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Data accessibility. The microscopy data are available from the corre- sponding author upon request and will be released via Figshare. Electronic supplementary material is available online at https://doi.org/10.6084/m9.figshare.c.5912878. ORCiD: Paola Vagnarelli, 0000-0002-0000-2271 Copyright © 2022 The Authors. Lamin A phosphorylation/de-phosphorylation is an important process during cells division as it allows for nuclear envelope (NE) disassembly at mitotic entry and its re-assembly during mitotic exit. Several kinases have been identified as responsible for these phosphorylations, but no protein phosphatase has been implicated in their reversal. One of the mitotic phosphosites in lamin A responsible for its dynamic behaviour is serine 22 (S22) which is de-phosphorylated during mitotic exit. Recent evidence has also linked the nuclear pool of lamin A S22ph in interphase to gene expression regulation. Previous work suggested that the phosphatase responsible for lamin A S22 de-phosphorylation is chromatin bound and interacts with lamin A via SUMO-SIM motives. We have previously reported that Repo-Man/protein phosphatase 1 (PP1) is a chromatin-associated phosphatase that regulates NE reformation. Here we propose that Repo-Man/PP1 phosphatase mediates lamin A S22 de-phosphorylation. We indeed show that depletion of Repo-Man leads to NE defects, causes hyperphosphorylation of lamin A S22 that can be rescued by a wild-type but not a SUMOylation-deficient mutant. Lamin A and Repo-Man interact in vivo and in vitro, and the interaction is mediated by SUMOylation. Moreover, the localization of Repo-Man/PP1 to the chromatin is essential for lamin A S22 de-phosphorylation. Wellcome Trust Investigator award 3 210742/Z/18/Z to Paola Vagnarelli.

09-10; International audience

Si les changements environnementaux liés à l'humanité ne font aucun doute, leur ampleur et leurs conséquences ne sont pas si faciles à évaluer. Pour le savant, il s'agit d'établir les liens de causalité et les impacts avec le plus de précision possible, puis de poser un diagnostic. Le présent dictionnaire s'appuie sur le concept récent d'anthropocène', qui a le mérite, qu'on l'approuve ou non, de relancer la réflexion sur les rapports entre nature et société, entre constat scientifique et action politique, à travers une approche spatiale et territoriale. Procédant de façon critique, et fruit d'une démarche collective, cette vaste entreprise éditoriale se fonde sur une pratique de terrain, attentive aux détails et méfiante à l'égard des discours pré-établis. Parmi les 330 notices, plusieurs thèmes sont au coeur des débats contemporains (biodiversité, changement climatique...), d'autres se réfèrent à des courants de pensée (écoféminisme, transhumanisme...). Les concepts mobilisés abordent des questions politiques (capitalocène, justice environnementale...), philosophiques (catastrophes, Gaïa...), ou épistémologiques (finitude, population...). Des notions classiques sont réinterrogées (nature, ressource...), tandis que des concepts sont précisés (biosphère, écosystème...). D'autres notices discutent de mécanismes environnementaux (érosion, tsunami...), de pratiques récentes (agroécologie, ville durable...), de phénomènes territorialisés (déforestation, désertification...) ou d'artefacts (aéroport, autoroute...). Certaines examinent des lieux emblématiques (Amazonie, Fukushima...). D'autres, enfin, offrent un regard original sur l'anthropocène, sa faune (chien, ours...), ses mutations socio-économiques, institutionnelles ou politiques (biopiraterie, ZAD...). Un dictionnaire de référence sur un concept devenu incontournable

15-10; International audience

15-07; International audience

Objectives: To evaluate the clinical and economic burden of head and neck squamous cell carcinoma (HNSCC) in France. Methods: All 53,255 incident adult patients discharged with a first diagnosis of HNSCC in 2010-2012 were identified from the 2008-2013 French National Hospital Discharge (PMSI) database. We conducted a retrospective longitudinal analysis of prognosis and direct costs attributable to HNSCC. Results: Direct medical costs attributable to HNSCC care amounted to 665 million euros in 2012 in France. The majority (62%) of incident patients were 64 years old or less at HNSCC diagnosis and incurred 1.3-fold higher mean direct costs as compared to elderly patients (41,909 vs 32,221 euros over 3 years, respectively; p

BackgroundHealth state utility (HSU) is a core component of QALYs and cost-effectiveness analysis, although HSU is rarely estimated among a representative sample of patients. We explored the feasibility of assessing HSU in head and neck cancer from the French National Hospital Discharge database.MethodsAn exhaustive sample of 53,258 incident adult patients with a first diagnosis of head and neck cancer was identified in 2010-2012. We used a cross-sectional approach to define five health states over two periods: three "cancer stages at initial treatment" (early, locally advanced or metastatic stage); a "relapse state" and otherwise a "relapse-free state" in the follow-up of patients initially treated at early or locally advanced stage. In patients admitted in post-acute care, a two-parameter graded response model (Item Response Theory) was estimated from all 144,012 records of six Activities of Daily Living (ADLs) and the latent health state scale underlying ADLs was calibrated with the French EQ-5D-3L social value set. Following linear interpolation between all assessments of the patient, daily estimates of utility in post-acute care were averaged by health state, patient and month of follow-up. Finally, HSU was estimated by health state and month of follow-up for the whole patient population after controlling for survivorship and selection in post-acute care.ResultsHead and neck cancer was generally associated with poor HSU estimates in a real-life setting. As compared to distant metastasis at initial treatment, mean HSU was higher in other health states, although numerical differences were small (0.45 versus around 0.54). It was primarily explained by the negative effects on HSU of an older age (38.4% aged >= 70years in early stage at initial treatment) and comorbidities (>50% in other health states). HSU estimates significantly improved over time in the relapse-free state (from 8 to 12months of follow-up).ConclusionsHSU estimates in head and neck cancer were primarily driven by age at diagnosis, comorbidities, and time to assessment of cancer survivors. This feasibility study highlights the potential of estimating HSU within and across severe conditions in a systematic way at the national level.

Background: Tyrosine kinase inhibitors (TKIs) have improved the survival of patients with chronic myeloid leukaemia. Many patients have deep molecular responses, a prerequisite for TKI therapy discontinuation. We aimed to define precise conditions for stopping treatment. Methods: In this prospective, non-randomised trial, we enrolled patients with chronic myeloid leukaemia at 61 European centres in 11 countries. Eligible patients had chronic-phase chronic myeloid leukaemia, had received any TKI for at least 3 years (without treatment failure according to European LeukemiaNet [ELN] recommendations), and had a confirmed deep molecular response for at least 1 year. The primary endpoint was molecular relapse-free survival, defined by loss of major molecular response (MMR; >0·1% BCR-ABL1 on the International Scale) and assessed in all patients with at least one molecular result. Secondary endpoints were a prognostic analysis of factors affecting maintenance of MMR at 6 months in learning and validation samples and the cost impact of stopping TKI therapy. We considered loss of haematological response, progress to accelerated-phase chronic myeloid leukaemia, or blast crisis as serious adverse events. This study presents the results of the prespecified interim analysis, which was done after the 6-month molecular relapse-free survival status was known for 200 patients. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01596114. Findings: Between May 30, 2012, and Dec 3, 2014, we assessed 868 patients with chronic myeloid leukaemia for eligibility, of whom 758 were enrolled. Median follow-up of the 755 patients evaluable for molecular response was 27 months (IQR 21–34). Molecular relapse-free survival for these patients was 61% (95% CI 57–64) at 6 months and 50% (46–54) at 24 months. Of these 755 patients, 371 (49%) lost MMR after TKI discontinuation, four (1%) died while in MMR for reasons unrelated to chronic myeloid leukaemia (myocardial infarction, lung cancer, renal cancer, and heart failure), and 13 (2%) restarted TKI therapy while in MMR. A further six (1%) patients died in chronic-phase chronic myeloid leukaemia after loss of MMR and re-initiation of TKI therapy for reasons unrelated to chronic myeloid leukaemia, and two (

The clinical value of imaging is well established for the follow-up of many lymphoid malignancies but not for chronic lymphocytic leukemia (CLL). A meta-analysis was performed with the dataset of 3 German CLL Study Group phase 3 trials (CLL4, CLL5, and CLL8) that included 1372 patients receiving first-line therapy for CLL. Response as well as progression during follow-up was reassessed according to the National Cancer Institute Working Group1996 criteria. A total of 481 events were counted as progressive disease during treatment or follow-up. Of these, 372 progressions (77%) were detected by clinical symptoms or blood counts. Computed tomography (CT) scans or ultrasound were relevant in 44 and 29 cases (9% and 6%), respectively. The decision for relapse treatment was determined by CT scan or ultrasound results in only 2 of 176 patients (1%). CT scan results had an impact on the prognosis of patients in complete remission only after the administration of conventional chemotherapy but not after chemoimmunotherapy. In conclusion, physical examination and blood count remain the methods of choice for staging and clinical follow-up of patients with CLL as recommended by the International Workshop on Chronic Lymphocytic Leukemia 2008 guidelines. These trials are registered at http://www.isrctn.org as ISRCTN 75653261 and ISRCTN 36294212 and at http://www.clinicaltrials.gov as NCT00281918.

IFP Energies nouvelles, CGGVeritas and GDF Suez have conducted together, since 1980, a series of seismic monitoring experiments in order to detect and follow the movements of the gas plume in natural gas geologic storages. Surface and well seismic surveys were carried out at different stages of the storage life. Permanent receiver arrays have been set down in wells. Permanent sources have been designed. Sources and receivers have been used to follow continuously the storage cycle during several years, providing time measurement accuracy within a tenth of a millisecond. Gas intrusion into an aquifer leads to an increase in the arrival times of reflections beneath the storage reservoir and to a variation of the reflection amplitudes at top and bottom of the reservoirs. Progressive variations of the seismic parameters may be followed during the initial infill period. Further movements of the gas plume with the annual in/out cycles are more difficult to follow, because of the simultaneous presence of gas and water in the pores. Arrival time variations of some tenths of a millisecond may be detected and measured. Saturations, using accurate picking of the arrival times, can be estimated in favourable cases. Because of the higher density of carbon dioxide, when stored in a supercritical phase, sensitivity of the seismic parameters, velocity, density and acoustic impedance to saturation variations will be about twice smaller for CO2 storages than it is for methane. IFP Energies nouvelles, la CGGVeritas et GDF Suez ont mené ensemble, depuis 1980, de nombreuses expériences de monitoring sismique afin de détecter et de suivre les mouvements du gaz dans des stockages géologiques de gaz naturel. Des acquisitions ont été réalisées à différents stades de la vie du stockage tant en sismique de surface qu’en sismique de puits. Des antennes de récepteurs permanentes ont été construites et implantées dans des puits. Des sources permanentes ont été conçues et utilisées de façon continue pendant plusieurs années pour suivre le cycle remplissage/extraction du stockage. Les dispositifs permanents ont permis d’améliorer la précision des mesures de temps d’arrivée jusqu’au dixième de milliseconde. L’arrivée de gaz dans un aquifère se traduit par une rapide variation de vitesse, qui a un impact à la fois sur les temps d’arrivée des réflexions sous les réservoirs et sur les amplitudes aux limites du réservoir. Les mouvements ultérieurs du contact gaz/eau avec le cycle de remplissage/soutirage sont plus difficiles à suivre et nécessitent une excellente précision des mesures de temps d’arrivée des réflexions. L’inversion de ces mesures pour l’estimation des saturations en gaz et en eau est délicate. Cette inversion a été tentée, avec un certain succès, dans le cas de Céré-la-Ronde. Du fait de la densité du dioxyde de carbone, au-delà d’une profondeur de 800 mètres environ, cette inversion risque d’être encore plus délicate pour les stockages de CO2 que pour les stockages de gaz naturel.

The aim of the Géocarbone-Monitoring research project was the evaluation and testing, as far as possible, of the different monitoring methods that might be applied in the specific context of the Paris Basin. Their main objectives are to: detect and map CO2 in the reservoir rocks; detect and quantify possible leaks between the reservoir and the surface. The partners developed several thoughts and research concerning the various monitoring methods. This enabled drawing up a critical overview of existing methods and proposing leads for further work. At the end of the project, recommendations were made for the stakeholders of CO2 storage, i.e. the government departments regulating storage, decision-makers, and future site operators. In addition, a proposal was made for the general design and implementation of a monitoring programme of an injection test in the Paris Basin, within a depleted reservoir or a deep aquifer. Le projet de recherche Géocarbone-Monitoring avait pour but principal d’évaluer et de tester, le cas échéant, les différentes méthodes de surveillance qui pourraient être appliquées au contexte géologique spécifique du Bassin Parisien. Les objectifs principaux de celles-ci sont de : détecter et cartographier le CO2 dans le réservoir ; détecter les fuites éventuelles entre le réservoir et la surface et être en mesure de les quantifier. Les recherches et les réflexions menées par les partenaires sur les méthodes de surveillance et de monitoring ont permis de dresser une vision critique des méthodologies existantes et de proposer des pistes de progrès. À l’issue du projet, des recommandations ont été rédigées à l’intention des parties prenantes du stockage de CO2 (administration chargée de mettre en oeuvre la réglementation des stockages, décideurs et futurs opérateurs de site) et un schéma général pour la conception et la mise en oeuvre d’un programme de monitoring pour un test d’injection dans le Bassin Parisien en réservoir déplété ou en aquifère profond a été proposé.

Seismic effects of the injection of CO2 into a partially depleted oil field have been evaluated. Seismic modelling yields small time-lapse effects, including 0.4 ms time-shifts and 4 to 6% amplitude variations at the top and bottom of the reservoir. Amplitude variations at the reservoir level should be slightly larger at large incidence angles, but wave equation modelling shows that picking these reflections will not be easy, because of the presence of shear waves generated at upper interfaces. In-situ fracturation generates azimuthal anisotropy with velocity and amplitude variations with the propagation direction. These variations bear some information about the crack density, about the relation between the fracture nets and the porous medium, and about the fluid content in the pores and fractures. All these effects are however weak and their measurement requires careful seismic data acquisition and processing. Les effets sismiques de l’injection de dioxyde de carbone dans un gisement de petrole deplete ont fait l’objet d’une simulation. Ces effets sont faibles. On peut s’attendre a une variation des temps d’arrivee des reflexions sur des interfaces situees en dessous des reservoirs, de l’ordre de la demi-milliseconde, et a une variation d’amplitude au toit et au mur du reservoir de l’ordre de 6 %. La variation d’amplitude sera legerement plus forte pour les reflexions a grand deport, mais le pointe des reflexions et la mesure des amplitudes seront probablement plus difficiles, en raison de la presence d’ondes converties. La mesure de l’anisotropie azimutale, due a la presence de fractures, peut nous donner des informations sur l’etat de fracturation du reservoir et sur la connexion entre ces fractures et la matrice poreuse. La mesure de ces variations subtiles necessitera une acquisition soignee et un traitement precautionneux des donnees.

International audience; Adult patients with acute lymphoblastic leukemia (ALL) and t(1;19)/E2A-PBX1 or t(4;11)/MLL-AF4 have a poor outcome. We have evaluated the impact of an intensified post-remission therapy using a high-dose chemotherapy course followed by allogeneic or autologous SCT on the outcome of 58 patients with t(1;19)/E2A-PBX1 (E2A group, n=24) or t(4;11)/MLL-AF4 (MLL group, n=34) treated in the LALA-94 multicenter prospective study. Patients in the MLL group had higher WBC counts and more frequent DIC. CR rates achieved by MLL and E2A groups were similar to other B-cell ALL (87, 82 and 86% respectively). While in CR, patients with a donor were assigned to alloSCT (n=22), the remaining patients with were randomized between autoSCT (n=15) or chemotherapy (n=8). Five-year overall survival was 31 and 45% for E2A and MLL groups, respectively. In both groups, DFS was higher in the alloSCT arm as compared to autoSCT and chemotherapy arms. The results of this study show that chemotherapy intensification did not overcome the poor prognosis of adults with t(1;19)/E2A-PBX1. Allogeneic SCT should thus be offered in first CR to patients with t(1;19)/E2A-PBX1 or t(4;11)/MLL-AF4. New therapeutic approaches are needed for patients without donor.

The expression of the apoptosis-regulating genes Bcl-2, Bcl-x, Bax, Mcl-1, and p53 analyzed in 4 cases of human immunodeficiency virus (HIV)-associated Hodgkin's disease, in 36 cases of HIV-related non-Hodgkin's lymphomas (NHLs), and in 109 cases of non-HIV-related NHLs by using immunohistochemistry. HIV-associated Hodgkin's disease samples were positive for all markers. For the HIV-related NHL samples, 36, 66, 88, 100, and 94% of the cases were Bcl-2, Bcl-x, Bax, Mcl-1, and p53 were found to be expressed in 69, 65, 82, 83, and 42%, respectively. No significant differences were observed in Bax and Mcl-1 staining between HIV-unrelated NHLs of B cell and T cell types. In contrast, Bcl-2 was positive in 66/79 (83%) and 10/30 (33%) of B cell and T cell HIV-unrelated NHLs, respectively (P2 < 0.001). Peculiar patterns were observed for hairy cell leukemia (Bax+, Bcl-2+, Mcl-1-) and for anaplastic large cell lymphoma (Bax+, Mcl-1+, Bcl-2-) in HIV-unrelated NHLs. Of interest, all cases with a positive expression of Bax were also found to express either Mcl-1 and/or Bcl-2, suggesting that Mcl-1 and Bcl-2 may counteract the pro-apoptosis function of Bax in vivo by protein-protein interaction within the tumor cell, as demonstrated previously in vitro. These results suggest that apoptosis regulation may have a role in the pathogenesis of some HIV-related and HIV-unrelated NHLs.

A group of 63 cases of anaplastic large cell lymphomas (variants of diffuse large cell lymphomas often diagnosed as "malignant histiocytosis") was characterized on both morphologic criteria and expression of epithelial membrane antigen (EMA) and Ki-1 antigen (CD30). On the basis of the reactivity of these tumors with anti-EMA and anti-Ki-1 antibodies, four subtypes could be distinguished. In the majority of cases (n = 49), neoplastic cells coexpressed EMA and Ki-1 antigens. Nineteen of these cases were tested for IL-2R, and all were positive (Type I, EMA+, Ki-1+, IL-2R+). In the second group (n = 5), the neoplastic cells expressed EMA but not the Ki-1 antigen. These cases were not tested for the presence of IL-2R (Type II, EMA+, Ki-1-, IL-2R?). There were tumors with similar morphology expressing only Ki-1 antigen (Type III, EMA-, Ki-1+, IL-2R-) or negative for both EMA and Ki-1 antigens (Type IV, EMA-, Ki-1-, IL-2R-). EMA appeared to occur predominantly on activated cells, as has been previously shown for Ki-1 antigen. Analysis using monoclonal antibodies to T-cell, B-cell, or macrophage-associated differentiation antigens showed that these tumors were heterogeneous in terms of cell lineage. Tumors coexpressing EMA, Ki-1, and IL-2R (Type I), were most commonly of T-cell origin (n = 12); the remainder in this type expressed B-cell markers (n = 4), a mixed B/T phenotype (n = 2), or no clear phenotype (n = 9). By contrast, tumors of Types II, III, and IV were mainly from B-cell origin (n = 6) or showed a mixed B/T phenotype (n = 1). Despite the fact that a significant proportion of these cases were initially classified morphologically as "malignant histiocytosis," only 3 of the 63 cases were possibly of histiocytic origin. These results confirm that true malignant histiocytosis is rare and that most tumors with histologic features currently regarded as being consistent with this diagnosis are lymphocytic in origin and express activation antigens such as EMA, Ki-1 antigen, and IL-2R.

Recent advances in central dihydropyridine (DHP)-binding sites are reviewed. DHP-binding sites are pre-synaptically and post-synaptically localized in the brain. The functional role of post-synaptic sites is still unknown, whereas pre-synaptic sites seem to contribute to the control of calcium uptake and of neurotransmitter release. DHP-binding sites may be modualated in physiological (age, sex) and pathological events (hypertension, ischaemia, neurological diseases) or after drug treatments (alcohol, morphine, etc.). The reviewed data suggest new therapeutic implications of DHP calcium channel antagonists in the treatment of other diseases and of drug withdrawal syndrome.

The aim of this study was to evaluate the incidence, etiology, clinical evolution and prognosis of cholestatic hepatitis during childhood.A retrospective study of 145 children hospitalized for acute hepatitis between December 1983 and September 1996 were studied. Cholestatic hepatitis was defined by a direct bilirubin higher than 50% of the total bilirubin.Five cases were identified, which represents 3.45% of all hospitalized hepatitis cases. The average age was 8 years. Cholestatic symptomatology was predominant in all cases with bilirubin values ranging from 10.5 to 32 mg/dl. Cytolysis ranged from moderate to intense. Regarding enzymes indicating cholestasis, the most elevated was 5'nucleotidase, followed by GGT. Quick's index was abnormal in 2 cases, one of which was not corrected by vitamin K. Cholesterol, triglycerides and gamma globulins were slightly increased. In only one case was there a thickening of the wall of the vesicula, which was dilated. Three cases corresponded to hepatitis A virus, one to hepatitis B virus and SMA (smooth muscle autoantibodies) were identified in the fifth. Evolution was favorable in all patients within 8 weeks, except for a girl with subacute hepatocellular insufficiency (SMA positive) where a normal state was achieved 3 months after immunosuppression treatment was started.1) Cholestatic hepatitis is an infrequent form of acute hepatitis evolution in childhood and can be promoted by hepatitis virus A or B. 2) It shows a favorable prognosis, except when it comes from a non-viral etiology.

The purpose of this investigation was to compare the convulsant activity of two quinolones differing, respectively, by the presence (pefloxacin) or absence (norfloxacin) of a methyl group on the piperazine moiety at the position 7 of their parent nuclei and consequently by their lipophilicity. An in vivo model was used, which can distinguish between ease in reaching pharmacological receptors at the central nervous system level, and ability to interact with these receptors. Male Sprague-Dawley rats (approximately 230g-300g) received an i.v. infusion of pefloxacin or norfloxacin at one of four different rates: 480, 960, 1440 and 1920 micromol/hr, until the onset of maximal seizures. This occurred after an average of 12.7 to 69.4 min. We found enough evidence to suggest that in these conditions the contribution of pefloxacin metabolites, including norfloxacin, to its convulsant activity was negligible. Doses of pefloxacin and concentrations in cerebrospinal fluid and plasma (total and unbound) at the pharmacodynamic endpoint were all independent of infusion rate, whereas only cerebrospinal fluid concentrations of norfloxacin were independent of infusion rate. The overall cerebrospinal fluid concentration of norfloxacin (47.3 +/- 9.9 micromol/liter) was about 8-fold lower than that of pefloxacin (380 +/- 27 micromol/liter), indicating that on average the "intrinsic convulsant activity" of norfloxacin is 8-fold greater than that of pefloxacin. However, total doses of pefloxacin and norfloxacin at the onset of maximal seizures were in the same order of magnitude (1500-2000 micromol/kg), suggesting that the higher ability of the more lipophilic pefloxacin to reach central nervous system compensates for its lower intrinsic convulsant activity.

This report describes the comparison between two adrenal medulla imaging agents, mIBG and I-CPP. Biodistribution demonstrated an early and preferential uptake by both adrenal glands and heart and then storage in the adrenal gland of both agents, however I-CPP is less stable in vivo than mIBG. Reserpine depletion study in rat indicated that the I-CPP and mIBG uptake mechanisms are not similar.

Despite of the predominant role of chemotherapy and surgery in pancreatic ductal adenocarcinoma (PDAC), radiotherapy (RT) still has a place in multimodal management of this disease where local tumour sequelae are fatal in about 40% of the patients. RT (chemoradiotherapy and stereotactic body radiotherapy) is used and investigated in the non-metastatic setting as part of definitive treatment strategies, in (neo)adjuvant settings and for locally recurrent disease. The ACROP committee was delegated by ESTRO to recommend target volume delineation for these clinical situations. The guidelines of this document are a result of a structured evaluation of the best available evidence by a panel of international experts in the field. Guidance for treatment planning including diagnostic imaging is provided. Recommendations are given for GTV delineation. The role and the definition of CTV volumes are critically discussed. Aspects of motion management and patient positioning are taken into account for PTV definition. Furthermore, aspects of delineation of organs at risk and of dose constraints are described in both, standard and hypofractionated, settings. This guideline has the purpose to support standardised and optimised processes of RT treatment planning for both, clinical practice and prospective studies. ispartof: RADIOTHERAPY AND ONCOLOGY vol:154 pages:60-69 ispartof: location:Ireland status: published

International audience

International audience; Prognosis of Philadelphia-positive (Ph(+)) acute lymphoblastic leukemia (ALL) in the elderly has improved during the imatinib era. We investigated dasatinib, another potent tyrosine kinase inhibitor, in combination with low-intensity chemotherapy. Patients older than age 55 years were included in the European Working Group on Adult ALL (EWALL) study number 01 for Ph(+) ALL (EWALL-PH-01 international study) and were treated with dasatinib 140 mg/day (100 mg/day over 70 years) with intrathecal chemotherapy, vincristine, and dexamethasone during induction. Patients in complete remission continued consolidation with dasatinib, sequentially with cytarabine, asparaginase, and methotrexate for 6 months. Maintenance therapy was dasatinib and vincristine/dexamethasone reinductions for 18 months followed by dasatinib until relapse or death. Seventy-one patients with a median age of 69 years were enrolled; 77% had a high comorbidity score. Complete remission rate was 96% and 65% of patients achieved a 3-log reduction in BCR-ABL1 transcript levels during consolidation. Only 7 patients underwent allogeneic hematopoietic stem cell transplantation. At 5 years, overall survival was 36% and up to 45% taking into account deaths unrelated to disease or treatment as competitors. Thirty-six patients relapsed, 24 were tested for mutation by Sanger sequencing, and 75% were T315I-positive. BCR-ABL1(T315I) was tested by allele-specific oligonucleotide reverse transcription-quantitative polymerase chain reaction in 43 patients and detection was associated with short-term relapses. Ten patients (23%) were positive before any therapy and 8 relapsed, all with this mutation. In conclusion, dasatinib combined with low-intensity chemotherapy was well-tolerated and gave long-term survival in 36% of elderly patients with Ph(+) ALL. Monitoring of BCR-ABL1(T315I) from diagnosis identified patients with at high risk of early relapse and may help to personalize therapy

International audience; PURPOSE: To evaluate toxicity, local tumor control, and survival after preoperative chemoradiation for operable bulky cervical carcinoma. METHODS AND MATERIALS: Between December 1991 and July 2006, 92 patients with operable bulky stage IB2, IIA, and IIB cervical carcinoma without pelvic or para-aortic nodes on pretreatment imaging were treated. Treatment consisted of preoperative external beam pelvic radiation therapy (EBRT) and concomitant chemotherapy (CT) during the first and fourth weeks of radiation combining 5-fluorouracil and cisplatin. The pelvic radiation dose was 40.5 Gy over 4.5 weeks. EBRT was followed by low-dose rate uterovaginal brachytherapy with a total dose of 20 Gy in 62 patients. After a median rest period of 44 days, all patients underwent Class II modified radical hysterectomy with bilateral pelvic lymphadenectomy. Thirty patients who had not received preoperative uterovaginal brachytherapy underwent postoperative low-dose-rate vaginal brachytherapy at a dose of 20 Gy. The mean follow-up was 46 months. RESULTS: Pathologic residual tumor was observed in 43 patients. After multivariate analysis, additional preoperative uterovaginal brachytherapy was the single significant predictive factor for pathologic complete response rate (p = 0.019). The 2- and 5-year disease-free survival (DFS) rates were 80.4% and 72.2%, respectively. Pathologic residual cervical tumor was the single independent factor decreasing the probability of DFS (p = 0.020). Acute toxicities were moderate. Two severe ureteral complications requiring surgical intervention were observed. CONCLUSIONS: Concomitant chemoradiation followed by surgery for operable bulky stage I-II cervical carcinoma without clinical lymph node involvement can be used with acceptable toxicity. Pathologic complete response increases the probability of DFS.