Publications by authors named "Bruno Chetaille"

56 Publications

Nationwide incidence of sarcomas and connective tissue tumors of intermediate malignancy over four years using an expert pathology review network.

PLoS One 2021 25;16(2):e0246958. Epub 2021 Feb 25.

Department of Biopathology, Institut Claudius Regaud et Institut Universitaire du Cancer de Toulouse-Oncopôle, Toulouse, France.

Background: Since 2010, nationwide networks of reference centers for sarcomas (RREPS/NETSARC/RESOS) collected and prospectively reviewed all cases of sarcomas and connective tumors of intermediate malignancy (TIM) in France.

Methods: The nationwide incidence of sarcoma or TIM (2013-2016) was measured using the 2013 WHO classification and confirmed by a second independent review by expert pathologists. Simple clinical characteristics, yearly variations and correlation of incidence with published clinical trials are presented and analyzed.

Results: Over 150 different histological subtypes are reported from the 25172 patients with sarcomas (n = 18712, 74,3%) or TIM (n = 6460, 25.7%), with n = 5838, n = 6153, n = 6654, and n = 6527 yearly cases from 2013 to 2016. Over these 4 years, the yearly incidence of sarcomas and TIM was therefore 70.7 and 24.4 respectively, with a combined incidence of 95.1/106/year, higher than previously reported. GIST, liposarcoma, leiomyosarcomas, undifferentiated sarcomas represented 13%, 13%, 11% and 11% of tumors. Only GIST, as a single entity had a yearly incidence above 10/106/year. There were respectively 30, 64 and 66 different histological subtypes of sarcomas or TIM with an incidence ranging from 10 to 1/106, 1-0.1/106, or < 0.1/106/year respectively. The 2 latter incidence groups represented 21% of the patients with 130 histotypes. Published phase III and phase II clinical trials (p<10-6) are significantly higher with sarcomas subtypes with an incidence above 1/106 per.

Conclusions: This nationwide registry of sarcoma patients, with exhaustive histology review by sarcoma experts, shows that the incidence of sarcoma and TIM is higher than reported, and that tumors with a very low incidence (1<106/year) are less likely to be included in clinical trials.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246958PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906477PMC
August 2021

MDM2 amplification and fusion gene ss18-ssx in a poorly differentiated synovial sarcoma: A rare but puzzling conjunction.

Neoplasia 2020 08 16;22(8):311-321. Epub 2020 Jun 16.

Laboratory of Solid Tumor Genetics, University Hospital of Nice-Côte d'Azur University, Nice, France; Laboratory of Solid Tumor Genetics, Institute for Research on Cancer and Aging of Nice (IRCAN), CNRS UMR 7284/INSERM U1081, Nice, France. Electronic address:

The detection of specific alterations by genetic analyses has been included in the diagnostic criterions of the World Health Organization's classification of soft tissues tumors since 2013. The presence of a SS18 rearrangement is pathognomonic of synovial sarcoma (SS). MDM2 amplification is strongly correlated to well-differentiated or dedifferentiated liposarcoma (DDLPS) in the context of sarcoma. We identified one case of poorly differentiated sarcoma harboring both SS18-SSX2 fusion and MDM2 amplification. The review of the literature showed high discrepancies, concerning the incidence of MDM2 amplification in SS: from 1.4% up to 40%. Our goal was to precisely determine the specific clinico-pathological features of this case and to estimate the frequency and characteristics of the association of SS18-SSX fusion/MDM2 amplification in sarcomas. We performed a retrospective and prospective study in 96 sarcomas, (56 SS and 40 DDLPS), using FISH and/or array-CGH to detect MDM2 amplification and SS18 rearrangement. None of the 96 cases presented both genetic alterations. Among the SS, only the index case (1/57: 1.7 %) presented the double anomaly. We concluded that MDM2 amplification in SS is a very rare event. The final diagnosis of the index case was a SS with SS18-SSX2 and MDM2 amplification as a secondary alteration. If the detection of MDM2 amplification is performed first in a poorly differentiated sarcoma, that may lead to not search other anomalies such as SS18 rearrangement and therefore to an erroneous diagnosis. This observation emphasizes the strong complementarity between histomorphology, immunohistochemistry and molecular studies in sarcoma diagnosis.
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http://dx.doi.org/10.1016/j.neo.2020.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303914PMC
August 2020

High-grade soft tissue sarcoma arising in a desmoid tumor: case report and review of the literature.

Clin Sarcoma Res 2015 30;5:25. Epub 2015 Nov 30.

Department of Medical Oncology, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, 232 Bd de Sainte-Marguerite, 13009 Marseille, France.

Desmoid tumors are rare benign monoclonal fibroblastic tumors. Their aggressiveness is local with no potential for metastasis or dedifferentiation. Here we report on a 61-year-old patient who presented a locally advanced breast desmoid tumor diagnosed 20 years after post-operative radiotherapy for breast carcinoma. After 2 years of medical treatment, a high-grade undifferentiated pleomorphic soft tissue sarcoma arose within the desmoid tumor. Despite extensive surgery removing both tumors, the patient showed locoregional relapse by the sarcoma, followed by multimetastatic progression, then death 25 months after the surgery. The arising of a soft tissue sarcoma in a desmoid tumor is an exceptional event since our case is the fourth one reported so far in literature. It reinforces the need for timely and accurate diagnosis when a new mass develops in the region of a preexisting desmoid tumor, and more generally when a desmoid tumor modifies its clinical or radiological aspect.
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http://dx.doi.org/10.1186/s13569-015-0040-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665918PMC
December 2015

[A deep-seated haemorrhagic tumor with spindle cells].

Ann Pathol 2015 Dec 14;35(6):532-4. Epub 2015 Nov 14.

Service d'anatomie et cytologie pathologiques, hôpital d'instruction des armées Sainte-Anne, BP 600, 83800 Toulon cedex 09, France.

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http://dx.doi.org/10.1016/j.annpat.2015.05.008DOI Listing
December 2015

Saccular aneurysm and kink of the extracranial internal carotid artery secondary to fibromuscular dysplasia.

J Vasc Surg 2015 Nov;62(5):1326-7

Service de Chirurgie Vasculaire, Faculté de Médecine de Marseille, Aix-Marseille Université, Assistance Publique Hôpitaux de Marseille-Hôpital de la Timone, Marseille, France.

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http://dx.doi.org/10.1016/j.jvs.2014.07.093DOI Listing
November 2015

Prognostic value of HMGA2, CDK4, and JUN amplification in well-differentiated and dedifferentiated liposarcomas.

Mod Pathol 2015 Nov 4;28(11):1404-14. Epub 2015 Sep 4.

Laboratory of Solid Tumor Genetics, IRCAN, Nice University Hospital, Nice, France.

HMGA2, CDK4, and JUN genes have been described as frequently coamplified with MDM2 in atypical lipomatous tumor, well-differentiated liposarcoma, and dedifferentiated liposarcoma. We studied the frequency of amplification of these genes in a series of 48 dedifferentiated liposarcomas and 68 atypical lipomatous tumors/well-differentiated liposarcomas. We correlated their amplification status with clinicopathological features and outcomes. Histologically, both CDK4 (P=0.007) and JUN (P=0.005) amplifications were associated with dedifferentiated liposarcoma, whereas amplification of the proximal parts of HMGA2 (5'-untranslated region (UTR) and exons 1-3) was associated with atypical lipomatous tumor/well-differentiated liposarcoma (P=0.01). CDK4 amplification was associated with axial tumors. Amplification of 5'-UTR and exons 1-3 of HMGA2 was associated with primary status and grade 1. Shorter overall survival was correlated with: age >64 years (P=0.03), chemotherapy used in first intent (P<0.001), no surgery (P=0.003), grade 3 (P<0.001), distant metastasis (P<0.001), node involvement (P=0.006), and CDK4 amplification (P=0.07). In multivariate analysis, distant metastasis (HR=8.8) and grade 3 (HR=18.2) were associated with shorter overall survival. A shorter recurrence-free survival was associated with dedifferentiated liposarcoma (P<0.001), grade 3 (P<0.001), node involvement (P<0.001), distant metastasis (P=0.02), recurrent status (P=0.009), axial location (P=0.001), and with molecular features such as CDK4 (P=0.05) and JUN amplification (P=0.07). Amplification of 5'-UTR and exons 1-3 (P=0.08) and 3'-UTR (P=0.01) of HMGA2 were associated with longer recurrence-free survival. Distant metastasis was associated with shorter recurrence-free survival (HR=5.8) in multivariate analysis. Dedifferentiated liposarcoma type was associated with axial location, grade 3 and recurrent status. In conclusion, we showed that the amplification of HMGA2 was associated with the atypical lipomatous tumor/well-differentiated liposarcoma histological type and a good prognosis, whereas CDK4 and JUN amplifications were associated with dedifferentiated liposarcoma histology and a bad prognosis. In addition, we also provided the first description of the molecular evolution of a well-differentiated liposarcoma into four successive dedifferentiated liposarcoma relapses, which was consistent with our general observations.
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http://dx.doi.org/10.1038/modpathol.2015.96DOI Listing
November 2015

Sarcoidosis Occurring After Solid Cancer: A Nonfortuitous Association: Report of 12 Cases and Review of the Literature.

Medicine (Baltimore) 2015 Jul;94(28):e928

From the Department of Internal Medicine, CHU Timone, Assistance Publique-Hôpitaux de Marseille, Marseille (AG, ME, EB, VV, J-RH, NS); Department of Internal Medicine, CHU Conception, Assistance Publique-Hôpitaux de Marseille, Aix-Marseille Université, Marseille (KM, RJ); Department of Hematology, Paoli Calmette Institute, Marseille (DC, TA-S, FB, RB); Department of Oncology, Paoli Calmette Institute, Marseille (GG, AG, MG); Department of Internal Medicine, Croix-Rousse Hospital, Lyon (PS); Department of Pathology, Paoli Calmette Institute, Marseille (BC); Department of Internal Medicine, Alpes du Sud Hospital, Gap (FG-B, TW); and Department of Oncology, Desgenettes Hospital, Lyon (MP), France.

The association between cancer and sarcoidosis is controversial. Some epidemiological studies show an increase of the incidence of cancer in patients with sarcoidosis but only few cases of sarcoidosis following cancer treatment have been reported. We conducted a retrospective case study from internal medicine and oncology departments for patients presenting sarcoidosis after solid cancer treatment. We also performed a literature review to search for patients who developed sarcoidosis after solid cancer. We describe the clinical, biological, and radiological characteristics and outcome of these patients. Twelve patients were included in our study. Various cancers were observed with a predominance of breast cancer. Development of sarcoidosis appeared in the 3 years following cancer and was asymptomatic in half of the patients. The disease was frequently identified after a follow-up positron emission tomography computerized tomography evaluation. Various manifestations were observed but all patients presented lymph node involvement. Half of the patients required systemic therapy. With a median follow-up of 73 months, no patient developed cancer relapse. Review of the literature identified 61 other patients for which the characteristics of both solid cancer and sarcoidosis were similar to those observed in our series. This report demonstrates that sarcoidosis must be considered in the differential diagnosis of patients with a history of malignancy who have developed lymphadenopathy or other lesions on positron emission tomography computerized tomography. Histological confirmation of cancer relapse is mandatory in order to avoid unjustified treatments. This association should be consider as a protective factor against cancer relapse.
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http://dx.doi.org/10.1097/MD.0000000000000928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617083PMC
July 2015

Germinal center reentries of BCL2-overexpressing B cells drive follicular lymphoma progression.

J Clin Invest 2014 Dec 10;124(12):5337-51. Epub 2014 Nov 10.

It has recently been demonstrated that memory B cells can reenter and reengage germinal center (GC) reactions, opening the possibility that multi-hit lymphomagenesis gradually occurs throughout life during successive immunological challenges. Here, we investigated this scenario in follicular lymphoma (FL), an indolent GC-derived malignancy. We developed a mouse model that recapitulates the FL hallmark t(14;18) translocation, which results in constitutive activation of antiapoptotic protein B cell lymphoma 2 (BCL2) in a subset of B cells, and applied a combination of molecular and immunofluorescence approaches to track normal and t(14;18)(+) memory B cells in human and BCL2-overexpressing B cells in murine lymphoid tissues. BCL2-overexpressing B cells required multiple GC transits before acquiring FL-associated developmental arrest and presenting as GC B cells with constitutive activation-induced cytidine deaminase (AID) mutator activity. Moreover, multiple reentries into the GC were necessary for the progression to advanced precursor stages of FL. Together, our results demonstrate that protracted subversion of immune dynamics contributes to early dissemination and progression of t(14;18)(+) precursors and shapes the systemic presentation of FL patients.
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http://dx.doi.org/10.1172/JCI72415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348942PMC
December 2014

EFA6B antagonizes breast cancer.

Cancer Res 2014 Oct 12;74(19):5493-506. Epub 2014 Aug 12.

Institut de Pharmacologie Moléculaire et Cellulaire, Université de Nice Sophia-Antipolis CNRS UMR7275, Valbonne, France.

One of the earliest events in epithelial carcinogenesis is the dissolution of tight junctions and cell polarity signals that are essential for normal epithelial barrier function. Here, we report that EFA6B, a guanine nucleotide exchange factor for the Ras superfamily protein Arf6 that helps assemble and stabilize tight junction, is required to maintain apico-basal cell polarity and mesenchymal phenotypes in mammary epithelial cells. In organotypic three-dimensional cell cultures, endogenous levels of EFA6B were critical to determine epithelial-mesenchymal status. EFA6B downregulation correlated with a mesenchymal phenotype and ectopic expression of EFA6B hampered TGFβ-induced epithelial-to-mesenchymal transition (EMT). Transcriptomic and immunohistochemical analyses of human breast tumors revealed that the reduced expression of EFA6B was associated with loss of tight junction components and with increased signatures of EMT, cancer stemness, and poor prognosis. Accordingly, tumors with low levels of EFA6B were enriched in the aggressive triple-negative and claudin-low breast cancer subtypes. Our results identify EFA6B as a novel antagonist in breast cancer and they point to its regulatory and signaling pathways as rational therapeutic targets in aggressive forms of this disease.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-0298DOI Listing
October 2014

FDG-PET/CT is a pivotal imaging modality to diagnose rare intravascular large B-cell lymphoma: case report and review of literature.

Hematol Oncol 2015 Jun 21;33(2):99-109. Epub 2014 May 21.

Department of Internal Medicine, CHU Conception, Marseille, France.

Intravascular large B-cell lymphoma (IVLBCL) remains a diagnostic challenge, because of non-specific findings on clinical, laboratory, and imaging studies. We present a case in which 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography was particularly useful to suspect the diagnosis, to detect unexpected locations, to guide contributive biopsy, and to assess the response to treatment. In case of initial negative results, FDG-PET should be repeated in the course of clinical evolution. In the presence of neurological or hormonal symptoms without brain magnetic resonance imaging abnormality, FDG-PET brain slices could depict additional pituitary and/or brain hypermetabolisms. We discuss the potential interests of FDG-PET in IVLBCL by a literature review.
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http://dx.doi.org/10.1002/hon.2140DOI Listing
June 2015

Nature and importance of follicular lymphoma precursors.

Haematologica 2014 May;99(5):802-10

It is now widely recognized that cancer development is a protracted process requiring the stepwise acquisition of multiple oncogenic events. In humans, this process can take decades, if not a lifetime, blurring the notion of 'healthy' individuals. Follicular lymphoma exemplifies this multistep pathway of oncogenesis. In recent years, variants of follicular lymphoma have been recognized that appear to represent clonal B-cell expansions at an early stage of follicular lymphoma lymphomagenesis. These include follicular lymphoma in situ, duodenal follicular lymphoma, partial involvement by follicular lymphoma, and in the blood circulating follicular lymphoma-like B cells. Recent genetic studies have identified similarities and differences between the early lesions and overt follicular lymphoma, providing important information for understanding their biological evolution. The data indicate that there is already genomic instability at these early stages, even in instances with a low risk for clinical progression. The overexpression of BCL2 in t(14;18)-positive B cells puts them at risk for subsequent genetic aberrations when they re-enter the germinal center and are exposed to the influences of activation-induced cytidine deaminase and somatic hypermutations. The emerging data provide a rationale for clinical management and, in the future, may identify genetic risk factors that warrant early therapeutic intervention.
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http://dx.doi.org/10.3324/haematol.2013.085548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4008113PMC
May 2014

Primary synovial sarcoma of the thyroid gland: case report and review of the literature.

Case Rep Oncol 2014 Jan 11;7(1):6-13. Epub 2014 Jan 11.

Department of Medical Oncology, Marseille, France ; Department of Aix-Marseille University, Marseille, France.

Synovial sarcoma (SVS) of the thyroid gland is exceedingly rare. We report the case of a 55-year-old man with a rapidly growing 7-cm neck mass. Because of suspicion of anaplastic thyroid carcinoma, a total thyroidectomy was planned, without preoperative cytology. During surgery, the tumor ruptured, leading to fragmented and incomplete resection. The morphological and immunohistochemical aspects suggested thyroid SVS, which was confirmed by fluorescent in situ hybridization (SYT gene rearrangement). The patient experienced immediate local relapse in close contact with large vessels and the thyroid cartilage and was referred to our institution. Doxorubicin-ifosfamide chemotherapy led to a minor response that authorized secondary conservative surgery. Because of microscopically incomplete resection, adjuvant radiotherapy was chosen and is ongoing 10 months after initial surgery. The prognosis of thyroid SVS is associated with a high risk for local and metastatic relapses. Pretreatment diagnosis is fundamental and may benefit from molecular analysis. Margin-free monobloc surgical excision is the best chance for cure, but adjuvant chemotherapy and radiotherapy deserve to be discussed.
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http://dx.doi.org/10.1159/000357913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3934617PMC
January 2014

Efficacy and safety of lenalinomide combined with rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma.

Leuk Lymphoma 2014 Nov 17;55(11):2508-13. Epub 2014 Mar 17.

Institut Paoli-Calmettes , Marseille , France.

Initial clinical trials demonstrated that lenalidomide monotherapy has a significant activity against some subtypes of lymphoma, but in diffuse large B-cell lymphoma (DLBCL) its activity is limited. The combination of lenalidomide with rituximab may be a promising therapeutic strategy. We retrospectively analyzed clinical outcomes in 17 patients with relapsed/refractory (R/R) DLBCL treated with lenalidomide, 25 mg/day for 21/28 days and rituximab, 375 mg/m(2) on day 7 of every lenalidomide cycle, for a maximum of 12 months. The overall response rate (ORR) was 41.2% with 35.3% complete response (CR), while median response duration was 26.5 months at a median follow-up of 24.9 months. Two patients with CR relapsed after 4 and 27 months of CR, and another four are actually in CR at + 13, + 23, + 24 and + 29 months. The estimated 24-month overall survival (OS) was 45% and progression-free survival (PFS) was 38%. Adverse events were manageable and mostly included thrombocytopenia and neutropenia. Lenalidomide-rituximab is active in R/R DLBCL with an important percentage of continuous CR.
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http://dx.doi.org/10.3109/10428194.2014.889822DOI Listing
November 2014

Brentuximab vedotin followed by allogeneic transplantation as salvage regimen in patients with relapsed and/or refractory Hodgkin's lymphoma.

Hematol Oncol 2014 Dec 3;32(4):187-91. Epub 2013 Dec 3.

Department of Hematology, Institut Paoli-Calmettes-Université de la Méditerranée, Marseille, France.

Patients with relapsed or refractory Hodgkin lymphoma (RR-HL) have poor outcomes. Brentuximab vedotin (BV), an antibody-drug conjugate comprising an anti-CD30 antibody conjugated to the potent anti-microtubule agent, monomethyl auristatin E, induces high tumour responses with moderate adverse effects. In a retrospective study, we describe objective response rates and subsequent allogeneic stem cell transplantation (allo-SCT) in patients with RR-HL treated by BV in a named patient program in two French institutions. Twenty-four adult patients with histologically proven CD30(+) RR-HL treated with BV were included from July 2009 to November 2012. Response to BV treatment was evaluated after four cycles. Eleven patients were in complete response (45.8%), while five patients were in partial response (20.8%), with an overall response rate of 66.6%. Eight patients failed to respond to BV (33.3%). All of the responding patients could receive consolidation treatment after BV: three patients underwent autologous stem cell transplantation (auto-SCT), three patients received a tandem auto-SCT/allo-SCT, nine patients received allo-SCT and one patient was treated with donor lymphocyte infusion. We found no treatment-related mortality at day 100 among the 12 patients who underwent BV following by allogeneic transplantation. With a median follow-up of 20 months (range 10.5-43.2), none of them relapsed or died. BV followed by allo-SCT represents an effective salvage regimen in patients with RR-HL.
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http://dx.doi.org/10.1002/hon.2119DOI Listing
December 2014

Early lesions of follicular lymphoma: a genetic perspective.

Haematologica 2014 Mar 25;99(3):481-8. Epub 2013 Oct 25.

or

The pathogenesis of follicular lymphoma is a multi-hit process progressing over many years through the accumulation of numerous genetic alterations. Besides the hallmark t(14;18), it is still unclear which other oncogenic hits contribute to the early steps of transformation and in which precursor stages these occur. To address this issue, we performed high-resolution comparative genomic hybridization microarrays on laser-capture micro-dissected cases of follicular lymphoma in situ (n=4), partial involvement by follicular lymphoma (n=4), and duodenal follicular lymphoma (n=4), assumed to represent, potentially, the earliest stages in the evolution of follicular lymphoma. Cases of reactive follicular hyperplasia (n=2), uninvolved areas from follicular lymphoma in situ lymph nodes, follicular lymphoma grade 1-2 (n=5) and follicular lymphoma grade 3A (n=5) were used as controls. Surprisingly, alterations involving several relevant (onco)genes were found in all entities, but at significantly lower proportions than in overt follicular lymphoma. While the number of alterations clearly assigns all these entities as precursors, the pattern of partial involvement by follicular lymphoma alterations was quantitatively and qualitatively closer to that of follicular lymphoma, indicating significant selective pressure in line with its faster rate of progression. Among the most notable alterations, we observed and validated deletions of 1p36 and gains of the 7p and 12q chromosomes and related oncogenes, which include some of the most recurrent oncogenic alterations in overt follicular lymphoma (TNFRSF14, EZH2, MLL2). By further delineating distinctive and hierarchical molecular and genetic features of early follicular lymphoma entities, our analysis underlines the importance of applying appropriate criteria for the differential diagnosis. It also provides a first set of candidates likely to be involved in the cascade of hits that pave the path of the various progression phases to follicular lymphoma development.
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http://dx.doi.org/10.3324/haematol.2013.094474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943311PMC
March 2014

Large B-cell lymphomas in adolescents and young adults in comparison to adult patients: a matched-control analysis in 55 patients.

Leuk Lymphoma 2014 Aug 14;55(8):1849-53. Epub 2014 Feb 14.

Department of Hematology, Institut J. Paoli-I. Calmettes, Université de la Méditerranée , Marseille , France.

The aim of our study was to assess whether large B-cell lymphoma (LBCL) in adolescents and young adults (AYA) should be considered as a clinocopathological entity, and to evaluate the prognostic value of age. Fifty-five patients aged > 15-30 years were fully matched to 365 adult patients aged 31-65 years. We found a high incidence of primary mediastinal thymic LBCL subtype (33% vs. 5%), while histological transformation was rare (2% vs. 14%). LBCL in AYA presented with a bulky mediastinal mass (51% vs. 21%), and the lactate dehydrogenase (LDH) value was significantly higher (73% vs. 54%). The complete response rate to chemotherapy was similar in the two groups. Five-year overall survival (OS) and event-free survival (EFS) of AYA were 73% and 68%, respectively. The matched-control analysis showed no difference for either OS or EFS. LBCL in AYA presents with some critical features which differ from those of older adults. However, the outcome is equivalent to that observed in older patients.
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http://dx.doi.org/10.3109/10428194.2013.858814DOI Listing
August 2014

BetaHCG secretion by a pulmonary adenocarcinoma.

World J Surg Oncol 2013 Sep 14;11:228. Epub 2013 Sep 14.

Department of Medical Oncology, Institut Paoli-Calmettes, 13009 Marseille, France.

We report a rare case of metastatic non-small-cell lung cancer in a 43-year-old woman with a history of smoking. The tumor secreted human chorionic gonadotropin and its beta subunit (BetaHCG). The patient presented with amenorrhea, a positive pregnancy test and chest pain. A physical examination and investigations revealed no pregnancy, and it was determined that a paraneoplastic syndrome stemming from a pulmonary tumor was responsible for the secretion of BetaHCG. This secretion decreased with tumor response to chemotherapy. Only a few reports of paraneoplastic BetaHCG secretion can be found in the literature for several different cancers.
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http://dx.doi.org/10.1186/1477-7819-11-228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847484PMC
September 2013

[Soft tissue sarcomas: clinical application of molecular biology].

Rev Prat 2013 Mar;63(3):309-13

Département de biopathologie, institut Paoli-Calmettes, 13273 Marseille Cedex 9, France.

Soft tissue sarcomas are rare and heterogeneous tumours. Histological diagnosis is often difficult because of the numerous types and subtypes reported and morphological similarities with benign lesions in certain cases. Molecular analyses performed in an appropriate clinical and histological context improve the patients' management in the case of sarcomas with simple genomic profile: the identification of a specific and objective molecular abnormality can confirm a diagnosis, rule out another one, provide prognostic information, and guide the selection of targeted therapy About 15% of sarcomas bear a specific translocation that can be identified by FISH or RT-PCR. The search for a MDM2 amplification, reflecting the presence of an amplicon in the 12q region, is a sensitive and specific tool for the diagnosis of atypical lipomatous tumors/well-differentiated liposarcomas and dedifferentiated iposarcomas. The presence and the type of KITor PDGFRA activating mutation guide the diagnosis and treatment of GIST. Certain molecular abnormalities are found in several tumour types, emphasizing the importance of integrating the results of any molecular study within the morphological and immunohistochemical context: In France, sarcoma diagnosis is structured around a reference network (RRePS) that provides every pathologist an access to these molecular analysis tools.
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March 2013

Dramatic and delayed response to Doxorubicin-dacarbazine chemotherapy of a giant desmoid tumor: case report and literature review.

Case Rep Oncol 2013 Jan 5;6(1):127-33. Epub 2013 Mar 5.

Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France.

Desmoid tumors are benign, slow-growing mesenchymal tumors. Aggressiveness is local with no potential for metastasis or dedifferentiation. The treatment is challenging, particularly in the case of huge intra-abdominal locations. We, herein, report on a 21-year-old patient with a giant intra-abdominal desmoid tumor occupying substantially the entire abdominal cavity. After failure of a first-line combination of celecoxib and tamoxifen, the patient was given doxorubicin-dacarbazine chemotherapy. The treatment was well tolerated, and rapidly, the clinical digestive symptoms improved. After 6 cycles, the computed tomography scan showed a partial response (regression of tumor volume by 55%). During follow-up, the tumor continued to regress: 25 months after the end of chemotherapy, the tumor volume had regressed by 95% when compared to the start of computed tomography and by 90% when compared to the end of chemotherapy. Thirty-three months after the diagnosis, the patient is alive without any symptom. Our case provides further evidence of the remarkable efficacy of a doxorubicin-dacarbazine regimen, especially in function- or life-threatening situations where a rapid response is required. We review the literature and discuss the challenging issue regarding treatment of desmoid tumors.
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http://dx.doi.org/10.1159/000349918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3618027PMC
January 2013

Peripheral T-cell lymphomas: analysis of histology, staging and response to treatment of 208 cases at a single institution.

Leuk Lymphoma 2013 Nov 27;54(11):2392-8. Epub 2013 Mar 27.

Centre de lutte contre le cancer Institut Paoli Calmettes , Marseille , France.

Peripheral T-cell lymphomas are characterized by a poor clinical outcome. We retrospectively analyzed 208 adults treated in our institution between 2000 and 2011. Median age at diagnosis was 55 years. Fifty-one percent had B symptoms and 51% serum elevated lactate dehydrogenase (LDH) levels. Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0-1 in 63% and 2-4 in 37%. According to Ann Arbor classification, 16% were at stage I-II and 84% at stage III-IV. Histological subtypes were: 39% peripheral T-cell non-Hodgkin lymphoma (NHL) unspecified (PTCL-U), 19.5% anaplastic large cell lymphoma (ALCL), with 9.5% ALK+ and 10% ALK-, and 25% angioimmunoblastic lymphoma (AILT). Primary extranodal lymphoma represented 17%, and 8% were diagnosed with hemophagocytosis. Induction chemotherapy was CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in 87% of patients. The median number of chemotherapy cycles was 2 (1-7). A complete response was obtained in 57% of the patients. Among them, 32% had an autologous stem cell transplant (ASCT) and 10% allogeneic SCT, while 38% were primary refractory. Five-year overall survival (OS) was 28.5% (22.3-36.3), and 5-year event-free survival (EFS) was 18.4% (13.4-25.3). A multivariate analysis showed that ALCL-ALK+ (p = 0.004), AILT (p < 0.01), extranodal involvement (p = 0.001), PS > 1 (p = 0.04), LDH < normal (p = 0.003) and hemophagocytosis (p = 0.001) were independent adverse factors for OS. We conclude that conventional chemotherapy with intensive treatment is not sufficient to improve the response rate. Optimal management is required.
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http://dx.doi.org/10.3109/10428194.2013.776680DOI Listing
November 2013

PD-1 is a novel regulator of human B-cell activation.

Int Immunol 2013 Feb 18;25(2):129-37. Epub 2012 Oct 18.

Inserm U1068, Centre de Recherche en Cancerologie de Marseille, F-13009 Marseille, France.

The outcome of the adaptive immune response is determined by the integration of both positive and negative signals, respectively, induced upon the triggering of co-signaling receptors. One of them, programmed cell death 1 (PDCD1/PD-1) has largely been shown to be involved in the negative regulation of T-cell activation. However, PD-1 is also expressed on human B cells, and its role(s) in the process of human B-cell activation remains uncertain thus far. In this study, we describe the expression of PD-1 on the major human B-cells subsets isolated from peripheral blood and lymph nodes. We showed that PD-1 was expressed on naive B cells, was differentially expressed on peripheral IgM memory as compared with memory B cells and was lost on germinal center B cells. Expression of PD-1 ligands (PD-Ls) was induced by TLR9 activation. Finally, we showed that PD-1 was recruited to the B-cell receptor upon triggering. We determined that during TLR9 activation, blockade of PD-1/PD-Ls pathways indeed increased B-cell activation, proliferation and the production of inflammatory cytokines. Altogether, our results show, that, as reported in T cells, PD-1/PD-Ls complexes acted as inhibitors of the B-cell activation cascade and highlight the importance of devising future therapies able to modulate lymphocyte activation through the targeting of the PD-1/PD-Ls pathways.
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http://dx.doi.org/10.1093/intimm/dxs098DOI Listing
February 2013

The Junctional Adhesion Molecule-B regulates JAM-C-dependent melanoma cell metastasis.

FEBS Lett 2012 Nov 12;586(22):4046-51. Epub 2012 Oct 12.

Centre de Recherche en Cancérologie de Marseille, Unité Mixte de Recherche, Institut National de la Santé et de la Recherche Médicale 1068/Centre National de la Recherche Scientifique 7258, Marseille, France.

Metastasis is a major clinical issue and results in poor prognosis for most cancers. The Junctional Adhesion Molecule-C (JAM-C) expressed by B16 melanoma and endothelial cells has been involved in metastasis of tumor cells through homophilic JAM-C/JAM-C trans-interactions. Here, we show that JAM-B expressed by endothelial cells contributes to murine B16 melanoma cells metastasis through its interaction with JAM-C on tumor cells. We further show that this adhesion molecular pair mediates melanoma cell adhesion to primary Lung Microvascular Endothelial Cells and that it is functional in vivo as demonstrated by the reduced metastasis of B16 cells in Jam-b deficient mice.
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http://dx.doi.org/10.1016/j.febslet.2012.10.005DOI Listing
November 2012

Impact of systematic EGFR and KRAS mutation evaluation on progression-free survival and overall survival in patients with advanced non-small-cell lung cancer treated by erlotinib in a French prospective cohort (ERMETIC project--part 2).

J Thorac Oncol 2012 Oct;7(10):1490-502

Service de Pneumologie-AH-HP Hôpital Tenon, Faculté de Médecine P&M Curie, université Paris 6 Paris, France.

Background: Epidermal growth factor and v-Ki-ras2 Kirsten ras sarcoma (KRAS) mutation status, although associated with EGFR- tyrosine kinase inhibitor (TKI) efficacy, has not been used in clinical practice until recently. The prospective Evaluation of the EGFR Mutation status for the administration of EGFR-TKIs in non small cell lung Carcinoma (ERMETIC) study aimed to implement these biomarkers in France.

Methods: Between March 2007 and April 2008, EGFR and KRAS were studied by sequencing DNA tumor specimens from 522 consecutive advanced non-small-cell lung cancer patients treated with EGFR-TKI, mostly in second- or third-line settings. Cox models were used to investigate the impact of patient characteristics and mutations on progression-free survival (PFS) and overall survival (OS). Added value from mutation status was evaluated using likelihood ratio (LR) tests. Classification and regression tree analysis aimed to identify homogeneous groups in terms of survival.

Results: Among the 522 patients, 87% were white, 32% were women, and 18% were never-smokers, with 65% presenting with adenocarcinoma. Biological data were available for 307 patients, showing 44 EGFR mutations (14%) and 42 KRAS (14%) mutations. Median PFS was 2.4 months (interquartile range, 1.4-4.6) and median OS 5.6 months (interquartile range, 2.2-14.0). Factors independently associated with PFS were performance status 1 or 2 to 3 (hazards ratio [HR] = 1.5, 95% confidence interval [CI] 1.1-1.9; and HR = 2.3, CI 1.7-3.1, respectively; p < 0.001); former or current smoker status (HR = 1.8, CI 1.4-2.4 and 2.0,CI 1.4-2.8, respectively; p < 0.001); nonadenocarcinoma histology (squamous cell: HR = 0.9 CI 0.7-1.2]; others: HR = 1.6, 1.3-2.1; p < 0.001); at least two metastatic sites (HR = 1.3, CI 1.1-1.6 and 1.6, CI 1.3-2.1, respectively; p < 0.001); prior taxane-based chemotherapy (HR = 1.3, CI 1.0-1.3, p = 0.01); non-white (HR = 0.7, CI 0.5-0.9, p = 0.009). Similar results were found for OS. In addition, EGFR and KRAS mutations were significantly associated with PFS (HR = 0.5, CI 0.3-0.7 and HR = 1.2, CI 0.8-1.8, respectively, versus no mutation; LR p = 0.001). In the OS model, adjusted HR was 0.7 (0.4-1.0) for EGFR mutation and 1.7 (1.1-2.4) for KRAS (LR p = 0.004). Classification and regression tree analysis revealed EGFR mutation to be the primary factor for identifying homogeneous patient subgroups in terms of PFS.

Conclusions: EGFR and KRAS status independently impacts outcomes in advanced non-small-cell lung cancer patients treated with EGFR-TKI. However, EGFR status impacts both PFS and OS whereas KRAS only impacts OS. These findings support the nationwide use of EGFR status for patient selection before EGFR-TKI therapy. The role of KRAS mutations remains to be elucidated.
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http://dx.doi.org/10.1097/JTO.0b013e318265b2b5DOI Listing
October 2012

Protection from inflammatory organ damage in a murine model of hemophagocytic lymphohistiocytosis using treatment with IL-18 binding protein.

Front Immunol 2012 8;3:239. Epub 2012 Aug 8.

Centre d'Immunologie de Marseille-Luminy, INSERM, U 1104 Marseille, France.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition due to the association of an infectious agent with lymphocyte cytotoxicity defects, either of congenital genetic origin in children or presumably acquired in adults. In HLH patients, an excess of lymphocyte or macrophage cytokines, such as IFN-γ and TNFα is present in serum. In animal models of the disease, IFN-γ and TNF-α have been shown to play a central pathogenic role. In humans, unusually high concentrations of IL-18, an inducer of IFN-γ, and TNF-α have been reported, and are associated with an imbalance between IL-18 and its natural inhibitor IL-18 binding protein (IL-18BP) resulting in an excess of free IL-18. Here we studied whether IL-18BP could reduce disease severity in an animal model of HLH. Mouse cytomegalovirus infection in perforin-1 knock-out mice induced a lethal condition similar to human HLH characterized by cytopenia with marked inflammatory lesions in the liver and spleen as well as the presence of hemophagocytosis in bone marrow. IL-18BP treatment decreased hemophagocytosis and reversed liver as well as spleen damage. IL-18BP treatment also reduced both IFN-γ and TNF-α production by CD8(+) T and NK cells, as well as Fas ligand expression on NK cell surface. These data suggest that IL-18BP is beneficial in an animal model of HLH and in combination with anti-infectious therapy may be a promising strategy to treat HLH patients.
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http://dx.doi.org/10.3389/fimmu.2012.00239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413989PMC
August 2012

Solitary fibrous tumor in the round ligament of the liver: a fortunate intraoperative discovery.

Case Rep Oncol 2012 Jan 18;5(1):187-94. Epub 2012 Apr 18.

Department of Surgical Oncology, Institut Paoli-Calmettes, Marseille, France.

Solitary fibrous tumors (SFTs) are mesenchymal neoplasms of fibroblastic origin, most commonly found in the pleura. Numerous extrathoracic locations have been reported during the last 2 decades. Herein, we report the first case of an SFT in the round ligament of the liver. A 46-year-old Caucasian man presented with a 12-month history of abdominal pain. An ultrasonography-guided microbiopsy first revealed a desmoid tumor. After failure of first- and second-line medical treatments (celecoxib and tamoxifen, then imatinib), histological reexamination was suspicious for a low-grade sarcoma. MRI was also suspicious for a malignant process. Hence, surgery was decided. Laparotomy found a huge and well-limited tumor that, unexpectedly, was appended to the round ligament of the liver and free from any other intra-abdominal contact. The tumor was easily removed. Excision was monobloc and macroscopically complete. Histological analysis diagnosed an SFT arising from the round ligament of the liver. No adjuvant treatment was given. Ten months after surgery, the patient is alive without any signs or symptoms of relapse. This is the first report of SFT arising from the round ligament of the liver. It illustrates the difficulty in diagnosing such tumors. Whilst diagnosis of SFT is rare, it should be kept in mind to allow early diagnosis and complete surgical resection, which provide the best chance for recovery.
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http://dx.doi.org/10.1159/000338616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364086PMC
January 2012

Solitary fibrous tumor of the prostate: case report and review of the literature.

Case Rep Oncol 2012 Jan 10;5(1):22-9. Epub 2012 Jan 10.

Department of Radiotherapy, University of Mediterranea, Marseille, Montreal, Que., Canada.

Solitary fibrous tumor (SFT), usually described in the pleura, is exceedingly rare in the prostate. We report a 60-year-old man with prostatic SFT revealed by obstructive urinary symptoms, and detected by ultrasonography. Computed tomography (CT) and magnetic resonance imaging suggested a prostatic origin. CT-guided tumor biopsy diagnosed a SFT. A cystoprostatectomy was performed. Pathologic examination showed a 15-cm tumor arising from the prostate and showing histological criteria suggestive of aggressiveness. The surgical resection margins were tumor-free. The patient was then regularly monitored and is still alive in complete remission, 28 months after surgery. In conclusion, we report a new exceptional case of prostatic SFT. We review the literature and discuss the challenging issues of misdiagnosis, prognosis and treatment.
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http://dx.doi.org/10.1159/000335680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3290003PMC
January 2012

Efficacy of epidermal growth factor receptor targeting in advanced chordoma: case report and literature review.

BMC Cancer 2011 Oct 4;11:423. Epub 2011 Oct 4.

Department of Medical Oncology, Institut Paoli-Calmettes, 232 bd Ste-Marguerite, Marseille, 13009, France.

Background: Chordomas are very rare low-grade malignant bone tumors that arise from the embryonic rests of the notochord. They are characterized by slow growth and long history with frequent local relapses, and sometimes metastases. While chemotherapy is not efficient, imatinib has shown antitumor activity.

Case Presentation: We report on a 76-year-old patient with EGFR-overexpressing advanced chordoma that progressed on imatinib and subsequently responded to erlotinib during 12 months.

Conclusions: We report the fourth case of advanced chordoma treated with an EGFR inhibitor. We also review the literature concerning the rationale and potential of EGFR targeting in chordoma.
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http://dx.doi.org/10.1186/1471-2407-11-423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3199017PMC
October 2011

Differential role for CD277 as a co-regulator of the immune signal in T and NK cells.

Eur J Immunol 2011 Dec 3;41(12):3443-54. Epub 2011 Nov 3.

Institut National de la Santé et de la Recherche Médicale, Unité 891, Centre de Recherche en Cancérologie de Marseille, Marseille, France.

The human butyrophilin (BTN) 3 or CD277 molecules belong to the B7 family members and are expressed in various immune cells such as T and NK cells. Here, we show that CD277 triggering considerably enhances TCR-induced cytokine production and cell proliferation, even when another co-stimulatory molecule, CD28, is engaged. These CD277-induced additive functional effects are in accordance with the detection of early T-cell activation events such as TCR-induced cell signaling being increased upon CD277 engagement. However, we found that CD277 triggering is not involved in CD16- or NKp46-induced NK cell activation. BTN3/CD277 comprises three structurally related members, BTN3A1, BTN3A2 and BTN3A3. CD277 antibodies recognize all isoforms and we describe a differential expression of BTN3 isoforms between T and NK cells that could explain differential CD277 functions between T and NK cells. Our results show that, while T cells express all BTN3/CD277 transcripts, NK cells express mostly BTN3A2, which lacks the B30.2 intracellular domain. Furthermore, NKp30-induced cytokine production is decreased by the specific engagement of BTN3A2, but not by BTN3A1 triggering. Thus, we provide new insights into the CD277 co-stimulatory pathway that may differentially participate in the regulation of various cell-mediated immune responses.
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http://dx.doi.org/10.1002/eji.201141404DOI Listing
December 2011

Primary leiomyosarcoma of the seminal vesicle: case report and review of the literature.

BMC Cancer 2011 Jul 29;11:323. Epub 2011 Jul 29.

Department of Radiotherapy, Institut Paoli-Calmettes, 27 bd Leï Roure, 13009, Marseille, France.

Background: Primary leiomyosarcoma of the seminal vesicle is exceedingly rare.

Case Presentation: We report a case of a 59-year-old man with tumour detected by rectal symptoms and ultrasonography. Computed tomography and magnetic resonance imaging suggested an origin in the right seminal vesicle. Transperineal biopsy of the tumour revealed leiomyosarcoma. A radical vesiculo-prostactectomy with bilateral pelvic lymphadenectomy was performed. Pathological examination showed a grade 2 leiomyosarcoma of the seminal vesicle. The patient received adjuvant radiotherapy. He developed distant metastases 29 months after diagnosis, and received chemotherapy. Metastatic disease was controlled by second-line gemcitabine-docetaxel combination. Fifty-one months after diagnosis of the primary tumour, and 22 months after the first metastases, the patient is alive with excellent performance status, and multiple asymptomatic stable lung and liver lesions.

Conclusions: We report the eighth case of primary leiomyosarcoma of the seminal vesicle and the first one with a so long follow-up.
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http://dx.doi.org/10.1186/1471-2407-11-323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3161040PMC
July 2011
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