Mené sur 151 patients présentant des métastases hépatiques d'origine colorectale, neuroendocrine ou autre (âge : 25 à 88 ans), cet essai multicentrique de phase II évalue l'efficacité, du point de vue de la survie sans progression et de la survie globale, et la sécurité d'une radioembolisation hépatique utilisant des microsphères contenant de l'Yttrium-90

Radioembolisation for liver metastases: Results from a prospective 151 patient multi-institutional phase II study

Benson Iii, Al B. ; Geschwind, Jean-Francois ; Mulcahy, Mary F. ; Rilling, William ; Siskin, Gary ; Wiseman, Greg ; Cunningham, James ; Houghton, Bonny ; Ross, Mason ; Memon, Khairuddin ; Andrews, James ; Fleming, Chad J. ; Herman, Joseph ; Nimeiri, Halla ; Lewandowski, Robert J. ; Salem, Riad

Purpose : To investigate the safety, response rate, progression-free and overall survival of patients with liver metastases treated with 90Y (glass) radioembolisation in a prospective, multicenter phase II study. Methods : 151 patients with liver metastases (colorectal n = 61, neuroendocrine n = 43 and other tumour types n = 47) refractory to standard of care therapies were enrolled in this prospective, multicenter, phase II study under an investigational device exemption. [...]

Menée in vitro et à l'aide d'une xénogreffe de cancer humain du pancréas, cette étude montre que l'inhibition de la protéine phosphatase 2A sensibilise les cellules tumorales aux rayonnements ionisants en activant CDC25C/CDK1 et en inhibant la réparation par recombinaison homologue de l'ADN

Inhibition of protein phosphatase 2A radiosensitizes pancreatic cancers by modulating CDC25C/CDK1 and homologous recombination repair

Wei, Dongping ; Parsels, Leslie ; Karnak, David ; Davis, Mary ; Parsels, Joshua ; Zhao, Lili L. ; Maybaum, Jonathan ; Lawrence, Theodore ; Sun, Yi ; Morgan, Meredith A.

Purpose : To identify targets whose inhibition may enhance the efficacy of chemoradiation in pancreatic cancer and thus improve survival, we performed an siRNA library screen in pancreatic cancer cells. We investigated PPP2R1A, a scaffolding subunit of protein phosphatase 2A (PP2A) as a lead radiosensitizing target. Experimental Design : We determined the effect of PP2A inhibition by genetic (PPP2R1A siRNA) and pharmacological (LB100, a small molecule entering Phase I clinical trials) [...]

A partir d'une revue systématique de la littérature publiée entre 1985 et 2012 (34 études, 1 916 patients), cette étude évalue l'efficacité, du point de vue de la survie sans maladie et de la survie globale, et la sécurité, du point de vue des taux de morbidité et de mortalité périopératoires, de différentes techniques chirurgicales de pleurectomie pour traiter un mésothéliome pleural malin

Systematic review of pleurectomy in the treatment of malignant pleural mesothelioma

Cao, Christopher ; Tian, David H. ; Pataky, Kristopher A. ; Yan, Tristan D.

Introduction : Pleurectomy/decortication (P/D) in the treatment of malignant pleural mesothelioma includes a number of procedures with different clinical indications and therapeutic intents. To unify the nomenclature, IMIG and IASLC recently defined P/D-related procedures according to surgical technique, including ‘extended P/D’, ‘P/D’ and ‘partial pleurectomy’. The present systematic review aimed to assess the safety and efficacy of these techniques. Methods : A systematic review of relevant [...]

A partir de données médicales portant sur 1 257 patients atteints d'un cancer de la prostate traité par prostatectomie radicale entre 2001 et 2009 (durée médiane de suivi : 49 mois), cette étude multicentrique japonaise évalue l'effet de l'indice de masse corporelle sur le taux de survie sans récidive biochimique et la survenue d'événements indésirables

Impact of body mass index on clinicopathological outcome and biochemical recurrence after radical prostatectomy

Narita, S. ; Mitsuzuka, K. ; Yoneyama, T. ; Tsuchiya, N. ; Koie, T. ; Kakoi, N. ; Kawamura, S. ; Kaiho, Y. ; Ohyama, C. ; Tochigi, T. ; Yamaguchi, T. ; Habuchi, T. ; Arai, Y.

Background : Accumulating evidence suggests that obesity is associated with tumor progression in prostate cancer (PCa) patients after radical prostatectomy (RP). We conducted a retrospective multicenter study to determine the effect of body mass index (BMI) on the clinicopathological characteristics and biochemical recurrence of PCa in Japanese men who underwent RP. Methods : The medical records of 1257 men with PCa treated by RP without neoadjuvant therapy at four medical institutes between [...]

A partir d'une revue systématique de la littérature publiée entre 2001 et 2011 (27 études ; durée minimale de suivi : 24 mois : nombre minimal de patients par étude : 50), cette étude compare l'efficacité de la chirurgie, de l'ablation par radiofréquence et de la radiothérapie stéréotaxique pour traiter localement des métastases pulmonaires ayant pour origine un cancer colorectal

What to choose as radical local treatment for lung metastases from colo-rectal cancer : Surgery or radiofrequency ablation?

Schlijper, Roel C. J. ; Grutters, Janneke P. C. ; Houben, Ruud ; Dingemans, Anne-Marie C. ; Wildberger, Joachim E. ; Raemdonck, Dirk Van ; Cutsem, Eric Van ; Haustermans, Karin ; Lammering, Guido ; Lambin, Philippe ; Ruysscher, Dirk De

Background : Long-term survival can be obtained with local treatment of lung metastases from colorectal cancer. However, it is unclear as to what the optimal local therapy is: surgery, radiofrequency ablation (RFA) or stereotactic radiotherapy (SBRT). Methods : A systematic review included 27 studies matching with the a priori selection criteria, the most important being 50 patients and a follow-up period of 24months. No SBRT studies were eligible. The review was therefore conducted on 4 RFA [...]

Menée à partir de données de registres américains portant sur 248 patientes habitant une région médicalement mal desservie et ayant reçu un traitement néo-adjuvant, subi une mastectomie puis une radiothérapie pour traiter un cancer du sein de stade II ou III, cette étude évalue l'impact du délai entre l'intervention chirurgicale et le début de la radiothérapie sur le contrôle locorégional de la maladie

Impact of Surgery-Radiation Interval on Locoregional Outcome in Patients Receiving Neo-adjuvant Therapy and Mastectomy

Desai, Shiv ; Hurley, Judith ; Takita, Cristiane ; Reis, Isildinha M. ; Zhao, Wei ; Rodgers, Steven E. ; Wright, Jean L.

Delays in the initiation of radiation are increasingly common for medically underserved patients. We evaluated the impact of delay in initiation of postmastectomy radiation (PMRT) in breast cancer patients treated with neo-adjuvant therapy (NAT) in a cohort of medically underserved patients with multiple barriers to timely care. We retrospectively reviewed medical records of 248 consecutively treated patients. Clinical stage was 34.4% II, 65.6% III. The median interval from surgery to PMRT was [...]

Cette étude de modélisation analyse les mécanismes d'adaptation du réseau microvasculaire tumoral à un agent anti-angiogénique

The relationship between tumor blood flow, angiogenesis, tumor hypoxia, and aerobic glycolysis

Ostergaard, Leif ; Tietze, Anna ; Nielsen, Thomas ; Drasbek, Kim R ; Mouridsen, Kim ; Jespersen, Sune N. ; Horsman, Michael R

Anti-angiogenic therapies are being pursued as means of starving tumors of their energy supply. While numerous studies show that such therapies render tumors hypoxic, just as many studies have, surprisingly, shown improved tumor oxygenation. These contradicting findings challenge both the original rationale for anti-angiogenic therapy and our understanding of the physiology of tissue oxygenation. The flow-diffusion equation, which describes the relation between blood flow and the extraction of [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels une inhibition de DNA-PKcs induit une apoptose des cellules de lymphome présentant un déficit en protéine ATM

Therapeutic Targeting of a Robust Non-Oncogene Addiction to PRKDC in ATM-Defective Tumors

Riabinska, Arina ; Daheim, Mathias ; Herter-Sprie, Grit S. ; Winkler, Johannes ; Fritz, Christian ; Hallek, Michael ; Thomas, Roman K. ; Kreuzer, Karl-Anton ; Frenzel, Lukas P. ; Monfared, Parisa ; Martins-Boucas, Jorge ; Chen, Shuhua ; Reinhardt, Hans Christian

When the integrity of the genome is threatened, cells activate a complex, kinase-based signaling network to arrest the cell cycle, initiate DNA repair, or, if the extent of damage is beyond repair capacity, induce apoptotic cell death. The ATM protein lies at the heart of this signaling network, which is collectively referred to as the DNA damage response (DDR). ATM is involved in numerous DDR-regulated cellular responses—cell cycle arrest, DNA repair, and apoptosis. Disabling mutations in the [...]

Menée in vitro et in vivo, cette étude met en évidence l'intérêt d'une stratégie basée sur l'inhibition de l'enzyme OXPHOS pour surmonter une résistance aux inhibiteurs de BRAF dans le traitement d'un mélanome métastatique

Overcoming Intrinsic Multidrug Resistance in Melanoma by Blocking the Mitochondrial Respiratory Chain of Slow-Cycling JARID1Bhigh Cells

Roesch, Alexander ; Vultur, Adina ; Bogeski, Ivan ; Wang, Huan ; Zimmermann, Katharina M ; Speicher, David ; Körbel, Christina ; Laschke, Matthias W ; Gimotty, Phyllis A ; Philipp, Stephan E ; Krause, Elmar ; Pätzold, Sylvie ; Villanueva, Jessie ; Krepler, Clemens ; Fukunaga-Kalabis, Mizuho ; Hoth, Markus ; Bastian, Boris C ; Vogt, Thomas ; Herlyn, Meenhard

Despite success with BRAFV600E inhibitors, therapeutic responses in patients with metastatic melanoma are short-lived because of the acquisition of drug resistance. We identified a mechanism of intrinsic multidrug resistance based on the survival of a tumor cell subpopulation. Treatment with various drugs, including cisplatin and vemurafenib, uniformly leads to enrichment of slow-cycling, long-term tumor-maintaining melanoma cells expressing the H3K4-demethylase JARID1B/KDM5B/PLU-1. [...]

Cet article passe en revue les travaux récents sur les mécanismes de nature immunitaire impliqués dans les cancers de l'épithélium ovarien

Immunity of human epithelial ovarian carcinoma: the paradigm of immune suppression in cancer

Lavoue, Vincent ; Thedrez, Aurelie ; Leveque, Jean ; Foucher, Fabrice ; Henno, Sebastien ; Jauffret, Vincent ; Belaud-Rotureau, Marc-Antoine ; Catros, Veronique ; Cabillic, Florian

Epithelial ovarian cancer (EOC) is a significant cause of cancer-related mortality in women, and there has been no substantial decrease in the death rates due to EOC in the last three decades. Thus, basic knowledge regarding ovarian tumor cell biology is urgently needed to allow the development of innovative treatments for EOC. Traditionally, EOC has not been considered an immunogenic tumor, but there is evidence of an immune response to EOC in patients. Clinical data demonstrate that an [...]

Menée in vitro, cette étude met en évidence le rôle joué par la surexpression de p14ARF dans la sensibilité au gefinitib de cellules d'adénocarcinomes pulmonaires

Anti-tumor impact of p14ARF on gefitinib-resistant non-small cell lung cancers

Saito, Ken ; Takigawa, Nagio ; Ohtani, Naoko ; Iioka, Hidekazu ; Tomita, Yuki ; Ueda, Ryuzo ; Fukuoka, Junya ; Kuwahara, Kazuhiko ; Ichihara, Eiki ; Kiura, Katsuyuki ; Kondo, Eisaku

Activation of the epidermal growth factor receptor (EGFR) has been observed in many malignant tumors and its constitutive signal transduction facilitates the proliferation of tumors. EGFR-tyrosine kinase inhibitors, such as gefitinib, are widely used as a molecular-targeting agent for the inactivation of EGFR signaling and show considerable therapeutic effect in non-small cell lung cancers harboring activating EGFR mutations. However, prolonged treatment inevitably produces tumors with [...]

Cet article passe en revue les travaux récents sur les fonctions du récepteur aux androgènes dans le cancer de la prostate résistant à la castration, d'une part, et sur les mécanismes de résistance à l'abiratérone et à l'enzalutamide, d'autre part

Androgen receptor functions in castration-resistant prostate cancer and mechanisms of resistance to new agents targeting the androgen axis

Yuan, X. ; Cai, C. ; Chen, S. ; Yu, Z. ; Balk, S. P.

The metabolic functions of androgen receptor (AR) in normal prostate are circumvented in prostate cancer (PCa) to drive tumor growth, and the AR also can acquire new growth-promoting functions during PCa development and progression through genetic and epigenetic mechanisms. Androgen deprivation therapy (ADT, surgical or medical castration) is the standard treatment for metastatic PCa, but patients invariably relapse despite castrate androgen levels (castration-resistant PCa, CRPC). Early [...]

Cet article passe en revue les travaux récents sur la biologie et le traitement d'un cancer de la prostate résistant à la castration

Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches

Karantanos, T. ; Corn, P. G. ; Thompson, T. C.

Prostate cancer is the second-leading cause of cancer-related mortality in men in Western societies. Androgen receptor (AR) signaling is a critical survival pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease. Although a majority of patients initially respond to ADT, most will eventually develop castrate resistance, defined as disease progression despite serum testosterone levels of [...]

Menée in vitro et in vivo, cette étude suggère l'intérêt d'une combinaison d'un inhibiteur de MEK, le selumetinib, et d'un modulateur de la signalisation Wnt/Calcium, la cyclosporine A, pour le traitement d'un cancer colorectal métastatique

Rational Combination of a MEK Inhibitor, Selumetinib, and the Wnt/Calcium Pathway Modulator, Cyclosporin A, in Preclinical Models of Colorectal Cancer

Spreafico, Anna ; Tentler, John J. ; Pitts, Todd M. ; Tan, Aik Choon ; Gregory, Mark A ; Arcaroli, John J. ; Klauck, Peter J ; McManus, Martine C ; Hansen, Ryan J. ; Kim, Jihye ; Micel, Lindsey N. ; Selby, Heather M ; Newton, Timothy P ; McPhillips, Kelly ; Gustafson, Daniel L ; DeGregori, James V ; Messersmith, Wells A. ; Winn, Robert A ; Eckhardt, S. Gail

Purpose: The MAPK pathway is a crucial regulator of cell proliferation, survival, and resistance to apoptosis. MEK inhibitors are being explored as a treatment option for patients with KRAS mutant colorectal cancer (CRC) who are not candidates for EGFR-directed therapies. Initial clinical results of MEK inhibitors have yielded limited single-agent activity in CRC, indicating that rational combination strategies are needed. Experimental Design: In this study, we performed unbiased GSEA and [...]

Menée à l'aide d'un modèle murin, cette étude évalue l'activité antitumorale d'un virus oncolytique, armé d'interleukine 12, pour le traitement d'un glioblastome

Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell model

Cheema, Tooba A. ; Wakimoto, Hiroaki ; Fecci, Peter E. ; Ning, Jianfang ; Kuroda, Toshihiko ; Jeyaretna, Deva S. ; Martuza, Robert L. ; Rabkin, Samuel D.

Glioblastoma (World Health Organization grade IV) is an aggressive adult brain tumor that is inevitably fatal despite surgery, radiation, and chemotherapy. Treatment failures are attributed to combinations of cellular heterogeneity, including a subpopulation of often-resistant cancer stem cells, aberrant vasculature, and noteworthy immune suppression. Current preclinical models and treatment strategies do not incorporate or address all these features satisfactorily. Herein, we describe a murine [...]

Mené sur 101 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I évalue la dose maximale tolérée d'un composé appelé AUY922, un inhibiteur de la protéine de choc thermique HSP90

First-in-Human Phase I Dose-Escalation Study of the HSP90 Inhibitor AUY922 in Patients with Advanced Solid Tumors

Sessa, Cristiana ; Shapiro, Geoffrey I. ; Bhalla, Kapil N. ; Britten, Carolyn ; Jacks, Karen S. ; Mita, Monica ; Papadimitrakopoulou, Vali ; Pluard, Tim ; Samuel, Thomas A. ; Akimov, Mikhail ; Quadt, Cornelia ; Fernandez-Ibarra, Cristina ; Lu, Hong ; Bailey, Stuart ; Chica, Sandra ; Banerji, Udai

Purpose: A phase I study was conducted with the primary objective of determining the maximum tolerated dose (MTD) of AUY922 in patients with advanced solid tumors. Secondary objectives included characterization of the safety, pharmacokinetic, and pharmacodynamic profiles. Patients and Methods: Patients with advanced solid tumors received 1-hour i.v. infusions of AUY922 once a week in a 28-day cycle. An adaptive Bayesian logistic regression model that employed observed dose-limiting toxicities [...]

Menée sur deux patients atteints d'un myélome ou d'un mélanome, cette étude met en évidence de graves effets cardiovasculaires indésirables, non prédits par les études précliniques, induits par une immunothérapie à base de lymphocytes T modifiés

Cardiovascular toxicity and titin cross-reactivity of affinity enhanced T cells in myeloma and melanoma

Linette, Gerald P. ; Stadtmauer, Edward A. ; Maus, Marcela V. ; Rapoport, Aaron P. ; Levine, Bruce L. ; Emery, Lyndsey ; Litzky, Leslie ; Bagg, Adam ; Carreno, Beatriz M. ; Cimino, Patrick J. ; Binder-Scholl, Gwendolyn K. ; Smethurst, Dominic P. ; Gerry, Andrew B. ; Pumphrey, Nick J. ; Bennett, Alan D. ; Brewer, Joanna E. ; Dukes, Joseph ; Harper, Jane ; Tayton-Martin, Helen K. ; Jakobsen, Bent K. ; Hassan, Namir J. ; Kalos, Michael ; June, Carl H.

An obstacle to cancer immunotherapy has been that the affinity of T cell receptors (TCRs) for antigens expressed in tumors is generally low. We initiated clinical testing of engineered T cells expressing an affinity-enhanced T cell receptor against HLA-A*01-restricted MAGE-A3. Open-labeled protocols to test the TCRs for patients with myeloma and melanoma were initiated. The first two treated patients developed cardiogenic shock and died within a few days of T cell infusion, events not predicted [...]

Cet article passe en revue les travaux récents sur les inhibiteurs de BRAF pour le traitement d'un mélanome métastatique

BRAF in Melanoma: Current strategies and future directions

Salama, April K.S. ; Flaherty, Keith T.

Selective BRAF inhibitors have now been established as a standard of care option for patients diagnosed with metastatic melanoma whose tumors carry a BRAF mutation. Their successful development represents a milestone in the treatment of this disease, and has the potential to impact therapy for other malignancies as well. The use of these agents, however, has introduced a number of critical questions regarding the optimal use and selection of patients for BRAF inhibitor therapy. This review [...]

Cet article fait le point sur les récentes avancées thérapeutiques (résection chirurgicale, radiothérapie, combinaisons de médicaments) dans le cancer du pancréas

Recent progress in pancreatic cancer

Wolfgang, Christopher L. ; Herman, Joseph M. ; Laheru, Daniel A. ; Klein, Alison P. ; Erdek, Michael A. ; Fishman, Elliot K. ; Hruban, Ralph H.

Pancreatic cancer is currently one of the deadliest of the solid malignancies. However, surgery to resect neoplasms of the pancreas is safer and less invasive than ever, novel drug combinations have been shown to improve survival, advances in radiation therapy have resulted in less toxicity, and enormous strides have been made in the understanding of the fundamental genetics of pancreatic cancer. These advances provide hope but they also increase the complexity of caring for patients. It is [...]

Menée sur 2 427 patients atteints d'un adénocarcinome de la prostate traité par curiethérapie avec ou sans radiothérapie externe (durée médiane de suivi : 78 mois), cette étude évalue, du point de vue de l'échec biochimique et en fonction de la dose biologique efficace de rayonnements, l'intérêt d'ajouter un traitement anti-androgénique au traitement initial

The relative importance of hormonal therapy and biological effective dose in optimizing prostate brachytherapy treatment outcomes

Stock, Richard G. ; Buckstein, Michael ; Liu, Jerry T. ; Stone, Nelson N.

Objectives : To compare the relative importance of radiation dose escalation vs androgen deprivation therapy (ADT) in the definitive treatment of prostate adenocarcinoma. Patients and Methods : In total, 2427 patients with prostate adenocarcinoma were treated with definitive brachytherapy or brachytherapy with external beam radiation with or without ADT. Over the 20-year period of the present study (median follow-up of 78 months), patients were treated with a range of doses that were converted [...]

A partir d'une revue systématique de la littérature publiée entre janvier 1980 et juillet 2012 (17 essais randomisés, 2 587 patients), cette méta-analyse évalue, du point de vue de la survie sans progression et de la survie globale, l'intérêt d'une chimiothérapie néoadjuvante pour traiter un adénocarcinome gastro-œsophagien non métastatique

Neoadjuvant Chemotherapy for Nonmetastatic Esophago-Gastric Adenocarcinomas : A Systematic Review and Meta-Analysis

Zhang, Chun-Dong ; Zeng, Yong-Ji ; Li, Hong-Wu ; Zhao, Zhe-Ming ; Zhang, Jia-Kui ; Dai, Dong-Qiu

Objective: A systematic review and meta-analysis was performed to investigate the efficacy of neoadjuvant chemotherapy for nonmetastatic esophago-gastric adenocarcinomas. Methods: Electronic databases were searched systematically from January 1980 to July 2012 and a total of 2,587 patients from 17 randomized controlled trials were subjected to meta-analysis. The odds ratios (ORs) for overall survival (OS) and progression-free survival (PFS) were calculated. Results: Seventeen randomized [...]