Menée in vitro et à l'aide de xénogreffes sur un modèle murin, cette étude montre que le blocage de l'expression de la protéine Hsp27 sensibilise les cellules tumorales de la tête et du cou aux rayonnements ionisants en affectant la réparation de l'ADN

Inhibition of Hsp27 Radiosensitizes Head-and-Neck Cancer by Modulating Deoxyribonucleic Acid Repair

Guttmann, David M. ; Hart, Lori ; Du, Kevin ; Seletsky, Andrew ; Koumenis, Constantinos

Purpose : To present a novel method of tumor radiosensitization through Hsp27 knockdown using locked nucleic acid (LNA) and to investigate the role of Hsp27 in DNA double strand break (DSB) repair. Methods and Materials : Clonogenic survival assays, immunoblotting, the proximity ligation assay, and  [...]

Menée sur 31 patients ayant reçu une radiothérapie externe pour traiter un cancer du foie, cette étude évalue la toxicité d'une radio-embolisation de sauvetage à base d'yttrium 90

Safety of 90Y Radioembolization in Patients Who Have Undergone Previous External Beam Radiation Therapy

Lam, Marnix G. E. H. ; Abdelmaksoud, Mohamed H. K. ; Chang, Daniel T. ; Eclov, Neville C. ; Chung, Melody P. ; Koong, Albert C. ; Louie, John D. ; Sze, Daniel Y.

Purpose : Previous external beam radiation therapy (EBRT) is theoretically contraindicated for yttrium-90 (90Y) radioembolization (RE) because the liver has a lifetime tolerance to radiation before becoming vulnerable to radiation-induced liver disease. We analyzed the safety of RE as salvage treatment in patients who had previously undergone EBRT. Methods and Materials : Between June 2004 and December 2010, a total of 31 patients who had previously undergone EBRT were treated with RE. [...]

Menée sur 101 patients présentant une tumeur osseuse traitée entre 1996 et 2011, cette étude multicentrique évalue, du point de vue du taux de récidive locale et du taux de survie globale cumulée à 5 ans, l'efficacité d'une chirurgie conservatrice comportant une irradiation extra-corporelle et une réimplantation de l'os atteint

Limb preservation surgery with extracorporeal irradiation in the management of malignant bone tumor: the oncological outcomes of 101 patients

Hong, A. M. ; Millington, S. ; Ahern, V. ; McCowage, G. ; Boyle, R. ; Tattersall, M. ; Haydu, L. ; Stalley, P. D.

Background : En bloc resection, extracorporeal irradiation (ECI) and reimplantation have been used selectively at our centers as part of limb preservation surgery of malignant bone tumors since 1996. We report the long-term oncological outcomes. Patients and methods : One hundred one patients were treated with ECI at two Australian centers between 1996 and 2011. A single dose of 50 Gy was delivered to the resected bone segments. The irradiated bones were reimplanted immediately as a biological [...]

Menée sur 200 patients atteints d'un cancer de la prostate traité entre 2010 et 2011 (âge médian des patients : 65 ans ; durée de suivi supérieure à 1 an), cette étude prospective évalue l'efficacité, du point de vue de la survie, de la qualité des marges de résection, de la récupération de la continence et de la fonction érectile, et les effets indésirables d'une prostatectomie radicale laparoscopique assistée par robot avec préservation de l'espace de Retzius

Beyond the Learning Curve of the Retzius-sparing Approach for Robot-assisted Laparoscopic Radical Prostatectomy : Oncologic and Functional Results of the First 200 Patients with ≥1 Year of Follow-up

Antonio, Galfano ; Dario Di, Trapani ; Francesco, Sozzi ; Elena, Strada ; Giovanni, Petralia ; Manuela, Bramerio ; Assunta, Ascione ; Marcello, Gambacorta ; Aldo Massimo, Bocciardi

Background : Robot-assisted laparoscopic radical prostatectomy (RARP) has become the main surgical option for localized prostate cancer. We recently developed a new approach for RARP, passing through the pouch of Douglas and avoiding all the Retzius structures involved in continence and potency preservation. Objective : To report the functional and oncologic results of our first 200 patients operated on using this new approach. Design, setting, and participants : This was a prospective, [...]

Menée à partir des données d'un registre américain des cancers portant sur 7 359 patientes atteintes d'un cancer du col de l'utérus de stade IB2-IVA et traitées par radiothérapie externe entre 1988 et 2009, cette étude analyse l'évolution du taux d'utilisation de la curiethérapie et évalue, en termes de survie, les bénéfices apportés par ce type de traitement

Trends in the Utilization of Brachytherapy in Cervical Cancer in the United States

Han, Kathy ; Milosevic, Michael ; Fyles, Anthony ; Pintilie, Melania ; Viswanathan, Akila

Purpose : To determine the trends in brachytherapy use in cervical cancer in the United States and to identify factors and survival benefits associated with brachytherapy treatment. Methods and Materials : Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified 7359 patients with stages IB2-IVA cervical cancer treated with external beam radiation therapy (EBRT) between 1988 and 2009. Propensity score matching was used to adjust for differences between patients who [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par la survivine 3B dans la résistance à une chimiothérapie

Survivin-3B potentiates immune escape in cancer but also inhibits the toxicity of cancer chemotherapy

Vegran, Frederique ; Mary, Romain ; Gibeaud, Anne ; Mirjolet, Céline ; Collin, Bertrand ; Oudot, Alexandra ; Charon-Barra, Céline ; Arnould, Laurent ; Lizard-Nacol, Sarab ; Boidot, Romain

Dysregulation in patterns of alternative RNA splicing in cancer cells is emerging as a significant factor in cancer pathophysiology. In this study we investigated the little known alternative splice isoform Survivin-3B (S-3B) that is overexpressed in a tumor-specific manner. Ectopic overexpression of S-3B drove tumorigenesis by facilitating immune escape in a manner associated with resistance to immune cell toxicity. This resistance was mediated by interaction of S-3B with pro-caspase-8, [...]

Cet article passe en revue les perspectives offertes par le ciblage des tyrosines kinases ABL1 et ABL2 pour le traitement de tumeurs solides

Role of ABL family kinases in cancer: from leukaemia to solid tumours

Greuber, Emileigh K. ; Smith-Pearson, Pameeka ; Wang, Jun ; Pendergast, Ann Marie

The Abelson (ABL) family of nonreceptor tyrosine kinases, ABL1 and ABL2, transduces diverse extracellular signals to protein networks that control proliferation, survival, migration and invasion. ABL1 was first identified as an oncogene required for the development of leukaemias initiated by retroviruses or chromosome translocations. The demonstration that small-molecule ABL kinase inhibitors could effectively treat chronic myeloid leukaemia opened the door to the era of targeted cancer [...]

Cet article passe en revue les perspectives thérapeutiques offertes par les connaissances sur le rôle des altérations de la signalisation ATM dans les cancers

ATM signalling and cancer

Cremona, C. A. ; Behrens, A.

ATM, the protein kinase mutated in the rare human disease ataxia telangiectasia (A-T), has been the focus of intense scrutiny over the past two decades. Initially this was because of the unusual radiosensitive phenotype of cells from A-T patients, and latterly because investigating ATM signalling has yielded valuable insights into the DNA damage response, redox signalling and cancer. With the recent explosion in genomic data, ATM alterations have been revealed both in the germline as a [...]

Cet article passe en revue les travaux récents sur le rôle des hélicases dans la réparation de l'ADN et les mécanismes de cancérogenèse

DNA helicases involved in DNA repair and their roles in cancer

Brosh Jr, Robert M.

Helicases have major roles in genome maintenance by unwinding structured nucleic acids. Their prominence is marked by various cancers and genetic disorders that are linked to helicase defects. Although considerable effort has been made to understand the functions of DNA helicases that are important for genomic stability and cellular homeostasis, the complexity of the DNA damage response leaves us with unanswered questions regarding how helicase-dependent DNA repair pathways are regulated and [...]

Cet article passe en revue les perspectives offertes par le développement d'agents ciblant les interactions entre le stroma et la tumeur pour le traitement d'un cancer métastatique du pancréas

Tumour–stroma interactions in pancreatic ductal adenocarcinoma: Rationale and current evidence for new therapeutic strategies

Heinemann, V. ; Reni, M. ; Ychou, M. ; Richel, D. J. ; Macarulla, T. ; Ducreux, M.

Most patients with pancreatic cancer present with advanced/metastatic disease and have a dismal prognosis. Despite the proven albeit modest benefits of gemcitabine demonstrated over a decade ago, subsequent advances have been slow, suggesting it may be time to take a different approach. It is thought that some key characteristics of pancreatic cancer, such as the desmoplasia, restricted vasculature and hypoxic environment, may prevent the delivery of chemotherapy to the tumour thereby [...]

Menée sur des lignées cellulaires de cancer de la prostate, cette étude met en évidence le rôle joué par la surexpression de la protéine ABCB1 dans la résistance au docétaxel

Inhibition of ABCB1 expression overcomes acquired docetaxel resistance in prostate cancer

Zhu, Yezi ; Liu, Chengfei ; Nadimity, Nagalakshmi ; Lou, Wei ; tummala, Ramakumar ; Evans, Christopher P ; Gao, Allen C

Docetaxel is the first-line standard treatment for castration resistant prostate cancer (CRPC). However, relapse eventually occurs due to the development of resistance to docetaxel. In order to unravel the mechanism of acquired docetaxel resistance, we established docetaxel-resistant prostate cancer cells, TaxR, from castration resistant C4-2B prostate cancer cells. The IC50 for docetaxel in TaxR cells was about 70-fold higher than parental C4-2B cells. Global gene expression analysis revealed [...]

Menée à l'aide d'un modèle murin, cette étude suggère l'intérêt d'un traitement à l'aide d'inhibiteurs de MEK pour les patients atteints d'un sarcome dont les tumeurs présentent une délétion du gène NF1

NF1 deletion generates multiple subtypes of soft-tissue sarcoma that respond to MEK inhibition

Dodd, Rebecca D ; Mito, Jeffrey K ; Eward, William C ; Chitalia, Rhea ; Sachdeva, Mohit ; Ma, Yan ; Barretina, Jordi ; Dodd, Leslie ; Kirsch, David G

Soft-tissue sarcomas are a heterogeneous group of tumors arising from connective tissue. Recently, mutations in the neurofibromin 1 (NF1) tumor suppressor gene were identified in multiple subtypes of human soft-tissue sarcomas. To study the effect of NF1 inactivation in the initiation and progression of distinct sarcoma subtypes, we have developed a novel mouse model of temporally and spatially restricted NF1-deleted sarcoma. To generate primary sarcomas, we inject adenovirus containing Cre [...]

Menée in vitro et in vivo, cette étude évalue l'activité antitumorale d'un inhibiteur allostérique de JAK2, appelé G5-7, pour le traitement d'un glioblastome

Blockade of Glioma Proliferation Through Allosteric Inhibition of JAK2

He, Kunyan ; Qi, Qi ; Chan, Chi-Bun ; Xiao, Ge ; Liu, Xia ; Tucker-Burden, Carol ; Wang, Liya ; Mao, Hui ; Lu, Xiang ; McDonald, Frank E. ; Luo, Hongbo ; Fan, Qi-Wen ; Weiss, William A. ; Sun, Shi-Yong ; Brat, Daniel J. ; Ye, Keqiang

The gene that encodes the epidermal growth factor receptor (EGFR) is frequently overexpressed or mutated in human cancers, including glioblastoma. However, the efficacy of EGFR-targeted small-molecule inhibitors or monoclonal antibodies in glioblastomas that also have mutation or deletion of the gene encoding phosphatase and tensin homolog (PTEN) has been modest. We found that EGFR signaling was blocked by a small molecule (G5-7) that selectively inhibited Janus kinase 2 (JAK2)–mediated [...]

Mené sur 38 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I évalue la toxicité et divers paramètres pharmacodynamiques d'un composé appelé AZD1480, un inhibiteur de JAK1 et JAK2

AZD1480: A Phase I Study of a Novel JAK2 Inhibitor in Solid Tumors

Plimack, Elizabeth R. ; LoRusso, Patricia M. ; McCoon, Patricia ; Tang, Weifeng ; Krebs, Annetta D. ; Curt, Gregory ; Eckhardt, S. Gail

Background: AZD1480 is a novel agent that inhibits Janus-associated kinases 1 and 2 (JAK1 and JAK2). The primary objective of this phase I study was to investigate the safety and tolerability of AZD1480 when administered as monotherapy to patients with solid tumors. Methods: Thirty-eight patients with advanced malignancies were treated at doses of 10–70 mg once daily (QD) and 20–45 mg b.i.d.. Results: Pharmacokinetic (PK) analysis revealed rapid absorption and elimination with minimal [...]

Mené sur 76 patients atteints d'un mésothéliome pleural malin non résécable, cet essai de phase II évalue, du point de vue de la survie sans progression, l'efficacité et la toxicité de l'ajout du bevacizumab à un traitement combinant pemetrexed et carboplatine

Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma

Ceresoli, G. L. ; Zucali, P. A. ; Mencoboni, M. ; Botta, M. ; Grossi, F. ; Cortinovis, D. ; Zilembo, N. ; Ripa, C. ; Tiseo, M. ; Favaretto, A. G. ; Soto-Parra, H. ; De Vincenzo, F. ; Bruzzone, A. ; Lorenzi, E. ; Gianoncelli, L. ; Ercoli, B. ; Giordano, L. ; Santoro, A.

Background: The aim of this open label phase II study (NCT00407459) was to assess the activity of the vascular endothelial growth factor (VEGF) inhibitor bevacizumab combined with pemetrexed and carboplatin in patients with previously untreated, unresectable malignant pleural mesothelioma (MPM). Methods: Eligible patients received pemetrexed 500 mg m−2, carboplatin area under the plasma concentration–time curve (AUC) 5 mg ml−1 per minute and bevacizumab 15 mg kg−1, administered intravenously [...]

A partir de données portant sur 10 250 patients atteints d'un cancer de la prostate de stade avancé entre 1997 et 2008, cette étude britannique évalue le risque d'atteinte rénale aiguë associée à un traitement anti-androgène (durée médiane de suivi : 4,1 ans)

Androgen deprivation therapy and risk of acute kidney injury in patients with prostate cancer

Lapi F, Azoulay L. Niazi M. Yin H. Benayoun S. Suissa S.

Importance  The use of androgen deprivation therapy (ADT) in the treatment of advanced prostate cancer has been shown to delay the clinical progression of the disease. However, the testosterone suppression associated with this therapy may lead to a hypogonadal condition that can have detrimental effects on renal function, thus raising the hypothesis that ADT-induced hypogonadism could potentially lead to acute kidney injury (AKI). Objective  To determine whether the use of ADT is associated [...]

Mené sur 53 patients atteints d'un sarcome des tissus mous ou d'une tumeur solide réfractaire (âge médian : 12,9 ans), cet essai de phase I évalue la toxicité et l'activité antitumorale du pazopanib, un inhibiteur de l'angiogenèse

Phase I Pharmacokinetic and Pharmacodynamic Study of Pazopanib in Children With Soft Tissue Sarcoma and Other Refractory Solid Tumors: A Children’s Oncology Group Phase I Consortium Report

Glade Bender, Julia L. ; Lee, Alice ; Reid, Joel M. ; Baruchel, Sylvain ; Roberts, Timothy ; Voss, Stephan D. ; Wu, Bing ; Ahern, Charlotte H. ; Ingle, Ashish M. ; Harris, Pamela ; Weigel, Brenda J. ; Blaney, Susan M.

Purpose Pazopanib, an oral multikinase angiogenesis inhibitor, prolongs progression-free survival in adults with soft tissue sarcoma (STS). A phase I pharmacokinetic and pharmacodynamic study of two formulations of pazopanib was performed in children with STS or other refractory solid tumors. Patients and Methods Pazopanib (tablet formulation) was administered once daily in 28-day cycles at four dose levels (275 to 600 mg/m2) using the rolling-six design. Dose determination for a powder [...]

Mené sur 442 patientes atteintes d'un cancer métastatique du sein ayant déjà été traité à l'aide d'anthracyclines et taxanes, cet essai de phase III évalue, du point de vue de la survie sans progression, l'efficacité et la toxicité de l'ajout de sunitinib à un traitement par capécitabine

Phase III Trial of Sunitinib in Combination With Capecitabine Versus Capecitabine Monotherapy for the Treatment of Patients With Pretreated Metastatic Breast Cancer

Crown, John P. ; Diéras, Véronique ; Staroslawska, Elzbieta ; Yardley, Denise A. ; Bachelot, Thomas ; Davidson, Neville ; Wildiers, Hans ; Fasching, Peter A. ; Capitain, Olivier ; Ramos, Manuel ; Greil, Richard ; Cognetti, Francesco ; Fountzilas, George ; Blasinska-Morawiec, Maria ; Liedtke, Cornelia ; Kreienberg, Rolf ; Miller, Wilson H. ; Tassell, Vanessa ; Huang, Xin ; Paolini, Jolanda ; Kern, Kenneth A. ; Romieu, Gilles

Purpose Metastatic breast cancer (MBC) remains an incurable illness in the majority of cases, despite major therapeutic advances. This may be related to the ability of breast tumors to induce neoangiogenesis, even in the face of cytotoxic chemotherapy. Sunitinib, an inhibitor of key molecules involved in neoangiogenesis, has an established role in the treatment of metastatic renal cell and other cancers and demonstrated activity in a phase II trial in MBC. We performed a randomized phase III [...]

Cet article fait le point sur l'efficacité de traitements néoadjuvants (chimiothérapie, chimioradiothérapie, combinaison de traitements) dans la prise en charge d'un cancer du pancréas non résécable ou à la limite de la résécabilité

Neoadjuvant treatment of borderline resectable and non-resectable pancreatic cancer

Heinemann, V. ; Haas, M. ; Boeck, S.

Neoadjuvant therapy is increasingly becoming a valid treatment option for patients with locally advanced pancreatic cancer (LAPC). In borderline resectable disease, neoadjuvant therapy is employed to improve the probability of margin-clear resections. In non-metastatic, non-resectable pancreatic cancer, treatment primarily aims to induce disease control, but may achieve conversion to surgical resectability in some patients. Several treatment modalities including chemotherapy, chemoradiotherapy [...]

Mené sur 40 patients atteints d'un cancer du poumon non à petites cellules de stade IIIA ou IIIB et non résécable, cet essai multicentrique de phase II évalue l'efficacité, du point de vue de la survie globale, et la toxicité d'un protocole thérapeutique combinant le cétuximab à une radiothérapie thoracique concomitante puis à une chimiothérapie de consolidation par carboplatine et paclitaxel

A multicenter phase II study of cetuximab in combination with chest radiotherapy and consolidation chemotherapy in patients with stage III non-small cell lung cancer

Ramalingam, S. S. ; Kotsakis, A. ; Tarhini, A. A. ; Heron, D. E. ; Smith, R. ; Friedland, D. ; Petro, D. P. ; Raez, L. E. ; Brahmer, J. R. ; Greenberger, J. S. ; Dacic, S. ; Hershberger, P. ; Landreneau, R. J. ; Luketich, J. D. ; Belani, C. P. ; Argiris, A.

Background : Cetuximab has demonstrated improved efficacy in combination with chemotherapy and radiotherapy. We evaluated the integration of cetuximab in the combined modality treatment of stage III non-small cell lung cancer (NSCLC). Methods : Patients with surgically unresectable stage IIIA or IIIB NSCLC were treated with chest radiotherapy, 73.5 Gy (with lung and tissue heterogeneity corrections) in 35 fractions/7 weeks, once daily (63 Gy without heterogeneity corrections). Cetuximab was [...]

Menée à partir d'échantillons tumoraux fixés au formol et inclus en paraffine après prélèvement sur 38 patients atteints d'un sarcome, cette étude montre que la radiothérapie favorise l'expression intratumorale de plusieurs effecteurs immunitaires

Radiotherapy of human sarcoma promotes an intratumoral immune effector signature

Sharma, Anu ; Bode, Beata ; Moch, Holger ; Okoniewski, Michal ; Knuth, Alexander ; von Boehmer, Lotta ; van den Broek, Maries

Purpose : The tumor immune microenvironment plays a crucial role in the development and progression of cancer. Sarcomas are a group of heterogeneous soft tissue malignancies that are often treated with radiotherapy as a part of the treatment concept. There is increasing evidence that radiotherapy leads to alterations in the tumor microenvironment, particularly with respect to the immune infiltrate. The present study has been carried out to develop a better understanding of such changes [...]

Mené sur 112 patients pédiatriques atteints d'un médulloblastome à risque élevé de récidive et traités par chirurgie (durée médiane de suivi : 6,4 ans), cet essai randomisé évalue, du point de vue de la survie sans événement et de la survie globale à 5 ans, l'efficacité d'une chimiothérapie par cisplatine-étoposide avant ou après une radiothérapie

High-Risk Medulloblastoma : A Pediatric Oncology Group Randomized Trial of Chemotherapy Before or After Radiation Therapy (POG 9031)

Tarbell, Nancy J. ; Friedman, Henry ; Polkinghorn, William R. ; Yock, Torunn ; Zhou, Tianni ; Chen, Zhengjia ; Burger, Peter ; Barnes, Patrick ; Kun, Larry

Purpose : To compare event-free survival (EFS) in children with high-risk medulloblastoma randomly assigned to receive either chemotherapy before radiation or chemotherapy after radiation. Patients and Methods : One hundred twelve patients were randomly assigned to each arm. Criteria used to categorize patients as high risk included M1-4 disease by modified Chang staging classification, T3b/T4 disease, or greater than 1.5 cm3 of residual tumor after surgery. Postoperatively, children with [...]

Menée en France sur 237 patientes atteintes d'un cancer du col de l'utérus de stade localement avancé et traitées par chimioradiothérapie entre 2004 et 2011, cette étude prospective multicentrique évalue l'impact thérapeutique d'une lymphadénectomie para-aortique laparoscopique avant traitement sur la survie des patientes

Prospective Multicenter Study Evaluating the Survival of Patients With Locally Advanced Cervical Cancer Undergoing Laparoscopic Para-Aortic Lymphadenectomy Before Chemoradiotherapy in the Era of Positron Emission Tomography Imaging

Gouy, Sebastien ; Morice, Philippe ; Narducci, Fabrice ; Uzan, Catherine ; Martinez, Alejandra ; Rey, Annie ; Bentivegna, Enrica ; Pautier, Patricia ; Deandreis, Desiree ; Querleu, Denis ; Haie-Meder, Christine ; Leblanc, Eric

Purpose : The aim of this prospective study conducted in three French comprehensive cancer centers was to evaluate the therapeutic impact on survival of laparoscopic para-aortic (PA) staging surgery in locally advanced cervical cancer (LACC) before chemoradiotherapy. Patients and Methods : We conducted a prospective multicenter study of 237 patients treated from 2004 to 2011 for LACC with negative positron emission tomography (PET) imaging of the PA area and undergoing laparoscopic PA [...]

Afin d'améliorer la qualité des travaux de recherche translationnelle, cet article plaide pour le développement de revues systématiques d'études menées sur des animaux

Progress in Using Systematic Reviews of Animal Studies to Improve Translational Research

Hooijmans, C. R. ; Ritskes-Hoitinga, M.

During the last decade, new developments and initiatives have been introduced to improve the quality and translational value of animal research. We summarize these here, focusing on quality of study conduct, reporting, and replication; systematic reviews and meta-analyses; and study registration, publication bias, and data sharing. Systematic reviews of animal studies should be conducted routinely. Funding agencies should subsidize systematic reviews, not simply for transparency, but also to [...]