a monogenic cancer predisposition syndrome. This has important implications for both the child and her/his family. The assessment of hereditary cancer predisposition is a challenging task for clinicians and genetic counselors in daily routine. It includes consideration of tumor genetics, specific features of the patient, and the medical/family history. To keep up with the pace of this rapidly evolving and increasingly complex field of genetic susceptibility, we suggest a systematic approach for the evaluation of the child with cancer and her/his family by an interdisciplinary team specialized in hereditary cancer predisposition.

6.
Am J Hematol ; 94(8): 880-890, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31095771

RESUMO

Severe infections (SI) significantly impact on non-relapse mortality after hematopoietic stem cell transplantation (HSCT). We assessed 432 children and adolescents with acute lymphoblastic leukemia (ALL) after total body irradiation based myeloablative HSCT within the multicenter ALL-BFM-SCT 2003 trial for SI grade 3 or higher according to common terminology criteria for adverse events. A total 172 patients experienced at least one SI. Transplantation from matched unrelated donors (MUD) was associated with any type of SI in the pre-engraftment period (hazard ratio [HR]: 2.57; P < .001), and with any SI between day +30 and + 100 (HR: 2.91; P = .011). Bacterial (HR: 2.24; P = .041) and fungal infections (HR: 4.06; P = .057) occurred more often in the pre-engraftment phase and viral infections more often before day +30 (HR: 2.66; P = .007) or between day +30 and + 100 (HR: 3.89; P = .002) after HSCT from MUD as compared to matched sibling donors. Chronic GvHD was an independent risk factor for any type of SI after day +100 (HR: 2.57; P < .002). We conclude that allogeneic HSCT from MUD in children and adolescents with pediatric ALL is associated with higher infection rates, which seems attributable to an intensified GvHD prophylaxis including serotherapy and methotrexate.

8.
Fam Cancer ; 18(3): 353-358, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30680470

RESUMO

Medulloblastoma is the most frequent malignant brain tumor in childhood. This highly malignant neoplasm occurs usually before 10 years of age and more frequently in boys. The 5-year event-free survival rate for high-risk medulloblastoma is low at 62% despite a multimodal therapy including surgical resection, radiation therapy and chemotherapy. We report the case of a boy, who was born to consanguineous parents. Prominently, he had multiple café-au-lait spots. At the age of 3 years he was diagnosed with a high-risk metastatic medulloblastoma. The patient died only 11 months after diagnosis of a fulminant relapse presenting as meningeal and spinal dissemination. Whole-exome sequencing of germline DNA was employed to detect the underlying mutation for this putative cancer syndrome presenting with the combination of medulloblastoma and skin alterations. After screening all possible homozygous gene SNVs, we identified a mutation of SON, an essential protein in cell cycle regulation and cell proliferation, as the most likely genetic cause.


Assuntos
Manchas Café com Leite/genética , Neoplasias Cerebelares/genética , Proteínas de Ligação a DNA/genética , Meduloblastoma/genética , Antígenos de Histocompatibilidade Menor/genética , Pré-Escolar , Consanguinidade , Evolução Fatal , Humanos , Masculino , Linhagem , Mutação Puntual , Síndrome
10.
Trends Cancer ; 4(11): 718-728, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30352675

RESUMO

Inherited diseases are not always expressed in the same way in every individual that carries the same variant in a disease-causing gene. This phenomenon is known as reduced or incomplete penetrance. Variable and incomplete penetrance may explain why inherited diseases are occasionally transmitted through unaffected parents, but also why clinically healthy individuals can carry potentially pathogenic variants without expressing features of the disease. Here, we will provide an overview of factors that play a fundamental role in the concept of penetrance and expressivity of cancer predisposing genes in children with malignancies. These findings are important to understand the complexity of inherited diseases and cancer development and to improve genetic counselling for the affected families.

11.
Oncogene ; 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30305723

RESUMO

The discovery of cancer-predisposing syndromes (CPSs) using next-generation sequencing (NGS) technologies is of increasing importance in pediatric oncology with regard to diagnosis, treatment, surveillance, family counselling and research. Recent studies indicate that a considerable percentage of childhood cancers are associated with CPSs. However, the ratio of CPSs that are caused by inherited vs. de novo mutations (DNMs), the risk of recurrence, and even the total number of genes, which should be considered as a true cancer-predisposing gene, are still unknown. In contrast to sequencing only single index patients, family-based NGS of the germline is a very powerful tool for providing unique insights into inheritance patterns (e.g., DNMs, parental mosaicism) and types of aberrations (e.g., SNV, CNV, indels, SV). Furthermore, functional perturbations of key cancer pathways (e.g., TP53, FA/BRCA) by at least two co-inherited heterozygous digenic mutations from each parent and currently unrecognized rare variants and unmeasured genetic interactions between common and rare variants may be a widespread genetic phenomenon in the germline of affected children. Therefore, family-based trio sequencing has the potential to reveal a striking new landscape of inheritance in childhood cancer and to facilitate the integration and efforts of individualized treatment strategies, including personalized and preventive medicine and cancer surveillance programs. Consequently, cancer genetics is becoming an increasingly common approach in modern oncology, so trio-sequencing should also be routinely integrated into pediatric oncology.

12.
Orphanet J Rare Dis ; 13(1): 112, 2018 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-29986738

RESUMO

BACKGROUND: Our objective was to evaluate children with metabolic diseases in paediatric palliative home care (PPC) and the process of decision-making. This study was conducted as single-centre retrospective cohort study of patients in the care of a large specialized PPC team. RESULTS: Between 01/2013 and 09/2016, 198 children, adolescents and young adults were in the care of our PPC team. Twenty-nine (14.6%) of these patients had metabolic conditions. Median age at referral was 2.6 years (0-24), median duration of care 352 days (3-2248) and median number of home visits 13 (1-80). Most patients are still alive (16; 55.2%). Median number of drugs administered was 5 (range 0-12), antiepileptics were given most frequently. Symptom burden was high in all children with metabolic disorders at referral and remained high throughout care. Predominant symptoms were gastrointestinal, respiratory and neurologic symptoms. Children with metabolic conditions, who were referred to PPC younger than 1 year of age had a shorter period of care and died earlier compared to those children, who were referred to PPC later in their lives (older than 10 years of age). Eleven (37.9%) of the children initially had no resuscitation restrictions and 7 (53.8%) of those who died, did so on ICU. CONCLUSIONS: About 15% of children with life-limiting conditions in PPC present with metabolic diseases. Symptom burden is high with neurologic, respiratory and gastrointestinal symptoms being the most frequent and most of those being difficult to treat. In these children, particular attention needs to be addressed to advance care planning.

13.
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.

15.
Oncotarget ; 9(25): 17867-17875, 2018 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-29707152

RESUMO

Pediatric advance care planning seeks to ensure end-of-life care conforming to the patients/their families' preferences. To expand our knowledge of advance care planning and "medical orders for life-sustaining treatment" (MOLST) in pediatric palliative home care, we determined the number of patients with MOLST, compared MOLST between the four "Together for Short Lives" (TfSL) groups and analyzed, whether there was a relationship between the content of the MOLST and the patients' places of death. The study was conducted as a single-center retrospective analysis of all patients of a large specialized pediatric palliative home care team (01/2013-09/2016). MOLST were available in 179/198 children (90.4%). Most parents decided fast on MOLST, 99 (55.3%) at initiation of pediatric palliative home care, 150 (83.4%) within the first 100 days. MOLST were only changed in 7.8%. Eighty/179 (44.7%) patients decided on a Do Not Attempt Cardio-Pulmonary Resuscitation (DNACPR) order, 58 (32.4%) on treatment limitations of some kind and 41 (22.9%) wished for the entire spectrum of life-sustaining measures (Full Code). Most TfSL group 1 families wanted DNACPR and most TfSL group 3/4 parents Full Code. The majority (84.9%) of all DNACPR patients died at home/hospice. Conversely, all Full Code patients died in hospital (80% in an intensive care setting). The circumstances of the childrens' deaths can therefore be predicted considering the content of the MOLST. Regular advance care planning discussions are thus a very important aspect of pediatric palliative home care.

16.
Leuk Lymphoma ; : 1-7, 2018 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-29718744

RESUMO

Osteonecrosis (ON) is a common and debilitating side effect of anti-leukemic treatment in children with acute lymphoblastic leukemia (ALL). However, the impact of leukemia itself on ON development remains elusive. We analyzed 76 children enrolled in the ongoing OPAL trial, who had magnetic resonance imaging (MRI) studies at diagnosis. MRI screening revealed 14 osteonecrotic lesions (5 × hips, 9 × knees) of any grade (I-III) in 7 (9.2%) patients. Six months on, the number of ON per patient increased (1 patient), remained constant (2), and decreased (2). The severity increased from grade I to II in two patients, remained constant (1), completely resolved (2), and decreased from grade III to osteoedema (1). No differences between adolescents initially presenting with/without ON were observed concerning age, pubertal stage, body mass index, leukemia characteristics, and clinical presentation. In MRI screening, a remarkable number of adolescents with ALL present with ON at diagnosis. The course of these ON remains highly unpredictable.

17.
Nature ; 555(7696): 321-327, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29489754

RESUMO

Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.


Assuntos
Genoma Humano/genética , Genômica , Mutação/genética , Neoplasias/classificação , Neoplasias/genética , Adolescente , Adulto , Criança , Cromotripsia , Estudos de Coortes , Variações do Número de Cópias de DNA/genética , Diploide , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa/genética , Humanos , Terapia de Alvo Molecular , Taxa de Mutação , Neoplasias/tratamento farmacológico , Proteína Supressora de Tumor p53/genética , Adulto Jovem
18.
BMC Infect Dis ; 18(1): 105, 2018 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-29506484

RESUMO

BACKGROUND: Mycobacterium tuberculosis (M. tuberculosis) disease is a generally well-known problem among immunocompromised adults and children. In pediatric oncology, only few cases of M. tuberculosis disease are reported so far. CASE PRESENTATION: We report a case of concomitant lymphnode tuberculosis in a 4-year-old German boy with relapsed ganglioneuroblastoma. 18 months after the initial diagnosis, relapse with new paravertebral lesions and new lesions in the left lower lobe of the lung and in the perihilar lymphnodes suspicious of metastases of the ganglioneuroblastoma were detected. While relapse in the tumor was confirmed, unexpectedly, pathologic examination revealed morphological diagnosis of lymphnode tuberculosis. The boy was of German background without previous history of tuberculosis exposure. Both, antituberculostatic and relapse treatment were immediately initiated. Three months on, MRI revealed regressive findings in the lung and lymphnodes and partial response in the tumor. The patient underwent second MiBG therapy and haploidentical stem cell transplantation. CONCLUSION: The diagnosis of lymphnode tuberculosis in a 4-year-old German boy with relapsed ganglioneuroblastoma was only made by chance, but most likely saved his life. Pediatric oncologist should be aware of tuberculosis as the incidence might increase over time and the timely diagnosis of a potentially preventable M. tuberculosis disease is irreplaceable. Further studies are needed to explore the incidence of M. tuberculosis infections and the value of IGRA, testing for latent tuberculosis infection prior to chemotherapy in children with underlying malignancies.


Assuntos
Ganglioneuroblastoma/diagnóstico , Tuberculose dos Linfonodos/diagnóstico , Antituberculosos/farmacologia , Pré-Escolar , Ganglioneuroblastoma/complicações , Humanos , Hospedeiro Imunocomprometido , Interferon gama/metabolismo , Pulmão/diagnóstico por imagem , Linfonodos/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Mycobacterium tuberculosis/isolamento & purificação , Recidiva Local de Neoplasia , Tuberculose dos Linfonodos/complicações , Tuberculose dos Linfonodos/tratamento farmacológico , Tuberculose dos Linfonodos/microbiologia
20.
Eur J Hum Genet ; 26(3): 440-444, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29302048

RESUMO

Constitutional mismatch repair deficiency (CMMRD) is an autosomal recessively inherited childhood cancer susceptibility syndrome caused by biallelic germline mutations in one of the mismatch repair (MMR) genes. The spectrum of CMMRD-associated tumours is very broad and many CMMRD patients additionally display signposting non-neoplastic features, most frequently café-au-lait macules and other pigmentation alterations. We report on a 13-month-old girl suspected of having CMMRD due to a desmoplastic medulloblastoma and a striking skin pigmentation that included multiple café-au-lait macules, hypopigmented areas and Mongolian spots. Whole-exome sequencing revealed homozygosity for MSH2 variant p.(Leu92Val) and MSH6 variant p.(Val809del), both variants of uncertain significance (VUS). Immunohistochemical analysis of the tumour tissue showed expression of all four MMR proteins and gMSI testing was negative. However, functional assays demonstrated that the cells of the patient displayed methylation tolerance and ex vivo microsatellite instability, which unequivocally confirmed the diagnosis of CMMRD. Taken together, the results render the MSH2 variant unlikely to be responsible for the phenotype, while they are compatible with MSH6-associated CMMRD. This case illustrates the diagnostic strategy of confirming CMMRD syndrome in patients with VUS.

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