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1.
Nature ; 524(7563): 47-53, 2015 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-26168399

RESUMO

We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.


Assuntos
Genoma Humano/genética , Genômica , Neoplasias Pulmonares/genética , Mutação/genética , Carcinoma de Pequenas Células do Pulmão/genética , Alelos , Animais , Linhagem Celular Tumoral , Pontos de Quebra do Cromossomo , Ciclina D1/genética , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Sistemas Neurossecretores/metabolismo , Sistemas Neurossecretores/patologia , Proteínas Nucleares/genética , Receptores Notch/genética , Receptores Notch/metabolismo , Proteína do Retinoblastoma/genética , Transdução de Sinais/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia , Proteína Tumoral p73 , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética
2.
Int J Cancer ; 146(6): 1503-1513, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31162856

RESUMO

In 2011, the U.S. National Lung Cancer Screening Trial (NLST) reported a 20% reduction of lung cancer mortality after regular screening by low-dose computed tomography (LDCT), as compared to X-ray screening. The introduction of lung cancer screening programs in Europe awaits confirmation of these first findings from European trials that started in parallel with the NLST. The German Lung cancer Screening Intervention (LUSI) is a randomized trial among 4,052 long-term smokers, 50-69 years of age, recruited from the general population, comparing five annual rounds of LDCT screening (screening arm; n = 2,029 participants) with a control arm (n = 2,023) followed by annual postal questionnaire inquiries. Data on lung cancer incidence and mortality and vital status were collected from hospitals or office-based physicians, cancer registries, population registers and health offices. Over an average observation time of 8.8 years after randomization, the hazard ratio for lung cancer mortality was 0.74 (95% CI: 0.46-1.19; p = 0.21) among men and women combined. Modeling by sex, however showed a statistically significant reduction in lung cancer mortality among women (HR = 0.31 [95% CI: 0.10-0.96], p = 0.04), but not among men (HR = 0.94 [95% CI: 0.54-1.61], p = 0.81) screened by LDCT (pheterogeneity = 0.09). Findings from LUSI are in line with those from other trials, including NLST, that suggest a stronger reduction of lung cancer mortality after LDCT screening among women as compared to men. This heterogeneity could be the result of different relative counts of lung tumor subtypes occurring in men and women.


Assuntos
Detecção Precoce de Câncer/métodos , Neoplasias Pulmonares/epidemiologia , Programas de Rastreamento/métodos , Mortalidade/tendências , Tomografia Computadorizada por Raios X , Idoso , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Incidência , Pulmão/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores Sexuais , Fumar/efeitos adversos , Análise de Sobrevida
3.
Cent Eur J Immunol ; 45(2): 195-201, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33456331

RESUMO

Asthma is an important chronic disease affecting a lot of people worldwide. Treatment options for asthma like biological agents are being developed more frequently nowadays. Despite a lot of treatment options, some patients still remain symptomatic. As more and more practitioners choose treatment with biologic agents as a convenient way of therapy, biologic agents and other valuable methods must be discovered in order to cope with a growing number of treatment agents. This manuscript emphasizes on new generation monoclonal human(ized) antibodies in asthmatics and off-label use . The first developed biologic agent is the anti-immunoglobulin E monoclonal antibody called omalizumab. Currently it is an approved treatment option for asthma.

4.
Am J Pathol ; 187(5): 973-979, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28279655

RESUMO

Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer. COPD is characterized by chronic airway inflammation and lung infections. The airways of patients with COPD are frequently colonized with bacteria [eg, nontypeable Haemophilus influenzae (NTHi)] that cause pulmonary inflammation and exacerbations. Pulmonary adenocarcinomas are frequently associated with an activating mutation in the KRAS gene. We determined the function of Toll-like receptor (TLR) signaling on the progression of Kras-induced early adenomatous lesions in the lung. Wild-type (WT) mice and mice doubly deficient in Tlr-2 and -4 (Tlr2/4-/-), both with an oncogenic Kras allele in lung epithelium, were exposed to NTHi for 4 weeks. Exposure to NTHi resulted in increased tumor proliferation and growth in WT mice, but not in Tlr2/4-/- mice. Alveolar adenomatous hyperplasia and adenocarcinoma were significantly increased in WT mice compared with Tlr2/4-/- mice. The average size of tumors was significantly larger in WT mice, whereas there was no difference in the number of alveolar lesions between WT and Tlr2/4-/- mice. NTHi-induced pulmonary neutrophilic inflammation and tumor-associated neutrophils were reduced in Tlr2/4-/- mice. Thus, subsequent to a driver mutation, NTHi-induced inflammation promotes proliferation of early adenomatous lesions in a TLR-dependent manner.


Assuntos
Genes ras/fisiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Receptor 2 Toll-Like/fisiologia , Receptor 4 Toll-Like/fisiologia , Adenocarcinoma/fisiopatologia , Animais , Proliferação de Células/fisiologia , Infecções por Haemophilus/fisiopatologia , Haemophilus influenzae/fisiologia , Neoplasias Pulmonares/fisiopatologia , Camundongos , Neutrófilos/fisiologia , Doença Pulmonar Obstrutiva Crônica/virologia , Transdução de Sinais/fisiologia , Receptor 2 Toll-Like/deficiência , Receptor 4 Toll-Like/deficiência , Proteínas ras/metabolismo
5.
RNA Biol ; 15(12): 1499-1511, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30499379

RESUMO

Aberrant expression of noncoding RNAs plays a critical role during tumorigenesis. To uncover novel functions of long non-coding RNA (lncRNA) in lung adenocarcinoma, we used a microarray-based screen identifying LINC00673 with elevated expression in matched tumor versus normal tissue. We report that loss of LINC00673 is sufficient to trigger cellular senescence, a tumor suppressive mechanism associated with permanent cell cycle arrest, both in lung cancer and normal cells in a p53-dependent manner. LINC00673-depleted cells fail to efficiently transit from G1- to S-phase. Using a quantitative proteomics approach, we confirm the modulation of senescence-associated genes as a result of LINC00673 knockdown. In addition, we uncover that depletion of p53 in normal and tumor cells is sufficient to overcome LINC00673-mediated cell cycle arrest and cellular senescence. Furthermore, we report that overexpression of LINC00673 reduces p53 translation and contributes to the bypass of Ras-induced senescence. In summary, our findings highlight LINC00673 as a crucial regulator of proliferation and cellular senescence in lung cancer.


Assuntos
Senescência Celular/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , RNA Longo não Codificante/genética , Adenocarcinoma/genética , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Técnicas de Silenciamento de Genes , Humanos , Modelos Biológicos , Mutação , Interferência de RNA , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
6.
Clin Anat ; 31(1): 60-63, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28556202

RESUMO

Acanthameoba keratitis is a serious ophthalmological condition with a potentially vision-threatening prognosis. Early diagnosis and recognition of relapse, and the detection of persistent Acanthamoeba cysts, are essential for informing the prognosis and managing the condition. We suggest the use of in vivo confocal microscopy not only to identify the early signs of relapse after keratoplasty in patients with Acanthamoeba keratitis, but also as an additional follow-up tool after antimicrobial crosslinking. This study shows that in vivo confocal microscopy is, in experienced hands, a quick and reliable diagnostic tool. Clin. Anat. 31:60-63, 2018. © 2017 Wiley Periodicals, Inc.


Assuntos
Ceratite por Acanthamoeba/patologia , Microscopia Intravital/métodos , Microscopia Confocal/métodos , Ceratite por Acanthamoeba/diagnóstico , Ceratite por Acanthamoeba/cirurgia , Adulto , Criocirurgia/métodos , Diagnóstico Precoce , Feminino , Humanos , Ceratoplastia Penetrante/métodos , Pessoa de Meia-Idade , Recidiva
7.
Am J Respir Crit Care Med ; 191(8): 902-13, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25607238

RESUMO

RATIONALE: In many organs, hypoxic cell death triggers sterile neutrophilic inflammation via IL-1R signaling. Although hypoxia is common in airways from patients with cystic fibrosis (CF), its role in neutrophilic inflammation remains unknown. We recently demonstrated that hypoxic epithelial necrosis caused by airway mucus obstruction precedes neutrophilic inflammation in Scnn1b-transgenic (Scnn1b-Tg) mice with CF-like lung disease. OBJECTIVES: To determine the role of epithelial necrosis and IL-1R signaling in the development of neutrophilic airway inflammation, mucus obstruction, and structural lung damage in CF lung disease. METHODS: We used genetic deletion and pharmacologic inhibition of IL-1R in Scnn1b-Tg mice and determined effects on airway epithelial necrosis; levels of IL-1α, keratinocyte chemoattractant, and neutrophils in bronchoalveolar lavage; and mortality, mucus obstruction, and structural lung damage. Furthermore, we analyzed lung tissues from 21 patients with CF and chronic obstructive pulmonary disease and 19 control subjects for the presence of epithelial necrosis. MEASUREMENTS AND MAIN RESULTS: Lack of IL-1R had no effect on epithelial necrosis and elevated IL-1α, but abrogated airway neutrophilia and reduced mortality, mucus obstruction, and emphysema in Scnn1b-Tg mice. Treatment of adult Scnn1b-Tg mice with the IL-1R antagonist anakinra had protective effects on neutrophilic inflammation and emphysema. Numbers of necrotic airway epithelial cells were elevated and correlated with mucus obstruction in patients with CF and chronic obstructive pulmonary disease. CONCLUSIONS: Our results support an important role of hypoxic epithelial necrosis in the pathogenesis of neutrophilic inflammation independent of bacterial infection and suggest IL-1R as a novel target for antiinflammatory therapy in CF and potentially other mucoobstructive airway diseases.


Assuntos
Fibrose Cística/patologia , Epitélio/patologia , Hipóxia/patologia , Inflamação/patologia , Neutrófilos/patologia , Receptores de Interleucina-1/metabolismo , Adolescente , Adulto , Idoso , Animais , Fibrose Cística/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise em Microsséries/métodos , Pessoa de Meia-Idade , Necrose , Neutrófilos/metabolismo , Transdução de Sinais/fisiologia
8.
Int J Cancer ; 137(7): 1539-48, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25784292

RESUMO

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death globally. To develop better diagnostics and more effective treatments, research in the past decades has focused on identification of molecular changes in the genome, transcriptome, proteome, and more recently also the metabolome. Phospholipids, which nevertheless play a central role in cell functioning, remain poorly explored. Here, using a mass spectrometry (MS)-based phospholipidomics approach, we profiled 179 phospholipid species in malignant and matched non-malignant lung tissue of 162 NSCLC patients (73 in a discovery cohort and 89 in a validation cohort). We identified 91 phospholipid species that were differentially expressed in cancer versus non-malignant tissues. Most prominent changes included a decrease in sphingomyelins (SMs) and an increase in specific phosphatidylinositols (PIs). Also a decrease in multiple phosphatidylserines (PSs) was observed, along with an increase in several phosphatidylethanolamine (PE) and phosphatidylcholine (PC) species, particularly those with 40 or 42 carbon atoms in both fatty acyl chains together. 2D-imaging MS of the most differentially expressed phospholipids confirmed their differential abundance in cancer cells. We identified lipid markers that can discriminate tumor versus normal tissue and different NSCLC subtypes with an AUC (area under the ROC curve) of 0.999 and 0.885, respectively. In conclusion, using both shotgun and 2D-imaging lipidomics analysis, we uncovered a hitherto unrecognized alteration in phospholipid profiles in NSCLC. These changes may have important biological implications and may have significant potential for biomarker development.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Fosfolipídeos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/química , Humanos , Neoplasias Pulmonares/química , Fosfatidilinositóis/metabolismo , Fosfolipídeos/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Esfingomielinas/metabolismo , Espectrometria de Massas em Tandem/métodos
9.
Eur Respir J ; 46(1): 219-29, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25792638

RESUMO

Erlotinib with bevacizumab showed promising activity in recurrent nonsquamous (NS) nonsmall cell lung cancer (NSCLC). The INNOVATIONS study was designed to assess in first-line treatment of unselected cisplatin-eligible patients this combination compared to cisplatin, gemcitabine and bevacizumab. Stage IIIB/IV patients with NS-NSCLC were randomised on erlotinib (150 mg daily) and bevacizumab (15 mg·kg(-1) on day 1, every 3 weeks) (EB) until progression, or cisplatin (80 mg·m(-2) on day 1, every 3 weeks) and gemcitabine (1250 mg·m(-2) on days 1 and 8, every 3 weeks) up to six cycles and bevacizumab (15 mg·kg(-1) on day 1, every 3 weeks) (PGB) until progression. 224 patients were randomised (EB n=111, PGB n=113). The response rate (12% versus 36%; p<0.0001), progression-free survival (median 3.5 versus 6.9 months; hazard ratio (HR) 1.85, 95% CI 1.39-2.45; p<0.0001) and overall survival (median 12.6 versus 17.8 months; HR 1.41, 95% CI 1.01-1.97; p=0.04) clearly favoured PGB. In patients with epidermal growth factor receptor mutations (n=32), response rate, progression-free survival and overall survival were not superior with EB. Platinum-based combination chemotherapy remains the standard of care in first-line treatment of unselected NS-NSCLC. Molecular targeted approaches strongly mandate appropriate testing and patient selection.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/administração & dosagem , Desoxicitidina/análogos & derivados , Cloridrato de Erlotinib/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Desoxicitidina/administração & dosagem , Progressão da Doença , Intervalo Livre de Doença , Receptores ErbB/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Modelos de Riscos Proporcionais , Resultado do Tratamento , Gencitabina
11.
Eur Respir J ; 43(1): 233-9, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23900983

RESUMO

Peripheral lung lesions are sometimes difficult to reach even with endobronchial ultrasound (EBUS) and insufficient material is often obtained by transbronchial forceps biopsy. Cryoprobes can be used for performing tissue biopsies. We evaluated the safety and feasibility of the cryoprobe in combination with EBUS for the diagnosis of peripheral lung lesion. Patients with peripheral lung lesions of up to 4 cm were enrolled. After identifying the lung lesion by radial EBUS, forceps biopsies and cryobiopsies were performed in a randomised order. We evaluated safety and feasibility, and compared diagnostic yield and sample size. 39 patients were randomised and the peripheral lung lesion was reached in 31. The overall diagnostic yield was 60.5% and, in the lesions reached by EBUS, it was 74.2%. In 19 cases, the diagnosis was made with forceps as well as cryobiopsy and, in four cases, only with cryobiopsy. Cryobiopsies were significantly larger than forceps biopsies (11.17 mm(2) versus 4.69 mm(2), p<0.001). We observed one case of moderate bleeding. Transbronchial cryobiopsy with EBUS guidance is safe and useful to obtain histological samples. Larger tissue samples can be obtained by cryoprobe.


Assuntos
Biópsia/métodos , Broncoscopia/métodos , Criocirurgia/métodos , Endossonografia/métodos , Neoplasias Pulmonares/patologia , Pulmão/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia/instrumentação , Estudos de Coortes , Criocirurgia/instrumentação , Estudos de Viabilidade , Feminino , Humanos , Pulmão/diagnóstico por imagem , Pulmão/cirurgia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Instrumentos Cirúrgicos , Tomografia Computadorizada por Raios X
12.
Eur Respir J ; 43(3): 872-83, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23988776

RESUMO

Numerous studies have been published on single aspects of pulmonary adenocarcinoma (ADC). To comprehensively link clinically relevant ADC characteristics, we evaluated established morphological, diagnostic and predictive biomarkers in 425 resected ADCs. Morphology was reclassified. Cytokeratin-7, thyroid transcription factor (TTF)1, napsin A, thymidylate synthase and excision repair cross-complementing rodent repair deficiency complementation group-1 expression, anaplastic lymphoma kinase rearrangements as well as epidermal growth factor receptor (EGFR), V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue (KRAS) and v-Raf murine sarcoma viral oncogene homologue B1 (BRAF) mutations were analysed. All characteristics were correlated with clinical and survival parameters. Morphological ADC subtypes were significantly associated with smoking history and distinct patterns of diagnostic biomarkers. KRAS mutations were prevalent in male smokers, while EGFR mutations were associated with female sex, nonsmoking and lepidic as well as micropapillary growth patterns. TTF1 expression (hazard ratio (HR) for overall survival 0.61, p=0.021) and BRAF mutations (HR for disease-free survival 2.0, p=0.046) were found to be morphology- and stage-independent predictors of survival in multivariate analysis. Adjuvant radio-/chemotherapy, in some instances, strongly impacted on the prognostic effect of both diagnostic and predictive biomarkers. Our data draw a comprehensive picture of the prevalence and interplay of established histological and molecular ADC characteristics. These data will help to develop time- and cost-effective diagnostic and treatment algorithms for ADC.


Assuntos
Adenocarcinoma/metabolismo , Receptores ErbB/genética , Genes ras , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Receptores Proteína Tirosina Quinases/genética , Adulto , Idoso , Algoritmos , Quinase do Linfoma Anaplásico , Ácido Aspártico Endopeptidases/metabolismo , Biomarcadores/metabolismo , Análise Custo-Benefício , Proteínas de Ligação a DNA/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imunofenotipagem , Queratina-7/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fumar , Timidilato Sintase/metabolismo , Fatores de Transcrição , Resultado do Tratamento
13.
Histopathology ; 65(2): 187-94, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24456475

RESUMO

AIMS: Molecular characterization of non-small-cell lung cancer (NSCLC) has revealed multiple druggable mutations for targeted therapies. Recently, chromosomal rearrangements involving c-ros oncogene 1, receptor tyrosine kinase (ROS1) were identified, and patients seem to benefit from crizotinib treatment. The aim of this study was to identify the clinicopathological characteristics of NSCLC with ROS1 expression and translocation. METHODS AND RESULTS: We screened 1478 NSCLCs with a ROS1-specific antibody, and tested positive cases with FISH. All positive cases were analysed for associated clinicopathological characteristics, including survival and molecular tumour composition. Sixty-eight cases (4.6%) showed ROS1 immunoreactivity, and ROS1 translocations were confirmed in nine cases (0.6%). ROS1 expression was predominantly found in female adenocarcinoma patients, in patients with low T stages, and in association with TTF1 and napsin expression, and certain histomorphological adenocarcinoma patterns (lepidic, acinar, and solid). ROS1 translocations occurred in conjunction with other driver mutations (EGFR, KRAS, and BRAF). ROS1 expression was found to be a stage-independent predictor of favourable survival. CONCLUSIONS: ROS1 translocations are rare events in resected NSCLCs from Caucasian patients. Immunohistochemical screening for ROS1 expression and clinicopathological parameters, including female sex, early tumour stages, adenocarcinomas with TTF1 and/or napsin expression, and a distinct histomorphological growth pattern, strongly facilitate case enrichment. Molecularly driven multistep concepts might not be optimal for case selection.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Proteínas Tirosina Quinases/biossíntese , Proteínas Proto-Oncogênicas/biossíntese , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Análise Serial de Tecidos , Translocação Genética
14.
Respiration ; 87(5): 432-8, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24457174

RESUMO

Minimally invasive diagnostic techniques are increasingly being used to obtain specimens for pathological diagnosis and prediction. Referring to lung cancer, both endobronchial and endoesophageal ultrasound are used worldwide as diagnostic routine methods. Consequently, an increasing number of pathological samples are cytological and fewer are histological. On the other hand, the requirements for specific and sensitive tumor subtyping complemented by predictive analyses are steadily increasing and are an essential basis for evidence-based treatment decisions. In this article we focus on the cell block method as a helpful tool for diagnostic and predictive analyses in lung cancer and point out its advantages and disadvantages in comparison to conventional cytological and biopsy specimens. Furthermore, we retrospectively analyze the diagnostic results of the cell block method in a high-volume center over 5 years. The main advantages of cell blocks are the availability of established and validated protocols, archiving and the opportunity to have serial sections from the same specimens to provide or repeat molecular analyses. Actually, in case of tumor progression, even additional biomarkers can be tested using the original cell block when re-biopsies are not feasible. The cell block method should be considered as a reliable, complimentary approach to conventional cytological or biopsy procedures, which is helpful to fulfill the increasing requirements of high-quality diagnostics and prediction.


Assuntos
Biomarcadores Tumorais/metabolismo , Biópsia/métodos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Neoplasias Pulmonares/diagnóstico , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Manejo de Espécimes/métodos , Broncoscopia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Coortes , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia
15.
Respiration ; 88(3): 199-207, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25115833

RESUMO

BACKGROUND: Pirfenidone is a novel antifibrotic drug for the treatment of mild-to-moderate idiopathic pulmonary fibrosis (IPF). However, adverse events may offset treatment benefits and compliance. OBJECTIVES: To assess recent course of disease, adverse events and compliance in patients who started pirfenidone. METHODS: In an observational cohort study, 63 patients with mild-to-moderate IPF who started pirfenidone between May 2011 and June 2013 were reviewed. Pulmonary function, adverse events and treatment compliance were recorded at each clinic visit. Disease progression was defined as a reduction of vital capacity ≥10% and/or diffusion capacity (DLCO) ≥15%. RESULTS: Follow-up time on pirfenidone treatment was 11 (±7) months. Sixty-six percent of the patients continued with pirfenidone monotherapy and 34% of the patients received pirfenidone combined with corticosteroids (CCS) and/or N-acetylcysteine (NAC). There was a nonsignificant reduction in mean decline of percent predicted forced vital capacity after treatment start (0.7 ± 10.9%) compared to the pretreatment period (6.6 ± 6.7%, p = 0.098). Sixty-two percent of the patients had stable disease on pirfenidone treatment. Adverse events affected 85% of the patients, leading to discontinuation of pirfenidone in 20%. Adverse events and treatment discontinuation were seen more frequently in patients with concomitant CCS and/or NAC treatment. CONCLUSIONS: Adverse events affect the majority of patients treated with pirfenidone, but are mostly manageable with supportive measures. In this heterogeneous patient group, a nonsignificant effect of pirfenidone treatment on pulmonary function was seen, underlining the need for more data on patient selection criteria and efficacy of pirfenidone, particularly in patients with coexistent emphysema and concomitant NAC/CCS treatment.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Piridonas/uso terapêutico , Acetilcisteína/uso terapêutico , Corticosteroides/uso terapêutico , Idoso , Estudos de Coortes , Progressão da Doença , Toxidermias/etiologia , Quimioterapia Combinada , Expectorantes/uso terapêutico , Fadiga/induzido quimicamente , Feminino , Gastroenteropatias/induzido quimicamente , Alemanha , Humanos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Estudos Retrospectivos , Centros de Atenção Terciária , Resultado do Tratamento , Capacidade Vital , Redução de Peso
16.
Genes Chromosomes Cancer ; 52(3): 250-64, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23074073

RESUMO

Invasion is a critical step in lung tumor progression. The interaction between tumor cells and their surroundings may play an important role in tumor invasion and metastasis. To better understand the mechanisms of tumor invasion and tumor-microenvironment interactions in lung tumors, total RNA was isolated from the inner tumor, tumor invasion front, adjacent lung, and distant normal lung tissue from 17 patients with primary squamous cell lung carcinoma using punch-aided laser capture microdissection. Messenger RNA expression profiles were obtained by microarray analysis, and microRNA profiles were generated from eight of these samples using TaqMan Low Density Arrays. Statistical analysis of the expression data showed extensive changes in gene expression in the inner tumor and tumor front compared with the normal lung and adjacent lung tissue. Only a few genes were differentially expressed between tumor front and the inner tumor. Several genes were validated by immunohistochemistry. Evaluation of the microRNA data revealed zonal expression differences in nearly a fourth of the microRNAs analyzed. Validation of selected microRNAs by in situ hybridization demonstrated strong expression of hsa-miR-196a in the inner tumor; moderate expression of hsa-miR-224 in the inner tumor and tumor front, and strong expression of hsa-miR-650 in the adjacent lung tissue. Pathway analysis placed the majority of genes differentially expressed between tumor and nontumor cells in intrinsic processes associated with inflammation and extrinsic processes related to lymphocyte physiology. Genes differentially expressed between the inner tumor and the adjacent lung/normal lung tissue affected pathways of arachidonic acid metabolism and eicosanoid signaling.


Assuntos
Carcinoma de Células Escamosas/genética , Perfilação da Expressão Gênica , Neoplasias Pulmonares/genética , Transcriptoma , Microambiente Tumoral/genética , Carcinoma de Células Escamosas/patologia , Análise por Conglomerados , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , MicroRNAs/genética , Reprodutibilidade dos Testes
17.
Eur Respir J ; 41(3): 656-63, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22743677

RESUMO

Basaloid carcinoma represents a rare variant of nonsmall cell lung cancer (NSCLC), which has shown a poor prognosis in a number of studies. Although it is considered to derive from a pluri- or multipotent pulmonary stem cells, little is known about the expression and clinical significance of stem cell antigens in this variant. Stage-specific embryonic antigen-4 (SSEA-4) was analysed by immunohistochemistry in 38 patients with resected early-stage basaloid NSCLC who had a median follow-up of 72.9 months. The expression of SSEA-4 was related to clinico-pathological characteristics, to the expression of the adult stem cell antigens CD117, CD133 and breast cancer resistance protein 1 (BCRP1), and to prognosis. SSEA-4 was positive in 37% of the specimens and showed no association with clinico-pathological characteristics or the expression of adult stem cell antigens. Cox proportional hazards regression analysis revealed a 6.0-fold increased risk of relapse (p = 0.001) and a 4.2-fold increased risk of disease-related mortality (p = 0.017) in SSEA-4-positive patients, while SSEA-4-negative patients showed a prognosis comparable with that of other early-stage NSCLC. SSEA-4 is expressed in a fraction of basaloid NSCLC and is associated with poor prognosis.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Antígenos Embrionários Estágio-Específicos/sangue , Antígeno AC133 , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Idoso , Antígenos CD/metabolismo , Biomarcadores Tumorais/sangue , Feminino , Perfilação da Expressão Gênica , Glicoproteínas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Peptídeos/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-kit/metabolismo , Transdução de Sinais
18.
Eur Respir J ; 42(6): 1668-76, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23060634

RESUMO

Patients with lung cancer are at risk of developing a second primary lung cancer (SPLC). However, the characteristics of patients at risk remain largely speculative. We reviewed 2816 lung cancer patients from our institution for the occurrence of SPLC. Any SPLC was categorised as synchronous when diagnosed within 2 years of the first primary lung cancer (FPLC) and after direct histological comparison of both tumours. All other SPLCs were considered as metachronous. 139 patients developed a second malignancy including 69 nonsmall cell lung cancer (NSCLC) and 9 small cell lung cancer. The median interval for diagnosis of metachronous SPLC (n=59) after FPLC occurrence was 72 months. SPLC detected within 5 years of FPLC diagnosis had a more favourable stage distribution (p=0.02). After diagnosis of SPLC, patients had a superior median overall survival compared to controls (57.7 versus 18.1 months; p<0.0001). Interestingly, comparing only stage IV NSCLC patients, a history of FPLC was also associated with a favourable survival (median 27.4 versus 8.97 months; p=0.007). In summary, previous lung cancer treatment does not lead to impaired prognosis after diagnosis of SPLC. Improved surveillance programmes beyond 5 years after FPLC treatment may result in more favourable disease stages for detected SPLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Risco , Fumar , Resultado do Tratamento , Adulto Jovem
19.
Eur Respir J ; 41(4): 943-51, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22835610

RESUMO

Recently, a novel classification system based on tumour architecture and with high prognostic impact has been proposed for pulmonary adenocarcinomas (ADCs). For imaging-based prediction of histological ADC subtypes and, thus, prognosis, it is of paramount importance to investigate the correlations of radio- and histomorphological parameters. Associations between histomorphological ADC growth patterns (lepidic, acinar, papillary, micropapillary and solid) and data from pre-operative assessment by computed tomography (CT) imaging of 174 resected pulmonary ADCs were analysed. Margin configuration as well as solidity/ground glass opacity of an ADC was associated with distinct histomorphological ADC growth patterns. Solid-predominant ADCs usually had smooth margins and were also solid in CT scans, while lepidic-predominant ADCs had no predominant margin pattern, were located in the periphery, showed a positive bronchogram and were frequently associated with solidity/ground glass opacity. In addition, nonspherical tumour growth was a negative predictor of overall and disease-specific patient survival. We defined CT morphological parameters that were associated with histomorphological growth patterns of pulmonary ADCs. These data may form the basis for the development of future prognostic algorithms in the palliative setting, which include an integrated evaluation of biopsy histomorphology and CT scan morphology of nonresectable pulmonary ADC.


Assuntos
Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Pulmão/patologia , Tomografia Computadorizada por Raios X , Algoritmos , Biópsia , Intervalo Livre de Doença , Detecção Precoce de Câncer , Humanos , Metástase Neoplásica , Prognóstico , Resultado do Tratamento
20.
Eur Respir J ; 40(5): 1221-7, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22408209

RESUMO

Recently, a novel classification for pulmonary adenocarcinomas (ADCs) was published, the cornerstone of which is the quantification of growth patterns. Data on reproducibility in the routine diagnostic setting are lacking. 100 constitutive cases of lung ADC resection specimens from our archives were classified independently by five pulmonary pathologists and two residents according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. The most frequent predominant pattern in our cohort was solid (37%), followed by acinar (35%), lepidic (20%), papillary (5%) and micropapillary (3%). κ-values for the denomination of the predominant pattern revealed substantial agreement for pulmonary pathologists (κ=0.44-0.72) and fair agreement for residents (κ=0.38-0.47). Interobserver variability was significantly higher in cases with higher slide numbers (p=0.028) and was considerably reduced after training. Intraobserver variability was low (κ=0.79-0.87). Papillary and micropapillary patterns were the most complicated patterns to evaluate, while evaluation of lepidic and solid tumour growth was straightforward. Our data imply that the novel classification of pulmonary ADC is applicable with acceptable interobserver variability if performed by specifically trained pathologists. Additional efforts are needed to harmonise the application of this novel and clinically important classification scheme of pulmonary ADC.


Assuntos
Adenocarcinoma/classificação , Adenocarcinoma/patologia , Neoplasias Pulmonares/classificação , Neoplasias Pulmonares/patologia , Humanos , Variações Dependentes do Observador , Sociedades Médicas/estatística & dados numéricos
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