Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 175
Filtrar
1.
ESMO Open ; 4(4): e000538, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31423337

RESUMO

Background: High-throughput genomic profiling of tumour specimens facilitates the identification of individual actionable mutations which could be used for individualised targeted therapy. This approach is becoming increasingly more common in the clinic; however, the interpretation of results from molecular profiling tests and efficient guiding of molecular therapies to patients with advanced cancer offer a significant challenge to the oncology community. Experimental design: MONDTI is a precision medicine platform for molecular characterisation of metastatic solid tumours to identify actionable genomic alterations. From 2013 to 2016, comprehensive molecular profiles derived from real-time biopsy specimens and archived tumour tissue samples of 295 patients were performed. Results and treatment suggestions were discussed within multidisciplinary tumour board meetings. Results: The mutational profile was obtained from 293 (99%) patients and a complete immunohistochemical (IHC) and cytogenetic profile was obtained in 181 (61%) and 188 (64%) patients. The most frequent cancer types were colorectal cancer (12%), non-Hodgkin's lymphomas (9.8%) and head and neck cancers (7.8%). The most commonly detected mutations were TP53 (39%), KRAS (19%) and PIK3CA (9.5%), whereas ≥1 mutation were identified in 217 (74%) samples. Regarding the results for IHC testing, samples were positive for phospho-mammalian target of rapamycin (phospho-mTOR) (71%), epidermal growth factor receptor (EGFR) (68%), mesenchymal epithelial transition (MET) (56%) and/or platelet-derived growth factor alpha (PDGFRα)-expression (48%). Of the 288 tumour samples with one or more genetic alteration detected, 160 (55.6%) targeted therapy recommendations through 67 multidisciplinary tumour board meetings were made; in 69 (24%) cases, an individual treatment concept was initiated. Conclusions: The results reveal that the open concept for all solid tumours characterised for molecular profile and immunotherapy could not only match individualised treatment concepts at a high rate but also underscores the challenges encountered when offering molecularly matched therapies to a patient population with an advanced stage cancer.

2.
ESMO Open ; 4(3): e000498, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31297240

RESUMO

The introduction of targeted treatments and more recently immune checkpoint inhibitors (ICI) to the treatment of metastatic non-small cell lung cancer (NSCLC) has dramatically changed the prognosis of selected patients. For patients with oncogene-addicted metastatic NSCLC harbouring an epidermal growth factor receptor (EGFR) or v-Raf murine sarcoma viral oncogene homologue B1 (BRAF) mutation or an anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) gene alteration (translocation, fusion, amplification) mutation-specific tyrosine kinase inhibitors (TKI) are already first-line standard treatment, while targeted treatment for other driver mutations affecting MET, RET, human epidermal growth factor receptor (HER) 2, tropomyosin receptor kinases (TRK) 1-3 and others are currently under investigation. The role of ICI in these patient subgroups is currently under debate. This article summarises a round-table discussion organised by ESMO Open in Vienna in July 2018. It reviews current clinical data on ICI treatment in patients with metastatic oncogene-addicted NSCLC and discusses molecular diagnostic assessment, potential biomarkers and radiological methods for response evaluation of ICI treatment. The round-table panel concluded ICI should only be considered in patients with oncogene-addicted NSCLC after exhaustion of effective targeted therapies and in some cases possibly after all other therapies including chemotherapies. More clinical trials on combination therapies and biomarkers for ICI therapy based on the specific differing characteristics of oncogene-addicted NSCLC need to be conducted.

3.
Res Pract Thromb Haemost ; 3(3): 503-514, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31294335

RESUMO

Background: Cancer-associated venous thromboembolism (VTE) is an important complication in the course of a malignant disease. Low ADAMTS-13 (a disintegrin-like and metalloproteinase with thrombospondin type 1 motif 13) and increased von Willebrand Factor (VWF) levels in cancer patients have been described numerously. Objectives: Investigation of the influence of ADAMTS-13 and VWF on the probability of VTE and survival in malignancy. Patients/Methods: In the framework of the ongoing prospective Cancer and Thrombosis Study (CATS) ADAMTS-13 activity and VWF antigen levels were investigated in cancer patients. Results: In total, 795 patients with various tumor types (364 female/431 male, median age 62 years) were included; of those, 56 developed VTE and 359 patients died during a median follow-up time of 730 days. The hazard ratio (HR) of VTE per doubling of VWF level was 1.56 (95% confidence interval [CI] 1.13-2.16) in multivariable competing risk analysis. ADAMTS-13 levels showed no correlation with the incidence of VTE in univariate competing risk analysis. The HR of mortality per doubling of VWF level was 1.46 (95% CI 1.28-1.66) and per SD increment of ADAMTS-13was 0.90 (95% CI 0.81-1.00) in multivariable Cox regression analysis. Patients with VWF >75th percentile and concomitant low (<25th percentile) or medium (25-75th percentile) ADAMTS-13 values had the highest probability of mortality (HR 4.31 and 4.75, respectively). Conclusions: High VWF levels were significantly associated with the risk of developing VTE in cancer patients, whereas ADAMTS-13 was not. Low ADAMTS-13 and increased VWF levels were independently associated with worse overall survival.

5.
ESMO Open ; 4(Suppl 2): e000514, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31231575
6.
Clin Cancer Res ; 25(9): 2737-2744, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30647078

RESUMO

PURPOSE: Brain metastases (BMs) are a rare but devastating condition in estrogen receptor (ER)-positive metastatic breast cancer (MBC). Although endocrine therapy (ET) is the mainstay of treatment in this disease subtype, only case reports have been published concerning the activity of ET in BMs henceforth. Therefore, we aimed to systematically investigate the impact of ET after diagnosis of BM on outcome and clinical course of disease in patients with ER-positive MBC. EXPERIMENTAL DESIGN: Patient characteristics, detailed information about BMs including diagnosis-specific graded prognostic assessment class (DS-GPA), and clinical outcome were obtained by retrospective chart review for all patients treated for ER-positive breast cancer BMs between 1990 and 2017 at an academic care center. Overall survival (OS) was measured as the interval from diagnosis of BM until death or last date of follow-up. RESULTS: Overall, 198 patients [female: 195/198 (98.5%); male: 3/198 (1.5%)] with ER-positive breast cancer BMs were available for this analysis. Eighty-eight of 198 patients (44.4%) received ET after diagnosis of BM including aromatase inhibitors (AIs; letrozole, anastrozole, exemestane), tamoxifen, and fulvestrant. Median OS was significantly longer in patients receiving ET after diagnosis of BM compared with patients who did not (15 vs. 4 months, P < 0.001; log-rank test). No significant difference in terms of OS was observed between patients receiving AIs, tamoxifen, or fulvestrant. In patients with concomitant leptomeningeal carcinomatosis (LC), ET prolonged median OS significantly as well (7 vs. 3 months, P = 0.012; log-rank test). In a multivariate analysis including DS-GPA and ET, only treatment with ET after diagnosis of BM (HR, 0.69; 95% confidence interval, 0.48-0.99; P = 0.046) was associated with prognosis (Cox regression model). CONCLUSIONS: Continuing ET after BM diagnosis was associated with a significantly prolonged OS in this large single-center cohort. No substantial differences between substances were observed. These findings should be validated in a prospective cohort.

7.
ESMO Open ; 3(5): e000368, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30167331

RESUMO

This article is the result of a round-table discussion organised by ESMO Open in Vienna in December 2017. Its purpose is to discuss the background and advances in the evidence regarding cyclin-dependent kinase 4/6 inhibitors (palbociclib, ribociclib and abemaciclib) in the treatment of metastatic and early-stage breast cancer and to explore what the key open research questions are and next steps should be.

8.
Oncotarget ; 9(41): 26491-26506, 2018 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-29899872

RESUMO

In recent years, numerous new targeted drugs, including multi-kinase inhibitors and epigenetic modulators have been developed for cancer treatment. Ponatinib blocks a variety of tyrosine kinases including ABL and fibroblast growth factor receptor (FGFR), and the BET bromodomain (BRD) antagonists JQ1 and dBET1 impede MYC oncogene expression. Both drugs have demonstrated substantial anti-cancer efficacy against several hematological malignancies. Solid tumors, on the other hand, although frequently driven by FGFR and/or MYC, are often unresponsive to these drugs. This is due, at least in part, to compensatory feedback-loops in the kinome and transcription network of these tumors, which are activated in response to drug exposure. Therefore, we hypothesized that the combination of the multi-kinase inhibitor ponatinib with transcription modulators such as JQ1 or dBET1 might overcome this therapeutic recalcitrance. Using 3H-thymidine uptake, cell cycle analysis, and caspase-3 or Annexin V labeling, we demonstrate that single drugs induce moderate dose-dependent growth-inhibition and/or apoptosis in colon (HCT116, HT29), breast (MCF-7, SKBR3) and ovarian (A2780, SKOV3) cancer cells. Ponatinib elicited primarily apoptosis, while JQ1 and dBET1 caused G0/G1 cell cycle arrest and very mild cell death. Phospho-FGFR and MYC, major targets of ponatinib and BET inhibitors, were downregulated after treatment with single drugs. Remarkably, ponatinib was found to sensitize cells to BET antagonists by enhancing apoptotic cell death, and this effect was associated with downregulation of MYC. In summary, our data shows that ponatinib sensitizes colon, breast, and ovarian cancer cells to BET bromodomain inhibitors. Further studies are warranted to determine the clinical value of this phenomenon.

9.
J Pathol ; 245(4): 387-398, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29570800

RESUMO

Deregulated DNA methylation leading to transcriptional inactivation of certain genes occurs frequently in non-small-cell lung cancers (NSCLCs). As well as protein-coding genes, microRNA (miRNA)-coding genes may be targets for methylation in NSCLCs; however, the number of known methylated miRNA genes is still small. Thus, we investigated methylation of miRNA genes in primary tumour (TU) samples and corresponding non-malignant lung tissue (NL) samples of 50 NSCLC patients by using methylated DNA immunoprecipitation followed by custom-designed tiling microarray analyses (MeDIP-chip), and 252 differentially methylated probes between TU samples and NL samples were identified. These probes were annotated, which resulted in the identification of 34 miRNA genes with increased methylation in TU samples. Some of these miRNA genes were already known to be methylated in NSCLCs (e.g. those encoding miR-9-3 and miR-124), but methylation of the vast majority of them was previously unknown. We selected six miRNA genes (those encoding miR-10b, miR-1179, miR-137, miR-572, miR-3150b, and miR-129-2) for gene-specific methylation analyses in TU samples and corresponding NL samples of 104 NSCLC patients, and observed a statistically significant increase in methylation of these genes in TU samples (p < 0.0001). In silico target prediction of the six miRNAs identified several oncogenic/cell proliferation-promoting factors (e.g. CCNE1 as an miR-1179 target). To investigate whether miR-1179 indeed targets CCNE1, we transfected miR-1179 gene mimics into CCNE1-expressing NSCLC cells, and observed downregulated CCNE1 mRNA expression in these cells as compared with control cells. Similar effects on cyclin E1 expression were seen in western blot analyses. In addition, we found a statistically significant reduction in the growth of NSCLC cells transfected with miR-1179 mimics as compared with control cells. In conclusion, we identified many methylated miRNA genes in NSCLC patients, and found that the miR-1179 gene is a potential tumour cell growth suppressor in NSCLCs. Overall, our findings emphasize the impact of miRNA gene methylation on the pathogenesis of NSCLCs. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Metilação de DNA , Neoplasias Pulmonares/genética , MicroRNAs/genética , Células A549 , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Proliferação de Células/genética , Imunoprecipitação da Cromatina/métodos , Ilhas de CpG , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Transdução de Sinais/genética
10.
ESMO Open ; 3(2): e000285, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29464109

RESUMO

The cancer burden is rising globally, exerting significant strain on populations and health systems at all income levels. In May 2017, world governments made a commitment to further invest in cancer control as a public health priority, passing the World Health Assembly Resolution 70.12 on cancer prevention and control within an integrated approach. In this manuscript, the 2016 European Society for Medical Oncology Leadership Generation Programme participants propose a strategic framework that is in line with the 2017 WHO Cancer Resolution and consistent with the principle of universal health coverage, which ensures access to optimal cancer care for all people because health is a basic human right. The time for action is now to reduce barriers and provide the highest possible quality cancer care to everyone regardless of circumstance, precondition or geographic location. The national actions and the policy recommendations in this paper set forth the vision of its authors for the future of global cancer control at the national level, where the WHO Cancer Resolution must be implemented if we are to reduce the cancer burden, avoid unnecessary suffering and save as many lives as possible.

12.
ESMO Open ; 2(4): e000216, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29067214

RESUMO

BACKGROUND: The European Society for Medical Oncology (ESMO) has developed the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS), a tool to assess the magnitude of clinical benefit from new cancer therapies. Grading is guided by a dual rule comparing the relative benefit (RB) and the absolute benefit (AB) achieved by the therapy to prespecified threshold values. The ESMO-MCBS v1.0 dual rule evaluates the RB of an experimental treatment based on the lower limit of the 95%CI (LL95%CI) for the hazard ratio (HR) along with an AB threshold. This dual rule addresses two goals: inclusiveness: not unfairly penalising experimental treatments from trials designed with adequate power targeting clinically meaningful relative benefit; and discernment: penalising trials designed to detect a small inconsequential benefit. METHODS: Based on 50 000 simulations of plausible trial scenarios, the sensitivity and specificity of the LL95%CI rule and the ESMO-MCBS dual rule, the robustness of their characteristics for reasonable power and range of targeted and true HRs, are examined. The per cent acceptance of maximal preliminary grade is compared with other dual rules based on point estimate (PE) thresholds for RB. RESULTS: For particularly small or particularly large studies, the observed benefit needs to be relatively big for the ESMO-MCBS dual rule to be satisfied and the maximal grade awarded. Compared with approaches that evaluate RB using the PE thresholds, simulations demonstrate that the MCBS approach better exhibits the desired behaviour achieving the goals of both inclusiveness and discernment. CONCLUSIONS: RB assessment using the LL95%CI for HR rather than a PE threshold has two advantages: it diminishes the probability of excluding big benefit positive studies from achieving due credit and, when combined with the AB assessment, it increases the probability of downgrading a trial with a statistically significant but clinically insignificant observed benefit.

13.
ESMO Open ; 2(3): e000166, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28761758

RESUMO

BACKGROUND: The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a new tool to quantify the clinical benefit that may be anticipated from a novel anticancer treatment. We present here an analysis on the feasibility of the ESMO-MCBS in less frequent tumour entities. METHODS: This study evaluates the practicability of the ESMO-MCBS for metastatic neuroendocrine tumours (NETs), soft tissue sarcomas, glioblastoma, thyroid cancer, pancreatic cancer, head/neck cancer, urothelial cancer and ovarian cancer at the Medical University Vienna. A three-step approach including data acquisition, assessment of ESMO-MCBS scores and evaluation of results with a focus on clinical feasibility was applied. RESULTS: In NET and thyroid cancer, all analysed trials were very comparable in design and efficacy, and the ESMO-MCBS scores appeared to be consistent with the clinical benefit seen in practice. For pancreatic cancer, it was more difficult to compare first-line trials due to diverging populations included in the respective studies. Concerning soft tissue sarcomas, the ESMO-MCBS was applicable for gastrointestinal stromal tumours(GIST) and 'non-GIST' soft tissue sarcoma with respect to data deriving from randomised studies. However, due to the heterogeneity of the disease itself and a limited number of controlled trials, limitations are noted. In ovarian cancer, the ESMO-MCBS supported the use of bevacizumab in high-risk patients. To date, there are only limited data for glioblastoma, head/neck cancer and urothelial cancer but whenever randomised trials were available, the ESMO-MCBS rating supported clinical decisions. Interestingly, nivolumab for salvage treatment of head/neck cancer rated extremely high. CONCLUSION: The ESMO-MCBS scores supported our common treatment strategies and highlight the potential of new immunomodulatory drugs. Our results encourage further development of the ESMO-MCBS.

14.
Sci Rep ; 7(1): 4851, 2017 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-28687745

RESUMO

Pancreatic cancer is a dismal disease with a mortality rate almost similar to its incidence rate. To date, there are neither validated predictive nor prognostic biomarkers for this lethal disease. Thus, the aim of the present study was to retrospectively investigate the capability of biochemical parameters and molecular profiles to predict survival of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who participated in a phase II clinical trial to test the safety and efficacy of the combination treatment of capecitabine plus nab-paclitaxel. Herein, we investigated the association of 18 biochemical parameters obtained from routine diagnosis and the clinical outcome of the 30 patients enrolled in the clinical trial. Furthermore, we analysed formalin-fixed paraffin-embedded (FFPE) tumour tissue to identify molecular biomarkers via RNA seq and the Illumina TruSeq Amplicon Cancer panel which covers 48 hotspot genes. Our analysis identified SERPINB7 as a novel transcript and a DNA mutation signature that might predict a poor outcome of disease. Moreover, we identified the bilirubin basal level as an independent predictive factor for overall survival in our study cohort.


Assuntos
Adenocarcinoma/diagnóstico , Adenocarcinoma/secundário , Albuminas/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Capecitabina/uso terapêutico , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/secundário , Paclitaxel/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Química do Sangue , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Ensaios Clínicos Fase II como Assunto , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas/patologia , Prognóstico , Estudos Retrospectivos , Análise de Sequência de RNA , Serpinas/análise , Serpinas/genética , Análise de Sobrevida , Resultado do Tratamento
15.
PLoS One ; 12(3): e0172911, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28253285

RESUMO

BACKGROUND: Even though trastuzumab is an effective therapy in early stage Her-2+ breast cancer, 40-50% of advanced Her-2+ breast cancer patients develop trastuzumab resistance. A potential resistance mechanism is aberrant downstream signal transmission due to loss of phosphatase and tensin homologue (PTEN). This study investigated the relationship between the expression of PTEN and trastuzumab response in Her-2 overexpressing metastatic breast cancer patients. METHODS: Between 2000 and 2007, 164 patients with Her-2+ metastatic breast cancer received trastuzumab-based therapy in our institution. We analyzed PTEN status by immunohistochemistry of 115 available tumor tissues and analyzed associations with other histopathological parameters, response rate, progression free survival (PFS) and overall survival (OS) with a median follow-up of 60 months. RESULTS: Eighty patients were PTEN positive (69.6%) and 35 patients PTEN negative (30.4%). We found a significant association of the expression of PTEN and p53 (p = 0.041), while there was no association with grading, hormone receptor status, IGFR or MIB. We found significantly more cases with progressive disease under trastuzumab-based therapy in patients with PTEN positive breast cancers (p = 0.018), while there was no significant correlation with PFS or OS. CONCLUSION: In Her-2-positive metastatic breast cancers, PTEN positivity was significantly associated with progressive disease, but not with PFS or OS.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , PTEN Fosfo-Hidrolase/metabolismo , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Adulto Jovem
16.
Eur Radiol ; 27(8): 3167-3173, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28050694

RESUMO

OBJECTIVES: To evaluate the prognostic relevance of temporal muscle thickness (TMT) in brain metastasis patients. METHODS: We retrospectively analysed TMT on magnetic resonance (MR) images at diagnosis of brain metastasis in two independent cohorts of 188 breast cancer (BC) and 247 non-small cell lung cancer (NSCLC) patients (overall: 435 patients). RESULTS: Survival analysis using a Cox regression model showed a reduced risk of death by 19% with every additional millimetre of baseline TMT in the BC cohort and by 24% in the NSCLC cohort. Multivariate analysis included TMT and diagnosis-specific graded prognostic assessment (DS-GPA) as covariates in the BC cohort (TMT: HR 0.791/CI [0.703-0.889]/p < 0.001; DS-GPA: HR 1.433/CI [1.160-1.771]/p = 0.001), and TMT, gender and DS-GPA in the NSCLC cohort (TMT: HR 0.710/CI [0.646-0.780]/p < 0.001; gender: HR 0.516/CI [0.387-0.687]/p < 0.001; DS-GPA: HR 1.205/CI [1.018-1.426]/p = 0.030). CONCLUSION: TMT is easily and reproducibly assessable on routine MR images and is an independent predictor of survival in patients with newly diagnosed brain metastasis from BC and NSCLC. TMT may help to better define frail patient populations and thus facilitate patient selection for therapeutic measures or clinical trials. Further prospective studies are needed to correlate TMT with other clinical frailty parameters of patients. KEY POINTS: • TMT has an independent prognostic relevance in brain metastasis patients. • It is an easily and reproducibly parameter assessable on routine cranial MRI. • This parameter may aid in patient selection and stratification in clinical trials. • TMT may serve as surrogate marker for sarcopenia.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Músculo Temporal/patologia , Adulto , Idoso , Encéfalo/patologia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Músculo Temporal/diagnóstico por imagem
17.
Neuro Oncol ; 19(9): 1255-1262, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28096493

RESUMO

Background: We aimed to investigate the potential of standard hematologic and serum biochemical parameters to provide an independent and substantial contribution to the prediction of survival in patients with newly diagnosed brain metastases (BM). Methods: Hemoglobin, white blood cell count, platelet count, serum albumin, creatinine, lactate dehydrogenase (LDH), and C-reactive protein (CRP) were assessed at diagnosis of BM in a discovery cohort of 1200 cancer patients. A multivariable Cox regression model was used to derive the LabBM score. The LabBM score was externally validated in an independent cohort consisting of 366 patients. Results: Hemoglobin below lower limit of normal (ULN; HR: 1.51; P < .001), and CRP >ULN (HR: 1.52; P < .001) were associated with survival in a multivariable Cox regression model and were included in the calculation of the LabBM score. Multivariable analysis including the LabBM score and graded prognostic assessment class revealed an independent and significant association of the LabBM score with overall survival (OS) (HR: 1.42; 95% CI: 1.29-1.57; P < .001). The strong and independent association of LabBM score (HR: 1.93; 95% CI: 1.54-2.42) with OS prognosis was confirmed in the validation cohort. Conclusion: Standard clinical blood parameters, combined in the easy-to-calculate LabBM score, provide strong and independent prognostic information in patients with BM. The LabBM score is an objective, inexpensive, and reproducible tool to plan clinical management strategies in BM patients and to improve patient selection and stratification for clinical trials.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/mortalidade , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Adulto Jovem
18.
Mol Cancer ; 16(1): 1, 2017 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-28093071

RESUMO

BACKGROUND: DNA methylation regulates together with other epigenetic mechanisms the transcriptional activity of genes and is involved in the pathogenesis of malignant diseases including lung cancer. In non-small cell lung cancer (NSCLC) various tumor suppressor genes are already known to be tumor-specifically methylated. However, from the vast majority of a large number of genes which were identified to be tumor-specifically methylated, tumor-specific methylation was unknown so far. Thus, the major aim of this study was to investigate in detail the mechanism(s) responsible for transcriptional regulation of the genes SPAG6 and L1TD1 in NSCLCs. METHODS: We analysed publically available RNA-sequencing data and performed gene expression analyses by RT-PCR. DNA methylation analyses were done by methylation-sensitive high-resolution melt analyses and bisulfite genomic sequencing. We additionally investigated protein expression using immunohistochemistry. Cell culture experiments included tumor cell growth, proliferation, viability as well as colony formation assays. Moreover, we performed xenograft experiments using immunodeficient mice. RESULTS: We observed frequent downregulation of SPAG6 and L1TD1 mRNA expression in primary tumor (TU) samples compared to corresponding non-malignant lung tissue (NL) samples of NSCLC patients. We furthermore observed re-expression of both genes after treatment with epigenetically active drugs in most NSCLC cell lines with downregulated SPAG6 and L1TD1 mRNA expression. Frequent tumor-specific DNA methylation of SPAG6 and L1TD1 was detected when we analysed TU and corresponding NL samples of NSCLC patients. ROC curve analyses demonstrated that methylation of both genes is able to distinguish between TU and NL samples of these patients. Immunohistochemistry revealed a close association between SPAG6/L1TD1 methylation and downregulated protein expression of these genes. Moreover, by performing functional assays we observed reduced cell growth, proliferation and viability of pCMV6-L1TD1 transfected NSCLC cells. In addition, reduced volumes of tumors derived from pCMV6-L1TD1 compared to pCMV6-ENTRY transfected NCI-H1975 cells were seen in a xenograft tumor model. CONCLUSIONS: Overall, our results demonstrate that SPAG6 and L1TD1 are tumor-specifically methylated in NSCLCs and that DNA methylation is involved in the transcriptional regulation of these genes. Moreover, in vitro as well as in vivo experiments revealed tumor-cell growth suppressing properties of L1TD1 in NSCLC cells.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Proteínas dos Microtúbulos/genética , Proteínas/genética , Transcrição Genética , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/genética , Bases de Dados Genéticas , Modelos Animais de Doenças , Inativação Gênica , Xenoenxertos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Proteínas dos Microtúbulos/metabolismo , Polimorfismo de Nucleotídeo Único , Proteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Deleção de Sequência , Carga Tumoral , Ensaio Tumoral de Célula-Tronco
19.
J Thorac Oncol ; 12(4): 752-762, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28017787

RESUMO

INTRODUCTION: Docetaxel and erlotinib are registered second-line treatments for wild-type EGFR NSCLC. Previous studies suggested a predictive value of the VeriStrat test in second-line therapy of NSCLC, classifying patients as either VeriStrat good or VeriStrat poor. EMPHASIS-lung aimed at exploring this predictive effect in patients with squamous cell NSCLC. The trial closed prematurely because of low accrual and results from other trials. Our analysis includes an exploratory combined analysis with results from the PROSE trial. METHODS: EMPHASIS-lung was a randomized phase III multicenter trial exploring the differential effect of second-line erlotinib versus docetaxel on progression-free survival (PFS) in VeriStrat good versus VeriStrat poor patients with squamous cell NSCLC. RESULTS: A total of 80 patients were randomized, with 72.5% categorized as VeriStrat good. Patient characteristics were balanced between VeriStrat status and treatment groups. The median PFS times with docetaxel and erlotinib treatment in the VeriStrat good cohort were 4.1 and 1.6 months, respectively, versus 1.9 and 2.1 months, respectively, in the VeriStrat poor cohort. The median overall survival (OS) times with docetaxel and erlotinib treatment in the VeriStrat good cohort were 7.8 and 8.4 months, respectively, and 4.4 and 5.2 months, respectively, in the VeriStrat poor cohort. An additional exploratory analysis was performed; in it, 47 patients from the squamous cell subgroup of PROSE were included in a combined analysis, contributing with 45 PFS and 41 OS events. CONCLUSIONS: The final analysis of EMPHASIS-lung did not show a differential effect on PFS for erlotinib versus docetaxel stratified by VeriStrat status. Similarly, in the combined analysis, no significant treatment by VeriStrat status interaction was observed (interaction p = 0.24 for PFS and 0.45 for OS, stratified by study).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Estudos de Coortes , Docetaxel , Cloridrato de Erlotinib/administração & dosagem , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Estadiamento de Neoplasias , Platina/administração & dosagem , Prognóstico , Taxa de Sobrevida , Taxoides/administração & dosagem
20.
ESMO Open ; 1(5): e000120, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27933216
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA