Adjuvant mitotane versus surveillance in low-grade, localised adrenocortical carcinoma (ADIUVO): an international, multicentre, open-label, randomised, phase 3 trial and observational study

BACKGROUND Adjuvant treatment with mitotane is commonly used after resection of adrenocortical carcinoma; however, treatment remains controversial, particularly if risk of recurrence is not high. We aimed to assess the efficacy and safety of adjuvant mitotane compared with surveillance alone following complete tumour resection in patients with adrenocortical carcinoma considered to be at low to intermediate risk of recurrence. METHODS ADIUVO was a multicentre, open-label, parallel, randomised, phase 3 trial done in 23 centres across seven countries. Patients aged 18 years or older with adrenocortical carcinoma and low to intermediate risk of recurrence (R0, stage I-III, and Ki67 ≤10%) were randomly assigned to adjuvant oral mitotane two or three times daily (the dose was adjusted by the local investigator with the target of reaching and maintaining plasma mitotane concentrations of 14-20 mg/L) for 2 years or surveillance alone. All consecutive patients at 14 study centres fulfilling the eligibility criteria of the ADIUVO trial who refused randomisation and agreed on data collection via the European Network for the Study of Adrenal Tumors adrenocortical carcinoma registry were included prospectively in the ADIUVO Observational study. The primary endpoint was recurrence-free survival, defined as the time from randomisation to the first radiological evidence of recurrence or death from any cause (whichever occurred first), assessed in all randomly assigned patients by intention to treat. Overall survival, defined as time from the date of randomisation to the date of death from any cause, was a secondary endpoint analysed by intention to treat in all randomly assigned patients. Safety was assessed in all patients who adhered to the assigned regimen, which was defined by taking at least one tablet of mitotane in the mitotane group and no mitotane at all in the surveillance group. The ADIUVO trial is registered with ClinicalTrials.gov, NCT00777244, and is now complete. FINDINGS Between Oct 23, 2008, and Dec 27, 2018, 45 patients were randomly assigned to mitotane and 46 to surveillance alone. Because the study was discontinued prematurely, 5-year recurrence-free and overall survival are reported instead of recurrence-free and overall survival as defined in the protocol. 5-year recurrence-free survival was 79% (95% CI 67-94) in the mitotane group and 75% (63-90) in the surveillance group (hazard ratio 0·74 [95% CI 0·30-1·85]). Two people in the mitotane group and five people in the surveillance group died, and 5-year overall survival was not significantly different (95% [95% CI 89-100] in the mitotane group and 86% [74-100] in the surveillance group). All 42 patients who received mitotane had adverse events, and eight (19%) discontinued treatment. There were no grade 4 adverse events or treatment-related deaths. INTERPRETATION Adjuvant mitotane might not be indicated in patients with low-grade, localised adrenocortical carcinoma considering the relatively good prognosis of these patients, and no significant improvement in recurrence-free survival and treatment-associated toxicity in the mitotane group. However, the study was discontinued prematurely due to slow recruitment and cannot rule out an efficacy of treatment. FUNDING AIFA, ENSAT Cancer Health F2-2010-259735 programme, Deutsche Forschungsgemeinschaft, Cancer Research UK, and the French Ministry of Health

Adjuvant mitotane versus surveillance in low-grade, localised adrenocortical carcinoma (ADIUVO): an international, multicentre, open-label, randomised, phase 3 trial and observational study

BACKGROUND: Adjuvant treatment with mitotane is commonly used after resection of adrenocortical carcinoma; however, treatment remains controversial, particularly if risk of recurrence is not high. We aimed to assess the efficacy and safety of adjuvant mitotane compared with surveillance alone following complete tumour resection in patients with adrenocortical carcinoma considered to be at low to intermediate risk of recurrence. METHODS: ADIUVO was a multicentre, open-label, parallel, randomised, phase 3 trial done in 23 centres across seven countries. Patients aged 18 years or older with adrenocortical carcinoma and low to intermediate risk of recurrence (R0, stage I-III, and Ki67 ≤10%) were randomly assigned to adjuvant oral mitotane two or three times daily (the dose was adjusted by the local investigator with the target of reaching and maintaining plasma mitotane concentrations of 14-20 mg/L) for 2 years or surveillance alone. All consecutive patients at 14 study centres fulfilling the eligibility criteria of the ADIUVO trial who refused randomisation and agreed on data collection via the European Network for the Study of Adrenal Tumors adrenocortical carcinoma registry were included prospectively in the ADIUVO Observational study. The primary endpoint was recurrence-free survival, defined as the time from randomisation to the first radiological evidence of recurrence or death from any cause (whichever occurred first), assessed in all randomly assigned patients by intention to treat. Overall survival, defined as time from the date of randomisation to the date of death from any cause, was a secondary endpoint analysed by intention to treat in all randomly assigned patients. Safety was assessed in all patients who adhered to the assigned regimen, which was defined by taking at least one tablet of mitotane in the mitotane group and no mitotane at all in the surveillance group. The ADIUVO trial is registered with ClinicalTrials.gov, NCT00777244, and is now complete. FINDINGS: Between Oct 23, 2008, and Dec 27, 2018, 45 patients were randomly assigned to mitotane and 46 to surveillance alone. Because the study was discontinued prematurely, 5-year recurrence-free and overall survival are reported instead of recurrence-free and overall survival as defined in the protocol. 5-year recurrence-free survival was 79% (95% CI 67-94) in the mitotane group and 75% (63-90) in the surveillance group (hazard ratio 0·74 [95% CI 0·30-1·85]). Two people in the mitotane group and five people in the surveillance group died, and 5-year overall survival was not significantly different (95% [95% CI 89-100] in the mitotane group and 86% [74-100] in the surveillance group). All 42 patients who received mitotane had adverse events, and eight (19%) discontinued treatment. There were no grade 4 adverse events or treatment-related deaths. INTERPRETATION: Adjuvant mitotane might not be indicated in patients with low-grade, localised adrenocortical carcinoma considering the relatively good prognosis of these patients, and no significant improvement in recurrence-free survival and treatment-associated toxicity in the mitotane group. However, the study was discontinued prematurely due to slow recruitment and cannot rule out an efficacy of treatment. FUNDING: AIFA, ENSAT Cancer Health F2-2010-259735 programme, Deutsche Forschungsgemeinschaft, Cancer Research UK, and the French Ministry of Health

Surgery, Octreotide, Temozolomide, Bevacizumab, Radiotherapy, and Pegvisomant Treatment of an AIP Mutation-Positive Child

UK India Education Research Initiative and the British Council (75-2014; to P.D.)Council of Scientific and Industrial Research, University Grants Commission, for financial support (2061330632; to A.R.).Medical Research Council (MR/M018539/1; to M.K

A Navigation Tool for Exploring Semantic Web Corpora

International audienceSemantic Web technologies provide a way to represent and to exploit data and can be particularly suitable for historical corpora. The Henri Poincaré correspondence corpus is composed of more than 2000 letters which constitute scientific, administrative and private exchanges. Several technologies have been used for this corpus: the rdf model, the rdfs knowledge representation language and the sparql query language. Recently, a navigation tool has been created to explore this correspondence corpus by exploiting similarities between resources. This tool can simplify corpus exploration and highlight unexpected relations between elements. It relies on the use of a flexible search mechanism based on the definition and the application of sparql query transformation rules. The system can be connected to any rdf database as long as underlying data is exposed through a public sparql endpoint

Identification par CGHarray de gènes candidats impliqués dans la tumorigénèse et le pronostic des tumeurs hypophysaires

The purpose of this work was to analyze the impact of copy number variations (CNV) on sporadic pituitary tumor prognosis.CGH array analysis was performed on 195 fresh-frozen pituitary tumors (56 gonadotroph, 11 immunonegatives, 56 somatotroph, 39 lactotroph and 33 corticotroph), with 5 years post- surgery follow-up.Firstly, we evaluated the reliability of aCGH centralization by comparing aCGH results with classical centralization vs. Fluorescent In Situ Hybridization results. We identified centralization errors, as FISH results and raw CGH log2(ratios) differed significantly in 11 tumors, and proposed a method able to correct the centralization bias.Then, the effect of alterations on recurrence was studied using logistic regression models. The quantity of CNV was dependent on tumor type: higher in lactotroph compared to corticotroph, somatotroph and lower in gonadotroph and immunonegative tumors. It was not predictive of recurrence in the whole cohort. In lactotroph tumors, genome instability, especially quantity of gains, significantly predicted recurrence independently of invasion and proliferation. However, no specific CNV was found as a prognostic marker. In somatotroph and corticotroph tumors, USP8 and GNAS mutations were not associated with quantity of CNV or recurrence respectively.CGH array analysis showed genome instability was dependent on pituitary tumor type. The quantity of altered genome was associated with poorer prognosis in lactotroph tumors whereas gonadotroph and immunonegative tumors showed a ‘quiet’ profile. The mechanism is unclear and analysis of microenvironment could be helpfulL'objectif de ce travail était d'analyser le lien entre variations du nombre de copies (CNV) et pronostic des tumeurs hypophysaires. Nous avons réalisé une analyse par CGHarray de 195 tumeurs hypophysaires (56 gonadotropes, 11 immunonégatives, 56 somatotropes, 39 lactotropes and 33 corticotropes) dont le suivi 5 ans après la chirurgie était disponible. La première partie de ce travail a consisté à mettre en place une méthode de centralisation basée sur l'hybridation in situ en fluorescence (FISH) suite à l'identification d'erreurs de centralisation. Les log2 (ratios) bruts et les résultats de FISH différaient significativement pour 11 tumeurs. Dans la seconde partie, le lien entre les altérations et la récurrence a été évalué à l'aide de modèles de régression logistique. La quantité d'altérations n'était pas associée au pronostic dans la cohorte complète, mais était associée au type tumoral : élevée dans les tumeurs lacotropes, elle était plus variable dans les tumeurs cortico et somatotropes, et très faible dans les tumeurs gonadotropes et immunonégatives. La quantité d'altérations était par contre associée à plus de récurrences dans les tumeurs lactotropes, après ajustement sur l'invasion et la prolifération. Aucun CNV pronostique a été mis en évidence. Dans les tumeurs somato et corticotropes, les mutations de GNAS et USP8 n'étaient pas associées à la récurrence ni à la quantité de CNV. En conclusion, l'instabilité génomique était associée au type tumoral, et à un pronostic défavorable dans les tumeurs lacotropes. Les mécanismes à l'origine de ces altérations ne sont pas entièrement compris et l'étude du microenvironnement pourait être une piste de réflexio

Indexing and Exploring a Digital Humanities Corpus

International audienceSemantic Web technologies have been chosen to structure and publish data of the Henri Poincaré correspondence corpus and to provide a set of tools for exploiting it. Two major issues have arisen during this work. The first one is related to the manual editing of triples in order to populate an RDF database. It is a tedious task for users with an important risk of error. That justifies the development of a dedicated tool to assist them during this process. It uses and combines different methods which are presented in this article. The second issue is related to the exploration of the corpus database. The need of an approximate and explained search has emerged. An engine based on the application of SPARQL query transformation rules has been designed. Different research tracks are considered to pursue this work which intends to apply in other contexts than the Henri Poincaré correspondence corpus

Un système d'interrogation flexible pour le Web sémantique : application au corpus de la correspondance d'Henri Poincaré

Numerous historical works are devoted to the life and works of Henri Poincaré (1854-1912), in particular through the study and the publication of his correspondence, which consists of about 2000 letters and includes academic, private and scientific exchanges. For several years, digital projects have been carried out to store, publish and exploit corpus data by implementing standards and technologies of the Semantic Web, including RDF, RDFS and SPARQL. When browsing an RDF graph, several situations may lead to a desire of flexible querying. This term describes search methods that go beyond conventional search systems, which are restricted to exact queries and allow limited or no expression of user preferences. The main contribution of this research work is the formalization, study and applications of a flexible query mechanism based on the use of SPARQL query transformation rules. This system allows, from an initial query, an RDF graph and a set of rules, to generate SPARQL queries which can provide alternative results to those initially returned. Some rules are generic, and therefore easily transposable to other graphs, and other rules are domain-dependent. Several tools based on this mechanism have been developed to assist the digital exploitation of the Henri Poincaré correspondence. A system has been implemented to assist the manual editing of RDF data, a task which can sometimes be tedious. This system relies on domain knowledge and the use of case-based reasoning to provide an ordered list of suggestions when editing an RDF triple. The proposed flexible querying system has also been integrated into a navigation tool, which provides an interface for visual exploration of RDF graphs, and which exploits similarities between resources in a graph to generate search filters. These tools exploit knowledge associated with the correspondence corpus which is represented through various transformation rules. Through the use of this mechanism, this work also considers the evolution of research practices in history, and tends to show how such a flexible querying system can contribute to the heuristic method. The methods and tools proposed can be applied to other corpora, in particular in the context of digital humanities projects.De nombreux travaux historiques s'intéressent à la vie et à l'œuvre d'Henri Poincaré (1854-1912), notamment par l'étude et la publication du corpus de sa correspondance, qui se compose d'environ 2000 lettres et qui comprend des échanges relevant du cadre académique, privé ou scientifique. Depuis plusieurs années, des travaux numériques se sont développés pour stocker, publier et exploiter les données de ce corpus par la mise en œuvre de standards et de technologies du Web sémantique, en particulier RDF RDFS et SPARQL. Lors de l'interrogation d'un graphe RDF plusieurs situations peuvent mener à une volonté de formuler des interrogations flexibles. Ce terme caractérise des méthodes de recherche allant au-delà des systèmes de recherche classiques, qui se cantonnent aux interrogations exactes et qui ne permettent pas ou peu d'exprimer des préférences utilisateurs. La contribution principale de ce travail de recherche s'intéresse à la formalisation, à l'étude et aux applications d'un mécanisme d'interrogation flexible s'appuyant sur l'utilisation de règles de transformation de requêtes SPARQL. Ce système permet, à partir d'une requête initiale, d'un graphe RDF et d'un ensemble de règles, de générer des requêtes SPARQL afin d'offrir des résultats alternatifs à ceux initialement retournés suite à l'interrogation d'un corpus. Les règles de transformation peuvent être génériques, et donc facilement transposables à d'autres graphes, ou être dépendantes d'un domaine d'application. Plusieurs outils s'appuyant sur ce mécanisme ont été développés pour assister l'exploitation numérique du corpus de la correspondance d'Henri Poincaré. Un outil d'aide à l'édition manuelle de données RDF a été implémenté pour assister cette tâche parfois longue et fastidieuse et comportant un risque d'erreurs significatif. Celui-ci s'appuie sur les connaissances du domaine et sur l'utilisation du raisonnement à partir de cas pour fournir une liste ordonnée de suggestions lors de l'édition d'un triplet RDF. Le système d'interrogation flexible défini a également été intégré à un outil de navigation, qui propose une interface pour l'exploration visuelle de graphes RDF, et qui exploite les similarités entre les ressources d'un graphe pour générer des filtres de recherche. Ces outils exploitent les connaissances associées au corpus de la correspondance qui sont intégrées à diverses règles de transformation. Au travers de l'utilisation de ce mécanisme, ces travaux s'interrogent également sur l'évolution des pratiques de recherche en histoire, et tendent à illustrer comment un tel système d'interrogation flexible peut contribuer à la méthode heuristique. Les méthodes et les outils proposés peuvent être appliqués pour d'autres corpus, en particulier dans le cadre de projets d'humanités numériques

Temporal Knowledge Representation and Exploitation for the Henri Poincaré (1854-1912) Correspondence Corpus

International audienc

Un système d'interrogation flexible pour le Web sémantique : application au corpus de la correspondance d'Henri Poincaré

Numerous historical works are devoted to the life and works of Henri Poincaré (1854-1912), in particular through the study and the publication of his correspondence, which consists of about 2000 letters and includes academic, private and scientific exchanges. For several years, digital projects have been carried out to store, publish and exploit corpus data by implementing standards and technologies of the Semantic Web, including RDF, RDFS and SPARQL. When browsing an RDF graph, several situations may lead to a desire of flexible querying. This term describes search methods that go beyond conventional search systems, which are restricted to exact queries and allow limited or no expression of user preferences. The main contribution of this research work is the formalization, study and applications of a flexible query mechanism based on the use of SPARQL query transformation rules. This system allows, from an initial query, an RDF graph and a set of rules, to generate SPARQL queries which can provide alternative results to those initially returned. Some rules are generic, and therefore easily transposable to other graphs, and other rules are domain-dependent. Several tools based on this mechanism have been developed to assist the digital exploitation of the Henri Poincaré correspondence. A system has been implemented to assist the manual editing of RDF data, a task which can sometimes be tedious. This system relies on domain knowledge and the use of case-based reasoning to provide an ordered list of suggestions when editing an RDF triple. The proposed flexible querying system has also been integrated into a navigation tool, which provides an interface for visual exploration of RDF graphs, and which exploits similarities between resources in a graph to generate search filters. These tools exploit knowledge associated with the correspondence corpus which is represented through various transformation rules. Through the use of this mechanism, this work also considers the evolution of research practices in history, and tends to show how such a flexible querying system can contribute to the heuristic method. The methods and tools proposed can be applied to other corpora, in particular in the context of digital humanities projects.De nombreux travaux historiques s'intéressent à la vie et à l'œuvre d'Henri Poincaré (1854-1912), notamment par l'étude et la publication du corpus de sa correspondance, qui se compose d'environ 2000 lettres et qui comprend des échanges relevant du cadre académique, privé ou scientifique. Depuis plusieurs années, des travaux numériques se sont développés pour stocker, publier et exploiter les données de ce corpus par la mise en œuvre de standards et de technologies du Web sémantique, en particulier RDF RDFS et SPARQL. Lors de l'interrogation d'un graphe RDF plusieurs situations peuvent mener à une volonté de formuler des interrogations flexibles. Ce terme caractérise des méthodes de recherche allant au-delà des systèmes de recherche classiques, qui se cantonnent aux interrogations exactes et qui ne permettent pas ou peu d'exprimer des préférences utilisateurs. La contribution principale de ce travail de recherche s'intéresse à la formalisation, à l'étude et aux applications d'un mécanisme d'interrogation flexible s'appuyant sur l'utilisation de règles de transformation de requêtes SPARQL. Ce système permet, à partir d'une requête initiale, d'un graphe RDF et d'un ensemble de règles, de générer des requêtes SPARQL afin d'offrir des résultats alternatifs à ceux initialement retournés suite à l'interrogation d'un corpus. Les règles de transformation peuvent être génériques, et donc facilement transposables à d'autres graphes, ou être dépendantes d'un domaine d'application. Plusieurs outils s'appuyant sur ce mécanisme ont été développés pour assister l'exploitation numérique du corpus de la correspondance d'Henri Poincaré. Un outil d'aide à l'édition manuelle de données RDF a été implémenté pour assister cette tâche parfois longue et fastidieuse et comportant un risque d'erreurs significatif. Celui-ci s'appuie sur les connaissances du domaine et sur l'utilisation du raisonnement à partir de cas pour fournir une liste ordonnée de suggestions lors de l'édition d'un triplet RDF. Le système d'interrogation flexible défini a également été intégré à un outil de navigation, qui propose une interface pour l'exploration visuelle de graphes RDF, et qui exploite les similarités entre les ressources d'un graphe pour générer des filtres de recherche. Ces outils exploitent les connaissances associées au corpus de la correspondance qui sont intégrées à diverses règles de transformation. Au travers de l'utilisation de ce mécanisme, ces travaux s'interrogent également sur l'évolution des pratiques de recherche en histoire, et tendent à illustrer comment un tel système d'interrogation flexible peut contribuer à la méthode heuristique. Les méthodes et les outils proposés peuvent être appliqués pour d'autres corpus, en particulier dans le cadre de projets d'humanités numériques