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2.
Blood Cancer J ; 7(4): e555, 2017 04 21.
Article in English | MEDLINE | ID: mdl-28430172

ABSTRACT

The histone methyltransferase EZH2 has an essential role in the development of follicular lymphoma (FL). Recurrent gain-of-function mutations in EZH2 have been described in 25% of FL patients and induce aberrant methylation of histone H3 lysine 27 (H3K27). We evaluated the role of EZH2 genomic gains in FL biology. Using RNA sequencing, Sanger sequencing and SNP-arrays, the mutation status, copy-number and gene-expression profiles of EZH2 were assessed in a cohort of 159 FL patients from the PRIMA trial. Immunohistochemical (IHC) EZH2 expression (n=55) and H3K27 methylation (n=63) profiles were also evaluated. In total, 37% of patients (59/159) harbored an alteration in the EZH2 gene (mutation n=46, gain n=23). Both types of alterations were associated with highly similar transcriptional changes, with increased proliferation programs. An H3K27me3/me2 IHC score fully distinguished mutated from wild-type samples, showing its applicability as surrogate for EZH2 mutation analysis. However, this score did not predict the presence of gains at the EZH2 locus. The presence of an EZH2 genetic alteration was an independent factor associated with a longer progression-free survival (hazard ratio 0.58, 95% confidence interval 0.36-0.93, P=0.025). We propose that the copy-number status of EZH2 should also be considered when evaluating patient stratification and selecting patients for EZH2 inhibitor-targeted therapies.


Subject(s)
Enhancer of Zeste Homolog 2 Protein/genetics , Histone-Lysine N-Methyltransferase/genetics , Lymphoma, Follicular/genetics , Adult , Aged , Cell Line, Tumor , Disease-Free Survival , Female , Gene Expression Regulation, Neoplastic/genetics , Histone Methyltransferases , Humans , Lymphoma, Follicular/drug therapy , Lymphoma, Follicular/pathology , Male , Methylation/drug effects , Middle Aged , Mutation/genetics , Polymorphism, Single Nucleotide/genetics , Sequence Analysis, RNA
3.
Ann Oncol ; 27(2): 306-14, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26598546

ABSTRACT

BACKGROUND: ALK-negative anaplastic large cell lymphoma associated with breast implant (i-ALCL) has been recently recognized as a distinct entity. Among 43 830 lymphomas registered in the French Lymphopath network since 2010, 300 breast lymphomas comprising 25 peripheral T-cell lymphomas (PTCL) were reviewed. Among PTCL, ALK-negative ALCL was the most frequent and all of them were associated with breast implants. PATIENTS AND METHODS: Since 2010, all i-ALCL cases were collected from different institutions through Lymphopath. Immuno-morphologic features, molecular data and clinical outcome of 19 i-ALCLs have been retrospectively analyzed. RESULTS: The median age of the patients was 61 years and the median length between breast implant and i-ALCL was 9 years. Most implants were silicone-filled and textured. Implant removal was performed in 17 out of 19 patients with additional treatment based on mostly CHOP or CHOP-like chemotherapy regimens (n = 10/19) or irradiation (n = 1/19). CHOP alone or ABVD following radiation without implant removal have been given in two patients. The two clinical presentations, i.e. effusion and less frequently tumor mass correlated with distinct histopathologic features: in situ i-ALCL (anaplastic cell proliferation confined to the fibrous capsule) and infiltrative i-ALCL (pleomorphic cells massively infiltrating adjacent tissue with eosinophils and sometimes Reed-Sternberg-like cells mimicking Hodgkin lymphoma). Malignant cells were CD30-positive, showed a variable staining for EMA and were ALK negative. Most cases had a cytotoxic T-cell immunophenotype with variable T-cell antigen loss and pSTAT3 nuclear expression. T-cell receptor genes were clonally rearranged in 13 out of 13 tested cases. After 18 months of median follow-up, the 2-year overall survival for in situ and infiltrative i-ALCL was 100% and 52.5%, respectively. CONCLUSIONS: In situ i-ALCLs have an indolent clinical course and generally remain free of disease after implant removal. However, infiltrative i-ALCLs could have a more aggressive clinical course that might require additional therapy to implant removal.


Subject(s)
Breast Implants/adverse effects , Lymphoma, Large-Cell, Anaplastic/pathology , Lymphoma, T-Cell, Peripheral/pathology , Silicones/adverse effects , Adult , Aged , Aged, 80 and over , Anaplastic Lymphoma Kinase , Female , Hodgkin Disease/pathology , Humans , Immunophenotyping , Ki-1 Antigen/metabolism , Lymphoma, Large-Cell, Anaplastic/chemically induced , Lymphoma, Large-Cell, Anaplastic/mortality , Lymphoma, T-Cell, Peripheral/chemically induced , Lymphoma, T-Cell, Peripheral/mortality , Middle Aged , Receptor Protein-Tyrosine Kinases/metabolism , Receptors, Antigen, T-Cell/metabolism , Retrospective Studies , STAT3 Transcription Factor/metabolism , T-Lymphocytes, Cytotoxic/immunology
5.
Virchows Arch ; 461(4): 379-83, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22961103

ABSTRACT

Epitheliomesenchymal biphasic neoplasms are extremely rare in the duodenum, and most of these are carcinosarcomas. Miettinen et al. (Am J Surg Pathol 33:1370-7, 2009) recently reported three cases of a novel distinctive epitheliomesenchymal biphasic tumor of the stomach in young adults. In view of the resemblance to other childhood blastomas, they proposed to refer to this entity as a gastroblastoma. Since none of the components were sufficiently atypical, the gastroblastoma seemed more comparable to this kind of tumor than carcinosarcomas or other aggressive and malignant biphasic tumors. This report describes a duodenal location of a similar epitheliomesenchymal biphasic tumor in a 22-year-old woman. To our knowledge, this is the first reported case occurring primarily in the duodenum and might be the first case of "duodenoblastoma."


Subject(s)
Duodenal Neoplasms/classification , Duodenal Neoplasms/pathology , Epithelium/pathology , Mesoderm/pathology , Digestive System Surgical Procedures/methods , Duodenal Neoplasms/surgery , Duodenum/diagnostic imaging , Duodenum/pathology , Duodenum/surgery , Female , Humans , Tomography, X-Ray Computed , Treatment Outcome , Young Adult
7.
Br J Haematol ; 142(1): 79-81, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18422778

ABSTRACT

The ubiquitous herpesvirus Epstein-Barr virus (EBV) is linked to the development of several malignancies, including nasopharyngeal carcinoma (UCNT) and Hodgkin lymphoma (HL). Despite the well-known oncogenic properties of the EBV latent membrane protein 1 (LMP-1), the different oncogenic pathways involved in the pathogenesis of each disease remain unclear. This study reported, for the first time, the case of a patient with sequential development of UCNT and HL. Polymerase chain reaction was used to determine the LMP-1 gene sequence and demonstrate that the two tumours contained different clonal viral genomes, suggesting a central and specific role of EBV infection.


Subject(s)
Epstein-Barr Virus Infections/genetics , Herpesvirus 4, Human/genetics , Hodgkin Disease/genetics , Nasopharyngeal Neoplasms/genetics , Neoplasms, Second Primary/genetics , Viral Matrix Proteins/genetics , Adult , Hodgkin Disease/virology , Humans , Male , Nasopharyngeal Neoplasms/virology , Neoplasms, Second Primary/virology , Nucleic Acid Amplification Techniques , Polymerase Chain Reaction
8.
Pathologica ; 100(5): 416-9, 2008 Oct.
Article in English | MEDLINE | ID: mdl-19253604

ABSTRACT

Multicystic peritoneal mesothelioma is a rare lesion occurring mainly in women in a reproductive age. Its pathogenesis is unclear. We report three cases of multicystic peritoneal mesothelioma in patients that were 28, 38 and 47 years of age (one male, two females). A history of abdominal surgery was reported in two cases. Explorative laparotomy was presumptive of a pseudomyxoma peritoni in two cases, and hyperthermic intraperitoneal chemotherapy was performed. Histological examination demonstrated multicystic lesions with mesothelial cells lining confirmed by immunohistochemical analysis. Unusual findings such as hyperplasia, hobnail features, cytoplasmic vacuolisation and papillary pattern were occasionally noted. The clinical presentation, pathogenesis and pathologic features including differential diagnosis of multicystic peritoneal mesothelioma are discussed.


Subject(s)
Mesothelioma, Cystic/pathology , Peritoneal Neoplasms/pathology , Abdominal Pain/etiology , Adult , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Appendectomy , Combined Modality Therapy , Dermoid Cyst , Diagnosis, Differential , Endometriosis/complications , Female , Humans , Hyperthermia, Induced , Intestinal Perforation/etiology , Laparotomy , Male , Mesothelioma, Cystic/complications , Mesothelioma, Cystic/diagnosis , Mesothelioma, Cystic/drug therapy , Mesothelioma, Cystic/surgery , Middle Aged , Neoplasms, Multiple Primary , Ovarian Neoplasms , Peritoneal Neoplasms/complications , Peritoneal Neoplasms/diagnosis , Peritoneal Neoplasms/drug therapy , Peritoneal Neoplasms/surgery , Peritonitis/etiology , Pseudomyxoma Peritonei/diagnosis , Remission Induction
9.
Oncogene ; 26(2): 298-307, 2007 Jan 11.
Article in English | MEDLINE | ID: mdl-16819513

ABSTRACT

Common fragile sites (CFSs) are regions of chromosomal break that may play a role in oncogenesis. The most frequent alteration occurs at FRA3B, within the FHIT gene, at chromosomal region 3p14. We studied a series of breast carcinomas for break of a CFS at 6q26, FRA6E, and its associated gene PARK2, using fluorescence in situ hybridization on tissue microarrays (TMA). We found break of PARK2 in 6% of cases. We studied the PARK2-encoded protein Parkin by using immunohistochemistry on the same TMA. Loss of Parkin was found in 13% of samples but was not correlated with PARK2 break. PARK2 break but not Parkin expression was correlated with prognosis. Alteration of PARK2/FRA6E may cause haplo-insufficiency of one or several telomeric potential tumor suppressor genes (TSG). The AF-6/MLLT4 gene, telomeric of PARK2, encodes the Afadin scaffold protein, which is essential for epithelial integrity. Loss of Afadin was found in 14.5% of cases, and 36% of these cases showed PARK2 break. Loss of Afadin had prognostic impact, suggesting that AF-6 may be a TSG. Loss of Afadin was correlated with loss of FHIT expression, suggesting fragility of FRA6E and FRA3B in a certain proportion of breast tumors.


Subject(s)
Acid Anhydride Hydrolases/genetics , Breast Neoplasms/genetics , Chromosome Breakage , Kinesins/genetics , Myosins/genetics , Neoplasm Proteins/genetics , Ubiquitin-Protein Ligases/genetics , Acid Anhydride Hydrolases/metabolism , Adult , Aged , Aged, 80 and over , Blotting, Western , Breast Neoplasms/diagnosis , Breast Neoplasms/metabolism , Carcinoma, Ductal, Breast/diagnosis , Carcinoma, Ductal, Breast/genetics , Carcinoma, Ductal, Breast/metabolism , Carcinoma, Lobular/diagnosis , Carcinoma, Lobular/genetics , Carcinoma, Lobular/metabolism , Chromosome Fragile Sites , Chromosomes, Human, Pair 6/genetics , Female , Fluorescent Antibody Technique , Genes, Tumor Suppressor , Humans , Immunoenzyme Techniques , In Situ Hybridization, Fluorescence , Kinesins/metabolism , MicroRNAs , Middle Aged , Myosins/metabolism , Neoplasm Invasiveness/pathology , Neoplasm Proteins/metabolism , Prognosis , RNA Interference , Survival Rate , Tissue Array Analysis , Ubiquitin-Protein Ligases/metabolism
10.
Bone Marrow Transplant ; 38(3): 217-22, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16770316

ABSTRACT

The potential benefit of rituximab as adjuvant to high-dose therapy (HDT) has been investigated in patients under 60 years with poor-risk (age-adjusted international prognostic index at 2-3) CD20+ diffuse large B-cell lymphoma (DLBCL). The treatment consisted of four cycles of high-dose CEOP (cyclophosphamide, epirubicin, vincristine, prednisone), plus etoposide and cisplatin during the two last cycles. Peripheral blood stem cells were collected after cycle 1, and reinfused after cycles 3 and 4. Four weekly rituximab infusions were subsequently delivered. Among the 36 patients included, 30 could complete chemotherapy schedule, and 24/36 received rituximab. A complete response occured in 26/36 patients (72%). With a median follow-up of 30 months, the estimated 5-year overall survival (OS) and event-free survival (EFS) rates (mean +/- s.d.) were 65 +/- 16 and 63 +/- 15%, respectively. For the 24 patients who received both chemotherapy and rituximab, the estimated 5-year OS and EFS rates were 86 +/- 14 and 82 +/- 15%. These data suggest that rituximab after HDT is feasible. Both complete remission rate and survival curves compare favorably with the poor outcome usually observed in high-risk DLBCL patients managed with HDT without rituximab.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, B-Cell/therapy , Lymphoma, Large B-Cell, Diffuse/therapy , Peripheral Blood Stem Cell Transplantation/methods , Adult , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Murine-Derived , Antigens, CD20/blood , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Cisplatin/administration & dosage , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Epirubicin/administration & dosage , Etoposide/administration & dosage , Female , Humans , Male , Middle Aged , Prednisone/administration & dosage , Prognosis , Rituximab , Survival Analysis , Transplantation, Autologous , Vincristine/administration & dosage
12.
Oncogene ; 25(15): 2273-84, 2006 Apr 06.
Article in English | MEDLINE | ID: mdl-16288205

ABSTRACT

A better molecular characterization of breast cell lines (BCL) may help discover new markers to apply to tumour samples. We performed gene and protein expression profiling of 31 BCL using whole-genome DNA microarrays and immunohistochemistry (IHC) on 'cell microarrays' (CMA), respectively. Global hierarchical clustering discriminated two groups of BCL: group I corresponded to luminal cell lines, group II to basal and mesenchymal cell lines. Correlations with centroids calculated from a published 'intrinsic 500-gene set' assigned 15 cell lines as luminal, eight as basal and four as mesenchymal. A set of 1.233 genes was differentially expressed between basal and luminal samples. Mesenchymal and basal subtypes were rather similar and discriminated by only 227 genes. The expression of 10 proteins (CAV1, CD44, EGFR, MET, ETS1, GATA3, luminal cytokeratin CK19, basal cytokeratin CK5/6, CD10, and ERM protein moesin) encoded by luminal vs basal discriminator genes confirmed the subtype classification and the validity of the identified markers. Our BCL basal/luminal signature correctly re-classified the published series of tumour samples that originally served to identify the molecular subtypes, suggesting that the identified markers should be useful for tumour classification and might represent promising targets for disease management.


Subject(s)
Biomarkers, Tumor/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Carcinoma, Basal Cell/metabolism , Gene Expression Profiling , Biomarkers, Tumor/genetics , Breast/metabolism , Breast/pathology , Breast Neoplasms/classification , Carcinoma, Basal Cell/genetics , Carcinoma, Basal Cell/pathology , Epithelial Cells , Female , Genes, erbB-2/physiology , Humans , Immunoenzyme Techniques , Mesoderm/metabolism , Oligonucleotide Array Sequence Analysis
13.
Oncogene ; 25(10): 1560-70, 2006 Mar 09.
Article in English | MEDLINE | ID: mdl-16288225

ABSTRACT

The classification of peripheral T-cell lymphomas (PTCL) is still a matter of debate. To establish a molecular classification of PTCL, we analysed 59 primary nodal T-cell lymphomas using cDNA microarrays, including 56 PTCL and three T-lymphoblastic lymphoma (T-LBL). The expression profiles could discriminate angioimmunoblastic lymphoma, anaplastic large-cell lymphoma and T-LBL. In contrast, cases belonging to the broad category of 'PTCL, unspecified' (PTCL-U) did not share a single molecular profile. Using a multiclass predictor, we could separate PTCL-U into three molecular subgroups called U1, U2 and U3. The U1 gene expression signature included genes known to be associated with poor outcome in other tumors, such as CCND2. The U2 subgroup was associated with overexpression of genes involved in T-cell activation and apoptosis, including NFKB1 and BCL-2. The U3 subgroup was mainly defined by overexpression of genes involved in the IFN/JAK/STAT pathway. It comprised a majority of histiocyte-rich PTCL samples. Gene Ontology annotations revealed different functional profile for each subgroup. These results suggest the existence of distinct subtypes of PTCL-U with specific molecular profiles, and thus provide a basis to improve their classification and to develop new therapeutic targets.


Subject(s)
Gene Expression Profiling , Lymph Nodes/pathology , Lymphoma, T-Cell/genetics , Lymphoma, T-Cell/pathology , Humans , Lymphoma, T-Cell/classification , Lymphoma, T-Cell/diagnosis , Polymerase Chain Reaction , Prognosis
18.
Rev Neurol (Paris) ; 159(5 Pt 1): 581-5, 2003 May.
Article in French | MEDLINE | ID: mdl-12773906

ABSTRACT

A 26-year-old woman complained of trijeminal nevralgy and ocular symptoms revealing a paracavernal tumor which had progressed for three months. Histopathological analysis after partial resection led to the diagnosis of Castleman's disease. Six months later, the patient was considered cured after focal adjuvant radiotherapy. Castleman's disease is a lymphoproliferative disorder. Solitary intracranial involvement is unusual. Unlike multifocal disease, localized Castleman's disease has an excellent prognosis.


Subject(s)
Castleman Disease/pathology , Temporal Lobe/pathology , Adult , Antigens, CD/immunology , Castleman Disease/immunology , Castleman Disease/surgery , Diplopia/etiology , Exophthalmos/etiology , Female , Humans , Magnetic Resonance Imaging , Trigeminal Neuralgia/etiology
19.
J Clin Oncol ; 21(7): 1271-7, 2003 Apr 01.
Article in English | MEDLINE | ID: mdl-12663714

ABSTRACT

PURPOSE: Because it is unclear whether T-cell/histiocyte-rich large B-cell lymphomas (H/TCRBCL) should be considered as a true clinicopathologic entity, we conducted a matched-control analysis comparing patients with H/TCRBCL and patients with diffuse large-B cell lymphoma (B-DLCL). PATIENTS AND METHODS: More than 4,500 patients were enrolled onto non-Hodgkin's lymphoma trials conducted by the Groupe d'Etude des Lymphomes de l'Adulte. After histologic review, 50 patients were subclassified as H/TCRBCL. They were matched to 150 patients with B-DLCL for each of the factors of the International Prognostic Index (IPI). RESULTS: Clinical characteristics of H/TCRBCL patients showed a male predominance and a median age of 47 years. Performance status was normal in 89% of patients, whereas lactate dehydrogenase level was increased in 60% of patients. The disease was disseminated in 81% of patients, and 48% had two or more involved extranodal sites. The IPI score was >or= 2 in 53% of patients. The complete response rate to chemotherapy was 63%, and 5-year overall survival (OS) and event-free survival (EFS) rates (mean +/- SD) were 58% +/- 18% and 53% +/- 16%, respectively. The matched-control analysis showed a trend toward a better response to chemotherapy for patients with B-DLCL (P =.06), whereas no difference was observed in OS (P =.9) and EFS (P =.8). CONCLUSION: H/TCRBCL is an aggressive disease that often presents with adverse prognostic factors. However, when treatment is adapted to the disease risk, outcome is equivalent to that observed in patients with B-DLCL. Thus H/TCRBCL should be considered a pathologic variant that belongs to the B-DLCL category.


Subject(s)
Histiocytes/pathology , Lymphoma, B-Cell/classification , Lymphoma, Large B-Cell, Diffuse/classification , T-Lymphocytes/pathology , Adult , Aged , Aged, 80 and over , Female , Humans , Lymphoma, B-Cell/drug therapy , Lymphoma, B-Cell/mortality , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/mortality , Male , Matched-Pair Analysis , Middle Aged , Prognosis , Survival Rate , Treatment Outcome
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