Menée in vitro et à l'aide de xénogreffes de tumeur stromale gastro-intestinale, cette étude évalue les effets antitumoraux d'une photothérapie dynamique utilisant un nouvel agent photosensibilisant combinant une chlorine et un glucose

Antitumor effects in gastrointestinal stromal tumors using photodynamic therapy with a novel glucose-conjugated chlorin

Tanaka, Mamoru ; Kataoka, Hiromi ; Yano, Shigenobu ; Ohi, Hiromi ; Moriwaki, Kazuhiro ; Akashi, Haruo ; Taguchi, Takahiro ; Hayashi, Noriyuki ; Hamano, Shingo ; Mori, Yoshinori ; Kubota, Eiji ; Tanida, Satoshi ; Joh, Takashi

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Except for surgical resection, no effective treatment strategies have been established. Photodynamic therapy (PDT) consists of intravenous administration of a photosensitizer, activated by a specific wavelength of light, which produces reactive oxygen species that directly kill tumor cells. We analyzed the efficacy of PDT using a newly developed photosensitizer, 5, 10, 15, 20-tetrakis [...]

Mené sur 65 patients atteints d'un adénocarcinome localement avancé de la partie distale de l'œsophage traité entre 2009 et 2011 (durée médiane de suivi : 26,3 mois), cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse pathologique complète, et la toxicité d'un traitement par docétaxel-cisplatine-panitumumab et radiothérapie avant une intervention chirurgicale

Phase II Study of Neoadjuvant Therapy with Docetaxel, Cisplatin, Panitumumab Plus Radiation Therapy Followed by Surgery in Patients with Locally Advanced Adenocarcinoma of the Distal Esophagus (ACOSOG Z4051)

Lockhart, A. C. ; Reed, C. E. ; Decker, P. A. ; Meyers, B. F. ; Ferguson, M. K. ; Oeltjen, A. R. ; Putnam, J. B. ; Cassivi, S. D. ; Montero, A. J. ; Schefter, T.E. ; American College of Surgeons Oncology Group

Purpose : Preoperative chemoradiotherapy (CRT) improves outcomes in patients with locally advanced but resectable adenocarcinoma of the esophagus. ACOSOG Z4051 evaluated CRT with docetaxel, cisplatin, and panitumumab (DCP) in this patient group with a primary endpoint of a pathologic complete response (pCR)≥35%. Patients and Methods : From 01/15/09 to 07/22/11, 70 patients with locally advanced but resectable distal esophageal adenocarcinoma were enrolled. Patients received docetaxel (40 [...]

Menée à partir des données des registres des cancers et de la base Medicare portant sur 13 434 patients atteints d'un cancer de la prostate traité entre 2004 et 2009, cette étude rétrospective compare, du point de vue de la qualité des marges de résection, du contrôle de la maladie et de l'utilisation additionnelle d'une radiothérapie ou d'un traitement anti-androgénique, l'efficacité d'une prostatectomie radicale assistée par robot et d'une prostatectomie radicale par voie ouverte

Comparative Effectiveness of Robot-assisted Versus Open Radical Prostatectomy Cancer Control

Jim C. Hu a , ; Giorgio Gandaglia b , ; Pierre I. Karakiewicz b , ; Paul L. Nguyen c , ; Quoc-Dien Trinh d , ; Ya-Chen Tina Shih e , ; Firas Abdollah b f , ; Karim Chamie a , ; Jonathan L. Wright g , ; Patricia A. Ganz h ; Maxine Sun b

Background : Robot-assisted radical prostatectomy (RARP) remains controversial, and no improvement in cancer control outcomes has been demonstrated over open radical prostatectomy (ORP). Objective : To examine population-based, comparative effectiveness of RARP versus ORP surgical margin status and use of additional cancer therapy. Design, setting, and participants : This was a retrospective observational study of 5556 RARP and 7878 ORP cases from 2004 to 2009 from Surveillance Epidemiology and [...]

Menée à partir des données des registres américains des cancers et de la base Medicare portant sur 42 483 patients atteints d'un cancer de la prostate et traités ou sous surveillance médicale entre 2001 et 2007, cette étude montre que la radiothérapie avec modulation d'intensité améliore la survie uniquement chez les patients à haut risque de récidive

Intensity-Modulated Radiation Therapy Leads to Survival Benefit Only in Patients with High-Risk Prostate Cancer: a Population-Based Study

Gandaglia, G. ; Karakiewicz, P.I. ; Briganti, A. ; Trinh, Q. ; Schiffmann, J. ; Tian, Z. ; Kim, S.P. ; Nguyen, P.L. ; Graefen, M. ; Montorsi, F. ; Sun, M. ; Abdollah, F.

Background : During the last years, there has been a rapid adoption of intensity-modulated radiation therapy (IMRT) in patients with prostate cancer (PCa), despite the lack of randomized trials evaluating its effectiveness. The aim of our study was to evaluate the survival benefit associated with IMRT in patients with PCa. Patients and Methods : Overall, 42,483 patients with PCa treated with IMRT or initial observation between 2001 and 2007 within the Surveillance, Epidemiology, and End Results [...]

Menée à partir des données de registres médicaux portant sur 65 patients présentant une masse rénale totalement endophytique traitée entre 2006 et 2012 (âge moyen : 56 ans), cette étude évalue l'efficacité, du point de vue de données péri-opératoires, du taux de marges positives et de la conservation des fonctions rénales, et la sécurité d'une néphrectomie partielle assistée par robot

Robot-assisted partial nephrectomy (RAPN) for completely endophytic renal masses: a single institution experience

Autorino, Riccardo ; Khalifeh, Ali ; Laydner, Humberto ; Samarasekera, Dinesh ; Rizkala, Emad ; Eyraud, Remi ; Stein, Robert J. ; Haber, Georges-Pascal ; Kaouk, Jihad H.

Objective : To analyse the outcomes of robot-assisted partial nephrectomy (RAPN) for completely endophytic renal tumours. Patients and Methods : Medical records of patients who had undergone RAPN for a completely endophytic (i.e. 3 points for the ‘E’ domain of the R.E.N.A.L. nephrometry score) enhancing renal mass at our Centre from 2006 to 2012 were retrieved from our prospectively maintained RAPN database and used for this analysis. Demographics, surgical and early postoperative outcomes were [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale du birinapant, une petite molécule mimétique de SMAC

Birinapant(TL32711), a Bivalent Smac Mimetic, Targets TRAF2-associated cIAPs, Abrogates TNF-induced NF-κB Activation and is Active in Patient-Derived Xenograft Models

Benetatos, Christopher A ; Mitsuuchi, Yasuhiro ; Burns, Jennifer M. ; Neiman, Eric M. ; Condon, Stephen M ; Yu, Guangyao ; Seipel, Martin E ; Kapoor, Gurpreet S ; LaPotre, Matthew G ; Rippin, Susan R ; Deng, Yijun ; Hendi, Mukta S ; Tirunahari, Pavan K ; Lee, Yu-Hua ; Haimowitz, Thomas ; Alexander, Matthew D ; Graham, Martin A ; Weng, David ; Shi, Yigong ; McKinlay, Mark A. ; Chunduru, Srinivas K

The acquisition of apoptosis resistance is a fundamental event in cancer development. Among the mechanisms used by cancer cells to evade apoptosis is the dysregulation of Inhibitor of Apoptosis (IAP) proteins. The activity of the IAPs is regulated by endogenous IAP antagonists such as SMAC (also termed DIABLO). Antagonism of IAP proteins by SMAC occurs via binding of the N-terminal tetrapeptide (AVPI) of SMAC to selected BIR domains of the IAPs. Small molecule compounds which mimic the AVPI [...]

Menée in vitro et in vivo, cette étude évalue l'activité antitumorale d'un composé appelé EPZ-6438, un inhibiteur de l'histone méthyltransférase EZH2, pour le traitement d'un lymphome non hodgkinien présentant des mutations du gène EZH2

Selective Inhibition of EZH2 by EPZ-6438 Leads to Potent Antitumor Activity in EZH2 Mutant Non-Hodgkin Lymphoma

Knutson, Sarah K ; Kawano, Satoshi ; Minoshima, Yukinori ; Warholic, Natalie M ; Huang, Kuan-Chun ; Xiao, Yonghong ; Kadowaki, Tadashi ; Uesugi, Mai ; Kuznetsov, Galina ; Kumar, Namita ; Wigle, Tim J ; Klaus, Christine R ; Allain, Christina J ; Raimondi, Alejandra ; Waters, Nigel J ; Smith, Jesse J ; Porter-Scott, Margaret ; Chesworth, Richard ; Moyer, Mikel P ; Copeland, Robert A ; Richon, Victoria M ; Uenaka, Toshimitsu ; Pollock, Roy ; Kuntz, Kevin W ; Yokoi, Akira ; Keilhack, Heike

Mutations within the catalytic domain of the histone methyltransferase (HMT) EZH2 have been identified in subsets of non-Hodgkin Lymphoma (NHL) patients. These genetic alterations are hypothesized to confer an oncogenic dependency on EZH2 enzymatic activity in these cancers. We have previously reported the discovery of EPZ005678 and EPZ-6438, potent and selective S-adenosyl-methionine-competitive small molecule inhibitors of EZH2. While both compounds are similar with respect to their mechanism [...]

Menée sur des échantillons tumoraux prélevés sur des patientes atteintes d'un cancer de l'ovaire et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels, en régulant l'expression de gènes dépendant de la signalisation NFkappaB, l'expression du gène RSF1 contribue au développement d'une résistance au paclitaxel

RSF1 is a positive regulator of NFkappaB-induced gene expression required for ovarian cancer chemoresistance

Yang, Yeong-In ; Ahn, Ji-Hye ; Lee, Kyung-Tae ; Shih, Ie-Ming ; Choi, Jung-Hye

Overexpression or amplification of the RSF1 gene has been associated with poor prognosis in various human cancers, including ovarian cancer. In previous work, RSF1 was identified as an amplified gene that facilitated the development of paclitaxel-resistant ovarian cancer. In the present study, we further demonstrated that RSF1 expression inversely correlated with paclitaxel response in ovarian cancer patients and mouse xenograft model. In addition, RSF1 overexpressing paclitaxel-resistant [...]

Cet article passe en revue les données cliniques et précliniques en faveur de l'hypothèse selon laquelle, même au stade précoce, un cancer du pancréas est une maladie systémique et que, en conséquence, il devrait être d'abord traité à l'aide de combinaisons de chimiothérapies de préférence à une approche chirurgicale

Pancreatic Adenocarcinoma: Treating a Systemic Disease With Systemic Therapy

Sohal, Davendra PS ; Walsh, R. Matthew ; Ramanathan, Ramesh K. ; Khorana, Alok A.

Pancreatic adenocarcinoma, even when resectable, remains highly lethal. Although surgical outcomes have improved considerably, median overall survival after surgery and adjuvant therapy such as single-agent gemcitabine remains less than 2 years. We discuss preclinical and clinical data supporting the contention that even early-stage pancreatic cancer is a systemic disease. Autopsy series reveal that 70% to 85% of patients die of systemic recurrence, rather than local disease, after pancreatic [...]

Menée à l'aide de modèles murins, cette étude suggère l'intérêt de combiner des anticorps monoclonaux anti-CD40 et anti-IL23 pour lutter contre la croissance d'une tumeur primitive et de métastases pulmonaires

Combined anti-CD40 and anti-IL-23 monoclonal antibody therapy effectively suppresses tumor growth and metastases

von Scheidt, Bianca ; Leung, Patrick SK ; Yong, Michelle CR ; Zhang, Yu ; Towne, Jennifer E ; Smyth, Mark J ; Teng, Michele W.L.

Tumor-induced immunosuppression remains one of the major obstacles to many potentially effective cancer therapies and vaccines. Host IL-23 suppresses the immune response during tumor initiation, growth and metastases, and neutralization of IL-23 causes IL-12-dependent anti-tumor effects. Here we report that combining agonistic anti-CD40 mAbs to drive IL-12 production, and anti-IL-23 mAbs to counter the tumor promoting effects of IL-23, has greater anti-tumor activity than either agent alone. [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par la protéine PUMA dans l'activité antitumorale des inhibiteurs de kinase Aurora pour le traitement d'un cancer colorectal

Aurora kinase inhibition induces PUMA via NF-kB to kill colon cancer cells

Sun, Jing ; Knickelbein, Kyle ; He, Kan ; Chen, Dongshi ; Dudgeon, Crissy ; Shu, Yongqian ; Yu, Jian ; Zhang, Lin

Aurora kinases play a key role in mitosis and are frequently overexpressed in a variety of tumor cells. Inhibition of aurora kinases results in mitotic arrest and death of cancer cells, and has been explored as an anticancer strategy. However, how aurora inhibition kills cancer cells is poorly understood. In this study, we found that inhibition of aurora kinases by siRNA or small-molecule inhibitors led to induction of PUMA, a BH3-only Bcl-2 family protein, in colorectal cancer cells [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en acquérant des mutations réactivant la signalisation ERK, les cellules de cancer colorectal développent une résistance aux thérapies ciblées anti EGFR (cetuximab ou panitumumab)

Blockade of EGFR and MEK Intercepts Heterogeneous Mechanisms of Acquired Resistance to Anti-EGFR Therapies in Colorectal Cancer

Misale, Sandra ; Arena, Sabrina ; Lamba, Simona ; Siravegna, Giulia ; Lallo, Alice ; Hobor, Sebastijan ; Russo, Mariangela ; Buscarino, Michela ; Lazzari, Luca ; Sartore-Bianchi, Andrea ; Bencardino, Katia ; Amatu, Alessio ; Lauricella, Calogero ; Valtorta, Emanuele ; Siena, Salvatore ; Di Nicolantonio, Federica ; Bardelli, Alberto

Colorectal cancers (CRCs) that are sensitive to the anti–epidermal growth factor receptor (EGFR) antibodies cetuximab or panitumumab almost always develop resistance within several months of initiating therapy. We report the emergence of polyclonal KRAS, NRAS, and BRAF mutations in CRC cells with acquired resistance to EGFR blockade. Regardless of the genetic alterations, resistant cells consistently displayed mitogen-activated protein kinase kinase (MEK) and extracellular signal–regulated [...]

Mené sur 31 patients atteints d'une tumeur solide avancée, cet essai de phase I évalue la dose limitante toxique et divers paramètres pharmacocinétiques d'un composé appelé PM01183 ou lurbinectedin

First-in-human Phase I Study of Lurbinectedin (PM01183) in Patients with Advanced Solid Tumors

Elez, Maria Elena ; Tabernero, Josep ; Geary, David RN, MSN, OCN ; Macarulla, Teresa ; Kang, Soonmo Peter ; Kahatt, Carmen ; Soto-Matos Pita, Arturo ; Fernandez-Teruel, Carlos ; Siguero, Mariano ; Cullell-Young, Martin ; Szyldergemajn, Sergio ; Ratain, Mark J.

Purpose: Lurbinectedin (PM01183) binds covalently to DNA and has broad activity against tumor cell lines. This first-in-human phase I study evaluated dose-limiting toxicities (DLTs) and defined a phase II recommended dose (RD) for PM01183 as a 1-hour intravenous (i.v.) infusion every 3 weeks (q3wk). Experimental design: Thirty-one patients with advanced solid tumors received escalating doses of PM01183 following an accelerated titration design. Results: PM01183 was safely escalated over [...]

Mené sur 84 patients atteints d'une tumeur solide de stade avancé et/ou réfractaire, cet essai de phase I/II évalue la toxicité, l'efficacité et des paramètres pharmacocinétiques du siltuximab, un anticorps monoclonal chimérique anti-interleukine 6

A phase 1/2, multiple-dose, dose-escalation study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with advanced solid tumors

Angevin, Eric ; Tabernero, Josep ; Elez, Maria Elena ; Cohen, Steven J. ; Bahleda, Rastilav ; Van Laethem, Jean-Luc ; Ottensmeier, Christian H ; Lopez-Martin, Jose A ; Clive, Sally ; Joly, Florence ; Ray-Coquard, Isabelle ; Dirix, Luc Y ; Machiels, Jean-Pascal ; Steven, Neil M ; Reddy, Manjula ; Hall, Brett ; Puchalski, Thomas A. ; Bandekar, Rajesh ; van de Velde, Helgi ; Tromp, Brenda ; Vermeulen, Jessica ; Kurzrock, Razelle

Purpose: This phase 1/2 study evaluated safety, efficacy, and pharmacokinetics of escalating, multiple doses of siltuximab, a chimeric anti-interleukin-6 mAb derived from a new CHO cell line in patients with advanced/refractory solid tumors. Experimental Design: In the phase 1 dose-escalation cohorts, 20 patients with advanced/refractory solid tumors received 2.8 or 5.5 mg/kg q2w or 11 or 15 mg/kg q3w IV. In the phase 1 expansion (n=24) and phase 2 cohorts (n=40), patients with KRAS mutant [...]

Mené sur 16 patients atteints d'une leucémie B lymphoblastique aiguë récidivante ou réfractaire, cet essai évalue l'efficacité, du point de vue du taux de réponse complète, et la toxicité d'un traitement à base de cellules T autologues exprimant le récepteur de l'antigène chimérique 19-28z

Efficacy and Toxicity Management of 19-28z CAR T Cell Therapy in B Cell Acute Lymphoblastic Leukemia

Davila, Marco L. ; Riviere, Isabelle ; Wang, Xiuyan ; Bartido, Shirley ; Park, Jae ; Curran, Kevin ; Chung, Stephen S. ; Stefanski, Jolanta ; Borquez-Ojeda, Oriana ; Olszewska, Malgorzata ; Qu, Jinrong ; Wasielewska, Teresa ; He, Qing ; Fink, Mitsu ; Shinglot, Himaly ; Youssif, Maher ; Satter, Mark ; Wang, Yongzeng ; Hosey, James ; Quintanilla, Hilda ; Halton, Elizabeth ; Bernal, Yvette ; Bouhassira, Diana C. G. ; Arcila, Maria E. ; Gonen, Mithat ; Roboz, Gail J. ; Maslak, Peter ; Douer, Dan ; Frattini, Mark G. ; Giralt, Sergio ; Sadelain, Michel ; Brentjens, Renier

We report on 16 patients with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL) that we treated with autologous T cells expressing the 19-28z chimeric antigen receptor (CAR) specific to the CD19 antigen. The overall complete response rate was 88%, which allowed us to transition most of these patients to a standard-of-care allogeneic hematopoietic stem cell transplant (allo-SCT). This therapy was as effective in high-risk patients with Philadelphia chromosome–positive (Ph+) [...]

Mené sur 83 patients atteints d'un mélanome avancé ne présentant pas de mutation du gène BRAF, cet essai de phase II évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité du selumétinib en complément du docétaxel

DOC-MEK: A double blind randomized phase 2 trial of docetaxel with or without selumetinib in wild-type BRAF advanced melanoma

Gupta, A. ; Love, S. ; Schuh, A. ; Shanyinde, M. ; Larkin, J. M. ; Plummer, R. ; Nathan, P. D. ; Danson, S. ; Ottensmeier, C. H. ; Lorigan, P. ; Collins, L. ; Wise, A. ; Asher, R. ; Lisle, R. ; Middleton, M. R.

Background Treatment options for wild-type BRAF melanoma patients remain limited. Selumetinib, a MEK 1/2 inhibitor, suppresses pERK levels independent of BRAF and NRAS mutation status, and combination with docetaxel has demonstrated synergy in xenograft models. The aim of this study was to assess the efficacy and safety of selumetinib plus docetaxel as first-line treatment in patients with wild-type BRAF advanced melanoma. Patients and methods In this double blind multicentre phase 2 trial [...]

Cet article passe en revue les résultats récents des essais cliniques ayant évalué le nab-paclitaxel en combinaison avec des thérapies ciblées pour le traitement d'un cancer du sein de stade précoce ou métastatique

nab-Paclitaxel in combination with biologically targeted agents for early and metastatic breast cancer

Megerdichian, Christine ; Olimpiadi, Yuliya ; Hurvitz, Sara A.

Taxanes are highly active chemotherapeutic agents used in the treatment of early-stage and metastatic breast cancer. Novel formulations have been developed to improve efficacy and decrease toxicity associated with these cytotoxic agents. nab-Paclitaxel is a biologically interactive, solvent-free, 130-nm-sized albumin-bound paclitaxel, developed to avoid the Cremophor vehicle used in solvent-based paclitaxel. Based on a pivotal phase 3 study, nab-paclitaxel was shown to be safely infused at a [...]

A partir d'une revue de la littérature (7 essais identifiés, 219 patients), cet article évalue l'efficacité et la toxicité du sorafenib pour le traitement d'un cancer métastatique de la thyroïde

Sorafenib in Metastatic Thyroid Cancer: A Systematic Review

Thomas, Ligy ; Lai, Stephen Y. ; Dong, Wenli ; Feng, Lei ; Dadu, Ramona ; Regone, Rachel M. ; Cabanillas, Maria E.

Background. Sorafenib was recently approved by the U.S. Food and Drug Administration for radioiodine-resistant metastatic differentiated thyroid cancer (DTC). In addition, two drugs (vandetanib and cabozantinib) have received U.S. Food and Drug Administration approval for use in medullary thyroid cancer (MTC). Several published phase II trials have investigated the efficacy of sorafenib in thyroid cancers, but to date, results from those studies have not been compared. Methods. A systematic [...]

Menée sur différents modèles de carcinome (pulmonaire de Lewis, colique ou mammaire), cette étude montre que la 5-Aza-2'-désoxycytidine, un inhibiteur de la méthyltransférase, améliore la réponse immunitaire antitumorale induite par la photothérapie dynamique

5-Aza-2′-deoxycytidine potentiates antitumour immune response induced by photodynamic therapy

Wachowska, Malgorzata ; Gabrysiak, Magdalena ; Muchowicz, Angelika ; Bednarek, Weronika ; Barankiewicz, Joanna ; Rygiel, Tomasz ; Boon, Louis ; Mroz, Pawel ; Hamblin, Michael R. ; Golab, Jakub

Photodynamic therapy (PDT) of tumours is based on administration of a photosensitiser followed by irradiation of the tumour with visible light leading to production of reactive oxygen species that cause direct tumour cell death and vascular damage. PDT also initiates acute local inflammation, which facilitates the development of adaptive antitumour immunity. It has recently been reported that PDT can induce strong antitumour immunity towards tumours cells expressing P1A, tumour-associated [...]

Menée sur des lignées cellulaires de cancer du sein, cette étude évalue, dans le cadre d'une immunothérapie, l'efficacité des rayonnements ionisants pour favoriser l'expression des molécules ciblées par les anticorps monoclonaux et améliorer la cytotoxicité à médiation cellulaire dépendante de l'anticorps

Expanding the use of monoclonal antibody therapy of cancer by using ionising radiation to upregulate antibody targets

Wattenberg, M. M. ; Kwilas, A. R. ; Gameiro, S. R. ; Dicker, A. P. ; Hodge, J. W.

Background : Monoclonal antibody (mAb) therapy for the treatment of solid and haematologic malignancies has shown poor response rates as a monotherapy. Furthermore, its use is limited to tumours expressing certain molecular targets. It has been shown that single-dose radiation can induce immunogenic modulation that is characterised by cell-surface phenotypic changes leading to augmented tumour cell/cytotoxic T-cell interaction. Methods : We examined radiation’s ability to upregulate mAb therapy [...]

Cet article analyse les enjeux et les coûts associés au partage de données cliniques à des fins de recherche

Approaches and costs for sharing clinical research data

Wilhelm, E. E. ; Oster, E. ; Shoulson, I.

The generation, dissemination, and sharing of research data are key ingredients in contributing to scientific progress and the public good. Data sharing has been encouraged to facilitate open science within the clinical research enterprise, improve the development of drugs and devices, and benefit public health. But sharing data is complex. Investigators generally tend to guard research data to retain ownership and property rights, avoid competition, protect confidentiality and privacy, or [...]