Palliative radiotherapy is used to alleviate cancer-related symptoms. Symptomatic responses to palliative radiotherapy may however take several weeks, meaning that patients need to survive long ...enough to derive a real benefit. Oncologists can be optimistic when estimating survival for patients with advanced cancer and as a consequence some patients receiving palliative radiotherapy die before experiencing any gain. Models of patient survival have limited accuracy, particularly for predicting whether patients will die within the next 30 days. Dedicated rapid access palliative radiotherapy clinics, in which patients are assessed, simulated and treated on the same day, reduce the number of patient visits to the radiation oncology department and hence the burden on the patient as well as costs. Teleconsultation and advanced practice nurses can play a crucial role in providing rapid access to palliative radiotherapy in a dedicated palliative radiotherapy service. Single-fraction palliative radiotherapy should be offered to eligible patients if they are able to attend treatment and could potentially benefit from symptom palliation, irrespective of predicted life expectancy. Technical and organizational innovations have been proposed in order to dispense with the computed tomography scanner by carrying out the dosimetry on a recent diagnostic scanner or a magnetic resonance imaging scanner with integrated linear acceleration system. Stereotactic body radiation therapy makes it possible to envisage greater and more lasting analgesic benefits in patients with painful bone metastasis and good prognosis. Flash radiotherapy remains at the preclinical stage.
Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET ...inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi
. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of Brd4 in mice
, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions
and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported
, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment
. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-075
. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.
Les sarcomes des tissus mous sont des tumeurs assez rares (1 % des tumeurs de l’adulte), de localisation ubiquitaire et de grande diversité morphologique (plus de 50 types et sous-types), dont le ...diagnostic et la prise en charge thérapeutique initiale qui en dépendent sont très importants pour le devenir des patients. Ainsi, la prise en charge doit être pluridisciplinaire au sein d’une équipe expérimentée. Les sarcomes des membres représentent plus de la moitié de l’ensemble des sarcomes. Le standard thérapeutique consiste en une chirurgie élargie conservatrice planifiée selon les résultats de la biopsie, souvent associée à une radiothérapie postopératoire mais qui peut aussi être préopératoire. Les indications de la radiothérapie préopératoire sont discutées en réunion de concertation pluridisciplinaire pour des tumeurs localement évoluées. La définition des volumes cibles en vue d’une radiothérapie conformationnelle nécessite la connaissance du dossier du patient (imagerie, aspects de la cicatrice et du lit opératoire, maladies associées éventuelles), mais également une lecture attentive des compte-rendus chirurgicaux et histologiques. Les définitions des volumes cibles allient une approche anatomique et géométrique. Le volume tumoral macroscopique correspond à la masse tumorale visible sur l’IRM préopératoire. Le volume cible anatomoclinique correspondant est défini par une extension automatique longitudinale plus importante que l’extension radiaire. Il est corrigé manuellement en tenant compte des barrières anatomiques à l’extension tumorale. Le volume cible prévisionnel correspond à une marge automatique concentrique pouvant varier d’une institution à une autre, selon les moyens de contention et les modes de vérification du repositionnement. Les techniques innovantes de radiothérapie permettent de diminuer en partie la taille des marges des volumes cibles et de mieux protéger les organes à risque.
Soft tissue sarcoma is a rare entity and heterogeneous disease and its management therefore requires an experienced multidisciplinary team in an expert center. Standard treatment for grade 2 and 3 sarcomas is a conservative, extended surgery planned according to the results of the biopsy, and radiotherapy usually administered postoperatively (or pre-operatively). The indications for preoperative radiotherapy are discussed in a multidisciplinary meeting for locally advanced tumours. The definition of target volumes for conformal radiation therapy requires a good knowledge of the patient record, radioanatomy, as well as a careful reading of surgical and histological reports. The definitions of target volumes combine anatomical and geometrical approach. The gross tumour volume is the visible tumour on MRI preoperatively. The corresponding clinical target volume is defined by a larger longitudinal automatic extension than the radial extension. It is manually corrected taking into account the anatomical barriers to tumour spread. The planning target volume is a concentric automatic margin that may vary from one institution to another, depending on the immobilisation devices and verification of repositioning. Innovative radiotherapy techniques may be used to reduce the size of the margins around target volumes and better protect the organs at risk.
Establishing and interpreting patterns of lithic assemblage variability is of great interest to archaeologists as they shed light on cultural adaptations in the deep past. Nowhere has this topic ...provoked more interest and debate than in the Middle Palaeolithic of southwestern France. The region's rich archaeological record has produced numerous sites, many of which have been recently excavated and thus provide a reliable dataset for better structuring Mousterian lithic variability. Researchers working with these types of datasets frequently employ the chaîne opératoire concept to approach lithic assemblage variability; however, the validity of such analyses has recently been questioned. Here we present results of a combined quantitative and qualitative technological analysis of a large sample of assemblages from numerous well-contextualised sites in the northeastern Aquitaine Basin. We selected clearly identifiable diagnostic elements typical of different flake production systems that can be quantified by different analysts in a replicable fashion. Our results show strong differences in assemblage composition in terms of dominant production systems as well as a smaller number of mixed assemblages that combine two or more flake production methods. When considered together, these results provide not only a means for defining lithic technocomplexes and subsequently comparing assemblages but also for investigating elements of Neanderthal material culture variability.
Stereotactic body radiation therapy is effective for the local management of oligometastases (at most five metastases) with a benefit in survival and local control. Most studies on the management of ...oligometastases focus on all oligometastatic sites in primary cancer and very few focus on a single oligometastatic site. In particular, there are few data on bone oligometastases, which represent one of the preferred sites for secondary cancer locations. This article focuses on the benefit of stereotactic radiotherapy for bone oligometastases of all cancers by histological types, and reviews the results of major studies in this field.
La radiothérapie stéréotaxique a fait ses preuves dans la prise en charge locale des oligométastases (au plus cinq métastases) avec un bénéfice sur la survie et le contrôle local. La plupart des études sur les oligométastases s’intéressent à l’ensemble des sites oligométastatiques d’un cancer primitif et très peu s’intéressent à un seul site oligométastatique. En particulier, il existe peu de données sur les oligométastases osseuses, qui représentent un des sites privilégiés de localisations secondaires cancéreuses. Cet article s’intéresse au bénéfice de la radiothérapie stéréotaxique des oligométastases osseuses tous cancers confondus et par types histologiques, et reprend les résultats des grands essais dans ce domaine.
The purpose of this study was to compare the planimetric capacities between HyperArc™-based stereotactic radiosurgery and robotic radiosurgery system-based planning using CyberKnife® M6 for single ...and multiple cranial metastases.
We evaluated 51 treatment plans for cranial metastases, including 30 patients with a single lesion and 21 patients with multiple lesions, treated with the CyberKnife® M6. These treatment plans were optimized using the HyperArc™ (HA) system with the TrueBeam. The comparison of the quality of the treatment plans between the two treatment techniques (CyberKnife and HyperArc) was performed using the Eclipse treatment planning system. Dosimetric parameters were compared for target volumes and organs at risk.
Coverage of the target volumes was equivalent between the two techniques, whereas median Paddick conformity index and median gradient index for all target volumes were 0.9 and 3.4, respectively for HyperArc plans, and 0.8 and 4.5 for CyberKnife plans (P<0.001). The median dose of gross tumor volume (GTV) for HyperArc and CyberKnife plans were 28.4 and 28.8, respectively. Total brain V18Gy and V12Gy-GTVs were 11cm3 and 20.2cm3 for HyperArc plans versus 18cm3 and 34.1cm3 for CyberKnife plans (P<0.001).
The HyperArc provided better brain sparing, with a significant reduction in V12Gy and V18Gy, associated with a lower gradient index, whereas the CyberKnife gave a higher median GTV dose. The HyperArc technique seems to be more appropriate for multiple cranial metastases and for large single metastatic lesions.
L’objectif de cette étude était de comparer les capacités planimétriques entre la radiochirurgie stéréotaxique avec la technique HyperArc™ et une planification basée sur un système de radiochirurgie robotisée utilisant le CyberKnife® M6 pour des métastases crâniennes uniques ou multiples.
Nous avons évalué 51 plans de traitement de métastases crâniennes, dont 30 patients étaient atteints d’une lésion unique et 21 patients de lésions multiples, traitées par CyberKnife® M6. Ces plans de traitement ont également été optimisés à l’aide de l’option HyperArc™ disponible avec le TrueBeam. La comparaison de la qualité des plans de traitement entre les deux techniques de traitement (HyperArc™ et CyberKnife®) a été effectuée à l’aide du système de planification des traitements Eclipse™. Les paramètres dosimétriques ont été comparés pour les volumes cibles et les organes à risque.
La couverture des volumes cibles était équivalente entre les deux techniques, alors que l’indice de conformité médian de Paddick et l’indice de gradient médian pour tous les volumes cibles étaient de 0,9 et 3,4, respectivement pour les plans HyperArc, et de 0,8 et 4,5 pour les plans CyberKnife (p<0,001). Les doses médianes dans le volume tumoral macroscopique pour les plans HyperArc™ et CyberKnife® étaient respectivement de 28,4 et 28,8. Les volumes recevant 18Gy (V18Gy) ou 12Gy (V12Gy) de l’encéphale total étaient de 11cm3 et 20,2cm3 pour les plans HyperArc contre 18cm3 et 34,1cm3 pour les plans du CyberKnife® (p<0,001).
L’HyperArc™ a permis une meilleure épargne encéphalique, avec une réduction significative des V12Gy et V18Gy associée à un indice de gradient plus faible, tandis que le CyberKnife® a donné une dose médiane dans le volume tumoral macroscopique plus élevée. La technique HyperArc™ semble être plus appropriée pour les lésions métastatiques crâniennes multiples ainsi que pour les grandes lésions métastatiques uniques.
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