Menée à partir d'une revue de la littérature publiée entre 1960 et 2014 (37 articles), cette étude présente les données cliniques et pré-cliniques mettant en évidence l'effet abscopal d'une radiothérapie localisée en combinaison ou non avec une immunothérapie

The abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant

Reynders, Kobe ; Illidge, Tim ; Siva, Shankar ; Chang, Joe Y. ; De Ruysscher, Dirk

Background : Recently, immunologic responses to localized irradiation are proposed as mediator of systemic effects after localized radiotherapy (called the abscopal effect). Here, we give an overview of both preclinical and clinical data about the abscopal effect in particular and link them with the immunogenic properties of radiotherapy. Methods : We searched Medline and Embase with the search term “abscopal” from 1960 until July, 2014. Only papers that cover radiotherapy in an oncological [...]

Menée sur 1 751 patients atteints d'un cancer de la prostate (âge moyen : 63,6 ans ; durée moyenne de suivi : 104 mois), cette étude évalue l'efficacité, du point de vue de la survie spécifique et de la survie globale, et les complications associées à une prostatectomie radicale laparoscopique en fonction du stade TNM de la maladie

Impact of laparoscopic radical prostatectomy on clinical T3 prostate cancer: experience of a single centre with long-term follow-up

Gözen, Ali S. ; Akin, Yigit ; Ates, Mutlu ; Hruza, Marcel ; Rassweiler, Jens

Objective : To investigate the oncological safety and effectiveness of laparoscopic radical prostatectomy (LRP) for patients with clinical T3 (cT3) prostate cancer compared with patients with cT1 and cT2 prostate cancer. Patients and Methods : In all, 2375 consecutive LRPs were evaluated between 1999 and 2013. Of the 1751 patients enrolled with complete follow-up data (>24 months), patients were divided into three groups according to clinical stage of prostate cancer using [...]

Menée à partir d'une revue systématique de la littérature publiée jusqu'en août 2014 (82 articles), cette étude évalue, du point de vue des complications, de la préservation des fonctions rénales, des résultats oncologiques et des coûts, l'intérêt de la cryoablation dans le traitement des tumeurs rénales de petite taille

Cryoablation for Small Renal Masses: Selection Criteria, Complications, and Functional and Oncologic Results

Zargar, Homayoun ; Atwell, Thomas D. ; Cadeddu, Jeffrey A. ; de la Rosette, Jean J. ; Janetschek, Gunther ; Kaouk, Jihad H. ; Matin, Surena F. ; Polascik, Thomas J. ; Zargar-Shoshtari, Kamran ; Thompson, R. Houston

Context : Cryoablation (CA) is a minimally invasive modality with low complication rates, but its use in urology is relatively recent. Objective : To summarize available evidence for CA for small renal masses (SRMs) and to assess the selection criteria, complications, and functional and oncologic results based on the latest CA literature. Evidence acquisition : A systematic literature search of the Medline, Embase, and Scopus databases was performed in August 2014 using Medical Subject Headings [...]

Cet article passe en revue les études récentes concernant l'efficacité, la sécurité et les coûts de la protonthérapie par rapport à d'autres techniques avancées de radiothérapie dans le traitement des cancers de la tête et du cou

Proton therapy for head and neck cancer

Lukens, J. Nicholas ; Lin, Alexander ; Hahn, Stephen M.

Purpose of review : Proton therapy for head and neck cancer is an area of active research as technological advances are increasingly integrated into clinical practice, and also the subject of heightened scrutiny due to the significant associated cost. This article will highlight recent research into proton dosimetry, studies evaluating its clinical benefit relative to other advanced radiotherapy modalities, and key safety and cost considerations. Recent findings : Recent dosimetric analyses [...]

Cet article passe en revue les travaux récents en matière d'immunothérapies des cancers

On being less tolerant: Enhanced cancer immunosurveillance enabled by targeting checkpoints and agonists of T cell activation

Lesokhin, Alexander M. ; Callahan, Margaret K. ; Postow, Michael A. ; Wolchok, Jedd D.

The recent approvals of two drugs that block the function of the immune checkpoint programmed cell death 1 (PD-1) have firmly planted tumor immunotherapy in the mainstream of clinical oncology. We provide a historical and immunologic context for these recent advances and discuss translational studies that provide insight into the efficacy of cancer immunotherapy at the individual patient level.

Menée à l'aide de modèles murins, cette étude suggère l'intérêt d'une thérapie ciblée sur l'interaction entre la protéine de fusion MLL et la ménine pour le traitement des patients atteints d'une leucémie avec réarrangement du gène MLL

Pharmacologic Inhibition of the Menin-MLL Interaction Blocks Progression of MLL Leukemia In Vivo

Borkin, Dmitry ; He, Shihan ; Miao, Hongzhi ; Kempinska, Katarzyna ; Pollock, Jonathan ; Chase, Jennifer ; Purohit, Trupta ; Malik, Bhavna ; Zhao, Ting ; Wang, Jingya ; Wen, Bo ; Zong, Hongliang ; Jones, Morgan ; Danet-Desnoyers, Gwenn ; Guzman, Monica L ; Talpaz, Moshe ; Bixby, Dale L ; Sun, Duxin ; Hess, Jay L ; Muntean, Andrew G ; Maillard, Ivan ; Cierpicki, Tomasz ; Grembecka, Jolanta

Chromosomal translocations affecting mixed lineage leukemia gene (MLL) result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. Here we report the development of highly potent and orally bioavailable small-molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, and show their profound effects in MLL leukemia cells and substantial survival benefit in [...]

Menée in vitro et in vivo sur des modèles de gliome, cette étude met en évidence plusieurs mécanismes de résistance aux thérapies ciblées anti EGFR

Development of resistance to EGFR targeted therapy in malignant glioma can occur through EGFR dependent and independent mechanisms

Klingler, Stefan ; Guo, Baofeng ; Yao, Jun ; Yan, Haiyan ; Zhang, Ling ; Vaseva, Angelina V ; Chen, Sida ; Canoll, Peter ; Horner, James W ; Wang, Y. Alan ; Paik, Ji-hye ; Ying, Haoquiang ; Zheng, Hongwu

Epidermal growth factor receptor (EGFR) is highly amplified, mutated and overexpressed in human malignant gliomas. Despite its prevalence and growth-promoting functions, therapeutic strategies to inhibit EGFR kinase activity have not been translated into profound beneficial effects in glioma clinical trials. To determine the roles of oncogenic EGFR signaling in gliomagenesis and tumor maintenance, we generated a novel glioma mouse model driven by inducible expression of a mutant EGFR (EGFR*). [...]

Cet article passe en revue les perspectives offertes par les travaux récents sur l'identification de nouvelles anomalies génomiques (autres que ALK et EGFR) pour le développement de thérapies ciblées dans le cancer avancé du poumon non à petites cellules

Beyond EGFR and ALK inhibition: Unravelling and exploiting novel genetic alterations in advanced non small-cell lung cancer

Califano, Raffaele ; Abidin, Aidalena ; Tariq, Noor-ul-Ain ; Economopoulou, Panagiota ; Metro, Giulio ; Mountzios, Giannis

During the last decade, thoracic oncology has witnessed an unprecedented outburst of knowledge regarding molecular biology of non small-cell lung cancer (NSCLC). The implementation of high-throughput sequencing analysis and genomic technologies has led to the identification of novel molecular events that characterize NSCLC transformation and may represent critical oncogenic drivers amenable to targeted therapy. Among these, the presence of activating mutations of the epidermal growth factor [...]

Menée à l'aide de plusieurs modèles murins de cancer du poumon, cette étude met en évidence des mécanismes par lesquels un inhibiteur de l'hélicase DDX3 exerce une activité antitumorale

Targeting DDX3 with a small molecule inhibitor for lung cancer therapy

Bol, Guus M. ; Vesuna, Farhad ; Xie, Min ; Zeng, Jing ; Aziz, Khaled ; Gandhi, Nishant ; Levine, Anne ; Irving, Ashley ; Korz, Dorian ; Tantravedi, Saritha ; Heerma van Voss, Marise R. ; Gabrielson, Kathleen ; Bordt, Evan A. ; Polster, Brian M. ; Cope, Leslie ; van der Groep, Petra ; Kondaskar, Atul ; Rudek, Michelle A. ; Hosmane, Ramachandra S. ; van der Wall, Elsken ; van Diest, Paul J. ; Tran, Phuoc T. ; Raman, Venu

Lung cancer is the most common malignancy worldwide and is a focus for developing targeted therapies due to its refractory nature to current treatment. We identified a RNA helicase, DDX3, which is overexpressed in many cancer types including lung cancer and is associated with lower survival in lung cancer patients. We designed a first-in-class small molecule inhibitor, RK-33, which binds to DDX3 and abrogates its activity. Inhibition of DDX3 by RK-33 caused G1 cell cycle arrest, induced [...]

Menée in vitro et in vivo sur des modèles de cancer de la prostate résistant à la castration, cette étude met en évidence des mécanismes par lesquels, en bloquant la signalisation du récepteur des androgènes, un inhibiteur de l'interaction MLL-ménine exerce une activité antitumorale

Targeting the MLL complex in castration-resistant prostate cancer

Malik, Rohit ; Khan, Amjad P. ; Asangani, Irfan A. ; Cieslik, Marcin ; Prensner, John R. ; Wang, Xiaoju ; Iyer, Matthew K. ; Jiang, Xia ; Borkin, Dmitry ; Escara-Wilke, June ; Stender, Rachell ; Wu, Yi-Mi ; Niknafs, Yashar S. ; Jing, Xiaojun ; Qiao, Yuanyuan ; Palanisamy, Nallasivam ; Kunju, Lakshmi P. ; Krishnamurthy, Pranathi M. ; Yocum, Anastasia K. ; Mellacheruvu, Dattatreya ; Nesvizhskii, Alexey I. ; Cao, Xuhong ; Dhanasekaran, Saravana M. ; Feng, Felix Y. ; Grembecka, Jolanta ; Cierpicki, Tomasz ; Chinnaiyan, Arul M.

Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Although prior work has focused on targeting AR directly, co-activators of AR signaling, which may represent new therapeutic targets, are relatively underexplored. Here we demonstrate that the mixed-lineage leukemia protein (MLL) complex, a well-known driver of MLL fusion-positive leukemia, acts as a co-activator of AR signaling. AR [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes de cancer de la prostate résistant à la castration, cette étude met en évidence le rôle joué par le gène PLZF dans la résistance à un traitement anti-androgènes

PLZF, a Tumor Suppressor Genetically Lost in Metastatic Castration Resistant Prostate Cancer, is a Mediator of Resistance to Androgen Deprivation Therapy

Hsieh, Chen-Lin ; Botta, Ginevra ; Gao, Shuai ; Li, Tiantian ; Van Allen, Eliezer M. ; Treacy, Daniel J ; Cai, Changmeng ; He, Housheng Hansen ; Sweeney, Christopher J. ; Brown, Myles ; Balk, Steven P. ; Nelson, Peter S. ; Garraway, Levi A ; Kantoff, Philip W

Whole exome sequencing of metastatic castration-resistant prostate cancer (mCRPC) reveal that 5~7% of tumors harbor promyelocytic zinc finger protein (PLZF) homozygous deletions. PLZF is a canonical androgen-regulated putative tumor suppressor gene whose expression is inhibited by androgen deprivation therapy (ADT). Here, we demonstrate that knockdown of PLZF expression promotes a CRPC and enzalutamide resistant phenotype in prostate cancer cells. Reintroduction of PLZF expression is sufficient [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes suggérant l'intérêt de combiner un inhibiteur d'histone désacétylase avec un inhibiteur de MEK pour le traitement de patients atteints d'un cancer colorectal présentant des mutations du gène BRAF

HDAC inhibition overcomes acute resistance to MEK inhibition in BRAF mutant colorectal cancer by down-regulation of c-FLIPL

Carson, Robbie ; Celtikci, Basak ; Fenning, Catherine S. ; Javadi, Arman ; Crawford, Nyree ; PEREZ-CARBONELL, LUCIA ; Lawler, Mark ; Longley, Daniel B. ; Johnston, Patrick G. ; Van Schaeybroeck, Sandra

Purpose: Activating mutations in the BRAF oncogene are found in 8-15% of colorectal cancer (CRC) patients and have been associated with poor survival. In contrast to BRAF mutant (MT) melanoma, inhibition of the MAPK pathway is ineffective in the majority of BRAFMT CRC patients. Therefore, identification of novel therapies for BRAFMT CRC is urgently needed. Experimental Design: BRAFMT and WT CRC models were assessed in vitro and in vivo. Small molecule inhibitors of MEK1/2, MET and HDAC were [...]

Menée à l'aide de modèles murins, cette étude suggère l'intérêt d'un inhibiteur de PARP (ABT888), en combinaison avec du carboplatine, pour le traitement de patientes atteintes d'un cancer du sein triplement négatif avec métastases cérébrales

Efficacy of Carboplatin Alone and in Combination with ABT888 in Intracranial Murine Models of BRCA-Mutated and BRCA–Wild-Type Triple-Negative Breast Cancer

Karginova, Olga ; Siegel, Marni B. ; Van Swearingen, Amanda E.D. ; Deal, Allison M. ; Adamo, Barbara ; Sambade, Maria J. ; Bazyar, Soha ; Nikolaishvili-Feinberg, Nana ; Bash, Ryan ; O'Neal, Sara ; Sandison, Katie ; Parker, Joel S. ; Santos, Charlene ; Darr, David ; Zamboni, William ; Lee, Yueh Z. ; Miller, C. Ryan ; Anders, Carey K.

Patients with breast cancer brain metastases have extremely limited survival and no approved systemic therapeutics. Triple-negative breast cancer (TNBC) commonly metastasizes to the brain and predicts poor prognosis. TNBC frequently harbors BRCA mutations translating to platinum sensitivity potentially augmented by additional suppression of DNA repair mechanisms through PARP inhibition. We evaluated brain penetrance and efficacy of carboplatin ± the PARP inhibitor ABT888, and investigated [...]

Menée sur 3 patients atteints d'un mélanome de stade avancé ayant été traité par ipilimumab, cette étude analyse la réponse immunitaire après l'injection d'un vaccin thérapeutique personnalisé à base de cellules dendritiques

A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells

Carreno, Beatriz M. ; Magrini, Vincent ; Becker-Hapak, Michelle ; Kaabinejadian, Saghar ; Hundal, Jasreet ; Petti, Allegra A. ; Ly, Amy ; Lie, Wen-Rong ; Hildebrand, William H. ; Mardis, Elaine R. ; Linette, Gerald P.

T cell immunity directed against tumor-encoded amino acid substitutions (AAS) occurs in some melanoma patients. This implicates missense mutations (MM) as a source of patient-specific neoantigens. However, a systematic evaluation of these putative neoantigens as validated targets of anti-tumor immunity is lacking. Moreover, whether vaccination can augment such responses is unknown. Here we show that a dendritic cell vaccine increased naturally occurring and revealed new HLA class I-restricted [...]

Cet article présente les arguments en défaveur de la prescription d'un traitement de première ligne comportant du cétuximab ou du panitumumab chez les patients atteints d'un cancer colorectal sans mutations du gène KRAS

The cost and value of anti–epidermal growth factor receptor therapies: Let's not be rash

Saltz, L. B.

I don't treat any of my patients with RAS wild-type colorectal cancer with first-line cetuximab- or panitumumab-containing regimens. I don't think you should either. Here's why. The skin rash from use of anti–epidermal growth factor receptor (EGFR) monoclonal antibodies is miserable, and the cost per dose is roughly double that of bevacizumab. Furthermore, anti-EGFR agents can be used in therapies other than first line to provide survival benefit to patients with RAS wild-type cancer, so their [...]

Mené sur 34 patients atteints d'un carcinome à cellules rénales de stade avancé et réfractaire aux traitements existants, cet essai de phase I évalue l'efficacité, du point de vue du taux de réponse objective et de la survie globale à 1, 2 ou 3 ans, et la toxicité du nivolumab

Survival, Durable Response, and Long-Term Safety in Patients With Previously Treated Advanced Renal Cell Carcinoma Receiving Nivolumab

McDermott, David F. ; Drake, Charles G. ; Sznol, Mario ; Choueiri, Toni K. ; Powderly, John D. ; Smith, David C. ; Brahmer, Julie R. ; Carvajal, Richard D. ; Hammers, Hans J. ; Puzanov, Igor ; Hodi, F. Stephen ; Kluger, Harriet M. ; Topalian, Suzanne L. ; Pardoll, Drew M. ; Wigginton, Jon M. ; Kollia, Georgia D. ; Gupta, Ashok ; McDonald, Dan ; Sankar, Vindira ; Sosman, Jeffrey A. ; Atkins, Michael B.

Purpose : Blockade of the programmed death-1 inhibitory cell-surface molecule on immune cells using the fully human immunoglobulin G4 antibody nivolumab mediates tumor regression in a portion of patients with advanced treatment-refractory solid tumors. We report clinical activity, survival, and long-term safety in patients with advanced renal cell carcinoma (RCC) treated with nivolumab in a phase I study with expansion cohorts. Patients and Methods : A total of 34 patients with previously [...]

Mené sur 65 patientes atteintes d'un cancer du sein HER2+, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse pathologique complète, et la toxicité d'un traitement néoadjuvant combinant afatinib, trastuzumab et une chimiothérapie à base de paclitaxel, épirubicine et cyclophosphamide

Dual blockade with Afatinib and trastuzumab as Neoadjuvant treatment for patients with locally advanced or operable breast cancer receiving taxane-anthracycline containing chemotherapy

Hanusch, Claus A ; Schneeweiss, Andreas ; Loibl, Sibylle ; Untch, Michael ; Paepke, Stefan ; Kümmel, Sherko ; Jackisch, Christian ; Huober, Jens ; Hilfrich, Jörn ; Gerber, Bernd ; Eidtmann, Holger ; Denkert, Carsten ; Costa, Serban-Dan ; Blohmer, Jens Uwe ; Engels, Knut ; Burchardi, Nicole ; von Minckwitz, Gunter

Background: Dual anti-HER2 blockade with trastuzumab/pertuzumab or trastuzumab/lapatinib in combination with anthracycline/taxane-based chemotherapy can reach pCR rates of up to 60% in HER2-positive breast cancer. The DAFNE phase II study (NCT015591477) investigated a dual blockade with the irreversible pan-HER inhibitor afatinib and trastuzumab in this setting. Methods: Participants with untreated, centrally HER2-positive breast cancer were treated for 6 weeks with afatinib (20mg/day) and [...]

Mené sur 9 patientes atteintes d'un cancer métastatique du col de l'utérus, cet essai évalue l'efficacité, du point de vue de la réponse tumorale, d'une injection de lymphocytes T infiltrant les tumeurs sélectionnés pour leur réactivité à des antigènes du papillomavirus humain

Complete Regression of Metastatic Cervical Cancer After Treatment With Human Papillomavirus–Targeted Tumor-Infiltrating T Cells

Stevanović, Sanja ; Draper, Lindsey M. ; Langhan, Michelle M. ; Campbell, Tracy E. ; Kwong, Mei Li ; Wunderlich, John R. ; Dudley, Mark E. ; Yang, James C. ; Sherry, Richard M. ; Kammula, Udai S. ; Restifo, Nicholas P. ; Rosenberg, Steven A. ; Hinrichs, Christian S.

Purpose : Metastatic cervical cancer is a prototypical chemotherapy-refractory epithelial malignancy for which better treatments are needed. Adoptive T-cell therapy (ACT) is emerging as a promising cancer treatment, but its study in epithelial malignancies has been limited. This study was conducted to determine if ACT could mediate regression of metastatic cervical cancer. Patients and Methods : Patients enrolled onto this protocol were diagnosed with metastatic cervical cancer and had [...]

Cet article passe en revue les différentes stratégies pour traiter un cancer du pancréas et analyse les perspectives offertes par les nouveaux traitements

Pancreatic cancer: from state-of-the-art treatments to promising novel therapies

Garrido-Laguna, Ignacio ; Hidalgo, Manuel

Pancreatic cancer is expected to be the second deadliest malignancy in the USA by 2020. The survival rates for patients with other gastrointestinal malignancies have increased consistently during the past 30 years; unfortunately, however, the outcomes of patients with pancreatic cancer have not changed significantly. Although surgery remains the only curative treatment for pancreatic cancer, therapeutic strategies based on initial resection have not substantially improved the survival of [...]

Menée sur une cohorte de 1 041 patients atteints d'un cancer du poumon non à petites cellules de stade IIIA traité par chirurgie entre 1998 et 2005, cette étude évalue, en fonction des doses de rayonnements administrées et du point de vue de la survie globale à 3 et 5 ans, l'efficacité et la toxicité d'une radiothérapie néoadjuvante avec escalade de doses en combinaison avec une chimiothérapie

Relationship Between Radiation Therapy Dose and Outcome in Patients Treated With Neoadjuvant Chemoradiation Therapy and Surgery for Stage IIIA Non-Small Cell Lung Cancer: A Population-Based, Comparative Effectiveness Analysis

Sher, David J. ; Fidler, Mary Jo ; Seder, Christopher W. ; Liptay, Michael J. ; Koshy, Matthew

Purpose : To compare, using the National Cancer Database, survival, pathologic, and surgical outcomes in patients with stage IIIA non-small cell lung cancer treated with differential doses of neoadjuvant chemoradiation therapy, with the aim to discern whether radiation dose escalation was associated with a comparative effectiveness benefit and/or toxicity risk. Methods and Materials : Patients in the National Cancer Database with stage IIIA non-small cell lung cancer treated with neoadjuvant [...]

Menée in vitro et à l'aide d'un modèle murin de cancer mammaire triplement négatif, cette étude montre que ZRBA1, une molécule ciblant le récepteur EGFR, peut améliorer la réponse des cellules tumorales aux rayonnements ionisants en retardant le processus de réparation des dommages causés à l'ADN

ZRBA1, a Mixed EGFR/DNA Targeting Molecule, Potentiates Radiation Response Through Delayed DNA Damage Repair Process in a Triple Negative Breast Cancer Model

Heravi, Mitra ; Kumala, Slawomir ; Rachid, Zakaria ; Jean-Claude, Bertrand J. ; Radzioch, Danuta ; Muanza, Thierry M.

Purpose : ZRBA1 is a combi-molecule designed to induce DNA alkylating lesions and to block epidermal growth factor receptor (EGFR) TK domain. Inasmuch as ZRBA1 downregulates the EGFR TK-mediated antisurvival signaling and induces DNA damage, we postulated that it might be a radiosensitizer. The aim of this study was to further investigate the potentiating effect of ZRBA1 in combination with radiation and to elucidate the possible mechanisms of interaction between these 2 treatment modalities. [...]

Menée par entretiens auprès de 14 experts participant à des groupes de rédaction de recommandations cliniques pour l'organisme britannique "National Institute for Health and Care Excellence", cette étude évalue les procédures mises en place pour gérer les conflits d'intérêts des rédacteurs

Managing Conflicts of Interest in the UK National Institute for Health and Care Excellence (NICE) Clinical Guidelines Programme: Qualitative Study

Graham, Tanya ; Alderson, Phil ; Stokes, Tim

Background : There is international concern that conflicts of interest (COI) may bias clinical guideline development and render it untrustworthy. Guideline COI policies exist with the aim of reducing this bias but it is not known how such policies are interpreted and used by guideline producing organisations. This study sought to determine how conflicts of interest (COIs) are disclosed and managed by a national clinical guideline developer (NICE: the UK National Institute for Health and Care [...]