Publications by authors named "Francois Labrousse"

72 Publications

Myxoid Meningioma: First Report of a Rare Metaplastic Meningioma Variant in the Pineal Region.

J Neuropathol Exp Neurol 2021 Jan;80(1):96-100

Department of Neuropathology, CHU Limoges, Limoges, France.

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http://dx.doi.org/10.1093/jnen/nlaa123DOI Listing
January 2021

Development of a Novel Orthotopic Primary Human Chordoma Xenograft Model: A Relevant Support for Future Research on Chordoma.

J Neuropathol Exp Neurol 2020 03;79(3):314-324

Service d'Anatomie et de Cytologie Pathologiques, Hôpital Lariboisère - AP-HP, Paris, France.

Chordomas are slow-growing rare malignant neoplasms. The aim of this study was to establish a primary model of chordoma in the lumbosacral orthotopic area, to compare the growth rate to the subcutaneous site, and to show that this new graft site optimizes tumor growth and bony invasion. Eleven chordoma samples were transplanted subcutaneously in the flank and/or in contact with the lumbosacral region and grown into nude mice. Engraftment rate was significantly more successful in the lumbosacral environment compared with the flank at P0. Two xenografts from 2 patients showed bone invasion. One tumor was maintained through multiple rounds of serial transplantation, creating a model for study. Histological and immunostaining analysis confirmed that tumor grafts recapitulated the primary tumor from which they were derived, consisting of a myxoid chordoma expressing brachyury, cytokeratin AE1, EMA, and VEGF. Clear destruction of the bone by the tumor cells could be demonstrated. Molecular studies revealed PIK3CA and PTEN mutations involved in PI3K signaling pathway and most of the frequently reported chromosomal alterations. We present a novel orthotopic primary xenograft model of chordoma implanted for the first time in the lumbosacral area showing bone invasion, PIK3CA, and PTEN mutations that will facilitate preclinical studies.
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http://dx.doi.org/10.1093/jnen/nlz121DOI Listing
March 2020

Analysis of CDKN2A gene alterations in recurrent and non-recurrent meningioma.

J Neurooncol 2019 Dec 15;145(3):449-459. Epub 2019 Nov 15.

Department of Pathology, Limoges University Hospital, 2 Avenue Martin-Luther-King, 87042, Limoges, France.

Purpose: Assessment of the risk of recurrence is essential to determine the therapeutic strategy of meningioma treatment. Many relapsing or aggressive meningiomas show elevated mitotic and/or Ki67 indices, reflecting cell cycle deregulation. As CDKN2A is a key tumor suppressor gene involved in cell cycle control, we investigated whether CDKN2A alterations may be involved in tumor recurrence.

Methods: We carried out a comparative analysis of 17 recurrent and 13 non-recurrent meningiomas. CDKN2A single nucleotide variations (SNVs), deletions, methylation status of the promotor, and p16 expression were investigated. Results were correlated with the recurrent or non-recurrent status and clinicopathological data.

Results: We identified a CDKN2A SNV (NM_000077, exon2, c.G442A, p.Ala148Thr) in five meningiomas that was significantly associated with recurrence (p = 0.03). This mutation, confirmed by Sanger sequencing and referenced in the COSMIC database in various cancers, has not been reported in meningioma. The presence of one of the three following CDKN2A alterations-p.(Ala148Thr) mutation, whole homozygous or heterozygous gene loss, or promotor methylation > 8%-was observed in 13 of the 17 relapsing meningiomas and was strongly associated with recurrence (p < 0.0001) and a Ki67 labeling index > 7% (p = 0.004).

Conclusion: We report an undescribed p.(Ala148Thr) CDKN2A mutation in meningioma that was only present in relapsing tumors. In our series, CDKN2A gene alterations were only found in recurrent meningiomas. However, our results need to be evaluated on a larger series to ensure that these CDKN2A alterations can be used as biomarkers of recurrence in meningioma.
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http://dx.doi.org/10.1007/s11060-019-03333-6DOI Listing
December 2019

, , and Status Predicts Prognosis in Glioma.

Cancers (Basel) 2019 Apr 15;11(4). Epub 2019 Apr 15.

EA3842 CAPTuR, Faculty of Medicine, University of Limoges, 2 Rue du Docteur Marcland, 87025 Limoges, France.

The aim of this study was to identify relevant biomarkers for the prognosis of glioma considering current molecular changes such as mutation and 1p19q deletion. Gene expression profiling was performed using the TaqMan Low Density Array and hierarchical clustering using 96 selected genes in 64 patients with newly diagnosed glioma. The expression dataset was validated on a large independent cohort from The Cancer Genome Atlas (TCGA) database. A differential expression panel of 26 genes discriminated two prognostic groups regardless of grade and molecular groups of tumors: Patients having a poor prognosis with a median overall survival (OS) of 23.0 ± 9.6 months (group A) and patients having a good prognosis with a median OS of 115.0 ± 6.6 months (group B) ( = 0.007). Hierarchical clustering of the glioma TCGA cohort supported the prognostic value of these 26 genes ( < 0.0001). Among these genes, and were identified as factors that can be associated with status and 1p/19q co-deletion to distinguish between prognostic groups of glioma from the TCGA cohort. Therefore, associated with seemed to be able to provide new information on glioma prognosis.
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http://dx.doi.org/10.3390/cancers11040544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521129PMC
April 2019

as a Promising Novel Biomarker of Colorectal Cancer.

Cancers (Basel) 2018 Oct 30;10(11). Epub 2018 Oct 30.

Glycosylation and Cell Differentiation, Limoges University, PEIRENE, EA 7500, F-87060 Limoges cedex, France.

Background: While protein -fucosyltransferase 1 () overexpression has been recently proposed as a potential biomarker for different cancer types, no study was carried out on POFUT1 implication in colorectal cancer (CRC).

Methods: Data from 626 tumors and 51 non-tumor adjacent tissues available in FireBrowse had been used in this study. Statistical analyses on expression and gene copy number, receptors (main targets of POFUT1 enzymatic activity) expression and association of and expressions with clinical parameters were investigated. Data were completed by POFUT1 histological labeling on six tumor tissues from patients with CRC.

Results: We found that is overexpressed from the stage I ( < 0.001) and 76.02% of tumors have a 20q11.21 amplification, associated in 90.13% of cases with a overexpression, compared to non-tumor adjacent tissues. The copy number in tumors is mainly between 2 and 3. is positively correlated with (r = 0.34, < 0.001), (r = 0.087, = 0.0297), and (r = 0.097, = 0.0148) expressions, while negatively correlated with expression (r = -0.098, = 0.0142). overexpression is markedly associated with rectal location, non-mucinous adenocarcinoma and cancer stages IV and M1. overexpression is only associated with rectal location and non-mucinous adenocarcinoma.

Conclusion: We conclude that is overexpressed in CRC from stage I, and its high expression is associated with metastatic process, probably through NOTCH pathway activation. Then, POFUT1 could represent a potential novel biomarker for CRC diagnosis.
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http://dx.doi.org/10.3390/cancers10110411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6266312PMC
October 2018

[Calcifying pseudoneoplasm of the neuraxis].

Ann Pathol 2018 Dec 30;38(6):391-394. Epub 2018 May 30.

Service d'anatomie pathologique, CHU Dupuytren, 2, avenue Martin-Luther-King, 87042 Limoges cedex, France. Electronic address:

Calcifying pseudoneoplasms of the neuraxis (CAPNON) are rare lesions of the central nervous system. To date, about 60 cases have been reported in literature. We present a case that had the peculiarity to occur in a pregnant woman. At 32 weeks of gestation, a 26-year-old woman was hospitalized to explore nocturnal epigastralgia. During the hospitalisation, the patient presented generalised seizures. As an eclampsia had been suspected, a caesarean delivery was performed. Post-operatively, the patient harboured memory disorders and neuro-imaging explorations were done. They showed an intracerebral calcified mass located in the left frontal lobe and surrounded by an oedema. A complete surgical resection was performed. Histological examination of the surgical specimen showed a calcified tissue containing a fibrillary or granular material. A dense and hyalinised eosinophilic material focally surrounded the calcifications and contained regular fusiform cells of fibroblastic type. Foci of lipomatous and osseous metaplasia were present. Immunohistochemical staining for EMA and STAT6 was negative. There was no associated meningioangiomatosis nor tumour proliferation. Forty-five months after surgery, the patient did not present any seizures and had no sequelae. CAPNON are rare lesions occurring at any age. Their location in the central nervous system is ubiquitous and they can be intra or extra axial. The treatment is surgical and the prognosis excellent. CAPNON must be recognized and distinguished from the other calcified lesions, tumoural or non-tumoural, to avoid an inadequate and potentially harmful treatment.
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http://dx.doi.org/10.1016/j.annpat.2018.04.006DOI Listing
December 2018

SCO-spondin oligopeptide inhibits angiogenesis in glioblastoma.

Oncotarget 2017 Oct 12;8(49):85969-85983. Epub 2017 Sep 12.

EA3842 Cellular Homeostasis and Diseases, University of Limoges, Faculty of Medicine, 87025 Limoges Cedex, France.

Angiogenesis plays a critical role in glioblastoma growth and progression. We therefore aimed at evaluating the anti-angiogenic properties of an oligopeptide originating from SCO-spondin (NX) on a model of human glioblastoma. To this end, we studied the impact of NX treatment on human brain endothelial cells (HBMECs) alone or co-cultured with glioblastoma cells (U87-MG) on apoptosis, proliferation, migration and release of angiogenic factors. We further investigated the anti-angiogenic potential of NX on human glioblastoma cells grown on chorio-allantoic membrane (CAM) or in glioblastoma xenografts. The results of our experiments showed that NX treatment impaired the microvascular network and induced a decrease in cell proliferation, vascularization and tumor growth in the CAM model as well as in xenotransplants. Interestingly, our experiments showed that NX impairs HBMECs migration but also regulates the release of angiogenic factors from U87-MG. These results are confirmed by the profiling of NX-treated U87-MG grown on CAM that highlighted modifications of several genes involved in angiogenesis. In conclusion, NX inhibits tumorigenesis by impairing the ability of glioblastoma cells to induce angiogenesis and by inhibiting endothelial cell migration. This molecule might therefore be an interesting candidate for future cancer therapies.
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http://dx.doi.org/10.18632/oncotarget.20837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5689660PMC
October 2017

Cytoplasmic overexpression of RNA-binding protein HuR is a marker of poor prognosis in meningioma, and HuR knockdown decreases meningioma cell growth and resistance to hypoxia.

J Pathol 2017 08 5;242(4):421-434. Epub 2017 Jul 5.

INSERM U954, Faculty of Medicine, Université de Lorraine, Vandoeuvre-lès-Nancy, France.

HuR regulates cytoplasmic mRNA stability and translatability, and the HuR expression level has been shown to correlate with poor disease outcome in several cancer types; however, the prognostic value and potential pro-oncogenic properties of HuR in meningioma remain unclear. Thus, in the present study, we analysed 85 meningioma tissue samples to establish the relationship between HuR expression, tumour cell proliferation, and/or patient survival. In addition, we examined the anti-proliferative effects of HuR knockdown in two meningioma cell lines (IOMM-Lee and Ben-Men-1) and conducted transcriptome-wide analyses (IOMM-Lee cells) to elucidate the molecular consequences of HuR knockdown. The results of the present study showed HuR cytoplasmic expression to correlate positively with tumour grade (p = 1.2 × 10 ) and negatively with progression-free and overall survival (p = 0.01) time in human meningioma tissues. In vitro, siHuR-induced HuR knockdown was shown to reduce the growth of both Ben-Men-1 (p = 2 × 10 ) and IOMM-Lee (p = 4 × 10 ) cells. Transcriptome analyses revealed HuR knockdown in IOMM-Lee cells to deregulate the HIF1A signalling pathway (p = 1.5 × 10 ) and to up-regulate the expression of genes essential for the assembly of the cytoplasmic mRNA processing body, global genome nucleotide-excision repair, poly(A)-specific ribonuclease activity, the positive regulation of apoptosis and of cell cycle arrest, and the negative regulation of RNA splicing [p(FDR) < 0.001]. Interestingly, HuR knockdown under hypoxic culture conditions further potentiated the effects of HuR knockdown on cell growth, apoptosis, and HIF1A expression. We thus conclude that cytoplasmic HuR expression is a marker of poor prognosis in meningioma and that HuR is a promising potential therapeutic target for use in tumours refractory to standard therapies. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4916DOI Listing
August 2017

Autophagy and TrkC/NT-3 signaling joined forces boost the hypoxic glioblastoma cell survival.

Carcinogenesis 2017 06;38(6):592-603

EA 3842, Cellular Homeostasis and Pathologies, Limoges University, France.

Glioblastoma multiform (GBM), the most common and aggressive primary brain tumor, is characterized by a high degree of hypoxia and resistance to therapy because of its adaptation capacities, including autophagy and growth factors signaling. In this study, we show an efficient hypoxia-induced survival autophagy in four different GBM cell lines (U87MG, M059K, M059J and LN-18) and an activation of a particular neurotrophin signaling pathway. Indeed, the enhancement of both TrkC and NT-3 was followed by downstream p38MAPK phosphorylation, suggesting the occurrence of a survival autocrine loop. Autophagy inhibition increased the hypoxia-induced expression of TrkC and its phosphorylated form as well as the phosphorylation of p38, suggesting a complementary effect of the two processes, leading to cell survival. Alone, autophagy inhibition reduced cellular growth without inducing cell death. However, the double inhibition of autophagy and TrkC signaling was necessary to bring cells to death as shown by PARP cleavage, particularly important in hypoxia. Moreover, a very high expression of TrkC and NT-3 was found in tumor sections from GBM patients, highlighting the importance of neurotrophic signaling in GBM tumor cell survival. These data suggest that a combined treatment targeting these two pathways could be considered in order to induce the death of GBM cells.
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http://dx.doi.org/10.1093/carcin/bgx029DOI Listing
June 2017

Molecular analysis of vascular smooth muscle cells from patients with giant cell arteritis: Targeting endothelin-1 receptor to control proliferation.

Autoimmun Rev 2017 Apr 14;16(4):398-406. Epub 2017 Feb 14.

Institut Cochin, INSERM U1016, CNRS UMR 8104, LabEx INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Pôle de Médecine Interne, Centre de Référence pour les vascularites nécrosantes et la sclérodermie systémique, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. Electronic address:

Objective: The pathophysiology of giant cell arteritis (GCA) and the mechanisms underlying vascular remodeling, are poorly understood. We aimed to compare vascular smooth muscle cells (VSMCs) from patients with GCA and controls by a proteomic and gene expression profile approach and to identify the signaling pathways involved in proliferation.

Methods: VSMCs were cultured from temporal artery biopsies (TABs) from patients with biopsy-proven GCA (TAB-GCA), biopsy-negative GCA (TAB-GCA), and diagnosis other than GCA (GCA-control). VSMCs from normal human aorta (HAoSMC) were used as controls. 2D-differential in-gel electrophoresis and Affymetrix chips were used to compare proteomes and gene expression profiles of VSMCs. Proliferation was assessed by BrdU incorporation assay. TAB-GCA and GCA-control TABs underwent immunohistochemistry staining for endothelin-1 (ET-1) and receptors ETR and ETR.

Results: We identified 16, 30 and 2 protein spots differentially expressed between TAB-GCA and GCA-control VSMCs, TAB-GCA and TAB-GCA VSMCs and TAB-GCA and GCA-control VSMCs, respectively (fold change ≥1.5 and p≤0.05). Among the 153 proteins differentially expressed between TAB-GCA and HAoSMC VSMCs, many were linked with ET-1. Genes differentially expressed between TAB-GCA and GCA-control VSMCs were involved in proliferation. ET-1 was identified as a link between genes of interest. Proliferation was reduced for TAB-GCA VSMCs on treatment with the endothelin antagonist macitentan and its active metabolite. Patients showing transmural expression of ET-1 in temporal artery lesions received a significantly higher glucocorticoid daily dose after 6-month follow-up.

Conclusion: Inhibiting the proliferation with macitentan, combined with glucocorticoids, might be a promising therapeutic approach for patients with GCA.
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http://dx.doi.org/10.1016/j.autrev.2017.02.006DOI Listing
April 2017

Molecular Analysis of Tumor Cell Components in Pilocytic Astrocytomas, Gangliogliomas, and Oligodendrogliomas.

Appl Immunohistochem Mol Morphol 2016 08;24(7):496-500

Departments of *Pathology †Neurosurgery, Dupuytren University Hospital, Limoges, France.

Gliomas and glioneuronal tumors are histologically polymorphous tumors. They can harbor a clear cell "oligodendroglial-like" component that can be difficult to distinguish from tumor cells of oligodendrogliomas or neurons, particularly on small samples. Thus, knowledge of the pattern of molecular markers in different tumor cell components is essential to ensure reliable diagnosis. Here, we screened 14 pilocytic astrocytomas (PA), 12 gangliogliomas, and 13 oligodendrogliomas for the KIAA1549-BRAF fusion gene, IDH1/2 mutations, and 1p19q losses in various areas of interest representative of the different tumor cell components. Molecular patterns were analyzed according to histologic type, tumor cell components, and clinical data. The KIAA1549-BRAF fusion gene was detected only in 8 out of 11 PAs (73%) and in 3 out of 9 gangliogliomas (33%) (P=0.003). Interestingly, all of the studied areas of interest within the same tumor exhibited the same KIAA1549-BRAF fusion gene status. IDH1-R132H and 1p19q loss were found only in 12 out of the 13 oligodendrogliomas (P<0.0001). Our study shows that cellular polymorphism in PAs and gangliogliomas does not affect the results of molecular analysis investigating the status of the KIAA1549-BRAF fusion gene. Thus, this molecular analysis can be reliably used even if the sample size is limited and the selection of different tumor areas is not possible.
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http://dx.doi.org/10.1097/PAI.0000000000000288DOI Listing
August 2016

Involvement and prognosis value of CD8(+) T cells in giant cell arteritis.

J Autoimmun 2016 08 25;72:73-83. Epub 2016 May 25.

INSERM, UMR1098, University of Bourgogne Franche-Comté, FHU INCREASE, France; Department of Internal Medicine and Clinical Immunology, François Mitterrand Hospital, Dijon University Hospital, Dijon, France. Electronic address:

CD8(+) T cells participate in the pathogenesis of some vasculitides. However, little is known about their role in Giant Cell Arteritis (GCA). This study was conducted to investigate CD8(+) T cell involvement in the pathogenesis of GCA. Analyses were performed at diagnosis and after 3 months of glucocorticoid treatment in 34 GCA patients and 26 age-matched healthy volunteers. Percentages of CD8(+) T-cell subsets, spectratype analysis of the TCR Vβ families of CD8(+) T cells, levels of cytokines and chemokines and immunohistochemistry of temporal artery biopsies (TAB) were assessed. Among total CD8(+) T cells, percentages of circulating cytotoxic CD8 T lymphocytes (CTL, CD3(+)CD8(+)perforin(+)granzymeB(+)), Tc17 (CD3(+)CD8(+)IL-17(+)), CD63(+)CD8(+) T cells and levels of soluble granzymes A and B were higher in patients than in controls, whereas the percentage of Tc1 cells (CD3(+)CD8(+)IFN-γ(+)) was similar. Moreover, CD8(+) T cells displayed a restricted TCR repertoire in GCA patients. Percentages of circulating CTL, Tc17 and soluble levels of granzymes A and B decreased after treatment. CXCR3 expression on CD8(+) T cells and its serum ligands (CXCL9, -10, -11) were higher in patients. Analyses of TAB revealed high expression of CXCL9 and -10 associated with infiltration by CXCR3(+)CD8(+) T cells expressing granzyme B and TiA1. The intensity of the CD8 T-cell infiltrate in TAB was predictive of the severity of the disease. This study demonstrates the implication and the prognostic value of CD8(+) T-cells in GCA and suggests that CD8(+) T-cells are recruited within the vascular wall through an interaction between CXCR3 and its ligands.
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http://dx.doi.org/10.1016/j.jaut.2016.05.008DOI Listing
August 2016

Mitotic index, microvascular proliferation, and necrosis define 3 pathological subgroups of prognostic relevance among 1p/19q co-deleted anaplastic oligodendrogliomas.

Neuro Oncol 2016 06;18(6):888-90

APHM, Hôpital de la Timone, Service d'Anatomie Pathologique et de Neuropathologie, Marseille, France (D.F.B.); Aix-Marseille Université, Inserm, CRO2 UMR_S 911, Marseille, France (D.F.B., C.C.); AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neuropathologie Raymond Escourolle, Paris, France (K.M.); Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMCUniv Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France (K.M., C.D., C.C., A.I., J.-Y.D.); AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, F75013, Paris, France (K.M., C.D., C.C., A.I., J.-Y.D.); Centre de Pathologie et de Neuropathologie Est, Bron, France (A.J.); CHU Toulouse, Hôpital Rangueil, Service d'Anatomie Pathologique et Histologie-Cytologie, Toulouse, France (E.U.-C.); Inserm U1037, Centre de Recherche en Cancérologie de Toulouse, Université de Toulouse, France (E.U.-C.); CHU Saint-Etienne, Hôpital Nord, Service d'Anatomie et Cytologie Pathologiques, Saint-Etienne, France (F.F., M.P.); CHU Lille, Pôle Pathologie Biologique, Service Anatomie Pathologique, Lille, France (C.-A.M.); CHU Nancy, Hôpital Central, Laboratoire d'Anatomie Pathologique, Nancy, France (J.-M.V.); APHP, Hôpital Lariboisière, Service d'Anatomie et Cytologie Pathologique, Paris, France (M.P.); CHU Caen, Hôpital de la Côte de Nacre, Service d'anatomie Pathologique, Caen, France (E.L.-Z.); CNRS, UMR 6301 ISTCT, CERVOxy, GIP CYCERON, Caen, France (E.L.-Z.); CHU Bordeaux, Hôpital Pellegrin, Service de Pathologie - Neuropathologie, Bordeaux, France (S.E.); EA2406, Histologie et pathologie moléculaire des tumeurs, Université Bordeaux Segalen, Bordeaux, France (S.E.); CHU Besançon, Hôpital Jean Minjoz, Service Anatomie et Cytologie Pathologiques, Besançon, France (G.V.); CHU Brest, Hôpital de la Cavale Blanche, Service Anatomie Pathologique, Brest, France (I.Q.-R.); CHU Dijon, Plateau technique de biologie G. Mack

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http://dx.doi.org/10.1093/neuonc/now085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864268PMC
June 2016

Supratentorial clear cell ependymomas with branching capillaries demonstrate characteristic clinicopathological features and pathological activation of nuclear factor-kappaB signaling.

Neuro Oncol 2016 07 15;18(7):919-27. Epub 2016 Mar 15.

Department of Pathology and Neuropathology, Assistance Publique des Hôpitaux de Marseille (APHM), CHU Timone, Marseille, France (D.F.-B, E.T., A.M.d.P, C.B.); Aix-Marseille Université, Inserm, Marseille, France (D.F.-B, E.T., C.B., C.C.); Department of Pathology, CHU Caen, Hôpital de la Côte de Nacre, Caen, France (E.L.-Z); Department of Neurooncology, APHM, Marseille, France (E.T.); Department of Neuropathology, University of Bonn, Medical Center Sigmund-Freud, Bonn, Germany (S.J., T.P.); Department of Pathology and Neuropathology, Hospices civils de Lyon, Bron, France (A.J.); Department of Pathology, CHU de Saint-Etienne, Saint-Etienne, France (F.F.); Department of Neuropathology, CHU Sainte Anne, Paris, France (F.A.); Department of Pathology, CHU de Brest, Hôpital de la Cavale Blanche, Brest, France (I.Q.-R); Department of Pathology, CHU de Tours, Hôpital Trousseau, Tours, France (M.-C.M.); Department of Pathology, CHR d'Orléans, Hôpital de la Source, Orléans, France (A.H.); Department of Pathology, CHU de Poitiers, Hôpital la Milétrie, Poitiers, France (S.M.); Department of Pathology, CHU d'Amiens, Amiens, France (H.S.); Department of Pathology, CHU de Clermont-Ferrand, Clermont-Ferrand, France (C.G.); Department of Pathology, CHU de Limoges, Limoges, France (F.L.); Department of Neurosurgery, APHM, CHU Timone, Marseille, France (P.M.); Department of Pediatric Neurosurgery, APHM, CHU Timone, Marseille, France (D.S.).

Background: Clear cell ependymoma is one of the 4 main histological subtypes of ependymomas defined by the World Health Organization (WHO) classification of tumors of the CNS. DNA methylation profiling can distinguish 4 subgroups of intracranial ependymomas, including supratentorial (ST) ependymomas with Yes-associated protein 1 fusion (YAP1), ST ependymomas with fusion of v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), posterior fossa ependymomas with balanced genome, and posterior fossa ependymomas with chromosomal instability. In addition, trisomy 19 is a genomic hallmark of ependymomas with rich branching capillaries. However, the relation of histological and molecular subtypes is unclear.

Methods: Here, we report a series of 20 ependymomas histologically defined by clear cells and branching capillaries.

Results: We observed a strong male predominance. Median age at surgery was 10.4 years (range, 0.8-68.4). All cases were ST, cortical, contrast enhancing, and most often frontal, cystic, and calcified. All tumors qualified as WHO grade III. Some of them exhibited neuronal differentiation. Trisomy 19 was recorded in 13 cases. All samples strongly accumulated p65RelA protein within nuclei, indicating pathological activation of the nuclear factor-kappaB pathway. We identified causative C11ORF95-RELA fusion in almost all cases. Median progression-free survival and overall survival were 11.4 years (95% CI: 5.1-17.8) and not reached, respectively.

Conclusion: ST clear cell ependymomas with branching capillaries display characteristic clinicopathological features and are associated with pathological activation of nuclear factor-kappaB signaling, which may indicate a potential novel target for therapy in these patients.
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http://dx.doi.org/10.1093/neuonc/now025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896549PMC
July 2016

Chemotherapy outcome predictive effectiveness by the Oncogramme: pilot trial on stage-IV colorectal cancer.

J Transl Med 2016 Jan 12;14:10. Epub 2016 Jan 12.

Centre hospitalier régional universitaire de Limoges Dupuytren, service de chirurgie digestive générale et endocrinienne, 2 avenue Martin Luther King, 87042, Limoges Cedex, France.

Background: Colorectal cancer (CRC) remains a major public concern. While conventional chemotherapeutic regimens have proved useful against advanced/metastatic diseases, progresses are to be made to effectively cure the large portion of patients not benefiting from these treatments. One direction to improve response rates is to develop chemosensitivity and resistance assays (CSRAs) efficiently assisting clinicians in treatment selection process, an already long preoccupation of oncologists and researchers. Several methods have been described to this day, none achieving yet sufficient reliability for recommended use in the clinical routine.

Methods: We led a pilot study on 19 metastatic CRC patients evaluating capacity of the Oncogramme, a standardized process using tumor ex vivo models, to provide chemosensitivity profiles and predict clinical outcome of patients receiving standard CRC chemotherapeutics. Oncogramme responses were categorized according to the method of percentiles to assess sensitivity, specificity and concordance.

Results: We report from a primary analysis a success rate of 97.4 %, a very good sensitivity (84.6 %), a below-average specificity (33.3 %), along with a global agreement of 63.6 % and a concordance between Oncogramme results and patients' responses (Kappa coefficient) of 0.193. A supplementary analysis, focusing on CRC patients with no treatment switch over a longer time course, demonstrated improvement in specificity and concordance.

Conclusions: Results establish feasibility and usefulness of the Oncogramme, prelude to a larger-scale trial. Advantages and drawbacks of the procedure are discussed, as well as the place of CSRAs within the future arsenal of methods available to clinicians to individualize treatments and improve patient prognosis.

Trial Registration: ClinicalTrials.gov database, registration number: NCT02305368.
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http://dx.doi.org/10.1186/s12967-016-0765-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721000PMC
January 2016

Prognostic and Therapeutic Markers in Chordomas: A Study of 287 Tumors.

J Neuropathol Exp Neurol 2016 Feb;75(2):111-20

Chordomas are slow-growing malignant neoplasms. Determination of histopathologic prognostic factors using a large cohort study has been limited by their low incidence. In this retrospective study, we investigated the clinical, histopathologic, and immunohistochemical prognostic factors in 287 chordomas from 111 patients assessed by central pathologic review. Expression patterns of a variety of markers, including vascular endothelial growth factor (VEGF), mTOR pathway, c-kit, HER2, epidermal growth factor receptor (EGFR) and STAT3, and KRAS, BRAF, EGFR, and PIK3CA mutations were analyzed. On univariate analysis, the results confirm surgery as the best treatment, as judged by patient progression-free survival (PFS) and overall survival (OS). Proton therapy, the presence of a dedifferentiated component, mitotic figures, and Ki67 and p53 labeling indices correlated with PFS . Necrosis and apoptosis correlated with OS. Based on these findings, we propose a histopathologic grading system that correlates with PFS and OS. On multivariate analysis, extent of resection, tumor grade, and proton therapy were independent prognostic factors of PFS; extent of resection, tumor location, and grade were independent prognostic factors of OS. Based on the expression of EGFR, pSTAT3, VEGF, and mTOR pathway proteins, (in 85.9%, 79.1%, 85.7%, and 46% of chordomas, respectively), and 2 new mutations in the PIK3CA gene, we also provide evidence for potential therapeutic targets.
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http://dx.doi.org/10.1093/jnen/nlv010DOI Listing
February 2016

Controlled Attenuation Parameter and Liver Stiffness Measurements for Steatosis Assessment in the Liver Transplant of Brain Dead Donors.

Transplantation 2015 Aug;99(8):1619-24

1 Department of Anesthesiology, Dupuytren Teaching Hospital, Limoges, France. 2 Department of Hepatology, Dupuytren Teaching Hospital, Limoges, France. 3 Medical University of Limoges, Limoges, France. 4 INSERM UMR 1092, Limoges, France. 5 Clinical Investigation Center, INSERM 0203, Pontchaillou Teaching Hospital, Rennes, France. 6 Department of Clinical Pharmacology, Teaching Hospital of Rennes, Rennes, France. 7 Department of Pathology, Dupuytren Teaching Hospital, Limoges, France. 8 Department of Critical Care, Dupuytren Teaching Hospital, Limoges, France. 9 Coordination Hospitalière des Prélèvements d'Organes et de Tissus, Dupuytren Teaching Hospital, Limoges, France.

Background: One of the main selection criteria of the quality of a liver graft is the degree of steatosis, which will determine the success of the transplantation. The aim of this study was to evaluate the ability of FibroScan and its related methods Controlled Attenuation Parameter and Liver Stiffness to assess objectively steatosis and fibrosis in livers from brain-dead donors to be potentially used for transplantation.

Methods: Over a period of 10 months, 23 consecutive brain dead donors screened for liver procurement underwent a FibroScan and a liver biopsy.

Results: The different predictive models of liver retrievability using liver biopsy as the gold standard have led to the following area under receiver operating characteristic curve: 76.6% (95% confidence intervals [95% CIs], 48.2%-100%) when based solely on controlled attenuation parameter, 75.0% (95% CIs, 34.3%-100%) when based solely on liver stiffness, and 96.7% (95% CIs, 88.7%-100%) when based on combined indices.

Conclusions: Our study suggests that a preoperative selection of brain-dead donors based on a combination of both Controlled Attenuation Parameter and Liver Stiffness obtained with FibroScan could result in a good preoperative prediction of the histological status and degree of steatosis of a potential liver graft.
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http://dx.doi.org/10.1097/TP.0000000000000652DOI Listing
August 2015

Neurotrophins are expressed in giant cell arteritis lesions and may contribute to vascular remodeling.

Arthritis Res Ther 2014 Nov 24;16(6):487. Epub 2014 Nov 24.

Introduction: Giant cell arteritis (GCA) is characterized by intimal hyperplasia leading to ischaemic manifestations that involve large vessels. Neurotrophins (NTs) and their receptors (NTRs) are protein factors for growth, differentiation and survival of neurons. They are also involved in the migration of vascular smooth muscle cells (VSMCs). Our aim was to investigate whether NTs and NTRs are involved in vascular remodelling of GCA.

Methods: We included consecutive patients who underwent a temporal artery biopsy for suspected GCA. We developed an enzymatic digestion method to obtain VSMCs from smooth muscle cells in GCA patients and controls. Neurotrophin protein and gene expression and functional assays were studied from these VSMCs. Neurotrophin expression was also analysed by immunohistochemistry in GCA patients and controls.

Results: Whereas temporal arteries of both GCA patients (n = 22) and controls (n = 21) expressed nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB) and sortilin, immunostaining was more intense in GCA patients, especially in the media and intima, while neurotrophin-3 (NT-3) and P75 receptor (P75NTR) were only detected in TA from GCA patients. Expression of TrkB, a BDNF receptor, was higher in GCA patients with ischaemic complications. Serum NGF was significantly higher in GCA patients (n = 28) vs. controls (n = 48), whereas no significant difference was found for BDNF and NT-3. NGF and BDNF enhanced GCA-derived temporal artery VSMC proliferation and BDNF facilitated migration of temporal artery VSMCs in patients with GCA compared to controls.

Conclusions: Our results suggest that NTs and NTRs are involved in vascular remodelling of GCA. In GCA-derived temporal artery VSMC, NGF promoted proliferation and BDNF enhanced migration by binding to TrkB and p75NTR receptors. Further experiments are needed on a larger number of VSMC samples to confirm these results.
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http://dx.doi.org/10.1186/s13075-014-0487-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274683PMC
November 2014

Prognostic Relevance of Histomolecular Classification of Diffuse Adult High-Grade Gliomas with Necrosis.

Brain Pathol 2015 Jul 31;25(4):418-28. Epub 2014 Dec 31.

Centre de Recherche de l'Institut du Cerveau et de la Moelle Épinière (CRICM), UMR 7225, Université Pierre et Marie Curie-Paris 6, Paris, France.

Diffuse adult high-grade gliomas (HGGs) with necrosis encompass anaplastic oligodendrogliomas (AOs) with necrosis (grade III), glioblastomas (GBM, grade IV) and glioblastomas with an oligodendroglial component (GBMO, grade IV). Here, we aimed to search for prognostic relevance of histological classification and molecular alterations of these tumors. About 210 patients were included (63 AO, 56 GBM and 91 GBMO). GBMO group was split into "anaplastic oligoastrocytoma (AOA) with necrosis grade IV/GBMO," restricted to tumors showing intermingled astrocytic and oligodendroglial component, and "GBM/GBMO" based on tumors presenting oligodendroglial foci and features of GBM. Genomic arrays, IDH1 R132H expression analyses and IDH direct sequencing were performed. 1p/19q co-deletion characterized AO, whereas no IDH1 R132H expression and intact 1p/19q characterized both GBM and GBM/GBMO. AOA with necrosis/GBMO mainly demonstrated IDH1 R132H expression and intact 1p/19q. Other IDH1 or IDH2 mutations were extremely rare. Both histological and molecular classifications were predictive of progression free survival (PFS) and overall survival (OS) (P < 10(-4) ). Diffuse adult HGGs with necrosis can be split into three histomolecular groups of prognostic relevance: 1p/19q co-deleted AO, IDH1 R132H-GBM and 1p/19q intact IDH1 R132H+ gliomas that might be classified as IDH1 R132H+ GBM. Because of histomolecular heterogeneity, we suggest to remove the name GBMO.
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http://dx.doi.org/10.1111/bpa.12227DOI Listing
July 2015

Study of MET protein levels and MET gene copy number in 72 sinonasal intestinal-type adenocarcinomas.

Head Neck 2015 Nov 22;37(11):1563-8. Epub 2014 Aug 22.

Department of Pathology, Dupuytren University Hospital, Limoges, France.

Background: Sinonasal intestinal-type adenocarcinomas (ITACs) have a poor prognosis, and are defined on the basis of their morphological similarities to colorectal adenocarcinomas. MET signaling pathway is involved in oncogenesis in various cancers. Nothing is currently known about the role of MET in ITACs.

Methods: In a series of 72 ITACs, we investigated MET protein levels by immunohistochemistry (IHC) and gene copy number by in situ hybridization. These findings were analyzed as a function of clinical data, histological typing, and patient outcome.

Results: MET protein was overproduced in 64% of cases and chromosome 7 polysomy was observed in 52% of cases. No tumor displayed MET amplification. The presence of mucinous or solid histological components, T3/T4 tumors, and incomplete resection were associated with a poor outcome.

Conclusion: MET is overproduced in about two third of ITACs, suggesting a role for the MET signaling pathway in the oncogenesis of these tumors.
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http://dx.doi.org/10.1002/hed.23795DOI Listing
November 2015

CD68-positive tumor-associated macrophages predict unfavorable treatment outcomes in classical Hodgkin lymphoma in correlation with interim fluorodeoxyglucose-positron emission tomography assessment.

Leuk Lymphoma 2015 Feb 27;56(2):332-41. Epub 2014 Jun 27.

Department of Hematology, CHU Limoges, Dupuytren Hospital , Limoges, F-87042 , France.

Finding new prognostic factors to identify patients with Hodgkin lymphoma (HL) at risk of treatment resistance or relapse remains challenging in daily practice. We evaluated the relationship between CD68 expression, interim positron emission tomography (iPET) results and outcome in 158 patients with HL diagnosed from February 1995 to July 2011. Immunohistochemistry (anti-CD68) gave two groups: low with ≤25% positive cells (121 patients) and high with >25% (37 patients). Five-year overall survival was higher in the low group (88.4% vs. 63.2%, p=0.0151), as was progression-free survival (74.5% vs. 40.7%, p=0.0003). In 68 patients evaluable, iPET correlated with CD68: 13/52 patients (25%) in the low group had positive iPET as compared to 11/16 patients (68%) in the high group (p=0.0016). This study confirms the prognostic value of CD68 in HL. We found a correlation between CD68 and iPET suggesting potential for a better stratification.
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http://dx.doi.org/10.3109/10428194.2014.917636DOI Listing
February 2015

Mitotic index, microvascular proliferation, and necrosis define 3 groups of 1p/19q codeleted anaplastic oligodendrogliomas associated with different genomic alterations.

Neuro Oncol 2014 Sep 9;16(9):1244-54. Epub 2014 Apr 9.

APHM, Hôpital de la Timone, Service d'Anatomie Pathologique et de Neuropathologie, Marseille, France (D.F.-B.); Aix-Marseille Université, Inserm, CRO2 UMR_S 911, Marseille, France (D.F.-B., C.Co.); AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neuropathologie Raymond Escourolle, Paris, France (K.M., A.I.); Université Pierre et Marie Curie - Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), UMRS 975, Paris, France (K.M., C.Ca., A.I.); Inserm U975, Paris, France (K.M., C.Ca., A.I.); AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2 - Mazarin, Paris, France (C.D.); Centre de Pathologie et de Neuropathologie Est, Bron, France (A.J.); CHU Toulouse, Hôpital Rangueil, Service d'Anatomie Pathologique et Histologie-Cytologie, Toulouse, France (E.U.-C.); Inserm U1037, Centre de Recherche en Cancérologie de Toulouse, Université de Toulouse, France (E.U.-C.); CHU Saint-Etienne, Hôpital Nord, Service d'Anatomie et Cytologie Pathologiques, Saint-Etienne, France (F.F., M.P.); CHU Lille, Pôle Pathologie Biologique, Service Anatomie Pathologique, Lille, France (C.-A.M.); CHU Nancy, Hôpital Central, Laboratoire d'Anatomie Pathologique, Nancy, France (J.-M.V.); AP-HP, Hôpital Lariboisière, Service d'Anatomie et Cytologie Pathologique, Paris, France (M.P.); CHU Caen, Hôpital de la Côte de Nacre, Service d'Anatomie Pathologique, Caen, France (E.L.-Z.); CNRS, UMR 6301 ISTCT, CERVOxy, GIP CYCERON, Caen, France (E.L.-Z.); CHU Bordeaux, Hôpital Pellegrin, Service de Pathologie - Neuropathologie, Bordeaux, France (S.E.); EA2406, Histologie et Pathologie Moléculaire des Tumeurs, Université Bordeaux Segalen, Bordeaux, France (S.E.); CHU Besançon, Hôpital Jean Minjoz, Service Anatomie et Cytologie Pathologiques, Besançon, France (G.V.); CHU Brest, Hôpital de la Cavale Blanche, Service Anatomie Pathologique, Brest, France (I.Q.-R.); CHU Dijon, Plateau Technique de Biologie G. Mack, Service Anatomie et

Background: The aim of this study was to correlate histological features and molecular characteristics in anaplastic oligodendrogliomas (AOs).

Methods: The histological characteristics of 203 AO patients, enrolled in the French national network POLA, were analyzed. The genomic profiles of 191 cases were studied using genomic arrays. IDH mutational status was assessed by immunohistochemistry and direct sequencing.

Results: 1p/19q codeletion was present in 79% of cases and was associated with alpha-internexin expression (P < 10(-4)), IDH1/2 mutation (P < 10(-4)), chromosome 4 loss (P < 10(-3)), and better overall survival (P < 10(-4)). Based on mitotic index, microvascular proliferation (MVP), and necrosis, 3 groups of 1p/19q codeleted AOs were identified: (group 1) AO with more than 5 mitoses per 10-HPF, no MVP, and no necrosis; (group 2) AO with MVP and no necrosis; and (group 3) AO with MVP and necrosis. Compared with group 1, groups 2 and 3 AOs had a higher mean Ki-67 proliferation index and a higher rate of 9p and 9q losses. Compared with group 2, group 3 AOs had a higher number of chromosomal alterations including chromosome 4 loss. In the subgroup of 157 1p/19q codeleted AOs, chromosomal instability was associated with shorter progression-free survival (P = .024) and shorter overall survival (P = .023).

Conclusions: The present study shows that oligodendrogliomas with classic histological features remain a molecularly heterogeneous entity and should be stratified according to 1p/19q status because of its major prognostic relevance. Moreover, 1p/19q codeleted AOs are also heterogeneous. Interestingly, mitotic index, MVP, and necrosis help to classify them into 3 groups associated with distinct genomic alterations.
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http://dx.doi.org/10.1093/neuonc/nou047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136899PMC
September 2014

Intravascular large B-cell lymphoma presenting as cauda equina syndrome and showing aberrant cytokeratin expression: a diagnostic challenge.

Pathology 2014 Apr;46(3):241-4

1Department of Pathology 2Department of Neurology, Dupuytren University Hospital Center, Limoges, France.

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http://dx.doi.org/10.1097/PAT.0000000000000089DOI Listing
April 2014

[About a rare maxillary tumour].

Ann Pathol 2013 Dec 20;33(6):430-2. Epub 2013 Nov 20.

Service d'anatomie pathologie, CHU Dupuytren, 2, avenue Martin-Luther-King, 87042 Limoges cedex, France. Electronic address:

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http://dx.doi.org/10.1016/j.annpat.2013.10.005DOI Listing
December 2013

[Two cases reports of pancreatic endocrine microadenoma incidentally found].

Ann Pathol 2013 Dec 11;33(6):406-9. Epub 2013 Nov 11.

Service d'anatomie pathologie, CHU Dupuytren, 2, avenue Martin-Luther-King, 87042 Limoges cedex, France.

A 59-year-old male, was admitted to our hospital for a tumor of the pancreatic tail. Serum CEA and CA 19-9 levels were normal. Splenopancreasectomy found a desmoid tumour. A 69-year-old male was referred to our institution for chronic anemia and inflammatory syndrome with splenomegaly. Splenectomy showed an important splenic congestion and siderosis. Both patients had a type 2 diabetes mellitus. Furthermore, histological examination revealed pancreatic endocrine microadenomas. The two patients' postoperative course was unremarkable. Eleven and 24 months respectively after the diagnosis, the patients are alive and well, with no tumor recurrence.
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http://dx.doi.org/10.1016/j.annpat.2013.10.003DOI Listing
December 2013

[Large cell calcifying Sertoli cell tumour: A case report].

Ann Pathol 2013 Aug 23;33(4):270-2. Epub 2013 May 23.

Service d'anatomie pathologie, CHU Dupuytren, Limoges cedex, France.

A 19-year-old male Caucasian, without prior medical history, noticed a painless right testicular mass. Physical examination revealed neither gynecomastia nor abnormal skin pigmentation. Serum alpha-fetoprotein, β-HCG and testosterone levels were normal. Sonography depicted an intratesticular diffusely hyperechoic lesion with acoustic shadowing. The patient underwent right orchiectomy. Histology revealed a benign large cell calcifying Sertoli cell tumour. This tumour is rare and may be associated with genetic abnormalities.
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http://dx.doi.org/10.1016/j.annpat.2013.03.001DOI Listing
August 2013

Epidermal growth factor receptor expression and KRAS and BRAF mutations: study of 39 sinonasal intestinal-type adenocarcinomas.

Hum Pathol 2013 Oct 20;44(10):2116-25. Epub 2013 Jun 20.

Department of Pathology, Dupuytren University Hospital, 2 Avenue Martin Luther King, 87042 Limoges, France.

Sinonasal intestinal-type adenocarcinomas (ITACs) are uncommon tumors of poor prognosis defined by their similarities to colorectal adenocarcinomas. The involvement of the epidermal growth factor receptor (EGFR) pathway in colorectal adenocarcinoma oncogenesis is well established, and the same is expected to apply to ITACs. In a series of 39 ITACs, we investigated EGFR amplification and chromosome 7 polysomy by fluorescence in situ hybridization; EGFR, KRAS, and BRAF mutational status by polymerase chain reaction sequencing; EGFR variant messenger RNA expression by quantitative reverse transcriptase polymerase chain reaction; and EGFR protein expression by immunohistochemistry with antibodies targeting the extracellular domain, the intracellular domain, and the phosphorylated isoform. The findings were analyzed with respect to clinical data, histologic typing, and patient outcome. EGFR amplification was observed in 3 cases with a focal distribution. EGFR proteins were overexpressed in all these foci with both extracellular domain and intracellular domain antibodies, suggesting involvement of the whole receptor. Chromosome 7 polysomy was observed in 15 cases and was not associated with EGFR protein expression. EGFR, KRAS, or BRAF mutations were observed in 5 different cases. The EGFRvIII mutant was not detected. In all cases, EGFR variants were expressed. There was no association between these molecular features and patient survival. In conclusion, (1) our study revealed various EGFR expression patterns in ITACs, indicating tumor heterogeneity; (2) EGFR amplification should be distinguished from chromosome 7 polysomy; (3) fluorescence in situ hybridization analysis could be guided by immunohistochemistry; and (4) ITACs share common alterations of the EGFR pathway with colorectal adenocarcinomas, except for a lower frequency of KRAS and BRAF mutations.
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http://dx.doi.org/10.1016/j.humpath.2013.03.019DOI Listing
October 2013