A partir des données de 3 essais prospectifs incluant 88 patients ayant reçu une chimioradiothérapie par carboplatine pour un carcinome cutané à cellules de Merkel de stade I ou II, cette étude évalue, en fonction du statut des marges de résection, l'effet d'une irradiation du volume tumoral résiduel sur le taux de récidive locorégionale à 5 ans

The Impact of Preradiation Residual Disease Volume on Time to Locoregional Failure in Cutaneous Merkel Cell Carcinoma—A TROG Substudy

Finnigan, Renee ; Hruby, George ; Wratten, Chris ; Keller, Jacqui ; Tripcony, Lee ; Dickie, Graeme ; Rischin, Danny ; Poulsen, Michael

This study evaluated the impact of margin status and gross residual disease in patients treated with chemoradiation therapy for high-risk stage I and II Merkel cell cancer (MCC). Data were pooled from 3 prospective trials in which patients were treated with 50 Gy in 25 fractions to the primary lesion and draining lymph nodes and 2 schedules of carboplatin based chemotherapy. Time to locoregional failure was analyzed according to the burden of disease at the time of radiation therapy, comparing [...]

Menée sur 338 patients atteints d'un cancer du poumon non à petites cellules de stade I, cette étude rétrospective compare, du point de vue du contrôle de la maladie, de la survie spécifique et de la survie globale, l'efficacité et les facteurs clinicopathologiques d'échec d'une résection lobaire (lobectomie ou pneumonectomie) et d'une radiothérapie corporelle stéréotaxique

Patterns of Failure after Stereotactic Body Radiation Therapy or Lobar Resection for Clinical Stage I Non-Small-Cell Lung Cancer

Robinson, Cliff G. ; DeWees, Todd A. ; El Naqa, Issam M. ; Creach, Kimberly M. ; Olsen, Jeffrey R. ; Crabtree, Traves D. ; Meyers, Bryan F. ; Puri, Varun ; Bell, Jennifer M. ; Parikh, Parag J. ; Bradley, Jeffrey D.

Introduction: The purpose of this study was to compare patterns of failure between lobar resection (lobectomy or pneumonectomy) and stereotactic body radiation therapy (SBRT) for patients with clinical stage I non-small-cell lung cancer (NSCLC). Methods: From January 2004 to January 2008, 338 patients underwent definitive treatment for pathologically confirmed clinical stage I NSCLC with lobar resection (n = 260) or SBRT (n = 78). Most surgical patients underwent lobectomy (n = 237). SBRT [...]

Menée sur 498 patients adultes ayant survécu à un cancer pédiatrique, cette étude montre, à l'aide de mesures par échocardiographie doppler, une augmentation de la vitesse du flux au travers de la valve tricuspide chez certains patients ayant reçu une radiothérapie dirigée vers la poitrine

Increased Tricuspid Regurgitant Jet Velocity by Doppler Echocardiography in Adult Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study

Armstrong, Gregory T. ; Joshi, Vijaya M. ; Zhu, Liang ; Srivastava, Deokumar ; Zhang, Nan ; Ness, Kirsten K. ; Stokes, Dennis C. ; Krasin, Matthew T. ; Fowler, James A. ; Robison, Leslie L. ; Hudson, Melissa M. ; Green, Daniel M.

Purpose To determine the prevalence of pulmonary hypertension, a late effect of cancer therapy not previously identified in aging survivors of childhood cancer, and associations with chest-directed radiation therapy (RT) and measures of current cardiac function, lung function, and exercise capacity.Patients and Methods Cross-sectional evaluation of 498 survivors at a median age of 38.0 years (range, 20.0 to 59.0 years) and a median of 27.3 years (range, 12.2 to 46.0 years) from primary cancer [...]

Mené sur 16 patients atteints d'un cancer de la prostate traité par radiothérapie avec modulation d'intensité, cet essai français de phase 2 évalue, en fonction de la dose administrée, l'efficacité d'une injection d'acide hyaluronique entre le rectum et la prostate pour réduire l'exposition de la paroi rectale aux rayonnements ionisants

Prostate Hypofractionated Radiation Therapy: Injection of Hyaluronic Acid to Better Preserve The Rectal Wall

Chapet, Olivier ; Udrescu, Corina ; Devonec, Marian ; Tanguy, Ronan ; Sotton, Marie-Pierre ; Enachescu, Ciprian ; Colombel, Marc ; Azria, David ; Jalade, Patrice ; Ruffion, Alain

The aim of this study was to evaluate the contribution of an injection of hyaluronic acid (HA) between the rectum and the prostate for reducing the dose to the rectal wall in a hypofractionated irradiation for prostate cancer. In a phase 2 study, 10 cc of HA was injected between the rectum and prostate. For 16 patients, the same intensity modulated radiation therapy plan (62 Gy in 20 fractions) was optimized on 2 computed tomography scans: CT1 (before injection) and CT2 (after injection). [...]

Menée sur 160 patientes atteintes d'un cancer du sein de stade précoce traité entre 2004 et 2010 (durée médiane de suivi : 3,5 ans), cette étude évalue, du point de vue de la survie sans récidive locale, de la survie sans maladie et de la survie globale à 5 ans, l'efficacité d'un traitement de 3 semaines combinant de manière concomitante une radiothérapie accélérée du sein entier et une dose de rayonnement additionnel du lit tumoral

Early-Stage Breast Cancer Treated With 3-Week Accelerated Whole-Breast Radiation Therapy and Concomitant Boost

Chadha, Manjeet ; Woode, Rudolph ; Sillanpaa, Jussi ; Lucido, David ; Boolbol, Susan K. ; Kirstein, Laurie ; Osborne, Michael P. ; Feldman, Sheldon ; Harrison, Louis B.

To report early outcomes of accelerated whole-breast radiation therapy with concomitant boost. This is a prospective, institutional review board-approved study. Eligibility included stage TisN0, T1N0, and T2N0 breast cancer. Patients receiving adjuvant chemotherapy were ineligible. The whole breast received 40.5 Gy in 2.7-Gy fractions with a concomitant lumpectomy boost of 4.5 Gy in 0.3-Gy fractions. Total dose to the lumpectomy site was 45 Gy in 15 fractions over 19 days. Between October 2004 [...]

A partir de données administratives portant sur 278 patients atteints d'un neuroblastome de stade 4 (âge au diagnostic : 18 mois ou plus), cet essai prospectif allemand identifie les types d'intervention chirurgicale réalisée avant ou après une chimiothérapie, évalue leur taux d'utilisation et analyse l'impact du traitement par chirurgie d'une tumeur primitive sur le contrôle de la maladie et la survie des patients

Role of Surgery in the Treatment of Patients With Stage 4 Neuroblastoma Age 18 Months or Older at Diagnosis

Simon, Thorsten ; Häberle, Beate ; Hero, Barbara ; von Schweinitz, Dietrich ; Berthold, Frank

Purpose Although intensive multimodal treatment has improved the prognosis of patients with metastatic neuroblastoma, the impact of primary tumor resection on outcome is a matter of medical debate.Patients and Methods Patients from the German prospective clinical trial NB97 with stage 4 neuroblastoma and age 18 months or older at diagnosis were included. Operation notes and imaging reports were reviewed by two independent experienced physicians. Finally, the extent of tumor resections was [...]

A partir d'une revue systématique de la littérature publiée jusqu'en juillet 2012 (1 essai, 8 études prospectives, 4 études rétrospectives ; nombre total de cas : 962), cette méta-analyse compare, du point de vue de données opératoires et périopératoires, l'efficacité de deux techniques de cystectomie radicale, l'une assistée par robot et l'autre par voie ouverte

Systematic review and meta-analysis of comparative studies reporting early outcomes after robot-assisted radical cystectomy versus open radical cystectomy

Li, Kaiwen ; Lin, Tianxin ; Fan, Xinxiang ; Xu, Kewei ; Bi, Liangkuan ; Duan, Yu ; Zhou, Yu ; Yu, Min ; Li, Jielin ; Huang, Jian

Background: Robot-assisted radical cystectomy (RARC) is increasingly being used in the management of bladder cancer. Studies comparing RARC and open radical cystectomy (ORC) have reported conflicting results. We conducted a systematic review and meta-analysis of the literature on the efficacy and advantages of RARC compared with ORC. Methods: An electronic database search of PubMed, Scopus, and the Cochrane Library was performed up to July 8, 2012. This systematic review and meta-analysis was [...]

Menée sur 300 patients atteints d'un carcinome rhinopharyngé traité par radiothérapie avec modulation d'intensité (durée médiane de suivi : 47,1 mois), cette étude prospective évalue, du point de vue du contrôle de la maladie, de la survie sans métastases distantes et de la survie globale à 4 ans, l'efficacité et la toxicité d'une radiothérapie avec modulation d'intensité

Definitive intensity-modulated radiation therapy for nasopharyngeal carcinoma: long-term outcome of a multicenter prospective study

Wang, Rensheng ; Wu, Fang ; Lu, Heming ; Wei, Bo ; Feng, Guosheng ; Li, Guisheng ; Liu, Meilian ; Yan, Haolin ; Zhu, Jinxian ; Zhang, Yong ; Hu, Kai

Purpose :To evaluate long-term outcome in nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy. Methods : Between January 2006 and August 2008, 300 patients with histologically proven NPC were enrolled in this multicenter prospective study. All patients received definitive IMRT. Cisplatin-based concurrent chemotherapy was given to patients with stages III-IVb disease. Results :Median follow-up time was 47.1 months (range 11–68 months). Median survival time was not [...]

Mené sur 47 patients atteints d'une tumeur solide de stade avancé, cet essai de phase Ib évalue l'ajout d'afatinib à un traitement combinant cisplatine et paclitaxel ou cisplatine et 5-fluorouracile

A phase Ib, open-label study to assess the safety of continuous oral treatment with afatinib in combination with two chemotherapy regimens: cisplatin plus paclitaxel and cisplatin plus 5-fluorouracil, in patients with advanced solid tumors

Vermorken, J. B. ; Rottey, S. ; Ehrnrooth, E. ; Pelling, K. ; Lahogue, A. ; Wind, S. ; Machiels, J.-P.

Background In this phase Ib, dose-escalation study, the oral irreversible ErbB family blocker afatinib (BIBW 2992) was combined with cisplatin (Cadila Healthcare Ltd, Ahmedabad, India) 50 or 75 mg/m2/paclitaxel (Bristol-Myers Squibb Pharmaceuticals Ltd, New York, USA) (Taxol)175 mg/m2 (regimen A) or cisplatin 75–100 mg/m2/5-fluorouracil 750–1000 mg/m2 (regimen B) in patients with advanced solid tumors. Patients and methods The primary objective was to assess dose-limiting toxicities (DLTs) [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un composé appelé GDC-0068, un inhibiteur sélectif de la signalisation Akt

Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models

Lin, Jie ; Sampath, Deepak ; Nannini, Michelle A. ; Lee, Brian B ; Degtyarev, Michael ; Oeh, Jason ; Savage, Heidi ; Guan, Zhengyu ; Hong, Rebecca ; Kassees, Robert ; Lee, Leslie B. ; Risom, Tyler ; Gross, Stefan D ; Liederer, Bianca ; Koeppen, Hartmut ; Skelton, Nicholas ; Wallin, Jeffrey J ; Belvin, Marcia ; Punnoose, Elizabeth A ; Friedman, Lori S. ; Lin, Kui

Purpose: We describe the preclinical pharmacology and anti-tumor activity of GDC-0068, a novel highly selective ATP-competitive pan-Akt inhibitor currently in clinical trials for the treatment of human cancers. Experimental Design: The effect of GDC-0068 on Akt signaling was characterized using specific biomarkers of the Akt pathway, and response to GDC-0068 was evaluated in human cancer cell lines and xenograft models with various genetic backgrounds, either as a single agent or in combination [...]

Cet article passe en revue les perspectives offertes par le ciblage de la voie de signalisation LKB1/AMPK/mTOR pour le traitement des cancers

Targeting LKB1/AMPK/mTOR signaling in cancer

Korsse, S. E. ; Peppelenbosch, M. P. ; Veelen, W. van

The serine/threonine kinase LKB1 is a master kinase involved in cellular responses such as energy metabolism, cell polarity and cell growth. LKB1 regulates these crucial cellular responses mainly via AMPK/mTOR signaling. Germ-line mutations in LKB1 are associated with the predisposition of the Peutz-Jeghers Syndrome in which patients develop gastrointestinal hamartomas and have an enormously increased risk for developing gastrointestinal, breast and gynecological cancers. In addition, somatic [...]

Menée à l'aide de modèles murins, cette étude met en évidence l'élimination de cellules tumorales CD133+, considérées comme des cellules initiatrices de tumeurs, par deux virus oncolytiques, MV-141.7 et MV-AC133

Specific Elimination of CD133+ Tumor Cells with Targeted Oncolytic Measles Virus

Bach, Patricia ; Abel, Tobias ; Hoffmann, Christopher ; Gal, Zoltan ; Braun, Gundula ; Voelker, Iris ; Ball, Claudia R. ; Johnston, Ian C.D. ; Lauer, Ulrich M. ; Herold-Mende, Christel ; Mühlebach, Michael D. ; Glimm, Hanno ; Buchholz, Christian J.

Tumor-initiating cells (TIC) are critical yet evasive targets for the development of more effective antitumoral strategies. The cell surface marker CD133 is frequently used to identify TICs of various tumor entities, including hepatocellular cancer and glioblastoma. Here, we describe oncolytic measles viruses (MV) retargeted to CD133. The viruses, termed MV-141.7 and MV-AC133, infected and selectively lysed CD133+ tumor cells. Both viruses exerted strong antitumoral effects on human [...]

Menée in vivo et sur 3 patients atteints d'une leucémie lymphocytaire chronique réfractaire, cette étude évalue l'activité antitumorale d'un composé appelé ABT-199, un inhibiteur sélectif de BCL-2 dérivé du navitoclax pour éviter ses effets indésirables sur les thrombocytes

ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets

Souers, Andrew J. ; Leverson, Joel D. ; Boghaert, Erwin R. ; Ackler, Scott L. ; Catron, Nathaniel D. ; Chen, Jun ; Dayton, Brian D. ; Ding, Hong ; Enschede, Sari H. ; Fairbrother, Wayne J. ; Huang, David C. S. ; Hymowitz, Sarah G. ; Jin, Sha ; Khaw, Seong Lin ; Kovar, Peter J. ; Lam, Lloyd T. ; Lee, Jackie ; Maecker, Heather L. ; Marsh, Kennan C. ; Mason, Kylie D. ; Mitten, Michael J. ; Nimmer, Paul M. ; Oleksijew, Anatol ; Park, Chang H. ; Park, Cheol-Min ; Phillips, Darren C. ; Roberts, Andrew W. ; Sampath, Deepak ; Seymour, John F. ; Smith, Morey L. ; Sullivan, Gerard M. ; Tahir, Stephen K. ; Tse, Chris ; Wendt, Michael D. ; Xiao, Yu ; Xue, John C. ; Zhang, Haichao ; Humerickhouse, Rod A. ; Rosenberg, Saul H. ; Elmore, Steven W.

Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2–like 1 (BCL-XL), which has shown clinical efficacy in some [...]

Menée sur des lignées cellulaires et des échantillons tumoraux prélevés sur 4 patients atteints d'un mélanome métastatique présentant la mutation V600E du gène BRAF, cette étude met en évidence le rôle joué par la perte du gène NF1 dans l'apparition d'une résistance à un traitement par inhibiteur de BRAF tel que le vemurafenib ou le dabrafenib

A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition

Whittaker, Steven R. ; Theurillat, Jean-Philippe ; Van Allen, Eliezer ; Wagle, Nikhil ; Hsiao, Jessica ; Cowley, Glenn S. ; Schadendorf, Dirk ; Root, David E ; Garraway, Levi A.

RAF inhibitors such as vemurafenib and dabrafenib block B-RAF-mediated cell proliferation and achieve meaningful clinical benefit in the vast majority of patients with B-RAFV600E-mutant melanoma. However, some patients do not respond to this regimen, and nearly all progress to therapeutic resistance. We employed a pooled RNA interference screen targeting >16,500 genes to discover loss of function events that could drive resistance to RAF inhibition. The highest-ranking gene was NF1, which [...]

Menée in vitro, cette étude présente une méthode permettant, à l'aide de cellules souches pluripotentes induites, d'engendrer des lymphocytes T spécifiques d'un antigène tumoral, l'épitope MART1 associé au mélanome

Regeneration of Human Tumor Antigen-Specific T Cells from iPSCs Derived from Mature CD8+ T Cells

Vizcardo, Raul ; Masuda, Kyoko ; Yamada, Daisuke ; Ikawa, Tomokatsu ; Shimizu, Kanako ; Fujii, Shin-ichiro ; Koseki, Haruhiko ; Kawamoto, Hiroshi

Antigen-specific T cells represent a potential therapeutic avenue for a variety of conditions, but current approaches for generating such cells for therapeutic purposes are limited. In this study, we established iPSCs from mature cytotoxic T cells specific for the melanoma epitope MART-1. When cocultured with OP9/DLL1 cells, these iPSCs efficiently generated TCR²+CD4+CD8+ double positive (DP) cells expressing a T cell receptor (TCR) specific for the MART-1 epitope. Stimulation of these DP cells [...]

Menée in vitro et in vivo, cette étude évalue les effets d'une ubiquitine-ligase, génétiquement modifiée pour dégrader la protéine KRAS, sur la prolifération de cellules tumorales d'un adénocarcinome canalaire du pancréas

Targeted Degradation of KRAS by an Engineered Ubiquitin Ligase Suppresses Pancreatic Cancer Cell Growth in vitro and in vivo

Ma, Yi-Hui ; Gu, Yu-Mei ; Zhang, Qiang ; Han, Yong-Qing ; Yu, Shuang-Ni ; Lu, Zhao-Hui ; Chen, Jie

KRAS is an attractive pancreatic ductal adenocarcinoma (PDAC) therapeutic target. E3 ligase is thought to be the component of the ubiquitin conjugation system that is directly responsible for substrate recognition. In this study, an engineered E3 ubiquitin ligase (RC-U) was generated to target the KRAS oncoprotein for ubiquitination and degradation. The engineered E3 ubiquitin ligases (RC-U) were constructed (pRC-U and lentivirus expressing RC-U). After transfecting the pRC-U plasmid into human [...]

Menée à l'aide de xénogreffes de carcinome basocellulaire, cette étude met en évidence l'existence d'une petite population de cellules initiatrices de tumeurs (CD200+ et CD45-) permettant de rendre compte de l'apparition d'une résistance aux traitements à l'aide d'antagonistes du récepteur Smoothened

CD200-expressing human basal cell carcinoma cells initiate tumor growth

Colmont, Chantal S. ; BenKetah, Antisar ; Reed, Simon H. ; Hawk, Nga V. ; Telford, William G. ; Ohyama, Manabu ; Udey, Mark C. ; Yee, Carole L. ; Vogel, Jonathan C. ; Patel, Girish K.

Smoothened antagonists directly target the genetic basis of human basal cell carcinoma (BCC), the most common of all cancers. These drugs inhibit BCC growth, but they are not curative. Although BCC cells are monomorphic, immunofluorescence microscopy reveals a complex hierarchical pattern of growth with inward differentiation along hair follicle lineages. Most BCC cells express the transcription factor KLF4 and are committed to terminal differentiation. A small CD200+ CD45− BCC subpopulation [...]

Menée in vitro et à l'aide de modèles murins, cette étude montre que l'itraconazole et l'anhydride arsénieux, seuls ou en combinaison, peuvent surmonter une résistance thérapeutique liée à la mutation SMOD477G dans le traitement d'un médulloblastome

Itraconazole and Arsenic Trioxide Inhibit Hedgehog Pathway Activation and Tumor Growth Associated with Acquired Resistance to Smoothened Antagonists

Kim, James ; Aftab, Blake T ; Tang, Jean Y ; Kim, Daniel ; Lee, Alex H ; Rezaee, Melika ; Kim, Jynho ; Chen, Baozhi ; King, Emily M ; Borodovsky, Alexandra ; Riggins, Gregory J ; Epstein, Ervin H ; Beachy, Philip A ; Rudin, Charles M

Recognition of the multiple roles of Hedgehog signaling in cancer has prompted intensive efforts to develop targeted pathway inhibitors. Leading inhibitors in clinical development act by binding to a common site within Smoothened, a critical pathway component. Acquired Smoothened mutations, including SMOD477G, confer resistance to these inhibitors. Here, we report that itraconazole and arsenic trioxide, two agents in clinical use that inhibit Hedgehog signaling by mechanisms distinct from that [...]

Cete étude de cristallographie permet de rendre compte du mécanisme d’action des agents anticancéreux qualifiés de "stabilisateurs des microtubules" (zampanolide, épothilone)

Molecular Mechanism of Action of Microtubule-Stabilizing Anticancer Agents

Prota, Andrea E. ; Bargsten, Katja ; Zurwerra, Didier ; Field, Jessica J. ; Díaz, José Fernando ; Altmann, Karl-Heinz ; Steinmetz, Michel O.

Microtubule-stabilizing agents (MSAs) are efficacious chemotherapeutic drugs widely used for the treatment of cancer. Despite the importance of MSAs for medical applications and basic research, their molecular mechanisms of action on tubulin and microtubules remain elusive. Here, we determined high-resolution crystal structures of αβ-tubulin in complex with two unrelated MSAs, zampanolide and epothilone A. Both compounds were bound to the taxane-pocket of β-tubulin and used their respective [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude évalue l'intérêt du pazopanib en combinaison avec le paclitaxel pour le traitement d’un cancer anaplasique de la thyroïde

Pazopanib Enhances Paclitaxel-Induced Mitotic Catastrophe in Anaplastic Thyroid Cancer

Isham, Crescent R. ; Bossou, Ayoko R. ; Negron, Vivian ; Fisher, Kelly E. ; Kumar, Rakesh ; Marlow, Laura ; Lingle, Wilma L. ; Smallridge, Robert C. ; Sherman, Eric J. ; Suman, Vera J. ; Copland, John A. ; Bible, Keith C.

Anaplastic thyroid cancer (ATC) has perhaps the worst prognosis of any cancer, with a median survival of only about 5 months regardless of stage. Pazopanib monotherapy has promising clinical activity in differentiated thyroid cancers (generally attributed to vascular endothelial growth factor receptor inhibition), yet has less effective single-agent activity in ATC. We now report that combining pazopanib with microtubule inhibitors such as paclitaxel produced heightened and synergistic [...]

Mené sur 21 patients atteints d'un carcinome hépatocellulaire et d'une cirrhose hépatique, cet essai de phase Ib évalue le tivantinib, un inhibiteur du facteur de transition épithélio-mésenchymateuse MET

A Phase-1b study of tivantinib (ARQ 197) in adult patients with hepatocellular carcinoma and cirrhosis

Santoro, A. ; Simonelli, M. ; Rodriguez-Lope, C. ; Zucali, P. ; Camacho, L. H. ; Granito, A. ; Senzer, N. ; Rimassa, L. ; Abbadessa, G. ; Schwartz, B. ; Lamar, M. ; Savage, R. E. ; Bruix, J.

Background: The mesenchymal-epithelial transition factor (MET) receptor is dysregulated in hepatocellular carcinoma (HCC), and tivantinib (ARQ 197) is an oral, selective, MET inhibitor. Methods: This Phase-1b study assessed tivantinib safety as primary objective in patients with previously treated HCC and Child-Pugh A or B liver cirrhosis. Patients received oral tivantinib 360 mg twice daily until disease progression or unacceptable toxicity. Results: Among 21 HCC patients, common drug-related [...]

Mené sur 227 patients atteints d'un lymphome B extranodal de la zone marginale, cet essai randomisé évalue, du point de vue du taux de réponse globale et de la survie sans événement, l'ajout de rituximab au chlorambucil (durée médiane de suivi : 62 mois)

Addition of Rituximab to Chlorambucil Produces Superior Event-Free Survival in the Treatment of Patients With Extranodal Marginal-Zone B-Cell Lymphoma: 5-Year Analysis of the IELSG-19 Randomized Study

Zucca, Emanuele ; Conconi, Annarita ; Laszlo, Daniele ; Lopez-Guillermo, Armando ; Bouabdallah, Reda ; Coiffier, Bertrand ; Sebban, Catherine ; Jardin, Fabrice ; Vitolo, Umberto ; Morschhauser, Franck ; Pileri, Stefano A. ; Copie-Bergman, Christiane ; Campo, Elias ; Jack, Andrew ; Floriani, Irene ; Johnson, Peter ; Martelli, Maurizio ; Cavalli, Franco ; Martinelli, Giovanni ; Thieblemont, Catherine

Purpose Apart from localized gastric disease, there is no consensus on standard initial treatment of mucosa-associated lymphoid tissue lymphoma. The IELSG-19 study (Randomized Trial of Chlorambucil Versus Chlorambucil Plus Rituximab Versus Rituximab in MALT Lymphoma) was launched to compare chlorambucil alone versus chlorambucil plus rituximab in patients not previously given systemic anticancer therapy. Patients and Methods Patients not responding to or not suitable for local therapy were [...]

Mené sur 118 patients atteints d'un lymphome non hodgkinien à cellules B CD20+/CD22+ récidivant ou réfractaire, cet essai de phase I/II évalue la dose maximale tolérée, la toxicité et, du point de vue de la survie sans progression, l'efficacité d'un traitement combinant le rituximab et un conjugué anticorps-médicament, l'inotuzumab ozogamicin

Safety and Clinical Activity of a Combination Therapy Comprising Two Antibody-Based Targeting Agents for the Treatment of Non-Hodgkin Lymphoma: Results of a Phase I/II Study Evaluating the Immunoconjugate Inotuzumab Ozogamicin With Rituximab

Fayad, Luis ; Offner, Fritz ; Smith, Mitchell R. ; Verhoef, Gregor ; Johnson, Peter ; Kaufman, Jonathan L. ; Rohatiner, Ama ; Advani, Anjali ; Foran, James ; Hess, Georg ; Coiffier, Bertrand ; Czuczman, Myron ; Giné, Eva ; Durrant, Simon ; Kneissl, Michelle ; Luu, Kenneth T. ; Hua, Steven Y. ; Boni, Joseph ; Vandendries, Erik ; Dang, Nam H.

Purpose Inotuzumab ozogamicin (INO) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. We performed a phase I/II study to determine the maximum-tolerated dose (MTD), safety, efficacy, and pharmacokinetics of INO plus rituximab (R-INO) for treatment of relapsed/refractory CD20+/CD22+ B-cell non-Hodgkin lymphoma (NHL). Patients and Methods A dose-escalation phase to determine the MTD of R-INO was followed by [...]

Mené sur 655 patients atteints d'un mélanome non résécable de stade IIIc ou IV, cet essai de phase III évalue, du point de vue de la survie globale, le tremelimumab en traitement de première ligne

Phase III Randomized Clinical Trial Comparing Tremelimumab With Standard-of-Care Chemotherapy in Patients With Advanced Melanoma

Ribas, Antoni ; Kefford, Richard ; Marshall, Margaret A. ; Punt, Cornelis J.A. ; Haanen, John B. ; Marmol, Maribel ; Garbe, Claus ; Gogas, Helen ; Schachter, Jacob ; Linette, Gerald ; Lorigan, Paul ; Kendra, Kari L. ; Maio, Michele ; Trefzer, Uwe ; Smylie, Michael ; McArthur, Grant A. ; Dréno, Brigitte ; Nathan, Paul D. ; Mackiewicz, Jacek ; Kirkwood, John M. ; Gomez-Navarro, Jesus ; Huang, Bo ; Pavlov, Dmitri ; Hauschild, Axel

Purpose In phase I/II trials, the cytotoxic T lymphocyte–associated antigen-4–blocking monoclonal antibody tremelimumab induced durable responses in a subset of patients with advanced melanoma. This phase III study evaluated overall survival (OS) and other safety and efficacy end points in patients with advanced melanoma treated with tremelimumab or standard-of-care chemotherapy. Patients and Methods Patients with treatment-naive, unresectable stage IIIc or IV melanoma were randomly assigned at [...]

Cet article passe en revue les travaux récents sur les traitements d'un cancer avancé de la prostate, en particulier pour les patients d'âge supérieur à 75 ans

New treatment developments applied to elderly patients with advanced prostate cancer

Mukherji, Deborah ; Pezaro, Carmel J. ; Shamseddine, Ali ; de Bono, Johann S.

Prostate cancer is a common disease amongst elderly men. Compared with younger patients, men over the age of 75 are more likely to present with advanced disease and have a greater risk of death from prostate cancer despite higher death rates from competing causes. Treatment options for advanced prostate cancer have improved considerably in the last two years. The immunotherapy sipuleucel-T, the cytotoxic cabazitaxel, the androgen biosynthesis inhibitor abiraterone acetate, the radioisotope [...]

Mené sur 2 887 patientes atteintes d'un cancer du sein avec envahissement ganglionnaire (durée médiane de suivi : 8 ans), cet essai compare, du point de vue de la survie globale et de la survie sans progression, deux protocoles combinant, en concomitant ou en séquentiel, le docétaxel et la doxorubicine

Overall survival benefit for sequential doxorubicin–docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer—8-year results of the Breast International Group 02-98 phase III trial

Oakman, C. ; Francis, P. A. ; Crown, J. ; Quinaux, E. ; Buyse, M. ; de Azambuja, E. ; Margeli Vila, M. ; Andersson, M. ; Nordenskjöld, B. ; Jakesz, R. ; Thürlimann, B. ; Gutiérrez, J. ; Harvey, V. ; Punzalan, L. ; Dell'Orto, P. ; Larsimont, D. ; Steinberg, I. ; Gelber, R. D. ; Piccart-Gebhart, M. ; Viale, G. ; Di Leo, A.

Background In women with node-positive breast cancer, the Breast International Group (BIG) 02-98 tested the incorporation of docetaxel (Taxotere) into doxorubicin (Adriamycin)-based chemotherapy, and compared sequential and concurrent docetaxel. At 5 years, there was a trend for improved disease-free survival (DFS) with docetaxel. We present results at 8-year median follow-up and exploratory analyses within biologically defined subtypes. Methods Patients were randomly assigned to one of four [...]

Menée sur 754 patients atteints de lymphome hodgkinien et ayant reçu un traitement combinant une chimiothérapie et une radiothérapie entre 1974 et 2003 (durée de suivi supérieure à 5 ans), cette étude évalue, en fonction du type de traitement, le risque de leucémie secondaire

Risk of Therapy-Related Secondary Leukemia in Hodgkin Lymphoma: The Stanford University Experience Over Three Generations of Clinical Trials

Koontz, Michael Zach ; Horning, Sandra J. ; Balise, Raymond ; Greenberg, Peter L. ; Rosenberg, Saul A. ; Hoppe, Richard T. ; Advani, Ranjana H.

Purpose To assess therapy-related acute myeloid leukemia/myelodysplastic syndrome (t-AML/MDS) risk in patients treated for Hodgkin lymphoma (HL) on successive generations of Stanford clinical trials.Patients and Methods Patients with HL treated at Stanford with at least 5 years of follow-up after completing therapy were identified from our database. Records were reviewed for outcome and development of t-AML/MDS.Results Seven hundred fifty-four patients treated from 1974 to 2003 were identified. [...]

Menée in vitro et sur un modèle murin, cette étude montre que l'administration de thrombopoïétine augmente l'efficacité de la protéine kinase dépendante de l'ADN, une enzyme impliquée dans la réparation de l'ADN, et réduit ainsi le risque de mutagenèse des cellules souches hématopoïétiques et des cellules progénitrices après une radiothérapie

Thrombopoietin-Increased DNA-PK-Dependent DNA Repair Limits Hematopoietic Stem and Progenitor Cell Mutagenesis in Response to DNA Damage

de Laval, Bérengère ; Pawlikowska, Patrycja ; Petit-Cocault, Laurence ; Bilhou-Nabera, Chrystèle ; Aubin-Houzelstein, Geneviève ; Souyri, Michèle ; Pouzoulet, Frédéric ; Gaudry, Murielle ; Porteu, Françoise

DNA double-strand breaks (DSBs) represent a serious threat for hematopoietic stem cells (HSCs). How cytokines and environmental signals integrate the DNA damage response and contribute to HSC-intrinsic DNA repair processes remains unknown. Thrombopoietin (TPO) and its receptor, Mpl, are critical factors supporting HSC self-renewal and expansion. Here, we uncover an unknown function for TPO-Mpl in the regulation of DNA damage response. We show that DNA repair following ³-irradiation (³-IR) or [...]

Cet article présente la mise à jour 2013 des recommandations "SPIRIT" pour la rédaction de protocoles d'essais cliniques

SPIRIT 2013: new guidance for content of clinical trial protocols

Chan, An-Wen ; Tetzlaff, Jennifer M. ; Altman, Douglas G. ; Dickersin, Kay ; Moher, David

The protocol is an important document that details the background, methods, ethical considerations, and administration of a clinical trial. The information contained in the protocol is useful for several groups. For those involved in the trial, the protocol provides the information needed for the study to be implemented consistently across collaborators in a way that mirrors the intentions of the principal investigators. For external groups who review the trial, such as research ethics [...]