Publications by authors named "Stéphanie Lacomme"

15 Publications

  • Page 1 of 1

Somatostatin analogue pasireotide (SOM230) inhibits catecholamine secretion in human pheochromocytoma cells.

Cancer Lett 2021 Oct 9. Epub 2021 Oct 9.

Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, F-67000, Strasbourg, France. Electronic address:

Increasingly common, neuroendocrine tumors (NETs) are regarded nowadays as neoplasms potentially causing debilitating symptoms and life-threatening medical conditions. Pheochromocytoma is a NET that develops from chromaffin cells of the adrenal medulla, and is responsible for an excessive secretion of catecholamines. Consequently, patients have an increased risk for clinical symptoms such as hypertension, elevated stroke risk and various cardiovascular complications. Somatostatin analogues are among the main anti-secretory medical drugs used in current clinical practice in patient with NETs. However, their impact on pheochromocytoma-associated catecholamine hypersecretion remains incompletely explored. This study investigated the potential efficacy of octreotide and pasireotide (SOM230) on human tumor cells directly cultured from freshly resected pheochromocytomas using an implemented catecholamine secretion measurement by carbon fiber amperometry. SOM230 treatment efficiently inhibited nicotine-induced catecholamine secretion both in bovine chromaffin cells and in human tumor cells whereas octreotide had no effect. Moreover, SOM230 specifically decreased the number of exocytic events by impairing the stimulation-evoked calcium influx as well as the nicotinic receptor-activated inward current in human pheochromocytoma cells. Altogether, our findings indicate that SOM230 acts as an inhibitor of catecholamine secretion through a mechanism involving the nicotinic receptor and might be considered as a potential anti-secretory treatment for patients with pheochromocytoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2021.10.009DOI Listing
October 2021

Prognostic Value of Histopathological Features and Loss of H3K27me3 Immunolabeling in Anaplastic Meningioma: A Multicenter Retrospective Study.

J Neuropathol Exp Neurol 2020 07;79(7):754-762

Sorbonne Universités, INSERM, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle Épinière, Paris, France.

The diagnosis of anaplastic meningioma (AM) (WHO grade III) is based on the presence of a high mitotic index (MI) and/or overt anaplasia. Only few data exist about the reproducibility and prognostic value of overt anaplasia. Additionally, the prognostic value of H3K27me3 loss in AM has not yet been demonstrated. Our objectives were to evaluate the reproducibility and prognostic value of WHO criteria and H3K27me3 loss in a multicenter series of 66 AM. Interobserver reproducibility was good for the determination of WHO grade (Kappa = 0.671) and MI (intraclass correlation coefficient [ICC] = 0.649), and fair for assessment of overt anaplasia (Kappa = 0.366). Patients with meningiomas showing high MI had significantly shorter overall survival (OS) than patients with meningiomas showing overt anaplasia without high MI (p = 0.009). OS was significantly lower in case of overt anaplasia with low MI (<20/1.6 mm2) than in atypical meningiomas (p = 0.008). H3K27me3 loss was present in 10/47 (21%) of AM and independently associated with shorter OS (p = 0.036; Cox multivariate analysis), with a good reproducibility (Kappa = 0.643). In conclusion, the presence of overt anaplasia could give additional prognostic information in tumors lacking high MI. Finally, loss of H3K27me3 is an easy-to-use and reproducible marker of poorer prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnen/nlaa038DOI Listing
July 2020

Redefining malignant pleural mesothelioma types as a continuum uncovers immune-vascular interactions.

EBioMedicine 2019 Oct 21;48:191-202. Epub 2019 Oct 21.

Toulouse University Hospital, Toulouse, France.

Background: Malignant Pleural Mesothelioma (MPM) is an aggressive disease related to asbestos exposure, with no effective therapeutic options.

Methods: We undertook unsupervised analyses of RNA-sequencing data of 284 MPMs, with no assumption of discreteness. Using immunohistochemistry, we performed an orthogonal validation on a subset of 103 samples and a biological replication in an independent series of 77 samples.

Findings: A continuum of molecular profiles explained the prognosis of the disease better than any discrete model. The immune and vascular pathways were the major sources of molecular variation, with strong differences in the expression of immune checkpoints and pro-angiogenic genes; the extrema of this continuum had specific molecular profiles: a "hot" bad-prognosis profile, with high lymphocyte infiltration and high expression of immune checkpoints and pro-angiogenic genes; a "cold" bad-prognosis profile, with low lymphocyte infiltration and high expression of pro-angiogenic genes; and a "VEGFR2+/VISTA+" better-prognosis profile, with high expression of immune checkpoint VISTA and pro-angiogenic gene VEGFR2. We validated the gene expression levels at the protein level for a subset of five selected genes belonging to the immune and vascular pathways (CD8A, PDL1, VEGFR3, VEGFR2, and VISTA), in the validation series, and replicated the molecular profiles as well as their prognostic value in the replication series.

Interpretation: The prognosis of MPM is best explained by a continuous model, which extremes show specific expression patterns of genes involved in angiogenesis and immune response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2019.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838392PMC
October 2019

Ki-67 and MCM6 labeling indices are correlated with overall survival in anaplastic oligodendroglioma, IDH1-mutant and 1p/19q-codeleted: a multicenter study from the French POLA network.

Brain Pathol 2020 05 10;30(3):465-478. Epub 2019 Oct 10.

Department of Pathology, CHRU, Nancy, France.

Anaplastic oligodendroglioma (AO), IDH-mutant and 1p/19q codeleted (IDHmut+/1p19qcodel), is a high-grade glioma with only limited prognostic markers. The primary objective of this study was to evaluate, by immunohistochemistry, the prognostic value of two proliferation markers, MCM6 and Ki-67, in a large series of IDHmut+/1p19qcodel AO included in the POLA ("Prise en charge des Oligodendrogliomes Anaplasiques") French national multicenter network. We additionally examined the transcriptome obtained from this series to understand the functional pathways dysregulated with the mRNA overexpression of these two markers. The labeling indices (LI) of MCM6 and Ki-67 were obtained via computer-assisted color image analyses on immunostained AO tissues of the cohort (n = 220). Furthermore, a subgroup of AO (n = 68/220) was used to perform transcriptomic analyses. A high LI of either MCM6 (≥50%) or Ki-67 (≥15%) correlated with shorter overall survival, both in univariate (P = 0.013 and P = 0.004, respectively) and multivariate analyses (P = 0.027; multivariate Cox model including age, mitotic index, MCM6 and Ki-67). MCM6 and Ki-67 LI also correlated with overall survival in an additional retrospective cohort of 30 grade II IDHmut+/1p19qcodel oligodendrogliomas. The prognostic value of MCM6 mRNA level was confirmed in The Cancer Genome Atlas (TCGA) IDHmut+/1p19qcodel gliomas. The transcriptomic approach revealed that high transcriptional expressions of MCM6 and MKI67 were both linked positively with cell cycle progression, DNA replication, mitosis, pro-neural phenotype as well as neurogenesis, and negatively with microglial cell activation, immune response, positive regulation of myelination, oligodendrocyte development, beta-amyloid binding and postsynaptic specialization. In conclusion, the overexpression of MCM6 and/or Ki-67 is independently associated to shorter overall survival in IDHmut+/1p19qcodel AO. These two easy-to-use and cost-effective markers could thus be used concurrently in routine pathology practice. Additionally, the transcriptomic analyses showed that AO with high proliferation index have down-regulated immune response and lower microglial cells activation, and bears pro-neural phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bpa.12788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018020PMC
May 2020

[Use of the PELICAN software for the creation and export of standardized pathology reports in central nervous system tumors: Example of meningiomas].

Ann Pathol 2019 Dec 8;39(6):414-424. Epub 2019 Mar 8.

Service d'anatomie et cytologie pathologiques, hôpital Central, CHRU de Nancy, 29, avenue du Maréchal-de-Lattre-de-Tassigny, 54000 Nancy, France; Centre de ressources biologiques BB-0033-00035, CHRU de Nancy, 54000 Nancy, France; Inserm U1256, équipe 3 MIGB, NGERE, université de Lorraine, 54500 Vandœuvre-lès-Nancy, France. Electronic address:

Introduction: PELICAN ("Partager Efficacement en Laboratoire les Informations des Comptes rendus ANatomopathologiques") is a software, which generates standardized reports, and allows to automatically create a database. It has been used in central nervous system tumor pathology at the University Hospital of Nancy since 2014. The purpose of this article was to illustrate the use of this application for meningiomas, with a first statistical evaluation.

Materials And Methods: The export of data included all cases of meningiomas recorded in the PELICAN application until July 2018. The PELICAN application is a Microsoft Excel file containing a software, written in Visual Basic for Applications, and used by the pathologist to create the report. The main clinical data were collected from the Hérault Register census form. Follow-up was systematically reported for atypical meningiomas.

Results: Two hundred and ninety-five meningiomas were analyzed, including 250 grade I meningiomas, 42 grade II meningiomas, and 3 grade III meningiomas. Grade II meningiomas were characterized by a significantly higher proportion of men (P=0.002) and dural infiltration (P<0.001), a significant increase in the Ki-67 index (P<0.0001), and a significant decrease in progesterone receptor expression (P<0.001). In atypical meningiomas, a Ki-67 index of more than 20 % was significantly correlated with a shorter progression-free survival (P=0.032).

Conclusion: The PELICAN software is an easy-to-use tool that allows to generate standardized reports and feed a database, opening very interesting perspectives from an epidemiological and scientific point of view.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.annpat.2019.01.016DOI Listing
December 2019

[Development and deployment of a standardized pathology report in lung cancer, basing on a data management software: The PELICAN software].

Ann Pathol 2019 Apr 6;39(2):87-99. Epub 2019 Feb 6.

Service d'anatomie et cytologie pathologiques, hôpital Central, CHRU de Nancy, 29, avenue du Maréchal-De-Lattre de Tassigny, 54000 Nancy, France; Centre de ressources biologiques BB-0033-00035, CHRU de Nancy, 54000 Nancy, France; INSERM U1256, équipe 3 MIGB, NGERE, université de Lorraine, 54500 Vandoeuvre-Les-Nancy, France. Electronic address:

Introduction: PELICAN (« Partager Éfficacement en Laboratoire les Informations des Comptes rendus ANatomopathologiques ») is a software which generates standardized reports and, in parallel, allows to automatically create a database that can be used for research purpose. This application has been used in our laboratory since 2014 for central nervous system tumors. The aim of this work was to extend it to another type of tumor, lung cancer.

Materials And Methods: The content of the pathology reports was previously defined using various standards (Société Française de Pathologie, Institut National du Cancer, WHO Classification 2015, …). A double codification was used with SNOMED and ADICAP codes. The PELICAN application is a Microsoft Excel file containing a software specifically developed for pathology laboratories, written in Visual Basic for Applications and respecting the CDA-R2 standard.

Results: After definition of the software specifications, a beta-version was installed in February 2018. After various updates, the 3.19 version was installed in July 2018. Almost all lung cancer surgical pathology reports are now generated with the PELICAN software; a total of 56 reports were validated at the time of writing this manuscript. The medical time for the generation of the report was globally the same or decreased for some pathologists. The secretarial time was greatly reduced.

Conclusion: The PELICAN software is an easy to use tool that allows to generate standardized reports in pulmonary pathology and to feed a database that can be easily used for statistical purposes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.annpat.2018.12.001DOI Listing
April 2019

Survival Impact of Stations of Pathological Lymph Nodes in N2 Non-small Cell Lung Cancer in a French Hospital.

Ann Surg Oncol 2018 May 14;25(5):1262-1268. Epub 2018 Feb 14.

Chest Department, University Hospital, Nancy, France.

Background: The prognosis of lung cancer remains poor; only 20% of patients can undergo surgery. N2 non-small cell lung cancer (NSCLC) is a heterogeneous disease. We conducted a retrospective study to analyze the impact of N2 location on survival.

Methods: This study included 342 NSCLC with N2 involvement between 1988 and 2014. Patient-related data were collected through the CRB biobank and included demographic, therapeutic, and survival data. Survival was analyzed according to Kaplan-Maier method. Cox's regression analysis and analysis of variance (ANOVA) were used to determine factors significantly associated with survival.

Results: The population average age was 61.6 years; 82.2% were men, a majority were former smokers (87.1%), and 45.3% had adenocarcinoma. The main prognostic factors were male gender (p = 0.01), number of nodes (p < 0.0001), and tumor size (p < 0.0001). N2 disease had a poor survival (16 months) compared with N0 (32 months) and N1 (21.1 months) disease (p < 0.0001). The patients with involvement of station 4 (survival = 17.8 months) seemed to have a prognosis between those with station 7 (survival = 10.5 months) and N1 (survival = 22.6 months), p = 0.0005.

Conclusions: N2 location has a prognostic impact in surgically NSCLC, and station 4 involvement has a better prognostic than station 7.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-018-6373-1DOI Listing
May 2018

Expression of neurotensin receptor 1 in endometrial adenocarcinoma is correlated with histological grade and clinical outcome.

Virchows Arch 2017 Oct 24;471(4):521-530. Epub 2017 Aug 24.

INSERM U954, Université de Lorraine, Vandœuvre-lès-Nancy, France.

The promalignant effects of neurotensin (NTS) are sustained in many solid tumors, including hormone-dependent cancers. As the endometrium is also subjected to hormonal regulation, we evaluated the contribution of NTS to endometrial carcinogenesis. Neurotensin receptor 1 (NTSR1) expression and NTSR1 promoter methylation (HM450) were analyzed in 385 cases of endometrial carcinoma from The Cancer Genome Atlas (TCGA). Additionally, from a series of 100 endometrial carcinomas, and 66 benign endometrium samples, NTS and NTSR1 labeling was evaluated by immunohistochemistry. Using TCGA series, NTSR1 messenger RNA (mRNA) level was negatively correlated with overall survival (OS) and progression-free survival (PFS) (p = 0.0012 and p = 0.0116, respectively), and positively correlated with the grade (p = 0.0008). When including only endometrioid carcinomas, NTSR1 mRNA level continued to be negatively correlated with OS (log-rank: p < 0.0001) and PFS (log-rank: p = 0.002). A higher NTSR1 mRNA level was significantly associated with a loss of NTSR1 promoter methylation. Immunohistochemical expression of NTS and NTSR1 was significantly increased in adenocarcinoma (n = 100), as compared to benign endometrium (p < 0.001). NTSR1 expression was positively correlated with grade (p = 0.004). High immunohistochemical expression of cytoplasmic NTSR1 was significantly correlated with a shorter OS and PFS (p < 0.001 and p = 0.001, respectively). This correlation remained significant when excluding non-endometrioid subtypes (p = 0.04 and p = 0.02, respectively). In multivariate analysis, the expression of NTSR1 was an independent prognostic factor (p = 0.004). NTSR1 overexpression is a poor prognostic factor in endometrial cancer, highlighting the contribution of NTS in endometrial cancer progression and its uses as a prognostic marker, and as a potential therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00428-017-2215-yDOI Listing
October 2017

Methyl(R217)HuR and MCM6 are inversely correlated and are prognostic markers in non small cell lung carcinoma.

Lung Cancer 2015 Aug 16;89(2):189-96. Epub 2015 May 16.

Department of Pathology, CHU Nancy, France; INSERM U954, Faculty of Medicine, Université de Lorraine, Nancy, France. Electronic address:

Objectives: In non small cell lung carcinoma (NSCLC), earlier studies supported a prognostic value of intra-cytoplasmic HuR expression. HuR is a RNA binding protein previously shown to stimulate proliferation, but the link between HuR and proliferation in NSCLC has not yet been evaluated. The first objective of this study was to analyze the expression of HuR in a series of NSCLC and to correlate this to two proliferation markers, Ki-67 and MCM6. As potential post-transcriptional regulatory mechanisms for HuR expression, two miRNAs, miR16 and miR519, were also analyzed. Finally, because HuR methylation could be involved in its nucleocytoplasmic shuttling, the expression of methyl(R217)HuR and its relation to cancer survival were determined.

Materials And Methods: Immunohistochemistry was used to evaluate the expression of HuR, methy(R217)HuR, Ki-67 and MCM6 in a series of 190 NSCLCs. The level of miR16 and miR519 was determined by qRT-PCR.

Results: Higher cytoplasmic HuR staining was found in tumor vs. control paired normal lung (p<0.0001), but without correlation with survival. The level of methyl(R217)HuR was correlated both significantly with intra-cytoplasmic HuR staining (p<0.001), and overall survival (p=0.01). MCM6 correlated to a poorer overall survival (p<0.01). Both MCM6 and Ki-67 were positively correlated with HuR nuclear staining (p<0.0001 and p<0.001, respectively). On the contrary, MCM6 and Ki-67 correlated inversely to methyl(R217)HuR (p<0.001 and p=0.01, respectively). The levels of miR16 and miR519 were significantly lower in tumor tissue vs. paired normal lung (p<0.0001), but only miR519 correlated inversely to HuR expression (p=0.01).

Conclusion: While overall cytoplasmic HuR level was higher in tumor tissues, we found unexpectedly that methyl(R217)HuR was a marker of good prognosis. Furthermore, our data suggest that HuR level could be regulated by miR519. Finally, we demonstrated that Ki-67 and MCM6, both correlated with HuR, are valuable markers of poor prognosis in NSCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2015.05.008DOI Listing
August 2015

Retinoid acid receptor expression is helpful to distinguish between adenoma and well-differentiated carcinoma in the thyroid.

Virchows Arch 2013 Jun 4;462(6):619-32. Epub 2013 May 4.

Department of Pathology, CHU, Nancy, France.

Retinoid receptors (RRs) play a key role in cell proliferation and differentiation. We characterized the expression of RA receptors and retinoid X receptors (RARs and RXRs) in a series of 111 thyroid tumors and investigated the mechanisms responsible for their deregulation: hypermethylation of the RARB2 promoter, loss of heterozygosity (LOH) in the regions of RARB and RXRA, and altered expression of CRBP1 and enzymes involved in RA biosynthesis (RDH10 and RALDH2). Expression of RALDH2 and RDH10 was conserved in 100 % of adenomas and in 90 and 98 %, respectively, of carcinomas, whereas staining for CRBP1 was decreased in 9 % of FAs and 28 % of carcinomas, mainly anaplastic carcinomas (55 %). We found an abnormal expression of RARA, RARB, RXRA, and RXRB in 67, 69, 66, and 73 %, respectively, of thyroid carcinomas (n = 78) and in 9, 9, 9, and 33 % of follicular adenomas (n = 33) (p < 0.001). An abnormal staining pattern of at least two of these markers had 90 % sensitivity and 91 % specificity for a diagnosis of malignancy. Promoter hypermethylation of RARB2 was observed in some anaplastic carcinomas (14 %). LOH was found to be common at the RARB locus (3p24-3p25) and the RXRA locus (9q34), respectively, in 44 and 55 % of carcinomas and in 27 and 43 % of adenomas. In conclusion, immunohistochemical staining for RARs and RXRs may help in the differential diagnosis between well-differentiated carcinoma and follicular adenoma. Further investigation should be carried out to determine whether the characterization of RR expression might identify patients who could benefit from therapy with RA derivatives.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00428-013-1419-zDOI Listing
June 2013

DNA methylation associated with polycomb repression in retinoic acid receptor β silencing.

FASEB J 2013 Apr 8;27(4):1468-78. Epub 2013 Jan 8.

CNRS-Pierre Fabre, Unité de Service et de Recherche 3388, Epigenetic Targeting of Cancer, Centre de Recherche et Développement Pierre Fabre, Toulouse, France.

Retinoic acid receptor β 2 (RARβ2) is a tumor suppressor gene whose loss of expression is recurrent in prostate cancers. Here we studied the epigenetic mechanisms leading to its stable silencing. First, we characterized all RARβ isoforms in 6 human tumor cell lines (prostate DU145, LNCaP, PC3, lung A549, breast Hs578T, and colon HCT116) by RT-PCR and Western blot. We excluded loss of heterozygosity (2D-FISH) and loss of RARa expression, an upstream regulator, as origin of RARβ2 silencing. All data concluded to an epigenetic silencing. In agreement, a DNA methylation inhibitor restored its expression. Second RARβ2 loss of expression was found associated with different epigenetic profiles in LNCaP and DU145 cells. According to bisulfite sequencing and ChIP analysis, we observed heavy methylation (97%) of the RARβ2 promoter with repressive histone mark H3K9me3 in LNCaP. While DNA methylation and polycomb repression are described to be mutually exclusive at CpG-rich promoters, we observed that in DU145, moderate DNA methylation (36%) and H3K9me3 mark were present concomitantly with H3K27me3, a signature of polycomb repression. In summary, we provide new insights on how the RARβ2 promoter is silenced, reveal the existence of two distinct repressive chromatin profiles at the same locus, and support a polycomb-mediated epigenetic repression process in prostate cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.12-210971DOI Listing
April 2013

BRAF, p53 and SOX2 in anaplastic thyroid carcinoma: evidence for multistep carcinogenesis.

Pathology 2011 Aug;43(5):447-52

Department of Pathology, Hôpital Central, CHU, Nancy, France.

Aims: The aim of this study was to genotype a series of papillary thyroid carcinomas (PTCs) and anaplastic thyroid carcinomas (ATCs) for BRAF mutation, and to evaluate p53 and SOX2 expression as factors implicated in tumour progression.

Methods: The study included 17 PTCs and 14 ATCs. Analysis of the exon 15 of BRAF was based on direct sequencing. Immunohistochemistry was used to evaluate p53 and SOX2 expression.

Results: V600E (c.1799T>A) mutation was observed in 53% (9/17) of PTCs. Two cases of ATCs (2/14; 14%), both with PTC component, harboured BRAF mutation: the classical V600E mutation and an undocumented duplication of codon 599 (c.1795_1797dup; p.Thr599dup). These mutations were present in ATC as well as PTC tumour cells. Overexpression of p53 and SOX2 was depicted respectively in 64% (9/14) and 29% (4/14) of ATCs, and absent in PTCs.

Conclusion: We confirm that V600E mutation is a frequent and specific event in PTC. BRAF-mutated ATCs are associated with a PTC component displaying the same mutation. We describe a new mutation of BRAF, T599dup, in a case of ATC with tall cell PTC component. Moreover, progression from PTC to ATC could be favoured by further TP53 mutation and SOX2 expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAT.0b013e3283486178DOI Listing
August 2011

Signalling with retinoids in the human lung: validation of new tools for the expression study of retinoid receptors.

BMC Cancer 2009 Dec 4;9:423. Epub 2009 Dec 4.

Faculté de Médecine, Laboratoire de Pathologie Cellulaire et Moléculaire en Nutrition, INSERM U724, Centre de Ressources Biologiques, CHU de Nancy, 54505 Vandoeuvre-Lès-Nancy, France.

Background: Retinoid Receptors are involved in development and cell homeostasis. Alterations of their expressions have been observed in lung cancer. However, retinoid chemoprevention trials in populations at risk to develop such tumors have failed. Therefore, the pertinence of new clinical trials using second generation retinoid requires prior better understanding of retinoid signalling. This is our aim when validating extensively research tools, focused on Retinoic Acid Receptor beta, whose major role in lung cancer is documented.

Methods: Biocomputing was used to assess the genomic organization of RAR beta. Its putative RAR-beta1' promoter features were investigated experimentally. Specific measures realized, with qRT-PCR Syber Green assays and a triplex of Taqman probes, were extensively validated to establish Retinoid Receptors mRNAs reference values for in vivo normal human bronchial cells, lung tumors and cell lines. Finally, a pan-RAR-beta antibody was generated and extensively validated by western-blot and immunoprecipitation.

Results: No promoter-like activity was found for RAR-beta1'. RAR-beta2 mRNAs increase signs the normal differentiation of the human bronchial epithelium while a decrease is observed in most lung cancer cell lines. Accordingly, it is also, along with RXR beta, down-regulated in lung tumors. When using nuclear extracts of BEAS-2B and normal lung cells, only the RAR-beta2 long protein isoform was recognized by our antibody.

Conclusion: Rigorous samples processing and extensive biocomputing, were the key factors for this study. mRNA reference values and validated tools can now be used to advance researches on retinoid signalling in the lung.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1471-2407-9-423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797528PMC
December 2009

Survey and biological insights of pemetrexed-related therapeutic improvement in mesothelioma: The Nancy Centre of Biological Resources' Mesothelioma Cohort.

J Thorac Oncol 2009 Oct;4(10):1259-63

The Centre for Biological Resources of Nancy/U724 INSERM, Central Hospital, Nancy, France.

Introduction: We report a survey of mesothelioma survival rates with insights into the survival benefit because of pemetrexed. We also studied a potential link between specific single nucleotide polymorphisms of transcobalamin II (TCII) gene and susceptibility to both asbestos and pemetrexed.

Methods: Clinical and occupational data from 287 consecutive mesothelioma patients were collected from the north-east region of France (1989-2007). Blood or paired tumoral and normal samples were collected from the last 210 French patients to study the TCII single nucleotide polymorphisms at the codon 259 (quantitative polymerase chain reaction). Results were compared with those obtained from a group of 263 French control healthy subjects and to a group of 91 German mesothelioma patients. Patients' characteristics and genotypes results were statistically analyzed for significant correlations.

Results: The mean overall patient's survival was 18.19 +/- 21.07 months. Pemetrexed increased the patients' survival by 50% (21.81 versus 16.99 months). The TCII allele Proline (Pro) was overrepresented into the mesothelioma cohort when compared with the controls (35 versus 19.77%). This also concerned German patients. The alleles Pro and Proline Arginine (ProArg) were more frequent among patients exposed to asbestos (p = 0.005, p < 0.001, respectively). The allele ProArg was associated with the longest survival while under pemetrexed (p = 0.007). No difference was found in the genotypes of patients untreated with pemetrexed.

Conclusions: Pemetrexed treatment is related to a survival increase in mesothelioma patients. The allele Pro seems overrepresented in mesothelioma patients. Those having the allele ProArg present a better outcome under pemetrexed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JTO.0b013e3181aba6bdDOI Listing
October 2009

Do evolving practices improve survival in operated lung cancer patients? A biobank may answer.

J Thorac Oncol 2009 Apr;4(4):505-11

Centre of Biological Resources/U 724 INSERM, Central Hospital, Cour d'Anatomie, Rue Lionnois, Nancy, France.

Introduction: Biobanks may play a pivotal role in lung cancer patients' management, research, and health policy. The Nancy "Centre of Biologic Resources" analyzed the evolving profiles of operated lung cancer patients and their management over 20 years.

Methods: A total of 1259 consecutive patients operated upon from 1988 till 2007 were included. Survival rates were statistically compared before and after 1997. The parameters associated with a significant improvement of survival were determined.

Results: After 1997, lung cancer was diagnosed at an earlier stage. For Squamous Cell Lung Cancer (SQCLC), stages IA increased from 5.4 to 19.5% and for Adenocarcinoma (ADC), stage IA increased from 9.9 to 24.7%. More women with stage I ADC were operated upon after 1997 (p = 0.01). More patients with Large Cell Lung Cancer were diagnosed recently. Recent patients received more adjuvant or neo-adjuvant chemotherapy (p < 0.001) and less radiotherapy (stage I SQCLC: p = 0.019, stage I ADC: p < 0.001). A longer overall patients' survival was observed after 1997 (chi test for SQLC and ADC independently p < or = 0.002). Among SQCLC long survivors, those at stage I-II, below 50 years, were more numerous. A longer survival was associated with early stage in ADC patients. Stage was the single constant factor for overall outcome.

Conclusion: Overall and stage-adjusted survival of operated lung cancer patients has been improved in the last decade due mainly to earlier diagnosis. The generalized use of computed tomography scan, chemotherapy, and a collegial management improved patients' survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JTO.0b013e31819c7a12DOI Listing
April 2009
-->