RESUMO
OBJECTIVES: The unicuspid aortic valve (UAV) is a rare cardiac malformation and is associated with the formation of ascending aortic aneurysms. To characterize its associated aortic wall changes, normal and aneurysmatic ascending aortic wall specimens were analysed, focusing on the potential mechanisms of aneurysm formation. Patients with tricuspid aortic valve (TAV) served as controls. METHODS: In a retrospective observational study, 74 specimens (dilated and non-dilated aortas; individuals with UAV and TAV) obtained intraoperatively were studied. Standard stains and immunohistochemical labelling of cleaved caspase-3, cluster of differentiation 31 and endothelial nitric oxide synthase (eNOS) were performed to assess the degree of apoptosis, distribution of eNOS within the aortic wall, smooth muscle cell (SMC) nuclei loss and mucoid extracellular matrix accumulation (MEMA). RESULTS: Deeper ingrowth of vasa vasorum was found in dilated aortas. Interestingly, eNOS was expressed mostly in vasa vasorum. More apoptosis was seen in UAV aortas compared to TAV aortas (P < 0.001). Both UAV and TAV aortas were comparable regarding SMC nuclei loss (P = 0.419). In dilated compared to non-dilated aortas regardless valve morphology SMC nuclei loss was increased (P = 0.005) and more pronounced translamellar MEMA was present (P = 0.011). The highest grade of distribution (P = 0.043) and the highest severity (P = 0.005) regarding MEMA were seen in TAV dilated specimens compared to UAV dilated specimens. CONCLUSIONS: Aneurysms with UAV show increased apoptosis, the role of which is unclear. Strikingly, more severe MEMA was found in TAV aneurysms compared to UAV aneurysms. Thus, UAV-associated aortic wall changes and resulting aneurysm may be less aggressive than aneurysms with TAV.
Assuntos
Aneurisma Aórtico , Doenças das Valvas Cardíacas , Aorta , Valva Aórtica , HumanosRESUMO
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.
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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 SobrevidaRESUMO
The aim of the present study was to assess the expression of epithelial-mesenchymal transition biomarkers (E-cadherin and vimentin) and their potential significance as prognostic markers in patients with stage IIIB/IV non-squamous non-small cell lung cancer (NSCLC) enrolled in the INNOVATIONS trial, receiving treatment with either erlotinib/bevacizumab (EB) or cisplatin/gemcitabine/bevacizumab (PGB). The tumor tissues of 104 patients were retrospectively analyzed using immunohistochemistry to assess the expression of E-cadherin and vimentin. The distribution between the treatment arms was 46 patients in the EB-arm and 58 in the PGB-arm. Comparing the treatment arms according to E-cadherin and vimentin expression, the analysis revealed that progression-free survival (PFS) was increased in the PGB treatment group when compared with EB treatment in patients with low expression of E-cadherin [hazard ratio (HR)=0.353; 95% confidence interval (CI) 0.189- 0.658; log-rank P=0.0007] and in those with high expression of vimentin [HR=0.276 (95% CI, 0.115- 0.659), log-rank P=0.0021]. In patients that exhibited high E-cadherin and were negative for vimentin, there was no difference in the PFS between the PGB and EB treatment groups. In conclusion, in non-squamous NSCLC with downregulated E-cadherin and upregulated vimentin, the efficacy of chemotherapy with PGB was superior compared with EB; but the same effect was not observed in patients with high E-cadherin and low vimentin. Although increased PFS was observed in patients with PGB treatment compared with EB treatment in the whole analysis populations, in the subgroup of patients with the mesenchymal phenotype, no prognostic or predictive value of either biomarker could be identified. The potential role of bevacizumab in overcoming chemotherapy resistance in the population with the mesenchymal phenotype has to be further explored.
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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/metabolismoRESUMO
BACKGROUND: The current classification of human lung adenocarcinoma defines five different histological growth patterns within the group of conventional invasive adenocarcinomas. The five growth patterns are characterised by their typical architecture, but also by variable tumor biological behaviour. AIMS: The aim of this study was to identify specific gene signatures of the five adenocarcinoma growth patterns defined by the joint IASLC/ATS/ERS working group. METHODS: Total RNA from microdissected adenocarcinoma tissue samples of ten lepidic, ten acinar, ten solid, nine papillary, and nine micropapillary tumor portions was isolated and prepared for gene expression analysis. Differential expression of genes was determined using the R package "LIMMA". The overall significance of each signature was assessed via global test. Gene ontology statistics were analysed using GOstat. For immunohistochemical validation, tissue specimens from 20 tumors with solid and 20 tumors with lepidic growth pattern were used. RESULTS: Microarray analyses between the growth patterns resulted in numerous differentially expressed genes between the solid architecture and other patterns. The comparison of transcriptomic activity in the solid and lepidic patterns revealed 705 up- and 110 downregulated non-redundant genes. The pattern-specific protein expression of Inositol-1,4,5-trisphosphate-kinase-A (ITPKA) and angiogenin by immunohistochemistry confirmed the RNA levels. The strongest differences in protein expression between the two patterns were shown for ITPKA (p = 0.02) and angiogenin (p = 0.113). CONCLUSIONS: In this study growth pattern-specific gene signatures in pulmonary adenocarcinoma were identified and distinct transcriptomic differences between lung adenocarcinoma growth patterns were defined. The study provides valuable new information about pulmonary adenocarcinoma and allows a better assessment of the five adenocarcinoma subgroups.
Assuntos
Adenocarcinoma/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Adenocarcinoma/classificação , Adenocarcinoma/metabolismo , Ontologia Genética , Humanos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/classificação , Neoplasias Pulmonares/metabolismo , Estadiamento de Neoplasias , Carga Tumoral/genéticaRESUMO
Prior studies have demonstrated an association between excision repair cross-complementation group 1 (ERCC1) expression level and outcomes in patients with advanced non-small cell lung cancer (NSCLC) treated with platinum-based chemotherapy. The aim of this study was to assess the impact of ERCC1 on survival for patients with stage IIIB/IV non-squamous NSCLC (NS-NSCLC) enrolled in the INNOVATIONS trial, thus receiving as treatment either erlotinib/bevacizumab (EB) or cisplatin/gemcitabine/bevacizumab (PGB). We retrospectively analyzed tumor tissue of 72 patients using immunohistochemistry to assess the expression of ERCC1. The distribution between treatment arms was equal (36 patients each). Two different H scores were calculated and correlated with survival. In ERCC1-positive patients, no significant difference in terms of progression-free survival (PFS) between treatment arms has been detected. ERCC1-negative patients benefited from PGB compared to EB arm (H score: HR = 0.377, 95% CI [0.167-0.849], p = 0.0151; modified H score: HR = 0.484, 95% CI [0.234-1.004], p = 0.0468). With respect to the scoring system, in the EB-arm, a significant superior PFS turned out in ERCC1-positive patients when employing the H-score (HR = 0.430, 95% CI [0.188-0.981], p = 0.0397; median 4.9 vs. 3.9 months), but not with the modified H-score. Our findings support the hypothesis that NS-NSCLC displaying a low ERCC1 expression might benefit from cisplatin-based chemotherapy. High expression indicated better PFS in the EB arm supporting the prognostic impact. However, as impact of ERCC1-assessment even might depend on scoring systems differences, the need in standardization of assessment methodology is emphasized.
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Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/administração & dosagem , Proteínas de Ligação a DNA/metabolismo , Endonucleases/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Bevacizumab/administração & dosagem , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Cloridrato de Erlotinib/administração & dosagem , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Resultado do Tratamento , GencitabinaRESUMO
OBJECTIVES: This study was performed to evaluate for a potentially important role of T cells in the pathophysiology and treatment sensitivity of large cell neuroendocrine lung carcinoma (LCNEC), an orphan disease with poor prognosis and scarce data to guide novel therapeutic strategies. MATERIALS AND METHODS: We performed T-cell receptor (TCR) ß-chain spectratyping on blood samples of patients treated within the CRAD001KDE37 trial (nâ¯=â¯35) using age-matched current or former (nâ¯=â¯11) and never smokers (nâ¯=â¯10) as controls. The data were analyzed in conjunction with the complete blood counts of the probands as well as the data about response to treatment and overall survival in the clinical trial. RESULTS AND CONCLUSION: Untreated stage IV LCNEC patients had significant T-cell repertoire alterations (pâ¯<â¯0.001) compared to age-matched smokers. These changes correlated positively with blood lymphocyte counts (râ¯=â¯0.49, pâ¯<â¯0.01), suggesting antigen-induced T-cell proliferation as the causative mechanism. At the same time, LCNEC patients showed mild lymphopenia (1.54 vs. 2.51/nl in median, pâ¯<â¯0.01), which reveals a second, antigen-independent mechanism of systemic immune dysregulation. More pronounced T-cell repertoire alterations and higher blood lymphocyte counts at diagnosis were associated with a better treatment response by RECIST and with a longer overall survival (441 vs. 157â¯days in median, pâ¯=â¯0.019). A higher degree of T-cell repertoire normalization after 3 months of therapy also distinguished a patient group with more favourable prognosis (median overall survival 617 vs. 316â¯days, pâ¯=â¯0.036) independent of radiological response. Thus, LCNEC induces clinically relevant changes of the T-cell repertoire, which are measurable in the blood and could be exploited for prognostic, predictive and therapeutic purposes. Their pathogenesis appears to involve antigen-induced oligoclonal T-cell expansions superimposed on TCR-independent lymphopenia.
Assuntos
Carcinoma de Células Grandes/imunologia , Carcinoma Neuroendócrino/imunologia , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T/genética , Neoplasias Pulmonares/imunologia , Linfócitos T/fisiologia , Idoso , Carcinoma de Células Grandes/diagnóstico , Carcinoma de Células Grandes/mortalidade , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/mortalidade , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Análise de SobrevidaAssuntos
Colo , Doenças do Colo/diagnóstico , Doenças do Íleo/diagnóstico , Íleo , Pneumatose Cistoide Intestinal/diagnóstico , Biópsia , Colo/diagnóstico por imagem , Colo/patologia , Doenças do Colo/diagnóstico por imagem , Doenças do Colo/patologia , Colonoscopia , Diagnóstico Diferencial , Humanos , Doenças do Íleo/diagnóstico por imagem , Doenças do Íleo/patologia , Íleo/diagnóstico por imagem , Íleo/patologia , Masculino , Pessoa de Meia-Idade , Pneumatose Cistoide Intestinal/diagnóstico por imagem , Pneumatose Cistoide Intestinal/patologia , Valor Preditivo dos Testes , Tomografia Computadorizada por Raios XRESUMO
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/metabolismoRESUMO
OBJECTIVES: This study sought to evaluate myocardial perfusion reserve index (MPRI) and diastolic strain rate, both assessed by cardiac magnetic resonance (CMR) as a noninvasive tool for the detection of microvasculopathy. BACKGROUND: Long-term survival of cardiac allograft recipients is limited primarily by cancer and cardiac allograft vasculopathy (CAV). Besides epicardial CAV, diagnosed by coronary angiography, stenotic microvasculopathy was found to be an additional independent risk factor for survival after heart transplantation. METHODS: Sixty-three consecutive heart transplant recipients who underwent CMR, coronary angiography, and myocardial biopsy were enrolled. Stenotic vasculopathy in microvessels was considered in myocardial biopsies by immunohistochemistry and CAV was graded during coronary angiography according to International Society of Heart and Lung Transplantation criteria. In addition, by CMR microvasculopathy was assessed by myocardial perfusion reserve during pharmacologic hyperemia with adenosine and strain-encoded magnetic resonance using a modified spatial modulation of magnetization tagging pulse sequence in all patients. RESULTS: Decreasing MPRI and diastolic strain rates were observed in patients with decreasing microvessel luminal radius to wall thickness ratio and decreasing capillary density (r = 0.45 and r = 0.61 for MPRI and r = 0.50 and r = 0.38 for diastolic strain rate, respectively; p < 0.005 for all). Using multivariable analysis, both MPRI and diastolic strain rate were robust predictors of stenotic microvasculopathy, independent of age, organ age, and CAV by International Society of Heart and Lung Transplantation criteria (hazard ratio: 0.07, p = 0.006 for MPRI; hazard ratio: 0.91, p = 0.002 for diastolic strain rate). Patients without stenotic microvasculopathy in the presence of no or mild CAV (n = 36) exhibited significantly higher median survival free of events, compared with patients with stenotic microvasculopathy in the presence of no or mild CAV (n = 18; p = 0.04 by log rank). CONCLUSIONS: CMR represents a valuable noninvasive diagnostic tool, which may be used for the early detection of transplant microvasculopathy before the manifestation of CAV during surveillance coronary angiographic procedures.
Assuntos
Doença da Artéria Coronariana/diagnóstico por imagem , Circulação Coronária , Vasos Coronários/diagnóstico por imagem , Transplante de Coração/efeitos adversos , Imageamento por Ressonância Magnética , Microcirculação , Contração Miocárdica , Imagem de Perfusão do Miocárdio/métodos , Adenosina/administração & dosagem , Adulto , Idoso , Aloenxertos , Biópsia , Angiografia Coronária , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/fisiopatologia , Vasos Coronários/fisiopatologia , Vasos Coronários/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Hiperemia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estresse Mecânico , Resultado do Tratamento , Vasodilatadores/administração & dosagemRESUMO
Lung cancer is the leading cause of cancer death. Beyond first line treatment, few therapeutic options are available, particularly for squamous cell carcinoma (SCC). Here, we have explored the phospholipidomes of 30 human SCCs and found that they almost invariably (in 96.7% of cases) contain phospholipids with longer acyl chains compared to matched normal tissues. This trait was confirmed using in situ 2D-imaging MS on tissue sections and by phospholipidomics of tumor and normal lung tissue of the L-IkkαKA/KA mouse model of lung SCC. In both human and mouse, the increase in acyl chain length in cancer tissue was accompanied by significant changes in the expression of acyl chain elongases (ELOVLs). Functional screening of differentially expressed ELOVLs by selective gene knockdown in SCC cell lines followed by phospholipidomics revealed ELOVL6 as the main elongation enzyme responsible for acyl chain elongation in cancer cells. Interestingly, inhibition of ELOVL6 drastically reduced colony formation of multiple SCC cell lines in vitro and significantly attenuated their growth as xenografts in vivo in mouse models. These findings identify acyl chain elongation as one of the most common traits of lung SCC discovered so far and pinpoint ELOVL6 as a novel potential target for cancer intervention.
Assuntos
Acetiltransferases/metabolismo , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Fosfolipídeos/química , Animais , Carcinoma de Células Escamosas/química , Elongases de Ácidos Graxos , Xenoenxertos , Humanos , Neoplasias Pulmonares/química , CamundongosRESUMO
OBJECTIVES: To explore patient and disease factors, and reasons behind the physician's choice of platinum backbone for the first-line treatment of non-small cell lung cancer (NSCLC), as observed in a European prospective observational study of patients receiving platinum-based chemotherapy as first-line treatment for advanced or metastatic NSCLC (the FRAME study). Additionally, overall survival (OS) for patients who received cisplatin or carboplatin was evaluated. MATERIALS AND METHODS: A post-hoc analysis of the prospective study population was conducted. Baseline characteristics of patients receiving cisplatin versus carboplatin were compared and summarized by propensity score. Survival for matched patients was summarized using the Kaplan-Meier approach. RESULTS: Of the 1564 patients who were included in the prospective study, 1520 received either cisplatin (54%) or carboplatin (46%) in combination with pemetrexed, gemcitabine, taxanes or vinorelbine. Patients treated with carboplatin were older than patients receiving cisplatin (mean age 67 versus 61 years; p<0.001), had poorer performance status (p<0.001), and more comorbidities (p<0.001). Cisplatin was most frequently combined with pemetrexed (47%), and carboplatin most frequently with taxanes (31%). Unadjusted median OS estimates for patients from the total prospective study sample were 11.5 months (95% confidence interval [CI] 10.1-12.9) for cisplatin recipients and 9.0 months (95% CI 8.1-10.6) for carboplatin recipients. Median (95% CI) overall survival for the matched cohorts was 10.8 months (8.8-14.3) for cisplatin versus 9.5 months (8.2-11.3) for carboplatin; p=0.086. CONCLUSION: This post-hoc analysis illustrated real-life differences in patients with NSCLC prescribed platinum-based first-line treatment, and suggested that baseline patient and disease characteristics were associated with physician's choice of platinum agent, with cisplatin being more frequently prescribed to younger and fitter patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Carboplatina/administração & dosagem , Cisplatino/administração & dosagem , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Estudos Prospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
Thoracic oncology HERMES: European curriculum recommendations for training in thoracic oncology http://ow.ly/mdqT300NHqO.
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PURPOSE: Current guidelines recommend postoperative radiation therapy (PORT) for incompletely resected non-small cell lung cancer (NSCLC). However, there is still a paucity of evidence for this approach. Hence, we analyzed survival in 78 patients following radiotherapy for incompletely resected NSCLC (R1) and investigated prognostic factors. PATIENTS AND METHODS: All 78 patients with incompletely resected NSCLC (R1) received PORT between December 2001 and September 2014. The median total dose for PORT was 60 Gy (range 44-68 Gy). The majority of patients had locally advanced tumor stages (stage IIA (2.6%), stage IIB (19.2%), stage IIIA (57.7%) and stage IIIB (20.5%)). 21 patients (25%) received postoperative chemotherapy. RESULTS: Median follow-up after radiotherapy was 17.7 months. Three-year overall (OS), progression-free (PFS), local (LPFS) and distant progression-free survival (DPFS) rates were 34.1, 29.1, 44.9 and 51.9%, respectively. OS was significantly prolonged at lower nodal status (pN0/1) and following dose-escalated PORT with total radiation doses >54 Gy (p=0.012, p=0.013). Furthermore, radiation doses >54 Gy significantly improved PFS, LPFS and DPFS (p=0.005; p=0.050, p=0.022). Interestingly, survival was neither significantly influenced by R1 localization nor by extent (localized vs. diffuse). Multivariate analyses revealed lower nodal status and radiation doses >54.0 Gy as the only independent prognostic factors for OS (p=0.021, p=0.036). CONCLUSION: For incompletely resected NSCLC, PORT is used for improving local tumor control. Local progression is still the major pattern of failure. Radiation doses >54 Gy seem to support improved local control and were associated with better OS in this retrospective study.
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Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/patologia , Neoplasia Residual/radioterapia , Período Pós-Operatório , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
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/genéticaRESUMO
PURPOSE: In recent years, immune therapeutic strategies against non-small cell lung cancer (NSCLC) based on tissue-derived biomarkers, for example PD1/PD-L1 (CD274), have evolved as novel and promising treatment options. However, the crosstalk between tumor and immune cells is poorly understood. Glycodelin (gene name PAEP), initially described in the context of pregnancy and trophoblastic implantation, is a secreted immunosuppressive glycoprotein with an as-of-yet largely unknown function in lung cancer. EXPERIMENTAL DESIGN: In this study, we characterized the expression and role of glycodelin in NSCLC through mRNA and protein expression analyses, functional knockdown experiments, and correlations with clinicopathologic parameters. RESULTS: Glycodelin mRNA expression was significantly elevated in tumors (n = 336) compared with matched normal tissue (P < 0.0001). Overall survival (OS) was significantly reduced in NSCLC with high glycodelin mRNA levels in women but not in men. Glycodelin was detected in the sera of patients, and the levels correlated with recurrence and metastatic disease. Knockdown of glycodelin with siRNAs in NSCLC cell lines resulted in significant upregulation of immune system modulatory factors such as PDL1, CXCL5, CXCL16, MICA/B, and CD83 as well as proliferation stimulators EDN1 and HBEGF. Furthermore, decreased migration of tumor cells was observed. CONCLUSIONS: Altogether, the comprehensive characterization of glycodelin in NSCLC provides strong support for its use as a biomarker with immune modulatory function.
Assuntos
Biomarcadores Tumorais/biossíntese , Carcinoma Pulmonar de Células não Pequenas/genética , Glicoproteínas/biossíntese , Imunomodulação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Glicodelina , Glicoproteínas/genética , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Gravidez , RNA Mensageiro/biossínteseRESUMO
INTRODUCTION: FRAME was a prospective observational study that captured real-world data on patients with advanced or metastatic non-small cell lung cancer (NSCLC) receiving platinum-based chemotherapies as first-line treatment (FLT) across Europe. As previously reported, most patients observed in the study had initiated FLT with either pemetrexed, gemcitabine, vinorelbine or taxanes in combination with a platinum. Baseline patient and disease characteristics including age, performance status, and histology varied (all p<0.01) across cohorts. METHODS: Consenting adult patients initiating FLT for advanced or metastatic NSCLC with platinum-based chemotherapy, with or without a targeted agent, entered the study between April 2009 and February 2011. The choice of FLT was left to physicians' discretion per routine clinical practice. The primary objective was to evaluate overall survival (OS) across platinum-based doublet chemotherapy cohorts and key secondary objectives included the evaluation of OS in patients with different histological subtypes of NSCLC. Survival outcomes were assessed using Kaplan-Meier analysis, and unadjusted estimates are presented. RESULTS: Median OS in months was 10.3 across cohorts (n=1524), 10.7 for pemetrexed (n=569), 10.0 for gemcitabine (n=360), 9.1 for taxanes (n=295), and 10.7 for vinorelbine (n=300). For patients with non-squamous NSCLC who received cisplatin (n=616, 40% of total), median OS in months was 10.6 across the cohorts, 11.6 for pemetrexed, 8.4 for gemcitabine, 9.6 for taxanes, and 9.9 for vinorelbine. CONCLUSIONS: FRAME describes real-world treatment patterns and survival for patients initiating FLT for advanced or metastatic NSCLC between 2009 and 2011 across Europe.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Pemetrexede/administração & dosagem , Estudos Prospectivos , Taxoides/administração & dosagem , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , Vinorelbina , GencitabinaRESUMO
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/métodosRESUMO
BACKGROUND: Idiopathic interstitial pneumonias (IIP) are associated with an increased lung cancer (LC) risk. However, data on the prognostic and therapeutic impact are limited. We therefore aimed to analyze the outcome of IIP patients with LC under different treatment modalities. METHODS: Patients with IIPs diagnosed in a tertiary interstitial lung diseases (ILD) center were reviewed for LC diagnosis. RESULTS: Of 265 patients with idiopathic pulmonary fibrosis (IPF), 142 with non-specific interstitial pneumonia (NSIP), and 71 with cryptogenic organizing pneumonia (COP), 16%, 4%, and 6% were affected byLC, respectively. Patient characteristics were: IPF: 93% male, median age 67 years, forced vital capacity (FVC) 82%, diffusion capacity for Carbon monoxide (DLCO) 41%, mean survival 20 months. NSIP: 67% male, median age 70 years, FVC 72%, DLCO 43%, mean survival 35 months. COP: 50% male, median age 66 years, FVC 93%, DLCO 77%, mean survival 88 months. Significant treatment-related toxicities occurred in 55% IPF, 20% NSIP und 0% COP patients. 30-days postoperative mortality was 25% in IPF, and 0% in NSIP/COP while rate of radiation pneumonitis was 24% in IPF. CONCLUSIONS: LC is a frequent comorbidity in IIP, with a higher incidence and reduced survival in IPF compared to other IIPs. LC treatment is associated with significant toxicity, specifically in IPF. Interdisciplinary evaluation of therapeutic options in IIP patients diagnosed with LC is therefore mandatory.
Assuntos
Pneumonias Intersticiais Idiopáticas/epidemiologia , Neoplasias Pulmonares/terapia , Pulmão , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Comorbidade , Feminino , Alemanha/epidemiologia , Humanos , Pneumonias Intersticiais Idiopáticas/diagnóstico , Pneumonias Intersticiais Idiopáticas/mortalidade , Pneumonias Intersticiais Idiopáticas/fisiopatologia , Estimativa de Kaplan-Meier , Pulmão/patologia , Pulmão/fisiopatologia , Pulmão/cirurgia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Fatores de Risco , Centros de Atenção Terciária , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
OBJECTIVES: We report on a post-hoc analysis of patients with brain metastases from a large prospective observational study of first-line treatment of non-small cell lung cancer (NSCLC). The aim was to describe baseline characteristics of NSCLC patients with brain metastases, understand their first-line treatment and report outcomes attained in real-world settings. MATERIALS AND METHODS: This post-hoc analysis included all patients in the European observational FRAME study who had brain metastases at initiation of first-line treatment. Descriptive statistics were used for continuous and categorical variables and survival outcomes were assessed using the Kaplan-Meier approach. RESULTS: Our data showed that 17% of patients (263/1564) had spread of the disease to the brain at initiation of first-line treatment. Patients with brain metastases were slightly younger, and more likely to have NSCLC of non-squamous histology than the overall study sample. 34% had received prior palliative radiotherapy to the brain. Our analysis showed a median overall survival (OS) of 7.2 months [95% confidence interval (CI) 6.1-8.2] for all patients with brain metastases treated with first-line platinum-based chemotherapy, ranging from 5.6 months for those treated with gemcitabine plus platinum up to 9.3 months for those treated with pemetrexed plus platinum. Further analysis showed that patients with brain metastases were more frequently treated with pemetrexed platinum-doublet therapy than with any other regimen. CONCLUSIONS: Our analysis provides a unique set of real-world data which adds to current understanding about treatment decisions and outcomes for NSCLC patients with brain metastases for whom there is little clinical trial data available.