Amélioration de la survie globale des patients porteurs de cancer du rein métastatique grâce aux thérapies ciblées (revue monocentrique depuis 2000)

Contexte : les thérapies ciblées ont radicalement modifiés la prise en charge thérapeutique des patients atteints de cancer du rein métastatique. Le but de ce travail est de déterminer dans la pratique clinique quotidienne l impact de ces nouvelles thérapies sur la survie globale. Methodes : Etude retrospective, mono-centrique, non interventionnelle incluant les cancers du rein métastatiques à cellules claires diagnostiqués depuis 2000 sur le Centre Hospitalier Universitaire de Grenoble. Les 2 cohortes ont été déterminées en fonction de la première ligne thérapeutique reçue (thérapies ciblées ou autres traitements). Résultats : Quatre-vingt dix-huit patients ont été inclus entre le 1er Janvier 2000 et le 31 Decembre 2010. Les 2 cohortes étaient comparables, en particulier la distribution des profils pronostiques. En premiere ligne, 58 patients ont reçus une thérapie ciblée dont 21% ont été traités par bevacizumab, 71% par sunitinib et 8% par temsirolimus. Dans l autre cohorte (n=40), 37,5% des patients ont reçus des cytokines, 15% une chimiothérapie cytotoxique ou une hormonothérapie. La médiane de survie globale des patients traités par thérapie ciblée est significativement augmentée (30 mois contre 13 mois; p<.003, log-rank test). Le Hazard Ratio (HR) de décès à 3 ans est de 0.53 (intervalle de confiance 95%, 0.33-0.85; p=.008, log-rank test). Le HR de décès à 3 ans ajusté sur le profil pronostique est de 0.43 (IC95%,0.27-0.71). Conclusion : Cette étude retrospective objective l amélioraton de survie globale des patients atteints de cancer du rein métastatique, quelque soit le groupe pronostique, grâce à l apport des thérapies ciblées.Introduction: Anti-angiogenic treatment had radically modified therapeutic strategy in metastatic renal cell carcinoma (mRCC). This study is aimed to determine the overall survival (OS) improvement in clinical practice. Patients and methods: Retrospective, monocentric and non-interventional study in mRCC diagnosed since 2000 with 2 cohorts of patients determined according to the first line treatment (targeted therapy or others treatment). Results: Between 1 January 2000 and 31 December 2010, 98 patients were included. The 2 cohorts were balanced with regard to baseline disease and demographic characteristics in particular for prognosis profiles distribution. As first line, 58 patients received targeted therapy whose 21% were treated by bevacizumab, 71% by sunitinib and 8% by temsirolimus. In non-targeted therapy cohort (n=40), 37.5% were treated by cytokines, 15% by cytotoxic chemotherapy or hormonal therapy. Patients treated with targeted therapy had a significantly longer median OS (30 months vs 13 months; p<.003, log-rank test). The Hazard Ratio (HR) of death at 3 years was 0.53 (95% Confidence Interval, 0.33-0.85; p=.008, log-rank test). When adjusted to the prognosis profile, the HR of death was 0.43 (95%CI, 0.27-0.71). Conclusions: This retrospective study demonstrated the improvement of OS due to targeted treatments, for all prognostic risk groups. This result supported the complete change of care of mRCC patients with extension of therapeutic indications and efficient therapeutic lines.GRENOBLE1-BU Médecine pharm. (385162101) / SudocSudocFranceF

Short-Term cost impact of compliance with clinical practice guidelines for initial sarcoma treatment

Background: The impact of compliance to clinical practice guidelines (CPG) on outcomes and/or costs of care has not been completely clarified.Objective: To estimate relationships between medical expenditures and compliance to CPG for initial sarcoma treatment.Research design: Selected cohorts of patients diagnosed with sarcoma in 2005 and 2006, and treated at the University hospital and/or the cancer centre of the Rhône-Alpes region, France (n=90). Main outcome measurements were: patient characteristics, compliance with CPG, health outcomes, and costs. Data were mainly extracted from patient records. The logarithm of treatment costs was modelled using linear and Tobit regressions.Results: Rates of compliance with CPG were 86%, 66%, 88%, 89%, and 95% for initial diagnosis, primary surgical excision, wide surgical excision, chemotherapy, and radiotherapy, respectively. Total average costs reached €24,439, with €1,784, €11,225, €10,360, and €1,016 for diagnosis, surgery (primary and wide surgical excisions), chemotherapy, and radiotherapy, respectively. Compliance of diagnosis with CPG decreased the cost of diagnosis, whereas compliance of primary surgical excision increased the cost of chemotherapy. Compliance of chemotherapy with CPG decreased the cost of radiotherapy.Conclusion: Since chemotherapy is one of the major cost drivers, these results support that compliance with guidelines increases medical care expenditures in short term.Oncology; Sarcoma; Cost; Clinical guidelines; Efficacy; Medical Practices; Government Policy; Regulation; Public Health

Identification and characterization of a novel testis-specific gene CKT2, which encodes a substrate for protein kinase CK2

Protein kinase CK2 is a serine/threonine kinase known to phosphorylate numerous substrates. CK2 is implicated in several physiologic and pathologic processes, particularly in cancer biology. CK2 is comprised of several subunits, including CK2α, CK2α′ and CK2β. Inactivation of CK2α′ leads to chromatin degeneration of germ cells, resulting in male sterility. To identify additional targets of CK2α′ in testes and to determine the role of CK2α′ in germ cell nuclear integrity, GST pull-down and protein–protein interaction assays were conducted. A novel testis-specific gene, CKT2 (CK2 Target protein 2), was found whose product interacts with and is phosphorylated by CK2 in vitro and in vivo. CKT2 is a 30.2 kDa protein with one coiled-coil domain and six putative phosphorylation sites. High expression of CKT2 correlated with chromatin condensation of spermatids in murine testes. Findings reported herein demonstrate that CKT2 is a target protein of native CK2α′ in testes and suggest that CKT2 plays a role in chromatin regulation of male germ cells

Identification of hematein as a novel inhibitor of protein kinase CK2 from a natural product library

<p>Abstract</p> <p>Background</p> <p>Casein kinase 2 (CK2) is dysregulated in various human cancers and is a promising target for cancer therapy. To date, there is no small molecular CK2 inhibitor in clinical trial yet. With the aim to identify novel CK2 inhibitors, we screened a natural product library.</p> <p>Methods</p> <p>We adopted cell-based proliferation and CK2 kinase assays to screen CK2 inhibitors from a natural compound library. Dose-dependent response of CK2 inhibitors <it>in vitro </it>was determined by a radioisotope kinase assay. Western blot analysis was used to evaluate down stream Akt phosphorylation and apoptosis. Apoptosis was also evaluated by annexin-V/propidium iodide (PI) labeling method using flow cytometry. Inhibition effects of CK2 inhibitors on the growth of cancer and normal cells were evaluated by cell proliferation and viability assays.</p> <p>Results</p> <p>Hematein was identified as a novel CK2 inhibitor that is highly selective among a panel of kinases. It appears to be an ATP non-competitive and partially reversible CK2 inhibitor with an IC₅₀value of 0.55 μM. In addition, hematein inhibited cancer cell growth partially through down-regulation of Akt phosphorylation and induced apoptosis in these cells. Furthermore, hematein exerted stronger inhibition effects on the growth of cancer cells than in normal cells.</p> <p>Conclusion</p> <p>In this study, we showed that hematein is a novel selective and cell permeable small molecule CK2 inhibitor. Hematein showed stronger growth inhibition effects to cancer cells when compared to normal cells. This compound may represent a promising class of CK2 inhibitors.</p

Evaluation de l'association 5-fluoro-uracile-acide folinique-gemcitabine-oxaliplatine (folfu-gemox) chez des patients porteurs d'adénocarcinome de site primitif inconnu

Une polychimiothérapie comportant du 5-FU, de l'acide folinique, de la gemcitabine et de l'oxaliplatine (FOLFU-GEMOX) a été proposée à 16 patients Présentant un adénocarcinome de site primitif inconnu et suivi au CHU de Grenoble entre juin 1998 et juin 2003. Le taux de réponse objective est de 19% avec une durée médiane de réponse de 25 semaines. Le taux de réponse objective et de stabilisation est de 62%. La médiane de survie est de 11,5 mois. Comparé aux études de phase II actuelles, le taux de réponse objective est décevant mais la médiane de survie est plutôt satisfaisante. Par contre, la toxicité hématologique est marquée avec 56% des patients présentant une toxicité de grade 3-4, dont 37% de neutropénies grade 3-4. La toxicité globale du traitement est à l'origine de son arrêt prématuré chez 25% des patients. L'ensemble de ces résultats ne permet pas d'envisager des études plus approfondies sur le FOLFU-GEMOX, dans cette indication.FOLFU-GEMOX regimen (5-fluorouracil, folinic acid, gemcitabine, oxaliplatin) has been administrated to 16 patients with a diagnosis of adenocarcinoma of unknown primary site, since 1998 to 2003. Ten patients (62%) experienced an objective response or a stable disease. The median duration of OR+SD is 25 weeks. Median overall survival is 11.5 months. FOLFU-GEMOX is a toxic regimen with 56% of grade 3-4 hematologic toxicity (37% of grade 3-4 neutropenia) and 30% of grade 3-4 stomatitis. Four patients (25%) have stopped their treatment because of toxicity. Therefore, to our mind, FOLFU-GEMOX is not an effective treatment of adenocarcinoma of unknown primary site.GRENOBLE1-BU Médecine pharm. (385162101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

La protéine kinase ck2 (corrélation de la surexpression de la sous-unité catalytique a en immuno-histochimie à des facteurs de mauvais pronostic sur une série de 111 adénocarcinomes de prostate)

La protéine CK2 est une sérine-thréonine kinase ubiquitaire et conservée au cours de l'évolution. Elle est composée d'un dimère de 2 sous-unités régulatrices b sur lequel s'associent 2 sous-unités catalytiques a. Dans ce travail, l'expression de la CK2a a été étudiée rétrospectivement par immuno-histochimie (IHC) sur cent onze adénocarcinomes de prostate (72 du CU de Grenoble et 39 sur une puce à tissus du commerce). Les patients ont été répartis dans 3 groupes : 0/1+ (expression faible), 2+ (expression modérée) et 3+ et plus (surexpression). La CK2a est plus exprimée dans les glandes prostatiques tumorales que dans les glandes normales et son expression est majoritairement cytoplasmique (p300. Its role in human cancerogenesis remains unclear, but data showed that it promotes proliferation and protect cancer cells against apoptosis. Cristallography depict an heterotetramere, with 2 regulatory subunits (CK2b) associated with 2 catalytic subunits (CK2a). In this study, we performed immunochemistry with a specific anti-CK2a polyclonal antibody. Analysis of 111 samples of human prostate adenocarcinoma showed an overexpression in 43.3% of cases. Patients in this subgroup ( overexpression group ) have bad prognostic factors: 85% with Gleason score up to 6, 48% are pT3-T4 tumors and 63.6% show perineural invasion. By comparison, these percentages are respectively 55.5%, 16% and 38% in the remaining group. Differences are statistically significant (p<0.001 to 0.05). Then, overexpression group seems to be clinically relevant, but survival data are lacking. Furthers investigations are needed to explore the exact role of CK2a in prostate cancer, and to establish if this protein represent a new biomarker.GRENOBLE1-BU Médecine pharm. (385162101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

La protéine kinase ck2 (corrélation de la surexpression de la sous-unité catalytique a en immuno-histochimie à des facteurs de mauvais pronostic sur une série de 111 adénocarcinomes de prostate)

La protéine CK2 est une sérine-thréonine kinase ubiquitaire et conservée au cours de l'évolution. Elle est composée d'un dimère de 2 sous-unités régulatrices b sur lequel s'associent 2 sous-unités catalytiques a. Dans ce travail, l'expression de la CK2a a été étudiée rétrospectivement par immuno-histochimie (IHC) sur cent onze adénocarcinomes de prostate (72 du CU de Grenoble et 39 sur une puce à tissus du commerce). Les patients ont été répartis dans 3 groupes : 0/1+ (expression faible), 2+ (expression modérée) et 3+ et plus (surexpression). La CK2a est plus exprimée dans les glandes prostatiques tumorales que dans les glandes normales et son expression est majoritairement cytoplasmique (p<0.001). Le groupe surexpression (3+) regroupe 43.3% des cancers et les facteurs pronostiques y sont péjoratifs : 85% des tumeurs 3+ ont un score de Gleason supérieur ou égal à 7, 48% correspondent à des stades pT3-T4 et 63,6% présentent des emboles péri-nerveux et/ou lymphatiques. Les tumeurs des groupes 0/1+ et 2+ rassemblés ont 55.5% de score de Gleason supérieur ou égal à 7, 16% sont des pT3-T4 et 38% comportent des emboles. Ces différences sont statistiquement significatives (p<0.001 à 0.05). Il n'y a pas de données de survie disponibles pour étudier l'impact du statut CK2a sur le devenir des patients. Des études complémentaires sont nécessaires.CK2 is an ubiquitinous and highly conserved serine/threonine protein kinase. Potential substrates are >300. Its role in human cancerogenesis remains unclear, but data showed that it promotes proliferation and protect cancer cells against apoptosis. Cristallography depict an heterotetramere, with 2 regulatory subunits (CK2b) associated with 2 catalytic subunits (CK2a). In this study, we performed immunochemistry with a specific anti-CK2a polyclonal antibody. Analysis of 111 samples of human prostate adenocarcinoma showed an overexpression in 43.3% of cases. Patients in this subgroup ( overexpression group ) have bad prognostic factors: 85% with Gleason score up to 6, 48% are pT3-T4 tumors and 63.6% show perineural invasion. By comparison, these percentages are respectively 55.5%, 16% and 38% in the remaining group. Differences are statistically significant (p<0.001 to 0.05). Then, overexpression group seems to be clinically relevant, but survival data are lacking. Furthers investigations are needed to explore the exact role of CK2a in prostate cancer, and to establish if this protein represent a new biomarker.GRENOBLE1-BU Médecine pharm. (385162101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

An impressive response with larotrectinib in a patient with a papillary thyroid carcinoma harboring an SQSTM1-NTRK1 fusion

NTRK rearrangements represent a very rare genomic abnormality among all cancers but can be detected in thyroid cancer with a non-negligible frequency of 2%. Dramatic clinical responses to therapies targeting NTRK chimeric proteins are now well described in the literature. SQSTM1-NTRK1 fusions have not yet been described in a full clinical case report. We report a patient with a papillary thyroid carcinoma harboring this unique rearrangement, with an impressive clinical and radiologic response to larotrectinib, a highly specific inhibitor

Nuclear localization of protein kinase CK2 catalytic subunit (CK2alpha) is associated with poor prognostic factors in human prostate cancer.

International audienceMany genomic abnormalities have been identified in various subsets of prostate cancer, but until now, few genes have been associated with the progression of this cancer. High activity of protein serine/threonine kinase CK2 has been observed in various solid tumours and this alteration has been linked both to growth-related functions and to suppression of cellular apoptosis. Here, we provide the first evidence for a strong association between a nuclear localization of CK2alpha, evaluated by immunohistochemistry, and poor prognostic factors in a retrospective cohort of 131 human prostate adenocarcinomas. Nuclear CK2alpha localization is significantly correlated with higher Gleason score, more locally advanced disease (cT3-T4) and more perineural or lymphatic invasion (p<0.0019 to 0.046). In contrast, despite a strong trend, no significant relationship was found between higher initial PSA and nuclear CK2alpha localization. Thus, this previously undescribed molecular heterogeneity is the first step in defining CK2 as both a potential biomarker and a promising target in human prostate cancer