Publications by authors named "Dominique Ranchère-Vince"

74 Publications

Embryonal rhabdomyosarcoma completely resected at diagnosis: The European paediatric Soft tissue sarcoma Study Group RMS2005 experience.

Eur J Cancer 2021 Feb 7;146:21-29. Epub 2021 Feb 7.

Hematology Oncology Division, Department of Women's and Children's Health, University of Padova, Padova, Italy.

Background: Rhabdomyosarcoma (RMS) is the most common form of soft tissue sarcoma in children. We report the results of the European paediatric Soft tissue sarcoma Study Group (EpSSG) RMS 2005 study, which prospectively evaluated the reduction of chemotherapy in patients with embryonal RMS (ERMS) after initial surgery.

Methods: Between October 2005 and December 2016, all patients with localised ERMS with an initial microscopically complete resection (IRS group I) with lymph node-negative (N0) were prospectively enrolled in the low-risk (n = 70, subgroup A; age < 10 years and tumour size ≤ 5 cm) or standard-risk group (n = 108, subgroup B; age ≥ 10 years or tumour size > 5 cm. Subgroup A received 8 courses of vincristine and dactinomycin (VA) for 22 weeks; subgroup B received 4 courses of VA with ifosfamide (IVA) and 5 courses of VA for 25 weeks.

Results: The 5-year event-free survival (EFS) and overall survival (OS) were 90.8% (95% confidence interval [CI]: 85.0-94.4) and 95.7% (95% CI: 90.5-98.1), respectively (n = 178). The EFS and OS were 95.5% (95% CI: 86.8-98.5) and 100% (subgroupA), and 87.8% (95% CI: 79.3-93.0) and 93.0% (95% CI: 84.8-96.8)(subgroup B), respectively. Bearman stage 2 veno-occlusive disease (VOD) occurred in 4 very young patients.

Conclusion: VA treatment for 8 courses was effective and well tolerated by the subgroup of patients with low-risk ERMS (group A). Four courses of IVA and 5 courses of VA instead of 9 courses of IVA also has very good results. Careful monitoring for liver toxicity is important in very young patients. European union drug regulating authorities clinical trials EUDRACT No. 2005-000217-35.
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http://dx.doi.org/10.1016/j.ejca.2020.12.025DOI Listing
February 2021

[Pathological and molecular features of malignancies underlined by BAF complexes inactivation].

Ann Pathol 2019 Dec 27;39(6):399-413. Epub 2019 Jun 27.

Département de biopathologie, institut Bergonie, 33000 Bordeaux, France; Université de Bordeaux, 33400 Talence, France; Inserm U1218, ACTION, 33000 Bordeaux, France. Electronic address:

BAF complexes are chromatin remodelling complexes made up of 15 subunits which overview transcription regulation. A subset of their subunits are notoriously linked to cancer, with the examples of SMARCB1, SMARCA4, ARID1A/1B and PBRM1. The complexes act as tumor suppressor genes, commonly mutated in a wide array of malignancies with an overrepresentation of sarcomas and tumors of the central nervous system. The recurrent inactivation of their genes points towards their driving role in the tumorigenesis of SMARCB1 in malignant rhabdoid tumors and SMARCA4 in small cell carcinoma of the ovary, hypercalcemic type. These tumors are morphologically similar composed of solid sheets of cells displaying vesicular nuclei dotted with clear chromatin and conspicuous nucleoli. Genomically, they share simple diploid profiles with no other alterations than in the culprit gene. Other mesenchymal tumors, distinct from malignant rhabdoid tumors are associated with BAF alterations, namely epithelioid sarcomas, SMARCA4-deficient thoracic sarcomas. BAF subunits are mostly inactivated through mutations or deletions but also occur through translocations in medullary carcinoma of the kidney and synovial sarcomas. Apart from tumors displaying recurrent alterations of the complexes, some variants or tumor variants display BAF alterations, including epithelioid malignant peripheral nerve sheet tumors and poorly differentiated chordomas. Lastly, some malignancies display low frequency of BAF alterations, in keeping with their passenger role in tumorigenesis with the example of dedifferentiated carcinomas, especially in colon, lung and uterus. BAF complexes alterations correlate with morphological features recognizable by microscopy, paving the way for their routine diagnosis and potential therapeutic prospects.
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http://dx.doi.org/10.1016/j.annpat.2019.05.001DOI Listing
December 2019

Trabectedin and RAdiotherapy in Soft Tissue Sarcoma (TRASTS): Results of a Phase I Study in Myxoid Liposarcoma from Spanish (GEIS), Italian (ISG), French (FSG) Sarcoma Groups.

EClinicalMedicine 2019 Mar 11;9:35-43. Epub 2019 Mar 11.

Biomedicine Institute of Seville (IBIS), Spain.

Background: Myxoid liposarcoma (ML) exhibits a special sensitivity to trabectedin (T) and radiation therapy (RT). Preclinical data suggest a synergistic effect. We aimed to study safety, feasibility and activity of the administration of pre-operative concurrent T and RT in patients affected by localized resectable ML.

Methods: Patients received 3 cycles (C) of T in combination with RT (45 Gy) in 25 fractions (1.8 Gy/fraction). Dose Levels for T were: - 1 (1.1 mg/m2), 0 (1.3 mg/m2) and 1 (1.5 mg/m2). Primary endpoint was safety; antitumor activity was assessed by RECIST and Choi criteria. This study is registered at ClinicalTrials.gov, number NCT02275286. The phase 1 part of the study is complete and phase 2 is ongoing.

Findings: From February 2015 to May 2016, 14 patients (M/F 7/7), median age 36 years (range 24-70) and median tumor size 12.5 cm (range 7-17 cm), were enrolled. One dose limiting toxicity (G3 transaminitis) occurred at Level 0 and one (sepsis due to catheter infection) at Level 1. All patients completed RT. Five patients achieved PR (36%), 8 SD (57%), 1 distant PD (7%) by RECIST, while 12 achieved PR (86%), 1 SD (7%) and 1 distant PD (7%) by Choi criteria. Twelve patients underwent surgery. Median viable residual tumor was 5% (0-60).

Interpretation: T in combination with RT showed a favorable safety profile and antitumor activity in localized ML. T dose of 1.5 mg/m2 is the recommended dose for the phase 2 study, which is ongoing.

Funding: This study was partially supported by Pharmamar.
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http://dx.doi.org/10.1016/j.eclinm.2019.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510725PMC
March 2019

Distal extremities soft tissue sarcomas: Are they so different from other limb localizations?

J Surg Oncol 2019 Mar 4;119(4):479-488. Epub 2019 Jan 4.

Faculté de Médecine de la Timone, Génétique Médicale et génomique fonctionnelle, UMR S910 Inserm, Université Aix-Marseille 2, Marseille, France.

Background And Objectives: Soft tissue sarcoma localization in distal extremities (DESTS) of the limbs (hand/fingers, and foot/toes) is unusual. The literature is scarce about their behavior and this study was designed to assess their epidemiological characteristics, outcomes, and prognosis compared to other limb localizations (OLSTS).

Methods: From 1980 to 2010, adult DESTS and OLSTS in 22 centers were included. Demographics, tumor type, treatment modalities, and latest follow-up status were collected. Primary endpoints were overall survival and local/metastatic recurrence incidences.

Results: Two hundred five DESTS and 3001 OLSTS were included. The patients were younger, with more female and smaller tumors in DESTS. There were more clear cell/epithelioid sarcomas, synovial sarcomas, and myxoid liposarcomas vs more dedifferentiated liposarcomas in OLSTS. DESTS tumors were less irradiated and more often amputated (24.3% vs 3.4%). The five-year survival rate was 78.2% compared to 68.6% in OLSTS and after multivariate analysis, STS localization did not impact survival or local/metastatic recurrence.

Conclusion: Though rare and smaller than other limb localizations, DESTS are to be considered as aggressive. Despite a higher amputation rate, the prognosis remains the same as in OLSTS. Limb sparing vs amputation should be carefully assessed in DESTS, especially if grade 3 or of a poor prognosis histological subtype.
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http://dx.doi.org/10.1002/jso.25359DOI Listing
March 2019

Pazopanib for treatment of advanced malignant and dedifferentiated solitary fibrous tumour: a multicentre, single-arm, phase 2 trial.

Lancet Oncol 2019 01 18;20(1):134-144. Epub 2018 Dec 18.

Department of Medical Oncology, University Hospital of Canarias, Tenerife, Spain.

Background: A solitary fibrous tumour is a rare soft-tissue tumour with three clinicopathological variants: typical, malignant, and dedifferentiated. Preclinical experiments and retrospective studies have shown different sensitivities of solitary fibrous tumour to chemotherapy and antiangiogenics. We therefore designed a trial to assess the activity of pazopanib in a cohort of patients with malignant or dedifferentiated solitary fibrous tumour. The clinical and translational results are presented here.

Methods: In this single-arm, phase 2 trial, adult patients (aged ≥ 18 years) with histologically confirmed metastatic or unresectable malignant or dedifferentiated solitary fibrous tumour at any location, who had progressed (by RECIST and Choi criteria) in the previous 6 months and had an ECOG performance status of 0-2, were enrolled at 16 third-level hospitals with expertise in sarcoma care in Spain, Italy, and France. Patients received pazopanib 800 mg once daily, taken orally without food, at least 1 h before or 2 h after a meal, until progression or intolerance. The primary endpoint of the study was overall response measured by Choi criteria in the subset of the intention-to-treat population (patients who received at least 1 month of treatment with at least one radiological assessment). All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02066285, and with the European Clinical Trials Database, EudraCT number 2013-005456-15.

Findings: From June 26, 2014, to Nov 24, 2016, of 40 patients assessed, 36 were enrolled (34 with malignant solitary fibrous tumour and two with dedifferentiated solitary fibrous tumour). Median follow-up was 27 months (IQR 16-31). Based on central radiology review, 18 (51%) of 35 evaluable patients had partial responses, nine (26%) had stable disease, and eight (23%) had progressive disease according to Choi criteria. Further enrolment of patients with dedifferentiated solitary fibrous tumour was stopped after detection of early and fast progressions in a planned interim analysis. 51% (95% CI 34-69) of 35 patients achieved an overall response according to Choi criteria. Ten (29%) of 35 patients died. There were no deaths related to adverse events and the most frequent grade 3 or higher adverse events were hypertension (11 [31%] of 36 patients), neutropenia (four [11%]), increased concentrations of alanine aminotransferase (four [11%]), and increased concentrations of bilirubin (three [8%]).

Interpretation: To our knowledge, this is the first trial of pazopanib for treatment of malignant solitary fibrous tumour showing activity in this patient group. The manageable toxicity profile and the activity shown by pazopanib suggests that this drug could be an option for systemic treatment of advanced malignant solitary fibrous tumour, and provides a benchmark for future trials.

Funding: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.
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http://dx.doi.org/10.1016/S1470-2045(18)30676-4DOI Listing
January 2019

Clinicopathologic Features of CIC-NUTM1 Sarcomas, a New Molecular Variant of the Family of CIC-Fused Sarcomas.

Am J Surg Pathol 2019 02;43(2):268-276

Cancer Research Center of Lyon, University of Lyon, Université Claude Bernard Lyon 1, CNRS 5286, INSERM U1052, Lyon.

CIC-fused sarcomas represent an emerging family of tumors, for long connected to the Ewing family group of tumors, but underlined by distinct CIC fusions with different partners. 3' Fusion partners include DUX4, FOXO4, and, as recently emphasized, NUTM1. In this study, we report the clinicopathologic and molecular features of a series of 6 CIC-NUTM1 sarcomas. Mean age at diagnosis was 6 years (2 to 27 y), and 4 patients were male individuals. Primary tumors were located in the central nervous system (n=3), paravertebral soft tissue and epidural spaces (n=1, each), and lung (n=1). Median overall survival was 17.5 months (7 to 37 mo), and all but one patient died of disease. All tumors displayed classic features of CIC-DUX4 sarcomas with round cell to epithelioid microscopic appearance. Most tumors expressed ETV4 and NUTM1 (n=5/6 and 6/6, respectively), whereas WT1cter was positive in only 2 cases. All tested tumors were positive for break-apart fluorescence in situ hybridization for CIC and NUTM1. Apart from CIC or NUTM1 genomic breakpoints, no other recurrent copy number alteration was seen on genomic profiles. Fusion transcripts were identified by RNA-sequencing on either formalin-fixed paraffin-embedded or frozen material. CIC and NUTM1 breakpoints were located between exons 16 and 20 and exons 2 and 5, respectively. Altogether, CIC-NUTM1 sarcomas represent a new molecular variant of CIC-fused sarcomas with a predilection for the central nervous system and younger pediatric population. Its phenotype may be confused with NUT carcinomas.
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http://dx.doi.org/10.1097/PAS.0000000000001187DOI Listing
February 2019

Evaluation of eight melanocytic and neural crest-associated markers in a well-characterised series of 124 malignant peripheral nerve sheath tumours (MPNST): useful to distinguish MPNST from melanoma?

Histopathology 2018 Dec 23;73(6):969-982. Epub 2018 Oct 23.

Department of Pathology, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France.

Aims: The diagnosis of malignant peripheral nerve sheath tumour (MPNST) may be challenging, especially in the sporadic setting. Owing to the lack of specific histological criteria, immunohistochemical and molecular diagnostic markers, several differential diagnoses must be considered, especially melanoma. Indeed, although S100 protein usually stains melanoma, other melanocytic markers are often negative, especially in spindle cell/desmoplastic types. This pattern of immunoreactivity resembles that of some nerve-derived tumours such as MPNST. Owing to their different clinical behaviours and therapeutic implications, accurate identification of these two different tumours is crucial.

Methods And Results: S100, SOX10, KBA62, MITF, HMB45, Melan-A, tyrosinase PNL2 and BRAF-V600E immunostaining was performed in a pathologically and genetically well-characterised cohort of primary MPNST (n = 124), including 66 (53%) NF1-associated tumours. Sox10 and KBA62 expression were found, respectively, in 102 (84%) and in 101 (83%) MPNST, whereas S100 was expressed in 64 cases (52%). We observed an increased loss of S100 with increasing histological grade (P = 0.0052). We found Melan-A expression in 14% (n = 17) of all MPNST, occurring in 82% (n = 14) of cases in an NF1 context. Six per cent (n = 8) of MPNST showed tyrosinase positivity, including seven (87%) NF1-associated. MITF expression was found in 10 (8%) MPNST. None expressed PNL2, HMB45 or BRAF-V600E.

Conclusion: MPNST (in NF1 and a sporadic setting) can quite often be positive for Melan-A, tyrosinase and MITF. Pathologists should be cognisant of these exceptions to prevent confusion with melanoma.
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http://dx.doi.org/10.1111/his.13740DOI Listing
December 2018

Alternative PDGFD rearrangements in dermatofibrosarcomas protuberans without PDGFB fusions.

Mod Pathol 2018 11 28;31(11):1683-1693. Epub 2018 Jun 28.

Cancer Research Center of Lyon, Université Claude Bernard Lyon 1, CNRS 5286, INSERM U1052, Lyon, France.

Dermatofibrosarcoma protuberans is underlined by recurrent collagen type I alpha 1 chain-platelet-derived growth factor B chain (COL1A1-PDGFB) fusions but ~ 4% of typical dermatofibrosarcoma protuberans remain negative for this translocation in routine molecular screening. We investigated a series of 21 cases not associated with the pathognomonic COL1A1-PDGFB fusion on routine fluorescence in situ hybridization (FISH) testing. All cases displayed morphological and clinical features consistent with the diagnosis of dermatofibrosarcoma protuberans. RNA-sequencing analysis was successful in 20 cases. The classical COL1A1-PDGFB fusion was present in 40% of cases (n = 8/20), and subsequently confirmed with a COL1A1 break-apart FISH probe in all but one case (n = 7/8). 55% of cases (n = 11/20) displayed novel PDGFD rearrangements; PDGFD being fused either to the 5' part of COL6A3 (2q37.3) (n = 9/11) or EMILIN2 (18p11) (n = 2/11). All rearrangements led to in-frame fusion transcripts and were confirmed at genomic level by FISH and/or array-comparative genomic hybridization. PDGFD-rearranged dermatofibrosarcoma protuberans presented clinical outcomes similar to typical dermatofibrosarcoma protuberans. Notably, the two EMILIN2-PDGFD cases displayed fibrosarcomatous transformation and homozygous deletions of CDKN2A at genomic level. We report the first recurrent molecular variant of dermatofibrosarcoma protuberans involving PDGFD, which functionally mimic bona fide COL1A1-PDGFB fusions, leading presumably to a similar autocrine loop-stimulating PDGFRB. This study also emphasizes that COL1A1-PDGFB fusions can be cytogenetically cryptic on FISH testing in a subset of cases, thereby representing a diagnostic pitfall that pathologists should be aware of.
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http://dx.doi.org/10.1038/s41379-018-0089-4DOI Listing
November 2018

Ultrasound Presentation of a Disseminated Fetal and Neonatal Rhabdoid Tumor.

Case Rep Obstet Gynecol 2018 31;2018:6073204. Epub 2018 Jan 31.

Department of Obstetrics and Gynaecology, CHU de Rennes, Hospital Anne de Bretagne, 16 Bd de Bulgarie, BP 90347, 35 203 Rennes Cedex 2, France.

This is a case report of a disseminated fetal rhabdoid tumor discovered at 32 weeks of gestation in a 29-year-old woman on immunosuppressive therapy. The mother consulted for a decrease in fetal movement. Fetal ultrasound showed signs of a disseminated tumor affecting the left armpit, liver, spleen, and limbs. A caesarian section was performed because of signs of fetal distress. Immunohistochemical analysis of a fetal biopsy showed deletion of the gene. Pathological analysis of the placenta showed a rhabdoid tumor invading both fetal and maternal compartments. The mother underwent a whole-body MRI, and no metastasis was found. To the best of our knowledge, this is the first report of a disseminated rhabdoid tumor invading both fetal and maternal compartments.
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http://dx.doi.org/10.1155/2018/6073204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833875PMC
January 2018

The cost-saving effect of centralized histological reviews with soft tissue and visceral sarcomas, GIST, and desmoid tumors: The experiences of the pathologists of the French Sarcoma Group.

PLoS One 2018 5;13(4):e0193330. Epub 2018 Apr 5.

Department of Anatomopathology, Institut Bergonié, Bordeaux, France.

Objective: This study examined the types of discordance occurring in the diagnosis of soft tissue and visceral sarcomas, gastrointestinal stromal tumors (GIST), and desmoid tumors, as well as the economic impact of diagnostic discrepancies.

Methods: We carried out a retrospective, multicenter analysis using prospectively implemented databases performed on a cohort of patients within the French RRePS network in 2010. Diagnoses were deemed to be discordant based on the 2013 World Health Organization (WHO) classification. Predictive factors of discordant diagnoses were explored. A decision tree was used to assess the expected costs of two strategies of disease management: one based on revised diagnoses after centralized histological review (option 1), the other on diagnoses without centralized review (option 2). Both were defined based on the patient and the disease characteristics, according to national or international guidelines. The time horizon was 12 months and the perspective of the French National Health Insurance (NHI) was retained. Costs were expressed in Euros for 2013. Sensitivity analyses were performed using low and high scenarios that included ± 20% estimates for cost.

Results: A total of 2,425 patients were included. Three hundred forty-one patients (14%) had received discordant diagnoses. These discordances were determined to mainly be benign tumors diagnosed as sarcomas (n = 124), or non-sarcoma malignant tumors diagnosed as sarcomas (n = 77). The probability of discordance was higher for a final diagnosis of desmoid tumors when compared to liposarcomas (odds ratio = 5.1; 95%CI [2.6-10.4]). The expected costs per patient for the base-case analysis (low- and high-case scenarios) amounted to €8,791 (€7,033 and €10,549, respectively) for option 1 and €8,904 (€7,057 and €10,750, respectively) for option 2.

Conclusions: Our findings highlight misdiagnoses of sarcomas, which were found to most often be confused with benign tumors. Centralized histological reviews are likely to provide cost-savings for the French NHI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193330PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886412PMC
July 2018

[Desmoplastic small round cell tumor in children, adolescents and young adults].

Bull Cancer 2018 May 22;105(5):523-536. Epub 2018 Mar 22.

Centre intégré de soins et de recherche en oncologie de l'enfant, adolescent et jeune adulte (SIREDO), université PSL, institut Curie, 75005 Paris, France. Electronic address:

Desmoplastic small round cell tumor (DSRCT) is a rare sarcoma that typically affects pediatric and young adult patients with a median age in the general and in the pediatric population of 24.6 years (range 4-58 years) and 15.0 years (range 0-21 years) respectively, with a strong male predominance. This tumor is characterized by a specific t(11;22)(p13;q12) that results in fusion of EWS and WT1 genes which can be demonstrated by RT-PCR or by FISH. DSRCT most frequently presents as an intra-abdominal primary mass associated with peritoneal seeding and a highly aggressive pattern of spread. Generally, all tumors showed the typical histologic findings of variably sized clusters of poly-phenotypic small, round, or spindled cells lying in a desmoplastic stroma. Treatment of this malignancy remains a challenge. The combination of polychemotherapy regimens and aggressive surgery followed by whole abdomen radiation therapy represents nowadays a classical protocol for DSRCT. The survival rate of DSRCT patients is still disappointing around 20 %. However, the survival of patients who had complete resection of the tumor appears better. Hopes are turning to targeted therapeutics against this simple genomic sarcoma. Authors summarize medical knowledge of this rare tumor.
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http://dx.doi.org/10.1016/j.bulcan.2018.01.014DOI Listing
May 2018

Genetic analyses of undifferentiated small round cell sarcoma identifies a novel sarcoma subtype with a recurrent CRTC1-SS18 gene fusion.

J Pathol 2018 06 16;245(2):186-196. Epub 2018 Apr 16.

Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.

In recent years, undifferentiated small round cell sarcomas (USRCSs) have been divided into a variety of new, rare, sarcoma subtypes, including the group of Ewing-like sarcomas, which have the morphological appearance of Ewing sarcomas, but carry CIC-DUX4, BCOR-CCNB3 and other gene fusions different from the classic EWSR1-ETS gene fusion. Using high-throughput RNA-sequencing (RNA-seq) analyses, we identified a novel recurrent gene fusion, CRTC1-SS18, in two cases of USRCS that lacked any known translocation. RNA-seq results were confirmed by reverse transcription polymerase chain reaction, long-range polymerase chain reaction, and fluorescence in situ hybridization. In vitro, we showed that the cells expressing the gene fusion were morphologically distinct and had enhanced oncogenic potential as compared with control cells. Expression profile comparisons with tumours of other sarcoma subtypes demonstrated that both cases clustered close to EWSR1-CREB1-positive tumours. Moreover, these analyses indicated enhanced NTRK1 expression in CRTC1-SS18-positive tumours. We conclude that the novel gene fusion identified in this study adds a new subtype to the USRCSs with unique gene signatures, and may be of therapeutic relevance. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5071DOI Listing
June 2018

Genomic complexity in pediatric synovial sarcomas (Synobio study): the European pediatric soft tissue sarcoma group (EpSSG) experience.

Cancer Med 2018 04 13;7(4):1384-1393. Epub 2018 Mar 13.

Biopathology Department, Institut d'Hematologie et d'Oncologie Pediatrique, Centre Léon Bérard, Lyon, France.

A genomic index (GI) tool using array comparative genomic hybridization (aCGH) on tumor cells has emerged as independent prognostic factor associated with the risk of metastatic relapse in synovial sarcoma (SS). The aim was to assess GI in pediatric patients with SS, to determine its value as a prognostic factor. All pediatric/adolescent/young adults' (<25 years) with localized SS prospectively included in the European EpSSG-NRSTS05 protocol with a contributive aCGH were selected. Definition of GI was A /C, where A is the total number of alterations (segmental gains and losses) and C is the number of involved chromosomes on aCGH results. GI group corresponds to cases with no copy number alterations (flat profile, GI = 0) and GI group cases with at least one or more copy number alterations (rearranged profile; GI ≥ 1). Samples were available from 61 patients. The median age of the cohort was 13 years (range: 4-24). Overall, 55.7% were GI group, and 44.3% GI . After a median follow-up of 62 months (range: 0.1-112), 10 tumor events occurred and five patients died. Respectively, for GI versus GI groups, five-year event-free survival (EFS) was 93.8 ± 4.2% versus 64.9 ± 10.1% (P < 0.006) and five-year Metastatic-Free Survival (MFS) 93.8 ± 4.2% versus 72.9 ± 9.5% (P < 0.04). In multivariate analysis, GI status as adjusted for IRS group, patient age, site, and tumor size remain independent prognostic for EFS with a relative risk (RR) of 6.4 [1.3-31.9] (P < 0.01) and RR for MFS is 4.8 [0.9-25.7] (P < 0.05). Genomic complexity evaluated through GI may explain the metastatic behavior of pediatric SS.
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http://dx.doi.org/10.1002/cam4.1415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911585PMC
April 2018

Transcriptomic definition of molecular subgroups of small round cell sarcomas.

J Pathol 2018 05 30;245(1):29-40. Epub 2018 Mar 30.

INSERM U830, Laboratory of Genetics and Biology of Cancer, Paris, France.

Sarcoma represents a highly heterogeneous group of tumours. We report here the first unbiased and systematic search for gene fusions combined with unsupervised expression analysis of a series of 184 small round cell sarcomas. Fusion genes were detected in 59% of samples, with half of them being observed recurrently. We identified biologically homogeneous groups of tumours such as the CIC-fused (to DUX4, FOXO4 or NUTM1) and BCOR-rearranged (BCOR-CCNB3, BCOR-MAML3, ZC3H7B-BCOR, and BCOR internal duplication) tumour groups. VGLL2-fused tumours represented a more biologically and pathologically heterogeneous group. This study also refined the characteristics of some entities such as EWSR1-PATZ1 spindle cell sarcoma or FUS-NFATC2 bone tumours that are different from EWSR1-NFATC2 tumours and transcriptionally resemble CIC-fused tumour entities. We also describe a completely novel group of epithelioid and spindle-cell rhabdomyosarcomas characterized by EWSR1- or FUS-TFCP2 fusions. Finally, expression data identified some potentially new therapeutic targets or pathways. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5053DOI Listing
May 2018

Presentation and outcome of frequent and rare sarcoma histologic subtypes: A study of 10,262 patients with localized visceral/soft tissue sarcoma managed in reference centers.

Cancer 2018 03 6;124(6):1179-1187. Epub 2017 Dec 6.

Department of Medical Oncology, Leon Berard Center, Lyon, France.

Background: The objective of this study was to describe characteristics at diagnosis and outcomes of adults with soft tissue sarcoma.

Methods: The authors conducted a retrospective multicenter study of 12,262 patients who were treated between January 1980 and 31 December 2013 in French Sarcoma Group centers and enrolled in the "Conticabase." Diagnoses were systematically reviewed by expert pathologists, and entities were classified according to the 2013 World Health Organization classification. Diagnostic characteristics, treatments, and outcomes are described for the entire cohort, for the subgroup of patients with translocation-related sarcomas, and for 9 different histologic subtypes.

Results: The results stressed the magnitude of heterogeneity among adult sarcomas. For example, compared with other sarcomas, translocation-related sarcomas (2143 tumors; 20.8%) were associated with a younger age at presentation (40.6 vs 60.0 years; P < .0001), a low rate of predisposing conditions (0.01% vs 22.3%; P < .0001), a higher rate of lymph node involvement (4.7% vs 1.3%; P < .0001), and a higher rate of synchronous metastasis (11.9% vs 6.7%; P < .001); and complete (R0) resection (41.6% vs 31.9%; P < .0001), receipt of (neo)adjuvant radiation therapy (62.6% vs 42.2%; P < .0001), and receipt of (neo)adjuvant chemotherapy (36.6% vs 22.3%; P < .0001) were significantly more frequent. Overall, translocation-related sarcomas were associated with a lower rate of local relapse (18.1% vs 26.0%; P < .0001) but a higher rate of metastatic relapse (42.0% vs 30.7%; P < .0001).

Conclusions: Collaborative efforts are urgently needed to better assess the natural history and management options for every histologic subtype of sarcoma. Cancer 2018;124:1179-87. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31176DOI Listing
March 2018

Posttransplantation relapse of pediatric chronic myelomonocytic leukemia cured using donor lymphocyte infusion.

Pediatr Blood Cancer 2018 02 12;65(2). Epub 2017 Sep 12.

Department of Pediatric Oncology and Hematology, Institut d'Hématologie et d'Oncologie Pédiatrique (IHOPe), Lyon, France.

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http://dx.doi.org/10.1002/pbc.26808DOI Listing
February 2018

Update on Families of Round Cell Sarcomas Other than Classical Ewing Sarcomas.

Surg Pathol Clin 2017 Sep 20;10(3):587-620. Epub 2017 Jun 20.

Departement de Biopathologie, Centre Leon Berard, Cheney B, 24 rue Laennec, Lyon 69000, France.

This article focuses on families of round cell sarcomas other than classical Ewing sarcomas. Until recently, these tumors were referred to as so-called Ewing-like tumors, as they morphologically resemble Ewing sarcomas but are negative for canonical fusion transcripts of Ewing sarcomas involving gene members of the ETS family of transcription factors. Clinicopathologic and molecular evidence has dramatically influenced the diagnostic approach of these tumors in recent years. Molecular data that support these sarcoma subtypes are biologically distinct from those of Ewing sarcomas, thereby advocating discarding the all-embracing and confusing terminology of "Ewing-like tumors."
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http://dx.doi.org/10.1016/j.path.2017.04.002DOI Listing
September 2017

Loss of H3K27 trimethylation is not suitable for distinguishing malignant peripheral nerve sheath tumor from melanoma: a study of 387 cases including mimicking lesions.

Mod Pathol 2017 12 28;30(12):1677-1687. Epub 2017 Jul 28.

Department of Biopathology, Institut Bergonié, Bordeaux, France.

The diagnosis of malignant peripheral nerve sheath tumor remains challenging, especially in the sporadic setting. Malignant peripheral nerve sheath tumor is a rare malignancy, and owing to the lack of specific histological criteria, immunohistochemical and molecular diagnostic markers, several differential diagnoses must be considered, in particular melanoma. Recently, inactivation of the polycomb repressive complex 2 (PRC2), induced by inactivating mutations in two of its critical constituents SUZ12 and EED, was reported in a large subset of malignant peripheral nerve sheath tumors. Homozygous PRC2 inactivation induces complete loss of trimethylation at lysine 27 of histone 3 (H3K27me3). Recent studies suggest that complete loss of H3K27me3 is highly specific for malignant peripheral nerve sheath tumor and may be a useful immunohistochemical diagnostic marker. Therefore, to determine the specificity of the complete loss of H3K27me3 expression in the context of the differential diagnosis of malignant peripheral nerve sheath tumor from melanoma (its major potential mimic), we performed H3K27me3 immunohistochemistry in a pathologically and genetically well-characterized cohort of primary (neurofibromatosis type 1 (NF1), radiation-associated and sporadic context) malignant peripheral nerve sheath tumors (n=122) and in a cohort or primary (desmoplastic) and metastatic melanomas (n=265). In total, 88 (72%) malignant peripheral nerve sheath tumors, including 46 (71%) NF1-associated, 4 (100%) radiation-associated, and 38 (72%) sporadic tumors, showed complete loss of H3K27me3. We observed increased loss of H3K27me3 with increasing histological grade. Interestingly, we found complete loss of H3K27me3 in 37% (n=98) of all melanomas, including 25% (n=9) of primary desmoplastic melanomas. Moreover, partial loss ('mosaic' pattern) was observed in 23 (19%) of all malignant peripheral nerve sheath tumors and in 136 (51%) of all melanomas. Complete loss of H3K27me3 detected by immunohistochemistry is not specific for malignant peripheral nerve sheath tumor and cannot be used safely when distinguishing malignant peripheral nerve sheath tumor from melanoma.
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http://dx.doi.org/10.1038/modpathol.2017.91DOI Listing
December 2017

Embryonic signature distinguishes pediatric and adult rhabdoid tumors from other SMARCB1-deficient cancers.

Oncotarget 2017 May;8(21):34245-34257

Paris-Sciences-Lettres, Institut Curie Research Center, INSERMU830 & SiRIC, Laboratory of Translational Research in Pediatric Oncology, 75248 Paris Cedex 5, France.

Extra-cranial rhabdoid tumors (RT) are highly aggressive malignancies of infancy, characterized by undifferentiated histological features and loss of SMARCB1 expression. The diagnosis is all the more challenging that other poorly differentiated cancers lose SMARCB1 expression, such as epithelioid sarcomas (ES), renal medullary carcinomas (RMC) or undifferentiated chordomas (UC). Moreover, late cases occurring in adults are now increasingly reported, raising the question of differential diagnoses and emphasizing nosological issues. To address this issue, we have analyzed the expression profiles of a training set of 32 SMARCB1-deficient tumors (SDT), with ascertained diagnosis of RT (n = 16, all < 5 years of age), ES (n = 8, all > 10 years of age), UC (n = 3) and RMC (n = 5). As compared with other SDT, RT are characterized by an embryonic signature, and up-regulation of key-actors of de novo DNA methylation processes. Using this signature, we then analysed the expression profiling of 37 SDT to infer the appropriate diagnosis. Thirteen adult onset tumors showed strong similarity with pediatric RT, in spite of older age; by exome sequencing, these tumors also showed genomic features indistinguishable from pediatric RT. In contrary, 8 tumors were reclassified within carcinoma, ES or UC categories, while the remaining could not be related to any of those entities. Our results demonstrate that embryonic signature is shared by all RT, whatever the age at diagnosis; they also illustrate that many adult-onset SDT of ambiguous histological diagnosis are clearly different from RT. Finally, our study paves the way for the routine use of expression-based signatures to give accurate diagnosis of SDT.
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http://dx.doi.org/10.18632/oncotarget.15939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470964PMC
May 2017

Patterns of care and outcomes of patients with METAstatic soft tissue SARComa in a real-life setting: the METASARC observational study.

BMC Med 2017 Apr 10;15(1):78. Epub 2017 Apr 10.

Department of Medicine, Institut Bergonié, Bordeaux, France.

Background: Well-designed observational studies of individuals with rare tumors are needed to improve patient care, clinical investigations, and the education of healthcare professionals.

Methods: The patterns of care, outcomes, and prognostic factors of a cohort of 2225 patients with metastatic soft tissue sarcomas who were diagnosed between 1990 and 2013 and documented in the prospectively maintained database of the French Sarcoma Group were analyzed.

Results: The median number of systemic treatments was 3 (range, 1-6); 27% of the patients did not receive any systemic treatment and 1054 (49%) patients underwent locoregional treatment of the metastasis. Half of the patients who underwent chemotherapy (n = 810) received an off-label drug. Leiomyosarcoma was associated with a significantly better outcome than the other histological subtypes. With the exception of leiomyosarcomas, the benefit of a greater than third-line regimen was very limited, with a median time to next treatment (TNT) and overall survival (OS) ranging between 2.3 and 3.7 months and 5.4 and 8.5 months, respectively. The TNT was highly correlated with OS. Female sex, leiomyosarcoma histology, locoregional treatment of metastases, inclusion in a clinical trial, and treatment with first-line polychemotherapy were significantly associated with improved OS in the multivariate analysis.

Conclusions: The combination of doxorubicin with a second drug, such as ifosfamide, represents a valid option, particularly when tumor shrinkage is expected to provide clinical benefits. After failure of the second-line therapy, best supportive care should be considered, particularly in patients with non-leiomyosarcoma histology who are not eligible to participate in a clinical trial. Locoregional treatment of metastasis should always be included in the therapeutic strategy when feasible. TNT may represent a useful surrogate endpoint for OS in clinical studies.
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http://dx.doi.org/10.1186/s12916-017-0831-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385590PMC
April 2017

Survival impact of centralization and clinical guidelines for soft tissue sarcoma (A prospective and exhaustive population-based cohort).

PLoS One 2017 3;12(2):e0158406. Epub 2017 Feb 3.

Department of Medical Oncology, Centre Léon Bérard, Lyon, France.

Purpose: The outcome of sarcoma has been suggested in retrospective and non-exhaustive studies to be better through management by a multidisciplinary team of experts and adherence to clinical practice guidelines (CPGs). The aim of this prospective and exhaustive population based study was to confirm the impact of adherence to CPGs on survival in patients with localized sarcoma.

Experimental Design: Between 2005 and 2007, all evaluable adult patients with a newly diagnosis of localized sarcoma located in Rhone Alpes region (n = 634), including 472 cases of soft-tissue sarcoma (STS), were enrolled. The prognostic impact of adherence to CPGs on progression-free survival (PFS) and overall survival (OS) was assessed by multivariate Cox model in this cohort.

Results: The median age was 61 years (range 16-92). The most common subtypes were liposarcoma (n = 133, 28%), unclassified sarcoma (n = 98, 20.7%) and leiomyosarcoma (n = 69, 14.6%). In the initial management phase, from diagnosis to adjuvant treatment, the adherence to CPGs for patients with localized STS was 36% overall, corresponding to 56%, 85%, 96% and 84% for initial surgery, radiation therapy, chemotherapy and follow-up, respectively. Adherence to CPGs for surgery was the strongest independent prognostic factor of PFS, along with age, gender, grade, and tumor size. For OS, multivariate analysis adherence to CPGs for surgery was a strong independent prognostic factor, with an important interaction with a management in the regional expert centers.

Conclusions: This study demonstrates impact of CPGs and treatment within an expert center on survival for STS patients in a whole population-based cohort.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158406PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291382PMC
August 2017

Time interval between surgery and start of adjuvant radiotherapy in patients with soft tissue sarcoma: A retrospective analysis of 1131 cases from the French Sarcoma Group.

Radiother Oncol 2016 07 17;120(1):156-62. Epub 2016 May 17.

Department of Radiation Oncology, Institut Bergonié, Bordeaux, France.

Purpose: The aim of this study was to evaluate the impact of the time interval (TI) between surgery and adjuvant radiotherapy (RT) in soft tissue sarcoma (STS).

Methods And Materials: Data from 1131 patients treated between 1990 and 2014 were retrospectively reviewed. Inclusion criteria were: limb or superficial trunk wall STS (R0 or R1 resection) and adjuvant RT. The impact of TI on 10-year local relapse-free survival (LRFS) and 10-year overall survival (OS) was analyzed using a Log-rank test and then Cox Model.

Results: The median TI was 82days (range, 18-346). With a median follow-up of 235months (range, 2-296months), the 10-year LRFS was 57.5% (±2%) and the 10-year OS was 64.2% (±2%). With a TI of 19-39days, 40-79days, 80-119days, and ⩾120days, 10-year LRFSs were 65.3%, 55.5%, 56.9% and 61.2% (p=0.465), and 10-year OSs were 72.8%, 60.7%, 66.4% and 62.1% (p=0.347), respectively. After adjustment for the factors significantly (p⩽0.05) associated with LRFS and OS, TI did not alter LRFS (p=0.182) either OS (p=0.335).

Conclusions: In this retrospective STS database study, the TI between surgery and start of adjuvant RT did not seem to affect outcomes.
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http://dx.doi.org/10.1016/j.radonc.2016.04.037DOI Listing
July 2016

Management of desmoid tumours: A nationwide survey of labelled reference centre networks in France.

Eur J Cancer 2016 May 11;58:90-6. Epub 2016 Mar 11.

Medical Oncology Department, Centre Léon Bérard, 28 rue Laennec, 69008 Lyon, France. Electronic address:

Purpose: The optimal management of rare tumours (i.e. from accurate diagnosis to management in reference centres) is a public health challenge. In 2009, the French National Cancer Institute (INCa) identified and financially supported the two expert networks for pathological and clinical diagnosis and management of soft tissue tumours.

Methods: The activities of both networks were prospectively collected using a nationwide database (rreps.org). Data describing the diagnosis management of 863 successive cases of desmoids tumours (DT) were prospectively collected from 2010 to 2013 and analysed.

Results: The number of confirmed DT constantly improved from January 2010 to December 2013 (from 173 to 273 cases per year); the expected incidence ranged from 132 to 330 cases/year. The rate of cases diagnosed with core-needle biopsies and CTNNB1 mutational status analysis increased from 30.6 to 40.7% and from 87.8 to 94.1%, respectively. The mean delay for pathological diagnosis confirmation constantly decreased from 107 to 47 d. Among the 846 adult patients, 414 (48.9%) patients were treated by reference centres. The rate of patients managed by reference centres constantly increased with time from 36.9 to 49.5% since 2010. The median management time of the referral centres constantly decreased from 440 to 67 d.

Conclusion: The two expert networks worked synergistically and improved diagnosis modalities of rare desmoid tumours at a national level. The impact of management by expert networks on the outcome will be prospectively analysed in the future.
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http://dx.doi.org/10.1016/j.ejca.2016.02.008DOI Listing
May 2016

Clinical effect of molecular methods in sarcoma diagnosis (GENSARC): a prospective, multicentre, observational study.

Lancet Oncol 2016 Apr 10;17(4):532-538. Epub 2016 Mar 10.

Laboratory of Solid Tumor Genetics, Nice University Hospital, Nice, France; Institute for Research on Cancer and Aging of Nice (IRCAN), Faculty of Medicine, University of Nice-Sophia-Antipolis, CNRS, Nice, France.

Background: Advances in molecular genetics of sarcoma have enabled the identification of type-specific aberrations. We aimed to assess the clinical effect of systematic implementation of molecular assays to improve sarcoma misdiagnosis.

Methods: In this multicentre, observational study, we recruited patients from 32 centres of the French Sarcoma Group/Reference Network in Pathology of Sarcomas. Eligibility criteria included: biopsy or surgical resection; suspicion of: dermatofibrosarcoma protuberans (cohort 1), dedifferentiated liposarcoma (cohort 2), Ewing's sarcoma family of tumours (cohort 3), synovial sarcoma (cohort 4), alveolar rhabdomyosarcoma (cohort 5), and myxoid or round cell liposarcoma (cohort 6); review by one sarcoma-expert pathologist; availability of frozen material (except for cohort 1 of patients with dermatofibrosarcoma protuberans because anti-CD34 immunohistochemistry is performed on paraffin-embedded tissue); and patient information. For each case, the pathologist made one primary diagnosis followed by up to two differential diagnoses, based on histological characteristics only. Each diagnosis was classified as certain, probable, or possible. For each case to determine the molecular classification, we did fluorescence in-situ hybridisation on paraffin-embedded samples. We also did comparative genomic hybridisation and quantitative PCR (cohort 2) or reverse transcriptase PCR (cohorts 3-6) on frozen and paraffin-embedded samples. We made a final diagnosis based on the molecular results. The clinical effect of diagnosis correction was assessed by a board of experts.

Finding: Between June 22, 2009, and Oct 30, 2012, 395 patients were enrolled in the study, of which 384 were eligible for inclusion. The diagnosis was eventually modified by molecular genetics for 53 patients: eight (16%) of 50 patients with dermatofibrosarcoma (cohort 1), seven (23%) of 30 patients with dedifferentiated liposarcoma (cohort 2), 13 (12%) of 112 with Ewing's sarcoma family of tumours (cohort 3), 16 (16%) of 97 patients with synovial sarcoma (cohort 4), seven (15%) of 46 patients with alveolar rhabdomyosarcoma (cohort 5), and two (4%) of 49 patients with myxoid or round cell liposarcoma (cohort 6), with an effect on primary management or prognosis assessment in 45 cases.

Interpretation: Molecular genetic testing should be mandatory for diagnostic accuracy of sarcoma and appropriate clinical management, even when histological diagnosis is made by pathologist experts in this field.

Funding: French National Cancer Institute and Nice University Hospital.
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http://dx.doi.org/10.1016/S1470-2045(15)00583-5DOI Listing
April 2016

The occurrence of intracranial rhabdoid tumours in mice depends on temporal control of Smarcb1 inactivation.

Nat Commun 2016 Jan 28;7:10421. Epub 2016 Jan 28.

Institut Curie, Paris Sciences et Lettres Research University, InsermU830, Laboratoire de Genetique et Biologie des Cancers, 26 rue d'Ulm, 75005 Paris, France.

Rhabdoid tumours (RTs) are highly aggressive tumours of infancy, frequently localized in the central nervous system (CNS) where they are termed atypical teratoid/rhabdoid tumours (AT/RTs) and characterized by bi-allelic inactivation of the SMARCB1 tumour suppressor gene. In this study, by temporal control of tamoxifen injection in Smarcb1(flox/flox);Rosa26-Cre(ERT2) mice, we explore the phenotypes associated with Smarcb1 inactivation at different developmental stages. Injection before E6, at birth or at 2 months of age recapitulates previously described phenotypes including embryonic lethality, hepatic toxicity or development of T-cell lymphomas, respectively. Injection between E6 and E10 leads to high penetrance tumours, mainly intra-cranial, with short delays (median: 3 months). These tumours demonstrate anatomical, morphological and gene expression profiles consistent with those of human AT/RTs. Moreover, intra- and inter-species comparisons of tumours reveal that human and mouse RTs can be split into different entities that may underline the variety of RT cells of origin.
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http://dx.doi.org/10.1038/ncomms10421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4738337PMC
January 2016

[Synovial sarcoma in children and adolescents].

Bull Cancer 2016 Feb 7;103(2):210-8. Epub 2016 Jan 7.

CHU de Nantes, hôpital mère-enfant, service d'oncologie pédiatrique, 7, quai Moncousu, 44093 Nantes, France. Electronic address:

Synovial sarcoma (SS) is a rare high-grade malignant mesenchymal tumor affecting children, adolescents, and young adults. Cytogenetically, more than 90% of SS is characterized by the t(X;18)(p11.2;q11.2), translocation resulting in two chimeric fusion genes SYT-SSX1 and SYT-SSX2, confirming histological diagnosis. Pediatric SS arises most often in soft tissues of the extremities (66% of cases), and is a localized tumor without spreading to regional lymph nodes (96% of cases) nor to metastatic sites (94% of cases). Although clinical and radiologic presentation, histologic analysis and tumor biology appear similar in pediatric and adolescent SS, outcome seems better in children than in adolescents, respectively 84% vs 60% of 5years overall survival (OS). If complete resection is the gold standard in SS, other therapeutic modalities differ between pediatric and adult populations, considering SS as an intermediate chemosensitive tumor more frequently by pediatric oncologists. Prognostic factors evaluation (tumor size, site of primary and IRS group) is necessary to establish optimal treatment strategies, with multimodal therapeutic approach in children and adolescents. Thus, recent results about the European prospective EpSSG NRSTS 05 study for children and adolescent patients with localized SS showed a 5years OS >90%. Moreover, recent somatic genetic data about SS open the debate on an appropriate strategy based and stratified on tumor genomic. Multinational prospective pediatric, adolescent and young adult study is necessary to improve optimal and appropriate approach in this rare tumor.
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http://dx.doi.org/10.1016/j.bulcan.2015.11.004DOI Listing
February 2016

KIT exon 10 variant (c.1621 A > C) single nucleotide polymorphism as predictor of GIST patient outcome.

BMC Cancer 2015 Oct 24;15:780. Epub 2015 Oct 24.

Department of medical oncology, Centre Leon Berard, 28 rue Laennec, Lyon, France.

Background: Tumor genotype plays a crucial role in clinical management of GIST. Whether genetic polymorphism of KIT may influence GIST patient outcome is unclear.

Methods: We investigated the biological and clinical significance of the presence of KIT exon 10 variant (c.1621 A > C), KIT (L541), in a transfected cell line (3 T3 L541) and in two retrospectively collected series of 109 GIST patients in total. The control group consisted of 60 healthy donors collected at the French department of blood transfusion.

Results: In the 3 T3 L541 cell line, KIT(L541) protein exhibited a spontaneous phosphorylation status comparable to that of wild-type KIT but displayed a phosphorylation pattern of AKT and ERK1/2 that was found similar to that of the classical mutated forms of the KIT receptor. Of 109 patients enrolled in this retrospective translational research study, 24 (22%) harboured KIT (L541), similarly to the control group of healthy donors (n = 10 of 60, 17%). A higher prevalence of the variant KIT (L541) was observed in patients with metastatic status at diagnosis (KIT (L541) correlated nine of 22 versus 15 of 87, p = 0.02). In addition, patients with KIT (L541) and localized GIST had a higher rate of relapse at 5 years and lower relapse free survival at 5 years in univariate, as well as in multivariate analysis. Response rate and duration of response to imatinib was similar in KIT (L541) and KIT (M541) patients.

Conclusion: KIT (L541) genotype is associated with a higher risk of metastasis at diagnosis and a higher risk of relapse in GIST patients.
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http://dx.doi.org/10.1186/s12885-015-1817-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619434PMC
October 2015

SMARCA4 inactivation defines a group of undifferentiated thoracic malignancies transcriptionally related to BAF-deficient sarcomas.

Nat Genet 2015 Oct 7;47(10):1200-5. Epub 2015 Sep 7.

Genetics and Biology of Cancer Unit, Institut Curie Research Center, Paris Sciences et Lettres Research University, Paris, France.

While investigating cohorts of unclassified sarcomas by RNA sequencing, we identified 19 cases with inactivation of SMARCA4, which encodes an ATPase subunit of BAF chromatin-remodeling complexes. Clinically, the cases were all strikingly similar, presenting as compressive mediastino-pulmonary masses in 30- to 35-year-old adults with a median survival time of 7 months. To help define the nosological relationships of these tumors, we compared their transcriptomic profiles with those of SMARCA4-mutated small-cell carcinomas of the ovary, hypercalcemic type (SCCOHTs), SMARCB1-inactivated malignant rhabdoid tumors (MRTs) and lung carcinomas (of which 10% display SMARCA4 mutations). Gene profiling analyses demonstrated that these tumors were distinct from lung carcinomas but related to MRTs and SCCOHTs. Transcriptome analyses, further validated by immunohistochemistry, highlighted strong expression of SOX2, a marker that supports the differential diagnosis of these tumors from SMARCA4-deficient lung carcinomas. The prospective recruitment of cases confirmed this new category of 'SMARCA4-deficient thoracic sarcomas' as readily recognizable in clinical practice, providing opportunities to tailor their therapeutic management.
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http://dx.doi.org/10.1038/ng.3399DOI Listing
October 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