Optimization of sentinel lymph node biopsy in breast cancer using an operative gamma camera

<p>Abstract</p> <p>Background</p> <p>Sentinel lymph node (SLN) procedure is now a widely accepted method of LN staging in selected invasive breast cancers (unifocal, size ≤ 2 cm, clinically N0, without previous treatment). Complete axillary clearance is no longer needed if the SLN is negative. However, the oncological safety of this procedure remains to be addressed in randomized clinical trials. One main pitfall is the failure to visualize SLN, resulting in incorrect tumor staging, leading to suboptimal treatment or axillary recurrence. Operative gamma cameras have therefore been developed to optimize the SLN visualization and the quality control of surgery.</p> <p>Case presentation</p> <p>A 44-year-old female patient with a 14-mm infiltrative ductal carcinoma underwent the SLN procedure. An operative gamma camera was used during and after the surgery. The conventional lymphoscintigraphy showed only one SLN, which was also detected by the operative gamma camera, then removed and measured (9.6 kBq). It was analyzed by frozen sections, showing no cancer cells. During this analysis, the exploration of the axillary area with the operative gamma camera enabled the identification of a second SLN with low activity (0.5 kBq) that conventional lymphoscintigraphy, surgical probe and blue staining had failed to visualize. Histological examination revealed a macrometastasis. Axillary clearance was then performed, followed by a postoperative image proving that no SLN remained. Therefore, the use of the operative gamma camera prevented an under-estimation of staging which would have resulted in a suboptimal treatment for this patient.</p> <p>Conclusion</p> <p>This case report illustrates that an efficient operative gamma camera may be able to decrease the risk of false negative rate of the SLN procedure, and could be an additional tool to control the quality of the surgery.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier: NCT00357487</p

Modulation of the ATM/autophagy pathway by a G-quadruplex ligand tips the balance between senescence and apoptosis in cancer cells

G-quadruplex ligands exert their antiproliferative effects through telomere-dependent and telomere-independent mechanisms, but the inter-relationships among autophagy, cell growth arrest and cell death induced by these ligands remain largely unexplored. Here, we demonstrate that the G-quadruplex ligand 20A causes growth arrest of cancer cells in culture and in a HeLa cell xenografted mouse model. This response is associated with the induction of senescence and apoptosis. Transcriptomic analysis of 20A treated cells reveals a significant functional enrichment of biological pathways related to growth arrest, DNA damage response and the lysosomal pathway. 20A elicits global DNA damage but not telomeric damage and activates the ATM and autophagy pathways. Loss of ATM following 20A treatment inhibits both autophagy and senescence and sensitizes cells to death. Moreover, disruption of autophagy by deletion of two essential autophagy genes ATG5 and ATG7 leads to failure of CHK1 activation by 20A and subsequently increased cell death. Our results, therefore, identify the activation of ATM by 20A as a critical player in the balance between senescence and apoptosis and autophagy as one of the key mediators of such regulation. Thus, targeting the ATM/autophagy pathway might be a promising strategy to achieve the maximal anticancer effect of this compound

Distribution of Exonic Variants in Glycogen Synthesis and Catabolism Genes in Late Onset Pompe Disease (LOPD)

Pompe disease (PD) is a monogenic autosomal recessive disorder caused by biallelic pathogenic variants of the GAA gene encoding lysosomal alpha-glucosidase; its loss causes glycogen storage in lysosomes, mainly in the muscular tissue. The genotype-phenotype correlation has been extensively discussed, and caution is recommended when interpreting the clinical significance of any mutation in a single patient. As there is no evidence that environmental factors can modulate the phenotype, the observed clinical variability in PD suggests that genetic variants other than pathogenic GAA mutations influence the mechanisms of muscle damage/repair and the overall clinical picture. Genes encoding proteins involved in glycogen synthesis and catabolism may represent excellent candidates as phenotypic modifiers of PD. The genes analyzed for glycogen synthesis included UGP2, glycogenin (GYG1-muscle, GYG2, and other tissues), glycogen synthase (GYS1-muscle and GYS2-liver), GBE1, EPM2A, NHLRC1, GSK3A, and GSK3B. The only enzyme involved in glycogen catabolism in lysosomes is alpha-glucosidase, which is encoded by GAA, while two cytoplasmic enzymes, phosphorylase (PYGB-brain, PGL-liver, and PYGM-muscle) and glycogen debranching (AGL) are needed to obtain glucose 1-phosphate or free glucose. Here, we report the potentially relevant variants in genes related to glycogen synthesis and catabolism, identified by whole exome sequencing in a group of 30 patients with late-onset Pompe disease (LOPD). In our exploratory analysis, we observed a reduced number of variants in the genes expressed in muscles versus the genes expressed in other tissues, but we did not find a single variant that strongly affected the phenotype. From our work, it also appears that the current clinical scores used in LOPD do not describe muscle impairment with enough qualitative/quantitative details to correlate it with genes that, even with a slightly reduced function due to genetic variants, impact the phenotype

Integrating Health Technology Assessment and Multi-Criteria Decision Analysis in Optimizing Diabetic Macular Edema Management: Results from an Italian Multi-Regional Study

Health Technology Assessment (HTA) is a widely implemented technical tool used to inform the decision-making process..

MED12 Alterations in Both Human Benign and Malignant Uterine Soft Tissue Tumors

The relationship between benign uterine leiomyomas and their malignant counterparts, i.e. leiomyosarcomas and smooth muscle tumors of uncertain malignant potential (STUMP), is still poorly understood. The idea that a leiomyosarcoma could derive from a leiomyoma is still controversial. Recently MED12 mutations have been reported in uterine leiomyomas. In this study we asked whether such mutations could also be involved in leiomyosarcomas and STUMP oncogenesis. For this purpose we examined 33 uterine mesenchymal tumors by sequencing the hot-spot mutation region of MED12. We determined that MED12 is altered in 66.6% of typical leiomyomas as previously reported but also in 11% of STUMP and 20% of leiomyosarcomas. The mutated allele is predominantly expressed in leiomyomas and STUMP. Interestingly all classical leiomyomas exhibit MED12 protein expression while 40% of atypical leiomyomas, 50% of STUMP and 80% of leiomyosarcomas (among them the two mutated ones) do not express MED12. All these tumors without protein expression exhibit complex genomic profiles. No mutations and no expression loss were identified in an additional series of 38 non-uterine leiomyosarcomas. MED12 mutations are not exclusive to leiomyomas but seem to be specific to uterine malignancies. A previous study has suggested that MED12 mutations in leiomyomas could lead to Wnt/β-catenin pathway activation however our immunohistochemistry results show that there is no association between MED12 status and β-catenin nuclear/cytoplasmic localization. Collectively, our results show that subgroups of benign and malignant tumors share a common genetics. We propose here that MED12 alterations could be implicated in the development of smooth muscle tumor and that its expression could be inhibited in malignant tumors

International Society of Gynecological Pathologists (ISGyP) Endometrial Cancer Project : Guidelines From the Special Techniques and Ancillary Studies Group:Guidelines From the Special Techniques and Ancillary Studies Group

The aim of this article is to propose guidelines and recommendations in problematic areas in pathologic reporting of endometrial carcinoma (EC) regarding special techniques and ancillary studies. An organizing committee designed a comprehensive survey with different questions related to pathologic features, diagnosis, and prognosis of EC that was sent to all members of the International Society of Gynecological Pathologists. The special techniques/ancillary studies group received 4 different questions to be addressed. Five members of the group reviewed the literature and came up with recommendations and an accompanying text which were discussed and agreed upon by all members of the group. Twelve different recommendations are made. They address the value of immunohistochemistry, ploidy, and molecular analysis for assessing prognosis in EC, the value of steroid hormone receptor analysis to predict response to hormone therapy, and parameters regarding applying immunohistochemistry and molecular tests for assessing mismatch deficiency in EC

Mi barrio es el paraíso, el infierno son los otros. Interacción y fragmentación socio-espacial en Victoria, San Fernando, R.M.B.A. 2014

Se ha elegido la zona de Victoria, San Fernando, Provincia de Buenos Aires, como un ejemplo de fragmentación urbana y segregación social. En un recorrido muy corto, de Oeste a Este, encontramos todas las clases sociales sucesivamente, coincidiendo la distancia geográfica y la social, desde la marginación en el Oeste (Reconquista) hasta la clase alta en la costa del Luján en el Este. En algún lugar de este recorrido observamos, muros y paredones sin comercios ni edificios comunes, solo depósitos, cementerios y barrios cerrados. Aunque las causas son variadas y algunas tienen su origen en la política urbana de los años noventa, en este artículo damos cuenta del problema urbanístico y social y estudiamos las diversas formas que ha tomado y toma la estrategia tanto de pobladores como de gestiones de gobierno para resistirse al cambio, que estaría representado por la interacción entre clases sociales, base de la vida ciudadana, casi ausente o muy débil en este caso. Parte del problema es geográfico, las barreras urbanas (Tren Mitre, Avenida Libertador, Tren de la Costa, Tren a Capilla del Señor, Autopista Acceso Norte) proliferaron desde el siglo XIX en adelante. Sin embargo en una comparación con el corredor Norte, solo San Fernando ha privatizado su costa. San Fernando (y Victoria) está fragmentado en tres grandes zonas a causa de estas barreras geográficas. Los conflictos se darán sólo en las fronteras (muro entre partidos) y en los bordes sociales, pero siempre tratando de evitar los grandes cambios. El corte temporal del estudio corresponde al período 2004-2014. A través de este estudio se verifica la importancia del aislamiento espacial producido por las barreras urbanas, que en su fragmentación van consolidando la segregación, la segmentación social y la exclusión como resultado último.The area of Victoria, San Fernando, Buenos Aires Province has been selected as an example of urban fragmentation and social segregation. On a very short tour we found all the social classes successively, matching the geographical and social distance, from the marginalization in the West (Renconquista) to the upper class on the shore of the Lujan river in the East. Somewhere along this tour, we observed thick walls without shops or ordinary buildings but only with stores, cemeteries and gated communities. Even though the causes are varied and some of them have their origin from urban politics in the 90’s. In this article we explain the urban and social problem and study the various forms of the strategy of both citizens and government management has taken and still takes to resist change, which would be represented by interaction of social classes, basis of the citizen life, which is almost absent or very weak in this case. Part of the problem is geographical, the urban barriers (Mitre train, Libertador, Tren de la Costa, train to Capilla del Señor, Acceso Norte) proliferated from the nineteenth century onwards. However, in a comparison with the Northern corridor, only San Fernando has privatized its shore. San Fernando (and Victoria) is fragmented into three big areas because of these geographical barriers. Conflicts will occur only in the borderlines (a wall between towns) and in social borders, but always trying to avoid big changes. The temporary cut of the study covers the period between 2004-2014.Fil: Guevara, Celia. Universidad de Buenos Aires. Facultad de Arquitectura y Urbanismo. Instituto de Arte Americano e Investigación Estéticas "Mario Buschiazzo"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; ArgentinaFil: Areco, Alberto. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; ArgentinaFil: Barneche, Javier. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; ArgentinaFil: Brandone, Sofía I.. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; ArgentinaFil: Camardon, Lucía. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; ArgentinaFil: Castañeda, María Lucía. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; ArgentinaFil: Castro, Leticia. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; ArgentinaFil: Croce, Federico. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; ArgentinaFil: Cuberos, Alfonso Javier. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; ArgentinaFil: Donadío, Laura E.. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; ArgentinaFil: Fuentes, Ariel Rodolfo. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gómez Salmerón, Fabián A.. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; ArgentinaFil: Pierro, Sabrina M.. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; ArgentinaFil: Plate, Lisandro. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; ArgentinaFil: Porta, Yanina. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; ArgentinaFil: Quiroga, Ayelén Rocio. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; ArgentinaFil: Raap, Johanna. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; ArgentinaFil: Solver, Juan Manuel. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; ArgentinaFil: Souza, Kelly. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; ArgentinaFil: Szencis Ferriolo, Jonathan Lucas. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; ArgentinaFil: Torrez, Jeannette. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; Argentin

Is there a link between genomic complexity and clinical outcome in uterine smooth muscle tumors?

Les sarcomes à génomique complexe sont caractérisés par un génome remanié en l’absence d’un évènement génomique récurrent connu et les léïomyosarcomes (LMS) font partie de ce groupe. Les tumeurs musculaires lisses utérines se divisent selon l’évolution clinique en léiomyomes (LM) et LMS et selon la morphologie en fusocellulaires, épithélioïdes et myxoïdes avec des critères diagnostiques distincts. Si ces critères sont suffisants pour un diagnostic lésionnel correct dans la majorité des cas, ils ne permettent pas la distinction entre un LM et un LMS dans un faible pourcentage de tumeurs. Dans ces cas la tumeur est dénommée « tumeur musculaire lisse utérine à potentiel de malignité incertain » (STUMP) posant un problème de prise en charge clinique. Certains variants comme le léiomyome à Noyaux Bizarres (LM-BN) pose un véritable problème diagnostique. D’évolution clinique bénigne, il présente un profil génomique hétérogène pouvant être complexe. L’analyse de la complexité du profil génomique basée sur le calcul du Genomic Index (GI) issu de la signature CINSARC (Complexity INdex in SARComas) a démontré sa valeur pronostique dans les sarcomes des tissus mous à génomique complexe, mais également dans les GIST. Notre hypothèse est qu’à l’instar des sarcomes des tissus mous le degré de complexité génomique est corrélé à l’évolution clinique dans les tumeurs musculaires lisses utérines. Le but de ce travail de thèse était d’étudier sur plusieurs tumeurs musculaires lisses utérines, bénignes, malignes et STUMP, de type fusiforme et les variantes à noyaux bizarres et épithélioïdes, le profil génomique par CGH-array et la signature d’expression CINSARC en utilisant la technique de Nanostring, en corrélation avec l’évolution clinique. Une première étude publiée a permis de confirmer que la complexité génomique est liée à l’évolution des tumeurs musculaires lisses utérines et peut être un outil diagnostique complémentaire à l’analyse morphologique. Nous avons testé cette hypothèse sur une série de 70 tumeurs musculaires lisses utérines et démontrer que le GI au seuil de 10 distingue les tumeurs sans récidive (LM) des tumeurs avec risque accru de récidive et d’évolution létale (LMS) en démembrant la catégorie de STUMP. Avec l’application de la signature CINSARC au matériel fixé en formol, par technologie Nanostring nous avons démontré sur une série de 60 LMS que cette signature est pronostique en survie globale et libre de maladie. De plus la signature CINSARC NANOCIND a montré sa valeur pronostique dans les LMS utérins de stade I pour lesquels la chimiothérapie adjuvante est discutée, sans efficacité prouvée. La signature CINSARC Nanocind® se propose comme un outil de randomisation dans les essais cliniques à venir. Nous avons par ailleurs analysé les profiles génomiques par array-CGH d’une série de 69 LM-BN et démontré que le LM-BN est une entité séparée du LM et du LMS identifiant 3 sous-types distincts de LM-BN : un groupe FH-déficient, un associé aux altérations de TP53 avec un génome plus remanié et un groupe sans altérations récurrentes. Notre étude souligne l´importance de l’intégration des données génomiques au contexte morphologique et clinique. Pour terminer nous avons validé le seuil du GI sur une plateforme génomique (AGILENT 180K) différente de celle d’origine (AGILENT 60K) et nous avons exploré le GI dans le variant à cellules épithélioïdes. Ainsi, la complexité génomique est corrélée à l’évolution clinique et l’étude du profil génomique des tumeurs musculaires lisses de l’utérus est utilisable en pratique quotidienne dans les lésions où la morphologie seule ne permet pas la distinction d’une tumeur bénigne d’une tumeur avec un potentiel évolutif, à condition d’intégrer ces données dans le contexte clinique et morphologique. La signature CINSARC dans les LMS de stade I peut permettre une meilleure prise en charge des patientesSarcomas with complex genomics such as leiomyosarcomas (LMS) are characterized by an altered genome in the absence of a known recurrent "driver" genomic event. According to their clinical outcome, smooth muscle uterine tumours are divided into leiomyomas (LM) and LMS, and as spindle, epithelioid and myxoid variants with distinct diagnostic criteria depending on their morphology. The morphologic criteria are efficient but with some exceptions. In these cases, the tumour should be termed « smooth muscle tumour with uncertain malignant potential” (STUMP) and only the outcome can confirm its benign or malignant nature. Moreover, for some LM variants such as Bizarre Nuclei leiomyoma (BN-LM), the diagnosis may be particularly difficult. Even though BN-LM has a favourable outcome, it can harbour a complex genomic profile. The analysis of the complexity of a tumour’s genomic profile based on its Genomic Index (GI) obtained with the CINSARC (Complexity INdex in SARComas) signature has demonstrated its prognostic value, not only in genomically complex soft tissue sarcomas but also in GIST. We hypothesized that, as in soft tissue sarcomas, the degree of genomic complexity in uterine smooth muscle tumours correlates with their clinical outcome. The aim of this PhD dissertation using array-CGH and the CINSARC signature by Nanostring was to study the genomic profile of several series of benign and malignant uterine tumours and STUMP tumours with spindle, epithelioid and Bizarre Nuclei variants and to correlate the results with clinical outcome. In our first paper, we demonstrated that the genomic complexity of uterine smooth muscle tumours is related to their clinical outcome and that genomic analysis by array-CGH is a useful diagnostic tool complementary to the morphological approach. We subsequently demonstrated in a larger series of 70 tumours that the GI at the threshold of 10 splits STUMP into two groups: those without recurrence and with a similar behaviour to LM, and a second group with a rate of recurrence and death akin to LMS but more indolent. We demonstrated the prognostic value of the CINSARC Nanocind® signature by Nanostring technology on 60 formalin-fixed, paraffin-embedded uterine LMS for overall and disease-free survival. These results were confirmed even on stage I LMS, for which the efficacy of adjuvant chemotherapy remains to be proven. The CINSARC Nanocind® signature could be a useful tool for randomization in future clinical trials evaluating the benefit of adjuvant treatment on uterine LMS, in particular at an early stage. We also analysed the genomic profiles of 69 BN-LM by array-CGH and demonstrated that BN-LM is an entity different from LM and LMS. We identified 3 distinct BN-LM subtypes: an FH-deficient group, a group associated to TP53 alterations with chromosomal instability. And a third without recurrent alterations. Our results highlight the importance of integrating genomic data into the morphological and clinical context. Finally, we validated the GI threshold on a genomic platform (AGILENT 180K) different from the original one (AGILENT 60K) and We explored genomic profiles also for the epithelioid variant. Thus, genomic complexity correlates with outcome so genome profile analysis is a diagnostic tool complementary to morphology for distinguishing benign tumours from tumours with a risk of recurrence. The CINSARC signature may allow better patient management, especially in stage I LMS

Existe-t-il un lien entre complexité génomique et évolution clinique dans les tumeurs musculaires lisses utérines ?

Sarcomas with complex genomics such as leiomyosarcomas (LMS) are characterized by an altered genome in the absence of a known recurrent "driver" genomic event. According to their clinical outcome, smooth muscle uterine tumours are divided into leiomyomas (LM) and LMS, and as spindle, epithelioid and myxoid variants with distinct diagnostic criteria depending on their morphology. The morphologic criteria are efficient but with some exceptions. In these cases, the tumour should be termed « smooth muscle tumour with uncertain malignant potential” (STUMP) and only the outcome can confirm its benign or malignant nature. Moreover, for some LM variants such as Bizarre Nuclei leiomyoma (BN-LM), the diagnosis may be particularly difficult. Even though BN-LM has a favourable outcome, it can harbour a complex genomic profile. The analysis of the complexity of a tumour’s genomic profile based on its Genomic Index (GI) obtained with the CINSARC (Complexity INdex in SARComas) signature has demonstrated its prognostic value, not only in genomically complex soft tissue sarcomas but also in GIST. We hypothesized that, as in soft tissue sarcomas, the degree of genomic complexity in uterine smooth muscle tumours correlates with their clinical outcome. The aim of this PhD dissertation using array-CGH and the CINSARC signature by Nanostring was to study the genomic profile of several series of benign and malignant uterine tumours and STUMP tumours with spindle, epithelioid and Bizarre Nuclei variants and to correlate the results with clinical outcome. In our first paper, we demonstrated that the genomic complexity of uterine smooth muscle tumours is related to their clinical outcome and that genomic analysis by array-CGH is a useful diagnostic tool complementary to the morphological approach. We subsequently demonstrated in a larger series of 70 tumours that the GI at the threshold of 10 splits STUMP into two groups: those without recurrence and with a similar behaviour to LM, and a second group with a rate of recurrence and death akin to LMS but more indolent. We demonstrated the prognostic value of the CINSARC Nanocind® signature by Nanostring technology on 60 formalin-fixed, paraffin-embedded uterine LMS for overall and disease-free survival. These results were confirmed even on stage I LMS, for which the efficacy of adjuvant chemotherapy remains to be proven. The CINSARC Nanocind® signature could be a useful tool for randomization in future clinical trials evaluating the benefit of adjuvant treatment on uterine LMS, in particular at an early stage. We also analysed the genomic profiles of 69 BN-LM by array-CGH and demonstrated that BN-LM is an entity different from LM and LMS. We identified 3 distinct BN-LM subtypes: an FH-deficient group, a group associated to TP53 alterations with chromosomal instability. And a third without recurrent alterations. Our results highlight the importance of integrating genomic data into the morphological and clinical context. Finally, we validated the GI threshold on a genomic platform (AGILENT 180K) different from the original one (AGILENT 60K) and We explored genomic profiles also for the epithelioid variant. Thus, genomic complexity correlates with outcome so genome profile analysis is a diagnostic tool complementary to morphology for distinguishing benign tumours from tumours with a risk of recurrence. The CINSARC signature may allow better patient management, especially in stage I LMS.Les sarcomes à génomique complexe sont caractérisés par un génome remanié en l’absence d’un évènement génomique récurrent connu et les léïomyosarcomes (LMS) font partie de ce groupe. Les tumeurs musculaires lisses utérines se divisent selon l’évolution clinique en léiomyomes (LM) et LMS et selon la morphologie en fusocellulaires, épithélioïdes et myxoïdes avec des critères diagnostiques distincts. Si ces critères sont suffisants pour un diagnostic lésionnel correct dans la majorité des cas, ils ne permettent pas la distinction entre un LM et un LMS dans un faible pourcentage de tumeurs. Dans ces cas la tumeur est dénommée « tumeur musculaire lisse utérine à potentiel de malignité incertain » (STUMP) posant un problème de prise en charge clinique. Certains variants comme le léiomyome à Noyaux Bizarres (LM-BN) pose un véritable problème diagnostique. D’évolution clinique bénigne, il présente un profil génomique hétérogène pouvant être complexe. L’analyse de la complexité du profil génomique basée sur le calcul du Genomic Index (GI) issu de la signature CINSARC (Complexity INdex in SARComas) a démontré sa valeur pronostique dans les sarcomes des tissus mous à génomique complexe, mais également dans les GIST. Notre hypothèse est qu’à l’instar des sarcomes des tissus mous le degré de complexité génomique est corrélé à l’évolution clinique dans les tumeurs musculaires lisses utérines. Le but de ce travail de thèse était d’étudier sur plusieurs tumeurs musculaires lisses utérines, bénignes, malignes et STUMP, de type fusiforme et les variantes à noyaux bizarres et épithélioïdes, le profil génomique par CGH-array et la signature d’expression CINSARC en utilisant la technique de Nanostring, en corrélation avec l’évolution clinique. Une première étude publiée a permis de confirmer que la complexité génomique est liée à l’évolution des tumeurs musculaires lisses utérines et peut être un outil diagnostique complémentaire à l’analyse morphologique. Nous avons testé cette hypothèse sur une série de 70 tumeurs musculaires lisses utérines et démontrer que le GI au seuil de 10 distingue les tumeurs sans récidive (LM) des tumeurs avec risque accru de récidive et d’évolution létale (LMS) en démembrant la catégorie de STUMP. Avec l’application de la signature CINSARC au matériel fixé en formol, par technologie Nanostring nous avons démontré sur une série de 60 LMS que cette signature est pronostique en survie globale et libre de maladie. De plus la signature CINSARC NANOCIND a montré sa valeur pronostique dans les LMS utérins de stade I pour lesquels la chimiothérapie adjuvante est discutée, sans efficacité prouvée. La signature CINSARC Nanocind® se propose comme un outil de randomisation dans les essais cliniques à venir. Nous avons par ailleurs analysé les profiles génomiques par array-CGH d’une série de 69 LM-BN et démontré que le LM-BN est une entité séparée du LM et du LMS identifiant 3 sous-types distincts de LM-BN : un groupe FH-déficient, un associé aux altérations de TP53 avec un génome plus remanié et un groupe sans altérations récurrentes. Notre étude souligne l´importance de l’intégration des données génomiques au contexte morphologique et clinique. Pour terminer nous avons validé le seuil du GI sur une plateforme génomique (AGILENT 180K) différente de celle d’origine (AGILENT 60K) et nous avons exploré le GI dans le variant à cellules épithélioïdes. Ainsi, la complexité génomique est corrélée à l’évolution clinique et l’étude du profil génomique des tumeurs musculaires lisses de l’utérus est utilisable en pratique quotidienne dans les lésions où la morphologie seule ne permet pas la distinction d’une tumeur bénigne d’une tumeur avec un potentiel évolutif, à condition d’intégrer ces données dans le contexte clinique et morphologique. La signature CINSARC dans les LMS de stade I peut permettre une meilleure prise en charge des patiente