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1.
Ann Oncol ; 29(10): 2068-2075, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30165392

RESUMO

Background: We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC). Patients and methods: ALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders. Results: Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4-5.6) versus 10.3 months (95% CI: 8.6-12.0), P < 0.001; OS 15.0 months (95% CI: 5.0-24.9) versus 50.0 months (95% CI: 22.9-77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3-4.1) versus 6.2 months (95% CI: 1.8-10.5), P = 0.021; OS 2.0 months (95% CI: 0.0-4.6) versus 9.0 months (95% CI: 6.1-11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9-7.2) versus 14.0 months (95% CI: 8.0-20.1), P < 0.001; OS 17.0 months (95% CI: 6.7-27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1-10.7) versus 9.9 months (95% CI: 6.4-13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001). Conclusions: In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.


Assuntos
Quinase do Linfoma Anaplásico/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Rearranjo Gênico , Neoplasias Pulmonares/mortalidade , Mutação , Proteína Supressora de Tumor p53/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Adenoescamoso/tratamento farmacológico , Carcinoma Adenoescamoso/genética , Carcinoma Adenoescamoso/mortalidade , Carcinoma Adenoescamoso/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Adulto Jovem
2.
BMC Gastroenterol ; 18(1): 75, 2018 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-29855275

RESUMO

BACKGROUND: Adenocarcinomas or combined adeno-neuroendocrine carcinomas (MANEC) of small bowel usually have a dismal prognosis with limited systemic therapy options. This is the first description of a patient showing a germline-related BRCA1 mutated MANEC of his ileum. The tumor presented a susceptibility to a combined chemotherapy and the PARP1-inhibitor olaparib. CASE PRESENTATION: A 74-year old male patient presented with a metastasized MANEC of his ileum. Due to clinical symptoms his ileum-tumor and the single brain metastasis were removed. We verified the same pathogenic (class 5) BRCA1 mutation in different tumor locations. There was no known personal history of a previous malignant tumor. Nevertheless we identified his BRCA1 mutation as germline-related. A systemic treatment was started including Gemcitabine followed by selective internal radiotherapy (SIRT) to treat liver metastases and in the further course Capecitabine but this treatment finally failed after 9 months and all liver metastases showed progression. The treatment failure was the reason to induce an individualized therapeutic approach using combined chemotherapy of carboplatin, paclitaxel and the Poly (ADP-ribose) polymerase- (PARP)-inhibitor olaparib analogous to the treatment protocol of Oza et al. All liver metastases demonstrated with significant tumor regression after 3 months and could be removed. In his most current follow up from December 2017 (25 months after his primary diagnosis) the patient is in a very good general condition without evidence for further metastases. CONCLUSION: We present first evidence of a therapy susceptible germline-related BRCA1 mutation in small bowel adeno-neuroendocrine carcinoma (MANEC). Our findings offer a personalized treatment option. The germline background was unexpected in a 74-year old man with no previously known tumor burden. We should be aware of the familiar background in tumors of older patients as well.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína BRCA1/genética , Carcinoma Neuroendócrino/tratamento farmacológico , Mutação em Linhagem Germinativa , Neoplasias do Íleo/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/secundário , Idoso , Neoplasias Encefálicas/secundário , Carboplatina/uso terapêutico , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/secundário , Humanos , Neoplasias do Íleo/genética , Neoplasias do Íleo/patologia , Neoplasias Hepáticas/secundário , Masculino , Paclitaxel/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
3.
Pathologe ; 38(2): 117-126, 2017 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-28258387

RESUMO

Approximately 9000 women are diagnosed with ovarian cancer in Germany each year. The most common subtype is high-grade serous ovarian cancer. A relevant proportion of these tumors are associated with mutations in the breast and ovarian cancer susceptibility genes (BRCA1 and BRCA2) representing highly penetrant tumor suppressor genes with autosomal inheritance and play a crucial role in DNA repair mechanisms. These patients have predominantly germline mutations and less frequently have somatic BRCA mutations. Tumors harboring BRCA mutations show a significant improvement in progression-free survival under therapy with poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors. In 2015 the first PARP inhibitor was approved for the therapy of high-grade serous ovarian cancer with BRCA mutations. Mutation analysis can be performed on formalin-fixed paraffin-embedded (FFPE) tumor tissue within a few days.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Feminino , Mutação em Linhagem Germinativa , Alemanha , Humanos , Mutação , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
4.
Ann Oncol ; 27 Suppl 3: iii25-iii34, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27573753

RESUMO

Comprehensive molecular genotyping of lung cancers has become a key requirement for guiding therapeutic decisions. As a paradigm model of implementing next-generation comprehensive diagnostics, Network Genomic Medicine (NGM) has established central diagnostic and clinical trial platforms for centralised testing and decentralised personalised treatment in clinical practice. Here, we describe the structures of the NGM network and give a summary of technologies to identify patients with anaplastic lymphoma kinase (ALK) fusion-positive lung adenocarcinomas. As unifying test platforms will become increasingly important for delivering reliable, quick and affordable tests, the NGM diagnostic platform is currently implementing a comprehensive hybrid capture-based parallel sequencing pan-cancer assay.


Assuntos
Adenocarcinoma/enzimologia , Neoplasias Pulmonares/enzimologia , Medicina de Precisão , Receptores Proteína Tirosina Quinases/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Adenocarcinoma de Pulmão , Quinase do Linfoma Anaplásico , Animais , Rearranjo Gênico , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Proteínas de Fusão Oncogênica/genética
5.
Artigo em Alemão | MEDLINE | ID: mdl-24170079

RESUMO

The advent of genomic medicine and sequencing analysis of entire cancer genomes has rapidly improved our understanding of cancer genomics and has defined pathogenetic lesions initiating and driving cancer phenotypes in a causative manner. Moreover rapid development of small molecule inhibitors and highly selective biologicals provided effective tools to intervene with oncogenic signalling resulting from such lesions in the cancer genome. Thereby, the pathologist is now in the position to diagnose causative lesions in the cancer genome as molecular biomarkers directing the selection of patients for effective and highly selective therapies. If oncogenic driver lesions are vigorously validated preclinically and a useful diagnostic test is available, it is possible to provide a proof-of-concept at a very early stage of clinical drug development with the possibility of immediate personal benefit for participants in such phase I/II studies. This approach has significantly changed clinical testing and avoids testing proof for efficacy in large stage III clinical trials at a high failure rate. Therefore, our review summarises recent and paradigmatic progress in lung cancer biomarker diagnostics and defines academic and regulatory requirements for biomarker analysis and selective personalised therapies.


Assuntos
Biomarcadores Tumorais/genética , Marcadores Genéticos/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Terapia de Alvo Molecular/métodos , Patologia Molecular/métodos , Farmacogenética/métodos , Predisposição Genética para Doença/genética , Humanos , Neoplasias Pulmonares/diagnóstico
7.
Mol Biol Cell ; 5(7): 763-72, 1994 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-7812045

RESUMO

Lymphoblasts of the normal embryonic follicles of the chicken bursa of Fabricius undergo rapid apoptosis when exposed to gamma-radiation or when cell-cell contacts are disrupted by mechanical dispersion in short term culture. We have observed previously that overexpression of v-myc sensitizes preneoplastic bursal lymphoblasts to induction of cell death, whereas resistance to induced cell death is acquired during progression to neoplasia. In this study we observed extensive DNA degradation in the large majority of the lymphoblast population within the first hour after dispersion-induced apoptosis. Paradoxically these cells continued to progress into S-phase with the bulk of DNA cleavage and death occurring in S-phase cells (i.e., in cells with more than 2C and less than 4C DNA content). We confirmed the S phase status of apoptotic cells by determining that detection of nuclear cyclin A in individual cells also corresponded with detection of DNA breakage. Levels of cyclin E, cyclin E-dependent H1 histone kinase, and p53 proteins were maintained during dispersion-induced DNA cleavage. gamma-radiation failed either to inhibit cell cycle progression or to raise p53 levels in dispersed bursal lymphoblasts. In intact bursal follicles low doses of gamma-radiation induced p53 whereas higher, apoptosis-inducing doses failed to induce p53 or prevent G1 to S-phase progression. These results suggest that normal DNA damage-induced cell cycle checkpoint controls are lost or overridden when apoptosis is induced in bursal lymphoblasts.


Assuntos
Apoptose , Bolsa de Fabricius/citologia , Ciclo Celular/fisiologia , Quinases Ciclina-Dependentes/análise , Ciclinas/análise , Dano ao DNA , Linfócitos/citologia , Proteína Supressora de Tumor p53/análise , Animais , Bolsa de Fabricius/efeitos da radiação , Ciclo Celular/efeitos da radiação , Células Cultivadas , Embrião de Galinha , Replicação do DNA , Raios gama , Linfócitos/efeitos da radiação , Fase S , Organismos Livres de Patógenos Específicos
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