•Metformin is an antidiabetic drug with potentially radiosensitizing properties.•Preclinical data propose numerous mechanisms.•Retrospective studies suggest benefits in PFS and OS in multiples ...localizations.•Metformin could also limit RT-induced toxicities on healthy tissue.•Several clinical trials are ongoing.
Several molecules are being investigated for their ability to enhance the anti-tumor effect of radiotherapy. The widely prescribed antidiabetic drug metformin has been suggested to possess anti-cancer activity; data indicate that metformin could also enhance radiation sensitivity. The purpose of this review is to summarize current knowledge on the specific effect of metformin in the field of RT, while also discussing the many unknowns that persist. Preclinical models point to multiple mechanisms involved in the radiosensitizing effects of metformin that are mainly linked to mitochondrial complex I inhibition and AMP-activated protein kinase. Transposition of results from bench to bedside will be discussed through the lens of the drug concentration, its potential limits in human settings, and possible alternatives. Clinical data suggest metformin improves progression-free and overall survival in patients for many different cancers treated with RT; nevertheless, the results are not always consistent. The main limitations of the reviewed literature are the retrospective nature of studies, and most of the time, a lack of information on MTF treatment duration and the administered dosages. Despite these limitations, the possible mechanisms of the role of metformin and its utility in enhancing radiotherapy treatments are analyzed. Ongoing clinical trials are also discussed.
Amphibian metamorphosis involves extensive, but selective, neuronal death and turnover, thus sharing many features with mammalian postnatal development. The antiapoptotic protein Bcl-X L plays an ...important role in postnatal mammalian neuronal survival. It is therefore of interest that accumulation of the mRNA encoding the Xenopus Bcl-X L homologue, termed xR11, increases abruptly in the nervous system, but not in other tissues, during metamorphosis in Xenopus tadpoles. This observation raises the intriguing possibility that xR11 selectively regulates neuronal survival during postembryonic development. To investigate this hypothesis, we overexpressed xR11 in vivo as a green fluorescent protein (GFP)-xR11 fusion protein by using somatic and germinal transgenesis. Somatic gene transfer showed that the fusion protein was effective in counteracting, in a dose-dependent manner, the proapoptotic effects of coexpressed Bax. When GFP-xR11 was expressed from the neuronal β-tubulin promoter by germinal transgenesis we observed neuronal specific expression that was maintained throughout metamorphosis and beyond, into juvenile and adult stages. Confocal microscopy showed GFP-xR11 to be exclusively localized in the mitochondria. Our findings show that GFP-xR11 significantly prolonged Rohon-Beard neuron survival up to the climax of metamorphosis, even in the regressing tadpole tail, whereas in controls these neurons disappeared in early metamorphosis. However, GFP-xR11 expression did not modify the fate of spinal cord motoneurons. The selective protection of Rohon-Beard neurons reveals cell-specific apoptotic pathways and offers approaches to further analyze programmed neuronal turnover during postembryonic development. transgenesis fusion protein green fluorescent protein Mauthner
L’hypofractionnement extrême en radiothérapie adjuvante mammaire suscite actuellement beaucoup d’intérêt. Nous proposons ici une synthèse des essais d’hypofractionnement ainsi que la présentation des ...projets intitulésDESTHE COL du centre Oscar Lambret et DESTHE GR de l'institut Gustave Roussy, encouragés par l’Institut National du Cancer (INCa), et visant à expérimenter des parcours de soins en vue de déployer des stratégies efficaces de désescalade du fardeau thérapeutique aptes à la diminution des séquelles après traitement d’un cancer.
Extreme hypofractionation in adjuvant breast radiotherapy currently generates a lot of interest. We propose here a synthesis of hypofractionation trials and present the DESTHE COL and DESTHE GR projects, encouraged by the French National Cancer Institute (INCa), which experiment care pathways in order to deploy effective strategies to de-escalate the therapeutics and to reduce sequelae after cancer treatment.
Survivin is a member of the inhibitor of apoptosis proteins (IAP) family. These proteins contain one to three zinc-binding motifs termed bacculoviral IAP-binding repeats (BIRs). Survivin contains a ...single BIR motif. Contrary to other members that directly interact with caspases and inhibit apoptosis, Survivin is believed to have both antiapoptotic and proliferative functions. In mammals, Survivin is not detected in most adult tissues except in endothelial cells of newly formed capillaries and large blood vessels. Importantly, Survivin is highly expressed in all common human cancers. To gain a better view of Survivin expression and function during development, we used the amphibian Xenopus developmental model. We show that the genomes of X. laevis, X. tropicalis, Zebrafish, fugu pufferfish, and rainbow trout encode two different Survivin genes (Su1 and Su2), contrary to mammalian genomes, which encode a single one. In X. laevis, these two genes have a differential spatiotemporal transcription pattern. Transgenic expression of Su1 leads to an enlargement of tadpole's blood vessels with an increase in the number of endothelial cells. This effect requires a functional BIR domain and the p34-cdc2 phosphorylation site. It does not seem to rely on the antiapoptotic activity of Su1 as it is not observed in tadpoles overexpressing other antiapoptotic factors such as XIAP or BclXL. We conclude that Su1 ubiquitous gain of function leads directly or indirectly to an increase in blood vessels size via the proliferation of endothelial cells.
L’irradiation adjuvante locorégionale des cancers du sein gauche est responsable d’une morbidité cardiaque à long terme. L’inspiration profonde est utilisée en radiothérapie conformationnelle ...tridimensionnelle pour diminuer les doses cardiaques. Peu d’études ont évalué la radiothérapie conformationnelle avec modulation d’intensité rotationnelle en inspiration profonde dans cette indication. L’objectif de notre étude était de comparer les données dosimétriques du cœur et de ses sous-structures, en inspiration profonde par rapport à la respiration libre pour la radiothérapie conformationnelle avec modulation d’intensité rotationnelle mammaire et ganglionnaire gauche.
Cette étude dosimétrique a porté sur les dossiers de neuf patientes prises en charge entre 2008 et 2012 et les traitements par irradiation en conditions stéréotaxiques ont concerné quatre seins et cinq parois thoraciques gauches et aires ganglionnaires. Outre les doses dans les organes à risque recommandées, les doses dans les artères coronaires, la région interventriculaire antérieure et la valve aortique ont été comparées.
Les plans de traitements étaient comparables pour les volumes cibles. L’inspiration profonde par rapport à la respiration libre diminuait la dose cardiaque (dose moyenne de 4,8Gy contre 6,6Gy, p=0,008 ; dose dans 2 % du volume de 16,8Gy contre 23,3Gy, p=0,008 ; volume recevant 25Gy de 0,8 % contre 2,2 %, p=0,008 ; volume recevant 30Gy de 0,4 % contre 1,2 %, p=0,009), dans les artères coronaires droite (dose moyenne de 6Gy contre 8,9Gy, p=0,028), dans l’artère interventriculaire antérieure (dose moyenne de 9,6Gy contre 14,6Gy, p=0,021), dans la région interventriculaire antérieures (dose dans 2 % du volume de 17,4Gy contre 24,6Gy, p=0,021), dans la valve aortique (dose moyenne de 4,8Gy contre 7Gy, p=0,028). Les doses dans d’autres organes à risque étaient comparables.
La radiothérapie conformationnelle avec modulation d’intensité rotationnelle en inspiration profonde permet une meilleure épargne du cœur, des artères coronaires droite et interventriculaire antérieure, et de la valve aortique par rapport aux techniques de respiration libre, pour l’irradiation adjuvante locorégionale des cancers du sein gauche.
Adjuvant left-sided breast cancer locoregional radiotherapy can be accounted for long-term cardiac toxicity. The deep inspiration breath hold techniques can reduce cardiac doses. Only a few studies have investigated rotational intensity-modulated radiotherapy with deep inspiration breath hold.
We conducted a dosimetric study comparing rotational intensity-modulated radiotherapy in free breathing with deep inspiration breath hold for irradiation of left breast cancer and locoregional lymph nodes. Doses to organs at risk were compared, as well as doses to coronary arteries, left anterior descending coronary artery region, and aortic valve.
The data from nine patients were included in the study. Treatment plans were comparable for target volumes. The deep inspiration breath hold delivery technique, compared with free breathing, reduced radiation dose to the heart (mean dose 4.8Gy vs. 6.6Gy, p=0.008; dose in 2% of the volume 16.8Gy vs. 23.3Gy, p=0.008; volume receiving 25Gy 0.8% vs. 2,2%, p=0.008; volume receiving 30Gy 0.4% vs. 1.2%, p=0.009), as well as to the right coronary artery (mean dose 6Gy vs. 8.9Gy, p=0.028), to the left anterior descending artery (mean dose 9.6Gy vs. 14.6Gy, p=0.021), to the left anterior descending coronary artery region (dose in 2% of the volume 17.4Gy vs. 24.6Gy, p=0.021), and to the aortic valve (mean dose 4.8Gy vs. 7Gy, p=0.028). Other doses to organs at risk were similar.
Rotational intensity-modulated radiotherapy with deep inspiration breath hold is associated with better sparing of the heart, on the right and left anterior descending coronary arteries, and on the aortic valve, compared with free breathing techniques, for adjuvant left breast cancer locoregional irradiation.
Amphibian metamorphosis involves extensive, but selective, neuronal death and turnover, thus sharing many features with mammalian postnatal development. The antiapoptotic protein Bcl-X
L
plays an ...important role in postnatal mammalian neuronal survival. It is therefore of interest that accumulation of the mRNA encoding the
Xenopus
Bcl-X
L
homologue, termed xR11, increases abruptly in the nervous system, but not in other tissues, during metamorphosis in
Xenopus
tadpoles. This observation raises the intriguing possibility that xR11 selectively regulates neuronal survival during postembryonic development. To investigate this hypothesis, we overexpressed xR11
in vivo
as a green fluorescent protein (GFP)-xR11 fusion protein by using somatic and germinal transgenesis. Somatic gene transfer showed that the fusion protein was effective in counteracting, in a dose-dependent manner, the proapoptotic effects of coexpressed Bax. When GFP-xR11 was expressed from the neuronal β-tubulin promoter by germinal transgenesis we observed neuronal specific expression that was maintained throughout metamorphosis and beyond, into juvenile and adult stages. Confocal microscopy showed GFP-xR11 to be exclusively localized in the mitochondria. Our findings show that GFP-xR11 significantly prolonged Rohon-Beard neuron survival up to the climax of metamorphosis, even in the regressing tadpole tail, whereas in controls these neurons disappeared in early metamorphosis. However, GFP-xR11 expression did not modify the fate of spinal cord motoneurons. The selective protection of Rohon-Beard neurons reveals cell-specific apoptotic pathways and offers approaches to further analyze programmed neuronal turnover during postembryonic development.
Survivin is a member of the inhibitor of apoptosis proteins (IAP) family. These proteins contain one to three zinc-binding motifs termed bacculoviral IAP-binding repeats (BIRs). Survivin contains a ...single BIR motif. Contrary to other members that directly interact with caspases and inhibit apoptosis, Survivin is believed to have both antiapoptotic and proliferative functions. In mammals, Survivin is not detected in most adult tissues except in endothelial cells of newly formed capillaries and large blood vessels. Importantly, Survivin is highly expressed in all common human cancers. To gain a better view of Survivin expression and function during development, we used the amphibian
Xenopus developmental model. We show that the genomes of
X. laevis,
X. tropicalis, Zebrafish, fugu pufferfish, and rainbow trout encode two different Survivin genes (Su1 and Su2), contrary to mammalian genomes, which encode a single one. In
X. laevis, these two genes have a differential spatiotemporal transcription pattern. Transgenic expression of
Su1 leads to an enlargement of tadpole's blood vessels with an increase in the number of endothelial cells. This effect requires a functional BIR domain and the p34/cdc2 phosphorylation site. It does not seem to rely on the antiapoptotic activity of Su1 as it is not observed in tadpoles overexpressing other antiapoptotic factors such as XIAP or BclXL. We conclude that Su1 ubiquitous gain of function leads directly or indirectly to an increase in blood vessels size via the proliferation of endothelial cells.
Évaluer automatiquement des méthodes de recalage rigide pour la localisation de la prostate sur les tomographies coniques (CBCT) et étudier l’impact de la distension rectale.
Cent-quinze tomographies ...coniques de dix patients atteints du cancer de la prostate ont été analysées rétrospectivement. Nous avons effectué différents recalages entre scanographies et tomographies coniques : (a) recalage rigide global, (b) recalage rigide osseux, (c) recalage rigide osseux affiné par un recalage rigide local tissu mou sur le volume cible anatomoclinique de la prostate élargie de 1, 3, 5, 8, 10, 12, 15 ou 20mm. Les contours automatiques sur les tomographies coniques ont été générés après propagation des contours manuels provenant de la scanographie de planification. Le coefficient Dice entre les contours manuel et propagé a été calculé. Nous avons estimé automatiquement la distension rectale entre les scanographies et les tomographies coniques, sans avoir recours aux contours des tomographies coniques, et nous l’avons corrélée aux échecs de recalage. Une évaluation visuelle en aveugle de la qualité des segmentations propagées a également été menée. Pour améliorer la qualité des recalages, l’air dans le rectum a été remplacé par du tissu mou au moyen d’un filtre. Nous avons comparé les résultats avec et sans filtrage.
Les médianes de Dice étaient de 0,785, 0,784, 0,785, 0,803, 0,816, 0,815, 0,801, 0,801, 0,800, 0,799, correspondant respectivement aux méthodes (a), (b), (c) 1mm, (c) 3mm, (c) 5mm, (c) 8mm, (c) 10mm, (c) 12mm, (c) 15mm, (c) 20mm, et 0.731 sans recalage. L’analyse statistique a abouti à des différences hautement significatives pour : (c) 8mm contre (a), (c) 8mm contre (b), (c) 8mm contre (c) 1mm, (c) 5mm contre (a), (c) 5mm contre (b), et (c) 5mm contre (c) 1mm. (c) 8mm a compté le moins d’échecs (95 % de réussites sans filtrage, 97 % avec filtrage). Ces échecs ont été corrélés avec une grande distension rectale. L’évaluation visuelle a confirmé la supériorité de (c) 8mm sur (b).
Le recalage rigide (c) 8mm a été le plus performant. Nous avons fourni une méthode automatique et facilement applicable en pratique clinique pour quantifier la distension rectale et prédire les échecs.
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