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Julien Mazières,
Caroline Catherinne,
Olivier Delfour,
Sandrine Gouin,
Isabelle Rouquette,
Marie-Bernadette Delisle,
Grégoire Prévot,
Roger Escamilla,
Alain Didier,
David H Persing,
Mike Bates,
Bernard Michot
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ABSTRACT: RNU2 exists in two functional forms (RNU2-1 and RNU2-2) distinguishable by the presence of a unique 4-bases motif. Detailed investigation of datasets obtained from deep sequencing of five human lung primary tumors revealed that both forms express at a high rate a 19-22nt fragment (miR-U2-1 and -2) from its 3' region and contains the 4-bases motif. Deep sequencing of independent pools of serum samples from healthy donors and lung cancer patients revealed that miR-U2-1 and -2 are pervasively processed in lung tissue by means of endonucleolytic cleavages and stably exported to the blood. Then, microarrays hybridization experiments of matched normal/tumor samples revealed a significant over-expression of miR-U2-1 in 14 of 18 lung primary tumors. Subsequently, qRT-PCR of miR-U2-1 using serum from 62 lung cancer patients and 96 various controls demonstrated that its expression levels identify lung cancer patients with 79% sensitivity and 80% specificity. miR-U2-1 expression correlated with the presence or absence of lung cancer in patients with chronic obstructive pulmonary disease (COPD), other diseases of the lung - not cancer, and in healthy controls. These data suggest that RNU2-1 is a new bi-functional ncRNA that produces a 19-22nt fragment which may be useful in detecting lung cancer non-invasively in high risk patients.
PLoS ONE 01/2013; 8(3):e60134. · 4.09 Impact Factor
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Isabelle Rouquette,
Valérie Lauwers-Cances,
Camille Allera,
Laurent Brouchet,
Julie Milia,
Yvan Nicaise,
Julie Laurent,
Marie-Bernadette Delisle,
Gilles Favre,
Alain Didier, Julien Mazières
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ABSTRACT: Based on epidemiological, clinical, and preclinical data, lung carcinogenesis can be distinctive in women, suggesting that women should be treated differently depending on the expression of various specific biomarkers. We aimed to describe the hormonal and genetic profile of lung cancer in both men and women to identify gender specificities. Primary lung-tumor tissues from surgically treated patients, (50 men, 50 women) were analyzed and compared for expression of estrogen receptors (ER) α and β, progesterone receptors (PR), epidermal growth-factor receptor (EGFR), and HER2 (for EGFR and K-Ras mutations). These data were combined with clinical and outcome data. Fewer women with lung cancer were smokers (p=0.001) and they smoked fewer cigarettes (p=0.001). We observed a higher rate of EGFR mutations (p=0.02) and ERα expression (p=0.006) in women. ERβ and EGFR were also expressed more frequently in women (p=0.29 and p=0.16). HER2 was overexpressed regardless of gender in three men and two women. K-Ras was mutated in 16% of both men and women. Interestingly, there was a positive link between EGFR expression and expression of ERα (p=0.028) and ERβ (p=0.047) in both men and women. Expression of ERα was associated with improved disease-free survival (p=0.007). Our findings provide further evidence on the specificities of lung cancer in women. The differential expression of specific biomarkers, which could be targeted by therapy, favors the development of gender-based treatment guided by biomarker expression.
Lung cancer (Amsterdam, Netherlands) 12/2011; 76(3):280-5. · 3.14 Impact Factor
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ABSTRACT: Biological therapies targeted at bronchial cancer have a mode of action different from that of the various types of chemotherapies and are therefore associated with different types of toxicity. EGFR inhibitors cause mainly cutaneous toxicity, which can be controlled by cyclin and local care. Antiangiogenic agents increase the risk of arterial thrombosis and the risk of minor (nosebleeds) or severe (hemoptysis) bleeding. Hypertension is also a frequent side effect, generally controlled by standard antihypertensive treatment, preferably calcium channel blockers or angiotensin-converting enzyme inhibitors. Combined management by an oncologist, specialists in the relevant organs (lungs, heart, and skin) and a general practitioner is essential for optimal management of these frequent but rarely severe drug events.
La Presse Médicale 03/2011; 40(4 Pt 1):415-9. · 0.67 Impact Factor
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ABSTRACT: Chronic immunosuppression after solid-organ transplantation is associated with increased risk of developing malignancies. The purpose of this study was to determine the clinical characteristics and the outcome of thoracic malignancies in patients who have undergone solid-organ transplantation.
Among a cohort of 2831 patients who received a transplant at our institution and were followed between 1984 and 2009, 24 patients (0.85%) developed thoracic malignancies. Risk factors for lung cancer, as well as demographic, cancer, and transplantation characteristics, were analyzed. Survival data were also collected.
Twenty-four patients were included (21 men, median age 61.7 years). Twenty-two patients were smokers. The most frequent histologic types were squamous cell carcinoma (n = 11, 46%) and adenocarcinoma (n = 9, 37%). The median time period between transplantation and diagnosis of lung cancer was 6.6 years. Ten lung malignancies occurred after kidney transplantation (0.5%), eight after liver transplantation (1.3%), and six after heart transplantation (2.8%). Seven patients underwent surgery, three had radiotherapy, four had chemotherapy, and six had multimodal treatment. The median survival time was 1.5 years, ranging from 6 months for stage IV to 3.7 years for stage I.
Solid-organ transplantation is associated with a high risk of lung cancer and may have an important synergetic part with other risk factors for lung cancer (tobacco). However, survival rates from lung cancer in our study population are similar to those of nontransplanted patients. In addition, surgery can result in favorable survival results.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 11/2010; 5(11):1789-95. · 4.55 Impact Factor
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ABSTRACT: Lung cancer is the leading cause of cancer-related death worldwide, mainly due to its highly metastatic properties. Previously, we reported an inverse correlation between RhoB expression and the progression of the lung cancer, occurring between preinvasive and invasive tumors. Herein, we mimicked the loss of RhoB observed throughout lung oncogenesis with RNA interference in nontumoral bronchial cell lines and analyzed the consequences on both cell transformation and invasion. Down-regulation of RhoB did not modify the cell growth properties but did promote migration and invasiveness. Furthermore, RhoB depletion was accompanied by modifications of actin and cell adhesion. The specific activation of the Akt1 isoform and Rac1 was found to be critical for this RhoB-mediated regulation of migration. Lastly, we showed that RhoB down-regulation consecutive to K-RasV12 cell transformation is critical for cell motility but not for cell proliferation. We propose that RhoB loss during lung cancer progression relates to the acquisition of invasiveness mediated by the phosphatidylinositol 3-kinase (PI3K)/AKT and Rac1 pathways rather than to tumor initiation.
Cancer Research 09/2009; 69(15):6092-9. · 7.86 Impact Factor
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ABSTRACT: No biologic signature of chemoradiotherapy sensitivity has been reported for patients with locally advanced non-small-cell lung cancer (NSCLC). We have previously demonstrated that basic fibroblast growth factor (FGF-2) and alphavbeta3 integrin pathways control tumor radioresistance. We investigated whether the expression of the proteins involved in these pathways might be associated with the response to treatment and, therefore, the clinical outcome.
FGF-2, beta3 integrin, angiopoietin-2, and syndecan-1 expression was studied using immunohistochemistry performed on biopsies obtained, before any treatment, from 65 patients exclusively treated with chemoradiotherapy for locally advanced NSCLC. The response to treatment was evaluated according to the Response Evaluation Criteria in Solid Tumors criteria using computed tomography at least 6 weeks after the end of the chemoradiotherapy. Local progression-free survival, metastasis-free survival, and disease-free survival were studied using the log-rank test and Cox proportional hazard analysis.
Among this NSCLC biopsy population, 43.7% overexpressed beta3 integrin (beta3(+)), 43% FGF-2 (FGF-2(+)), 41.5% syndecan-1, and 59.4% angiopoietin-2. Our results showed a strong association between FGF-2 and beta3 integrin expression (p = .001). The adjusted hazard ratio of local recurrence for FGF-2(+)/beta3(+) tumors compared with FGF-2(-)/beta3(-) tumors was 6.1 (95% confidence interval, 2.6-14.6, p = .005). However, the risk of local recurrence was not increased when tumors overexpressed beta3 integrin or FGF-2 alone. Moreover, the co-expression of these two proteins was marginally associated with the response to chemoradiotherapy and metastasis-free survival.
The results of this study have identified the combined profile FGF-2/beta3 integrin expression as a signature of local control in patients treated with chemoradiotherapy for locally advanced NSCLC.
International journal of radiation oncology, biology, physics 05/2009; 75(3):696-702. · 4.59 Impact Factor
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ABSTRACT: Adenoid cystic carcinoma (ACC) is a common head and neck tumor originating from salivary glands but that can also exceptionally develop in the trachea and major bronchi. ACC is generally considered as a slow-growing, low-grade malignancy with prolonged clinical course. Metastases are very unusual and recurrences are more often local. Treatment for localized ACC is surgery. We here report for the first time a case of lung ACC with a synchronous liver metastasis proved by biopsy. Moreover, we report the interest of performing a 18FDG PET-CT as both primary tumor and liver metastasis presented an intense FDG uptake. The specificity of the liver 18FDG uptake was confirmed by Glut-1 positive immunostaining. We propose that 18FDG PET-CT should be considered in the initial staging of lung ACC in selected patients.
Lung Cancer 02/2008; 59(1):133-6. · 3.43 Impact Factor
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Laurent Brouchet,
Eric Bauvin,
Bertrand Marcheix,
Laurence Bigay-Game,
Claire Renaud,
Jean Berjaud,
Pierre Emmanuel Falcoze,
Nicolas Venissac,
Dan Raz,
David Jablons, Julien Mazières,
Marcel Dahan
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ABSTRACT: A main drawback of neoadjuvant chemotherapy is that it may increase operative morbidity and mortality. The aim of this study was to determine the impact of chemotherapy on these complications.
Patient data were collected from the Epithor database. From June 2002 to June 2004, 3888 successive observations of surgery for lung cancer have been reported from 51 thoracic surgery departments throughout France. Logistic regression analysis was performed to identify preoperative clinical characteristics of patients with significant postoperative complications.
Of 3888 patients, 555 (14.3%) received induction chemotherapy. The groups were similar with respect to sex and the number of comorbidities. The in-hospital mortality rate was 3.01%. The multivariate analysis allows us to identify age (older than 65 years), sex (male), preoperative clinical score (moderate and severe), surgical procedure (right pneumonectomy and bilobectomy) as significantly associated with in-hospital mortality. No statistical difference was observed according to the delivery or preoperative chemotherapy. In total, 1219 patients (31.4%) had at least one postoperative complication. Using a multivariate analysis, we observed a significant correlation between morbidity and age (older than 65 years), sex (male), presence of comorbidities (two or more), clinical score (moderate), and type of operation (bilobectomy). Preoperative administration of chemotherapy did not significantly influenced postoperative morbidity.
Preoperative chemotherapy is not associated with an increase in either the mortality rate or major surgical complications. Future randomized trials are warranted to confirm the survival benefit of this strategy.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 08/2007; 2(7):626-31. · 4.55 Impact Factor
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ABSTRACT: RhoB is down-regulated in most lung cancer cell lines and tumor tissues when compared with their normal counterparts. The mechanism of this loss of expression is not yet deciphered.
Since no mutation has been reported in the RhoB sequence, we investigated the epigenetic regulation of RhoB expression by analyzing the effect of HDAC inhibitors and methyltransferase inhibitors, by direct sequencing after bisulfite treatment and by methylation specific PCR.
We first showed that histone deacetylase (HDAC) inhibitors induce a significant RhoB re-expression in lung cancer cell lines whereas only a slight effect was observed with methyl transferase inhibitors. As promoter methylation is the most common epigenetic process in lung cancer, we performed methylation specific PCR and sequence analysis after bisulfite treatment and demonstrated that RhoB was methylated neither in lung cancer cell lines nor in tumor tissues. We also showed that a variable number of tandem repeats sequences in the 5' region of the RhoB gene was involved in HDAC response.
We thus propose that RhoB regulation of expression occurs mainly by histone deacetylation rather than by promoter hypermethylation and that this process can be modulated by specific 5' sequences within the promoter.
BMC Cancer 02/2007; 7:220. · 3.01 Impact Factor
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ABSTRACT: RhoB is a low molecular weight GTPase that is both farnesylated (RhoB-F) and geranylgeranylated (RhoB-GG) in cells. Based on data from rodent cell models, it has been suggested that RhoB displays differential effects on cell transformation, according to the nature of its prenylation. To test directly this hypothesis, we generated GTPase-deficient RhoB mutants that are exclusively either farnesylated or geranylgeranylated. We show that in Ras-transformed murine NIH-3T3 cells, RhoB-F enhances, whereas RhoB-GG and RhoB (F/GG) suppresses anchorage-dependent and -independent cell growth as well as tumor growth in nude mice. We then demonstrate that Ras constitutive activation of the tumor survival pathways Akt and NF-kappa B are blocked by RhoB-GG, but not by RhoB-F, providing further support for the opposing role of RhoB-F and RhoB-GG in Ras malignant transformation in NIH-3T3 cells. In addition, both RhoB (F/GG) and RhoB-GG induce apoptosis in Ras-transformed NIH-3T3 cells whereas RhoB-F has no effect. Our data demonstrate that RhoB-F and RhoB-GG which differ only by a 5-carbon isoprene behave differently in rodent cells highlighting the important role of prenyl groups in protein function and emphasize the potency of RhoB to regulate negatively the oncogenic signal.
Experimental Cell Research 05/2005; 304(2):354-64. · 3.58 Impact Factor
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ABSTRACT: Streptococcus pneumoniae is the most commonly identified pathogen in patients with community-acquired pneumonia. 40% of isolated strains in France are of decreased sensibility to penicillin, two third being multiresistant to antibiotics. However, high doses of some beta-lactams are effective in vivo against the majority of circulating strains (MIC > 2 mg/L). For this reason according to French guidelines amoxicillin (3 g/day) is the first line recommended treatment. Telithromycin is an alternative, or ceftriaxone (1 g/day) in more severe cases. If the level of resistance increases (MIC > 4 mg/L) guidelines would be revisited. Effectiveness of pneumococcal vaccination has been confirmed in cases of bacteriemic pneumococcal pneumonia (elderly patients included). Vaccine is recommended among persons with comorbiditie(s) and 65 years old population.
La Revue du praticien 09/2003; 53(13):1451-7.
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ABSTRACT: Some patients exhibiting severe multisegmental bilateral bronchiectasis are no longer improved with antibiotic treatment and drainage and, most of the time, operation is contraindicated. In our institution, limited operation has been offered to select patients for this indication. We report our data regarding the feasibility and utility of such a procedure.
We studied 16 patients who underwent surgical removal of nonlocalized disease between 1990 and 1999. We report the mortality and morbidity rates of this surgical procedure and the clinical, bacteriological, and functional data for each patient.
There was no mortality and the morbidity was low (18%, all with favorable outcome). Symptoms such as hemoptysis, sputum production, or dyspnea were also improved. The recurring infections decreased in frequency in 8 patients and disappeared completely in 5 others. The bacteriological data assessment revealed disappearance of germs in 4 patients and persistence of chronic colonization in others. Postoperative spirometric data were not worsened and postoperative computed tomographic scans did not show progression of lesions not removed.
These results suggest that, in properly selected patients, lasting symptomatic improvement can be achieved by resection. Limited operation may be indicated in nonlocalized bilateral bronchiectasis, provided that a target can be identified. This procedure is supported by physiopathologic arguments and is particularly relevant to patients with bronchiectasis with cystic and functionless territories.
The Annals of Thoracic Surgery 03/2003; 75(2):382-7. · 3.74 Impact Factor
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ABSTRACT: The fact that proteins such as Ras require farnesylation to induce malignant transformation prompted many investigators to design farnesyl transferase inhibitors (FTI) as novel anticancer drugs. FTIs inhibit the growth of ras transformed cells in vitro and induce tumor regression in ras dependent tumor in vivo. Moreover, FTIs inhibit tumor progression in human tumor xenograft models. Currently, FTIs are undergoing phase I and II trials in various cancer types. They show impressive antitumour efficacy and they lack toxicity. Despite these promising results, the development of such molecules in hindered by the absence of appropriate clinical endpoints and of surrogate biological markers. Indeed, it seems likely that Ras is not the critical target of FTIs and that inhibition of the farnesylation of proteins such as RhoB, might also contribute to the observed antitumour properties. Identification of targets that underlie their biological effect is essential in order to predict and evaluate their efficacy.
Medecine sciences: M/S 03/2003; 19(2):211-6. · 0.64 Impact Factor
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ABSTRACT: Large cell neuroendocrine carcinoma of the lung (LCNEC) has been recently redefined by the World Health Organisation (WHO) classification but the appropriate treatment remains unclear. We reviewed 18 consecutive resected cases of LCNEC. Two pathologists assessed diagnosis by applying rigorously the last WHO criteria. We reported the pathological features and the clinical outcome of this particular tumour. All patients were men with a median age of 63 years. Clinicopathologic stages corresponded to stage I (n = 8), II (n = 8) and IIIA (n = 2). All patients were treated as non-small cell lung carcinoma (NSCLC) and underwent surgery without any adjuvant treatment except four post-operative radiotherapy for N2 or T3 disease. The evolution was pejorative for 14 patients: one patient died of post-operative complications and 13 patients relapsed with distant metastases that occurred in 10 cases within 6 months after surgery. One-year survival rate was 27% and survival rate at the end of follow-up was 22%, which were both less than expected for stage-comparable NSCLC. Survival was neither influenced by lymph node status nor by pathological or molecular findings. Among the 10 evaluable patients with metastatic disease that received palliative platin-etoposide chemotherapy only two had partial tumour regressions (20%). Our study suggests that applying to LCNEC the NSCLC standard treatment lead to poor prognosis even in localised disease with a high incidence of early metastatic spread and a low response rate to chemotherapy. This way of relapse underlies the necessity of an efficient chemotherapy in order to improve survival.
Lung Cancer 10/2002; 37(3):287-92. · 3.43 Impact Factor
