Menée sur 79 patients atteints d'un chondrosarcome de la base du crâne traité entre 1998 et 2008 (durée médiane de suivi après traitement : 91 mois), cette étude évalue l'efficacité, du point de vue du taux de contrôle local de la maladie et du taux de survie globale à 3, 5 et 10 ans, et la toxicité d'une radiothérapie par ions carbone

High control rate in patients with chondrosarcoma of the skull base after carbon ion therapy: First report of long-term results

Uhl, Matthias ; Mattke, Matthias ; Welzel, Thomas ; Oelmann, Jan ; Habl, Gregor ; Jensen, Alexandra D. ; Ellerbrock, Malte ; Haberer, Thomas ; Herfarth, Klaus K. ; Debus, Jurgen

BACKGROUND : The current study was performed to evaluate the safety and effectiveness of irradiation with carbon ions using raster scanning as well as prognostic factors in patients with skull base chondrosarcomas. METHODS : Between 1998 and 2008, 79 patients with chondrosarcoma of the skull base were treated using carbon ions in raster scanning. The applied median total dose was 60 gray equivalent (GyE) at 3 GyE per fraction. Local control and overall survival (OS) were evaluated using the [...]

A partir d'une revue sytématique de la littérature (33 études incluant 28 162 patients), cette méta-analyse évalue la largeur optimale des marges de résection pour réduire au minimum le risque de récidive ipsilatérale chez les patientes atteintes d'un cancer invasif du sein de stade I ou II et recevant un traitement conservateur combinant chirurgie et radiothérapie du sein entier

Society of Surgical Oncology–American Society for Radiation Oncology Consensus Guideline on Margins for Breast-Conserving Surgery With Whole-Breast Irradiation in Stages I and II Invasive Breast Cancer

Moran, Meena S. ; Schnitt, Stuart J. ; Giuliano, Armando E. ; Harris, Jay R. ; Khan, Seema A. ; Horton, Janet ; Klimberg, Suzanne ; Chavez-MacGregor, Mariana ; Freedman, Gary ; Houssami, Nehmat ; Johnson, Peggy L. ; Morrow, Monica

Purpose : Controversy exists regarding the optimal margin width in breast-conserving surgery for invasive breast cancer. Methods : A multidisciplinary consensus panel used a meta-analysis of margin width and ipsilateral breast tumor recurrence (IBTR) from a systematic review of 33 studies including 28,162 patients as the primary evidence base for consensus. Results : Positive margins (ink on invasive carcinoma or ductal carcinoma in situ) are associated with a two-fold increase in the risk of [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels l'expression de HGMA2, une protéine chaperon connue pour son implication dans le maintien de l'intégrité du génome des cellules souches embryonnaires, protège également les cellules souches cancéreuses de l'action des traitements endommageant l'ADN

Chaperoning HMGA2 Protein Protects Stalled Replication Forks in Stem and Cancer Cells

Yu, Haojie ; Lim, Hong Hwa ; Tjokro, Natalia O ; Sathiyanathan, Padmapriya ; Natarajan, Suchitra ; Chew, Tian Wei ; Klonisch, Thomas ; Goodman, Steven D ; Surana, Uttam ; Dröge, Peter

Maintaining genome integrity requires the accurate and complete replication of chromosomal DNA. This is of the utmost importance for embryonic stem cells (ESCs), which differentiate into cells of all lineages, including germ cells. However, endogenous and exogenous factors frequently induce stalling of replication forks in every cell cycle, which can trigger mutations and chromosomal instabilities. We show here that the oncofetal, nonhistone chromatin factor HMGA2 equips cells with a highly [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par les cellules stromales mésenchymateuses de la moelle osseuse dans la résistance à une chimiothérapie

Bone Marrow-Derived Mesenchymal Stromal Cells Promote Survival and Drug Resistance in Tumor Cells

Bergfeld, Scott A ; Blavier, Laurence ; DeClerck, Yves A.

Bone marrow mesenchymal stromal cells (BMMSC) have anti-tumorigenic activities. Here we hypothesized that circulating BMMSC are incorporated into tumors and protect tumor cells from therapy-induced apoptosis. Adherent cells harvested from murine bone marrow and expressing phenotypic and functional characteristics of BMMSC were tested for their anti-tumor activity against murine 4T1 mammary adenocarcinoma and LL/2 Lewis lung carcinoma cells. BMMSC but not NIH3T3 or murine skin fibroblasts [...]

Menée in vitro et in vivo, cette étude évalue l'activité d'un composé appelé BKT140, un inhibiteur de CXCR4, en combinaison avec l'imatinib pour le traitement d'une leucémie myéloïde chronique

Combination of Imatinib with CXCR4 antagonist BKT140 overcomes the protective effect of stroma and targets CML in vitro and in vivo

Beider, Katia ; Darash-Yahana, Merav ; Blaier, Orly ; Koren-Michowitz, Maya ; Abraham, Michal ; Wald, Hanna ; Wald, Ori ; Galun, Eithan ; Eizenberg, Orly ; Peled, Amnon ; Nagler, Arnon

Functional role of CXCR4 in CML progression was evaluated. Elevated CXCR4 significantly increased the in vitro survival and proliferation in response to CXCL12. CXCR4 stimulation resulted in activation of Erk1/2, Akt, S6K, STAT3 and STAT5 pro-survival signaling pathways. In accordance, we found that in vitro treatment with CXCR4 antagonist BKT140 directly inhibited the cell growth and induced cell death of CML cells. Combination of BKT140 with sub-optimal concentrations of imatinib [...]

Menée à l'aide d'un modèle murin de cancer de l'ovaire, cette étude évalue l'activité antitumorale d'anticorps monoclonaux anti PD-1 et anti-GITR

Combined PD-1 blockade and GITR triggering induce a potent antitumor immunity in murine cancer models and synergizes with chemotherapeutic drugs

Lu, Lei ; Xu, Xiaobing ; Zhang, Bin ; Zhang, Rongsheng ; Ji, Hongzan ; Wang, Xuan

BACKGROUND:The coinhibitory receptor Programmed Death-1 (PD-1) inhibits effector functions of activated T cells and prevents autoimmunity, however, cancer hijack this pathway to escape from immune attack. The costimulatory receptor glucocorticoid-induced TNFR related protein (GITR) is up-regulated on activated T cells and increases their proliferation, activation and cytokine production. We hypothesize that concomitant PD-1 blockade and GITR triggering would synergistically improve the effector [...]

Cet article passe en revue les travaux récents sur le développement de nouveaux composés pour traiter les patients atteints d'un cancer du poumon non à petites cellules résistant au crizotinib

Overcoming the resistance to Crizotinib in patients with Non-Small Cell Lung Cancer harboring EML4/ALK translocation

Perez, Cesar A. ; Velez, Michel ; Raez, Luis E. ; Santos, Edgardo S.

The large knowledge learned in molecular biology specifically in the oncology field during the last ten years has resulted in fruitful results for the treatment of non-small cell lung cancer. The first pathway to be effectively targeted in lung cancer was the epidermal growth factor receptor. The acceptance of epidermal growth factor receptor mutation as a strong predictive biomarker in non-small cell lung carcinoma has encouraged the search for more targets. In 2011, regulatory entities [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels des mutations du gène SPOP favorisent le développement d'une résistance aux traitements anti-androgènes chez les patients atteints d'un cancer de la prostate

Destruction of Full-Length Androgen Receptor by Wild-Type SPOP, but Not Prostate-Cancer-Associated Mutants

An, Jian ; Wang, Chenji ; Deng, Yibin ; Yu, Long ; Huang, Haojie

The SPOP E3 ubiquitin ligase gene is frequently mutated in human prostate cancers. Here, we demonstrate that SPOP recognizes a Ser/Thr-rich degron in the hinge domain of androgen receptor (AR) and induces degradation of full-length AR and inhibition of AR-mediated gene transcription and prostate cancer cell growth. AR splicing variants, most of which lack the hinge domain, escape SPOP-mediated degradation. Prostate-cancer-associated mutants of SPOP cannot bind to and promote AR destruction. [...]

Menée sur une cohorte de patients pédiatriques atteints d'une leucémie lymphoblastique aiguë Ph+, cette étude américaine évalue les niveaux de maladie résiduelle à la suite d'un traitement d'induction à base d'inhibiteurs de tyrosine kinase

Impact of tyrosine kinase inhibitors on minimal residual disease and outcome in childhood Philadelphia chromosome-positive acute lymphoblastic leukemia

Jeha, Sima ; Coustan-Smith, Elaine ; Pei, Deqing ; Sandlund, John T. ; Rubnitz, Jeffrey E. ; Howard, Scott C. ; Inaba, Hiroto ; Bhojwani, Deepa ; Metzger, Monika L. ; Cheng, Cheng ; Choi, John K. ; Jacobsen, Jeffrey ; Shurtleff, Sheila A. ; Raimondi, Susana ; Ribeiro, Raul C. ; Pui, Ching-Hon ; Campana, Dario

BACKGROUND Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) tyrosine kinase inhibitors (TKIs) improve the outcome of patients with childhood Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) when they are incorporated into postremission induction chemotherapy. To date, no data are available on the impact of TKIs on minimal residual disease (MRD) at the end of induction therapy among patients who have a poor early response to 2 weeks of [...]

Mené sur 39 patients atteints d'un lymphome hodgkinien nodulaire à prédominance lymphocytaire, cet essai de phase II évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité du rituximab (durée médiane de suivi : 9,8 ans)

Mature Results of a Phase II Study of Rituximab Therapy for Nodular Lymphocyte–Predominant Hodgkin Lymphoma

Advani, Ranjana H. ; Horning, Sandra J. ; Hoppe, Richard T. ; Daadi, Sarah ; Allen, John ; Natkunam, Yasodha ; Bartlett, Nancy L.

Purpose Universal expression of CD20 by malignant cells in nodular lymphocyte–predominant Hodgkin lymphoma (NLPHL) led us to evaluate rituximab (R) as a therapeutic option. Patient and Methods Patients with previously treated or newly diagnosed NLPHL were treated with R (375 mg/m2 once per week for 4 weeks) or, after a protocol amendment, with R plus R maintenance (MR; administered once every 6 months for 2 years). Primary and secondary outcome measures were progression-free survival (PFS) and [...]

Menée sur 342 patients atteints d'un mélanome métastatique traité à l'aide de vemurafenib (277 patients) ou de dabrafenib (65 patients), cette étude met en évidence des différences dans la réponse du système immunitaire de l'hôte alors que l'efficacité clinique des deux thérapies ciblées est comparable

Differential influence of vemurafenib and dabrafenib on patients’ lymphocytes despite similar clinical efficacy in melanoma

Schilling, B. ; Sondermann, W. ; Zhao, F. ; Griewank, K. G. ; Livingstone, E. ; Sucker, A. ; Zelba, H. ; Weide, B. ; Trefzer, U. ; Wilhelm, T. ; Loquai, C. ; Berking, C. ; Hassel, J. ; Kähler, K. C. ; Utikal, J. ; Al Ghazal, P. ; Gutzmer, R. ; Goldinger, S. M. ; Zimmer, L. ; Paschen, A. ; Hillen, U. ; Schadendorf, D. ; on behalf of DeCOG

Background Since the majority of melanomas eventually become resistant and progress, combining selective BRAF inhibitors (BRAFi) with immunotherapies has been proposed to achieve more durable treatment responses. Here, we explored the impact of selective BRAFi on the hosts' immune system. Patients and methods Clinical data, whole blood counts (WBC) and serum lactate dehydrogenase (LDH) of 277 vemurafenib- and 65 dabrafenib-treated melanoma patients were evaluated. The frequency and phenotype of [...]

Mené sur 66 patients atteints d'un cancer avancé du poumon non à petites cellules sans mutation du gène KRAS, cet essai de phase III évalue l'efficacité, du point de vue du taux de réponse objective, et la toxicité du dacomitinib après l'échec d'un ou deux protocoles de chimiothérapie et d'erlotinib

A phase 2 trial of dacomitinib (PF-00299804), an oral, irreversible pan-HER (human epidermal growth factor receptor) inhibitor, in patients with advanced non–small cell lung cancer after failure of prior chemotherapy and erlotinib

Reckamp, Karen L. ; Giaccone, Giuseppe ; Camidge, D. Ross ; Gadgeel, Shirish M. ; Khuri, Fadlo R. ; Engelman, Jeff A. ; Koczywas, Marianna ; Rajan, Arun ; Campbell, Alicyn K. ; Gernhardt, Diana ; Ruiz-Garcia, Ana ; Letrent, Stephen ; Liang, Jane ; Taylor, Ian ; O'Connell, Joseph P. ; Jänne, Pasi A.

BACKGROUND This phase 2 trial (ClinicalTrials.gov identifier NCT00548093) assessed the efficacy, safety, and impact on health-related quality of life of dacomitinib (PF-00299804), an irreversible tyrosine kinase inhibitor (TKI) of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, in patients with KRAS wild-type non–small cell lung cancer (NSCLC). METHODS Patients with advanced NSCLC, progression on 1 or 2 regimens of chemotherapy and erlotinib, KRAS wild-type or known [...]

Menée en Allemagne auprès de 497 patients atteints d'un cancer colorectal métastatique (âge médian : 66 ans), cette étude analyse l'impact de comorbidités et de l'âge du patient sur l'efficacité thérapeutique d'un traitement par cétuximab et irinotecan

Influence of comorbidity, age and performance status on treatment efficacy and safety of cetuximab plus irinotecan in irinotecan-refractory elderly patients with metastatic colorectal cancer

Jehn, C. F. ; Böning, L. ; Kröning, H. ; Pezzutto, A. ; Lüftner, D.

We investigated the influence of comorbidity, Eastern Cooperative Oncology Group (ECOG) performance status and age on the efficacy and safety profile of cetuximab and irinotecan in elderly irinotecan-pretreated patients with mCRC. 497 patients with mCRC were entered in the database of this non-interventional study (NIS). Comorbid conditions were recorded. A total of 247 and 250 patients aged <65 and >65years, respectively, with a median age of 66 y were documented; 78% of the patients showed a [...]

Mené sur 121 patients atteints d'un sarcome avec translocations de stade avancé ou métastatique, cet essai de phase III compare l'efficacité, du point de vue de la survie sans progression, et la toxicité de la trabectédine et d'une chimiothérapie à base de doxorubicine en traitement de première ligne

Randomised phase III trial of trabectedin versus doxorubicin-based chemotherapy as first-line therapy in translocation-related sarcomas

Blay, Jean-Yves ; Leahy, Michael G. ; Nguyen, Binh Bui ; Patel, Shreyaskumar R. ; Hohenberger, Peter ; Santoro, Armando ; Staddon, Arthur P. ; Penel, Nicolas ; Piperno-Neumann, Sophie ; Hendifar, Andrew ; Lardelli, Pilar ; Nieto, Antonio ; Alfaro, Vicente ; Chawla, Sant P.

This randomised phase III trial evaluated first-line trabectedin versus doxorubicin-based chemotherapy (DXCT) in patients with advanced/metastatic translocation-related sarcomas (TRS). Patients were randomly assigned (1:1) to receive trabectedin 1.5mg/m2 24-h intravenous (i.v.) infusion every 3weeks (q3wk) (Arm A), or doxorubicin 75mg/m2 i.v. q3wk, or doxorubicin 60mg/m2 i.v. plus ifosfamide (range, 6–9g/m2) i.v. q3wk (Arm B). Progression-free survival (PFS) by independent review was the [...]

A partir de données portant sur 2 028 patientes de plus de 66 ans ayant reçu du trastuzumab en traitement adjuvant d'un cancer du sein entre 2005 et 2009, cette étude américaine analyse le taux de patientes dont la durée de traitement a dépassé 270 jours et le taux de séjours hospitaliers pour événement cardiaque

Duration and Toxicity of Adjuvant Trastuzumab in Older Patients With Early-Stage Breast Cancer: A Population-Based Study

Vaz-Luis, Ines ; Keating, Nancy L. ; Lin, Nancy U. ; Lii, Huichuan ; Winer, Eric P. ; Freedman, Rachel A.

Purpose Few data are available regarding adjuvant trastuzumab use in older women with early-stage breast cancer. We examined rates and predictors of adjuvant trastuzumab completion and cardiac events in this population. Patients and Methods We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data to identify patients age ≥ 66 years with stage I to III breast cancer diagnosed between 2005 and 2009 who received trastuzumab. Completion of trastuzumab was defined as receipt of more [...]

Mené sur 78 patientes atteintes d'un cancer métastatique du sein (âge supérieur à 65 ans), cet essai multicentrique de phase III compare l'efficacité, du point de vue de la survie sans progression et de la survie globale, et la toxicité de la doxorubicine liposomale pégylée et de la capécitabine en traitement de première ligne

A randomized phase III study comparing pegylated liposomal doxorubicin with capecitabine as first-line chemotherapy in elderly patients with metastatic breast cancer: results of the OMEGA study of the Dutch Breast Cancer Research Group BOOG

Smorenburg, C. H. ; de Groot, S. M. ; van Leeuwen-Stok, A. E. ; Hamaker, M. E. ; Wymenga, A. N. ; de Graaf, H. ; de Jongh, F. E. ; Braun, J. J. ; Los, M. ; Maartense, E. ; van Tinteren, H. ; Nortier, J. W. R. ; Seynaeve, C.

Background Prospective data on chemotherapy for elderly patients with metastatic breast cancer (MBC) remain scarce. We compared the efficacy and safety of first-line chemotherapy with pegylated liposomal doxorubicin (PLD) versus capecitabine in MBC patients aged ≥65 years in a multicentre, phase III trial. Patients and methods Patients were randomized to six cycles of PLD (45 mg/m2 every 4 weeks) or eight cycles of capecitabine (1000 mg/m2 twice daily, day 1–14 every 3 weeks). Results The study [...]

Cet article fait le point sur les avancées récentes concernant le traitement des métastases osseuses ou cérébrales ayant pour origine un cancer du poumon

Bone and brain metastasis in lung cancer: recent advances in therapeutic strategies

D'Antonio, Chiara ; Passaro, Antonio ; Gori, Bruno ; Del Signore, Ester ; Migliorino, Maria Rita ; Ricciardi, Serena ; Fulvi, Alberto ; de Marinis, Filippo

Bone and brain metastases are a very common secondary localization of disease in patients with lung cancer. The prognosis of these patients is still poor with a median survival of less than 1 year. Current therapeutic approaches include palliative radiotherapy and systemic therapy with chemotherapy and targeted agents. For bone metastasis, zoledronic acid is the most commonly used bisphosphonate to prevent, reduce the incidence and delay the onset of skeletal-related events (SREs). Recently, [...]

Menée sur 172 patientes atteintes d'un cancer inflammatoire du sein métastatique, cette étude met en évidence le bénéfice, en termes de contrôle de la maladie et de survie, d'une résection tumorale dans le cadre d'une chimiothérapie combinée ou non à une radiothérapie

Primary tumor resection as a component of multimodality treatment may improve local control and survival in patients with stage IV inflammatory breast cancer

Akay, Catherine L. ; Ueno, Naoto T. ; Chisholm, Gary B. ; Hortobagyi, Gabriel N. ; Woodward, Wendy A. ; Alvarez, Ricardo H. ; Bedrosian, Isabelle ; Kuerer, Henry M. ; Hunt, Kelly K. ; Huo, Lei ; Babiera, Gildy V.

BACKGROUND : To the authors' knowledge, the benefit of primary tumor resection among patients with metastatic inflammatory breast cancer (IBC) is unknown. METHODS : The authors reviewed 172 cases of metastatic IBC. All patients received chemotherapy with or without radiotherapy and/or surgery. Patients were classified as responders or nonresponders to chemotherapy. The 5-year overall survival (OS) and distant progression-free survival (DPFS) and local control at the time of last follow-up were [...]

Menée sur 4 lignées cellulaires de glioblastome et in vivo, cette étude montre que l'inhibition de la protéine HSP90 favorise l'inhibition de l'enzyme PI-3 kinase et augmente la sensibilité des cellules tumorales aux rayonnements ionisants

Hsp90 inhibition enhances PI-3 kinase inhibition and radiosensitivity in glioblastoma

Wachsberger, PhyllisR ; Lawrence, YaacovRichard ; Liu, Yi ; Rice, Barbara ; Feo, Nicholas ; Leiby, Benjamin ; Dicker, AdamP

Purpose : Combined targeting with a PI3-kinase inhibitor, BKM120, and an Hsp90 inhibitor, HSP990, was investigated as a multi-targeted approach to potentiate cell death in glioblastoma (GBM). Additionally, the effect of dual drug treatment combined with cytotoxic stress (radiation therapy) was examined. Methods : Four human GBM cell lines containing wild-type or mutated PTEN and/or p53 were studied. The effects of drug treatments on cell viability, apoptosis induction, pAKt activity, cell cycle [...]

Mené sur 25 patients atteints d'un carcinome épidermoïde de la tête et du cou de stade III–IVB (âge : 46 à 84 ans), cet essai de phase I évalue l'efficacité, du point de vue de la survie globale à 2 ans, et la toxicité de différentes doses hebdomadaires de nab-paclitaxel et de cetuximab combinées de manière concomitante à une radiothérapie avec modulation d'intensité

Phase I study of weekly nab-paclitaxel + weekly cetuximab + intensity-modulated radiation therapy (IMRT) in patients with stage III–IVB head and neck squamous cell carcinoma (HNSCC)

Fury, M. G. ; Sherman, E. J. ; Rao, S. S. ; Wolden, S. ; Smith-Marrone, S. ; Mueller, B. ; Ng, K. K. ; Dutta, P. R. ; Gelblum, D. Y. ; Lee, J. L. ; Shen, R. ; Kurz, S. ; Katabi, N. ; Haque, S. ; Lee, N. Y. ; Pfister, D. G.

Background : There is a clinical need to improve the efficacy of standard cetuximab + concurrent intensity-modulated radiation therapy (IMRT) for patients with locally and/or regionally advanced HNSCC. Taxanes have radiosensitizing activity against HNSCC, and nab-paclitaxel may offer therapeutic advantage in comparison with other taxanes. Patients and methods : This was a single-institution phase I study with a modified 3 + 3 design. Four dose levels (DLs) of weekly nab-paclitaxel were explored [...]

Menée sur 171 patients atteints d'un cancer oropharyngé, cette étude rétrospective compare, du point de vue de la survie globale à 5 ans et en fonction du niveau du risque de récidive des patients établi selon le système de classification Ang, l'efficacité de différentes stratégies thérapeutiques comportant une intervention chirurgicale suivie d'une radiothérapie ou d'une chimioradiothérapie avec ou sans chimiothérapie d'induction par docétaxel-cisplatine-5-fluorouracile

Treatment-related outcome of oropharyngeal cancer patients differentiated by HPV dictated risk profile: a tertiary cancer centre series analysis

Bossi, P. ; Orlandi, E. ; Miceli, R. ; Perrone, F. ; Guzzo, M. ; Mariani, L. ; Granata, R. ; Locati, L. ; Fallai, C. ; Cortelazzi, B. ; Pilotti, S. ; Scaramellini, G. ; Gloghini, A. ; Licitra, L.

Background : To date, no treatment modality has been identified as more effective for oropharyngeal cancer (OPC), and no predictive factors are known to guide treatment decision for this disease. This retrospective study evaluates the differential effects of diverse treatment options for OPC according to patient risk profiles. Patients and methods : We considered two series of locally advanced squamous cell OPC patients treated with either surgery followed by radiotherapy (surgical series) or [...]

Cet article passe en revue les perspectives offertes par la biologie des systèmes pour améliorer l'efficacité des thérapies ciblées des cancers

Cancer Systems Biology: a peek into the future of patient care?

Werner, Henrica M. J. ; Mills, Gordon B. ; Ram, Prahlad T.

Traditionally, scientific research has focused on studying individual events, such as single mutations, gene function, or the effect that mutating one protein has on a biological phenotype. A range of technologies is beginning to provide information that will enable a holistic view of how genomic and epigenetic aberrations in cancer cells can alter the homeostasis of signalling networks within these cells, between cancer cells and the local microenvironment, and at the organ and organism level. [...]