Glioblastomas (GBM) are some bad prognosis brain tumors despite a conventional treatment associating surgical resection and subsequent radio-chemotherapy. Among these heterogeneous tumors, a ...subpopulation of chemo- and radioresistant GBM stem-like cells appears to be involved in the systematic GBM recurrence. Moreover, recent studies showed that differentiated tumor cells may have the ability to dedifferentiate and acquire a stem-like phenotype, a phenomenon also called plasticity, in response to microenvironment stresses such as hypoxia. We hypothesized that GBM cells could be subjected to a similar dedifferentiation process after ionizing radiations (IRs), then supporting the GBM rapid recurrence after radiotherapy. In the present study we demonstrated that subtoxic IR exposure of differentiated GBM cells isolated from patient resections potentiated the long-term reacquisition of stem-associated properties such as the ability to generate primary and secondary neurospheres, the expression of stemness markers and an increased tumorigenicity. We also identified during this process an upregulation of the anti-apoptotic protein survivin and we showed that its specific downregulation led to the blockade of the IR-induced plasticity. Altogether, these results demonstrated that irradiation could regulate GBM cell dedifferentiation via a survivin-dependent pathway. Targeting the mechanisms associated with IR-induced plasticity will likely contribute to the development of some innovating pharmacological strategies for an improved radiosensitization of these aggressive brain cancers.
•This EANO-ESMO Clinical Practice Guideline provides key recommendations on the management of neurological and vascular complications of brain tumours.•Authorship includes a multidisciplinary group ...of experts from different institutions and countries in Europe and abroad.•Treatment recommendations are provided, including levels of evidence and grades of recommendation where applicable.•Brain tumour patients need close clinical monitoring because of the frequency of neurological and vascular complications.•Early recognition and appropriate management of complications are key.
We aimed to identify subventricular zone (SVZ)-related prognostic factors of survival and patterns of recurrence among patients with glioblastoma.
Forty-three patients with primary diagnosed ...glioblastoma treated in our Cancer Center between 2006 and 2010 were identified. All patients received surgical resection, followed by temozolomide-based chemoradiation. Ipsilateral (iSVZ), contralateral (cSVZ) and bilateral (bSVZ) SVZs were retrospectively segmented and radiation dose-volume histograms were generated. Multivariate analysis using the Cox proportional hazards model was assessed to examine the relationship between prognostic factors and time to progression (TTP) or overall survival (OS).
Median age was 59 years (range: 25-85). Median follow-up, OS and TTP were 22.7 months (range 7.5-69.7 months), 22.7 months (95% CI 14.5-26.2 months) and 6.4 months (95% CI 4.4-9.3 months), respectively. On univariate analysis, initial contact to SVZ was a poor prognostic factor for OS (18.7 vs 41.7 months, p = 0.014) and TTP (4.6 vs 12.9 months, p = 0.002). Patients whose bSVZ volume receiving at least 20 Gy (V20Gy) was greater than 84% had a significantly improved TTP (17.7 months vs 5.2 months, p = 0.017). This radiation dose coverage was compatible with an hippocampal sparing. On multivariate analysis, initial contact to SVZ and V20 Gy to bSVZ lesser than 84% remained poor prognostic factors for TTP (HR = 3.07, p = 0.012 and HR = 2.67, p = 0.047, respectively).
Our results suggest that contact to SVZ, as well as insufficient bSVZ radiation dose coverage (V20Gy <84%), might be independent poor prognostic factors for TTP. Therefore, targeting SVZ could be of crucial interest for optimizing glioblastoma treatment.
From surviving fraction to tumour curability, definitions of tumour radioresistance may vary depending on the view angle. Yet, mechanisms of radioresistance have been identified and involve ...tumour-specific oncogenic signalling pathways, tumour metabolism and proliferation, tumour microenvironment/hypoxia, genomics. Correlations between tumour biology (histology) and imaging allow theragnostic approaches that use non-invasive biological imaging using tracer functionalization of tumour pathway biomarkers, imaging of hypoxia, etc. Modelling dose prescription function based on their tumour radio-resistant factor enhancement ratio, related to metabolism, proliferation, hypoxia is an area of investigation. Yet, the delivery of dose painting by numbers/voxel-based radiotherapy with low lineal energy transfer particles may be limited by the degree of modulation complexity needed to achieve the doses needed to counteract radioresistance. Higher lineal energy transfer particles or combinations of different particles, or combinations with drugs and devices such as done with radioenhancing nanoparticles may be promising.
Si les définitions de la radiorésistance des tumeurs peuvent varier selon l’angle de vue, radiobiologique ou clinique, les mécanismes de la radiorésistance sont partiellement identifiés. Ils impliquent des voies de signalisation oncogènes spécifiques aux tumeurs, le métabolisme et la prolifération des tumeurs, le microenvironnement tumoral/hypoxie, et peuvent reposer sur une génomique somatique spécifique. Les corrélations entre la biologie des tumeurs (histologie) et l’imagerie permettent des approches théragnostiques qui utilisent une imagerie biologique non invasive (fonctionnalisation de traceurs des biomarqueurs des voies tumorales, imagerie de l’hypoxie, etc). La modélisation de la fonction de prescription des doses en fonction de leur rapport d’amélioration d’un facteur de radiorésistance des tumeurs, lié au métabolisme, à la prolifération, à l’hypoxie est un domaine en cours d’investigations. Pourtant, la délivrance d’une irradiation très modulée, voxel par voxel, avec des particules à faible transfert d’énergie linéal, peut être limitée par le degré de complexité de la modulation nécessaire pour obtenir les doses requises pour contrer la radiorésistance tumorale. Des particules à transfert d’énergie linéal plus élevé ou des combinaisons de différentes particules, ou des combinaisons avec des médicaments et dispositifs comme celles réalisées avec des nanoparticules améliorant la radioprotection peuvent être envisagées.
Purpose
Patients with locally advanced grade 2–3 extremity/truncal soft tissue sarcomas (STS) are at high risk of recurrence. The objective of this study was to assess the efficacy and feasibility of ...neoadjuvant concurrent chemoradiotherapy (cCRT) in selected grade 2–3 patients with limb or trunk wall STS, and to compare this schedule to a sequential approach combining neoadjuvant chemotherapy and adjuvant radiotherapy.
Methods
We retrospectively included patients who underwent neoadjuvant cCRT at two comprehensive cancer centers from 1992–2016. We then compared these results to those of patients treated with preoperative chemotherapy and postoperative radiotherapy from a third comprehensive cancer center with a propensity score matched analysis.
Results
A total of 53 patients were treated by neoadjuvant cCRT; 58 patients could be matched with 29 patients in each treatment group after propensity score matching. Disease-free survival and overall survival at 5 years were 54.9 and 63.5%, respectively with neoadjuvant cCRT, with no significant difference when compared to the sequential treatment group. R0 resection rate was higher (90.9 vs 44.8%,
p
< 0.01) in the cCRT group than in the sequential treatment group during a shorter therapeutic sequence (118 vs 210.5 days,
p
< 0.01), with no impact on the surgical procedure or postoperative complications.
Conclusion
cCRT is feasible with acceptable immediate and late toxicities. It could facilitate surgery by increasing the R0 resection rate and improve patient compliance by shortening the therapeutic sequence.
We aimed to assess the efficacy of stereotactic irradiation for patients with recurrent high-grade glioma (HGG) and identify predictive factors of progression-free survival (PFS) and overall survival ...(OS) following reirradiation. We identified 32 patients with recurrent brain HGG who had been treated with either single-dose (stereotactic radiosurgery) or fractionated stereotactic radiotherapy between April 2008 and October 2015. Median follow up was 21.4 months (range 12.9–23.2) and median PFS was and 3.3 months (95% CI 2.3–4.7), respectively. OS was 90.40% (95% CI 73.09–96.80) at 6 months and 79.55% (95% CI 59.9–90.29) at 12 months. Univariate analysis showed that biological effective dose at isocenter ≤ 76 Gy was a poor prognostic factor for both OS (83.33 vs. 100% at 6 months,
p
= 0.032) and median PFS (2.7 vs. 4.7 months,
p
= 0.025), as was gross tumor volume (GTV) above 1 cm
3
for OS (86.15 vs. 94.12% at 6 months,
p
= 0.043). Contact with the subventricular zone (SVZ) was also a poor prognostic factor for median PFS (2.3 vs. 4.7 months,
p
= 0.002). Multivariate analysis showed that SVZ contact remained a poor prognostic factor for PFS (hazard ratio = 3.44, 95% CI 1.21–9.82,
p
= 0.021). Results suggest that reirradiation is a safe and effective treatment option for recurrent HGG in patients with a good Karnosfsky Performance Scale score, a long progression-free interval since first radiation and limited GTV, and that contact to SVZ is a strong prognostic factor for PFS.
The RadioTransNet programme launched under the auspices of French societies for radiation oncology (SFRO) and medical physics (SFPM) was approved by the French national cancer institute (INCa) in ...December 2018 and is dedicated to proposing a relevant national and transversal structure for preclinical research including translational research in radiation oncology with well-defined priority areas of research. Its activities, coordinated by a scientific committee that includes radiation oncologists, medical physicists, academic biologists, are structured around several main areas, i.e.: target volume definition, interaction of radiation with normal tissues, combined treatments and modern dose calculation approaches. Four work packages have been created in these areas and are associated with other objectives pertaining to fundamental radiobiology, early implementation of new drugs in a preclinical setting, contribution of imaging in this task, research in medical physics including transversal components such as medical oncology, radiology, nuclear medicine and also cost/efficiency evaluation. All these tasks will be included in a national network that uses the complementary expertise provided by partners involved in the scheme. Calls for proposals will be selected by the scientific council to be submitted to INCa and the various academic associations to obtain funding for the human and technical resources required to conduct under optimal conditions projects in preclinical and translational research in radiation-oncology.
Le programme RadioTransNet, porté par la Société française de radiothérapie oncologique (SFRO) en association avec la Société française de physique médicale (SFPM), a été labellisé par l’Institut national du cancer (INCa) en décembre 2018. Il est destiné à proposer une structuration cohérente, nationale et transversale de la recherche préclinique et translationnelle en radiothérapie oncologique, en identifiant des priorités de recherche. Ses activités sont coordonnées par un conseil scientifique, composé d’oncologues-radiothérapeutes, de physiciens médicaux et de chercheurs biologistes académiques, qui a organisé ses activités autour de quatre axes majeurs qui sont : la définition des volumes cible, l’interaction des radiations ionisantes avec les tissus sains, les traitements combinés et les approches modernes de calcul de doses. À ces quatre axes majeurs sont associés différents objectifs concernant la radiobiologie fondamentale, les études d’implémentation de nouvelles drogues en préclinique, l’apport de l’imagerie dans cette problématique, la recherche en physique médicale, en intégrant une dimension transversale intéressant l’oncologie médicale, la radiologie médicale, la médecine nucléaire, sans oublier les considérations de coût/efficacité. Les thèmes retenus constituent la base des projets étudiés et développés en faisant appel, au sein du réseau aux compétences complémentaires de toutes les plateformes partenaires impliquées. Des propositions d’appels d’offres sélectionnées par le conseil scientifique seront soumises à l’INCa et aux différentes associations académiques, pour financer les moyens humains et techniques nécessaires à conduire, dans les meilleures conditions, cette recherche préclinique et translationnelle en radiothérapie.
Objective
To identify relevant relative cerebral blood volume biomarkers from T2* dynamic-susceptibility contrast magnetic resonance imaging to anticipate glioblastoma progression after ...chemoradiation.
Methods
Twenty-five patients from a prospective study with glioblastoma, primarily treated by chemoradiation, were included. According to the last follow-up MRI confirmed status, patients were divided into: relapse group (n = 13) and control group (n = 12). The time of last MR acquisition was t
end
; MR acquisitions performed at t
end-2M
, t
end-4M
and t
end-6M
(respectively 2, 4 and 6 months before t
end
) were analyzed to extract relevant variations among eleven perfusion biomarkers (B). These variations were assessed through R(B), as the absolute value of the ratio between ∆B from t
end-4M
to t
end-2M
and ∆B from t
end-6M
to t
end-4M
. The optimal cut-off for R(B) was determined using receiver-operating-characteristic curve analysis.
Results
The fraction of hypoperfused tumor volume (F_hP
g
) was a relevant biomarker. A ratio R(F_hP
g
) ≥ 0.61 would have been able to anticipate relapse at the next follow-up with a sensitivity/specificity/accuracy of 92.3 %/63.6 %/79.2 %. High R(F_hPg) (≥0.61) was associated with more relapse at t
end
compared to low R(F_hPg) (75 % vs 12.5 %, p = 0.008).
Conclusion
Iterative analysis of F_hP
g
from consecutive examinations could provide surrogate markers to predict progression at the next follow-up.
Key Points
•
Related rCBV biomarkers from DSC were assessed to anticipate GBM progression.
•
Biomarkers were assessed through their patterns of variation during the follow-up.
•
The fraction of hypoperfused tumour volume (F_hP
g
) seemed to be a relevant biomarker.
•
An innovative ratio R(F_hP
g
) could be an early surrogate marker of relapse.
•
A significant time gain could be achieved in the management of GBM patients.
Angiogenesis is essential in tumor progression and metastatic process, and increased angiogenesis has been associated with poor prognosis and relapse of colorectal cancer (CRC). VEGF has become the ...main target of anti-angiogenic therapy. However, most patients relapse after an initial response or present a resistance to the treatment. Identification of new pro-angiogenic factors may help to improve anti-angiogenic therapy. In this study, we demonstrated that the pro-hormone progastrin (PG), over-expressed in CRC, recognized as a growth factor, is a potent pro-angiogenic factor. In transgenic mice and human colorectal HPs producing high levels of PG, we correlated PG overexpression with an increased vascularization. In vitro, exogenous PG and conditioned media (CM) from CRC cells producing PG increased endothelial cell proliferation and migration. We also showed that treatment with exogenous PG can increase the ability of endothelial cells to form capillary-like structures. Moreover, we demonstrated that PG enhanced endothelial permeability. The finding that PG stimulated the phosphorylation of vascular endothelial (VE)-cadherin, p125-FAK, paxillin and induced actin remodelling was consistent with a role of these components in PG-stimulated endothelial cell migration and permeability. The pro-angiogenic effects observed with CM were significantly inhibited when CRC cells expressed a PG shRNA. In vivo, we found an important decrease in tumor growth and neovascularization when the CRC cells expressing the PG shRNA were xenografted in mice or in the chick chorioallantoic membrane model. We also observed an increase in the coverage of blood vessels by pericytes and a decrease in endothelial permeability when PG expression was blocked. Our results demonstrate that PG is a new pro-angiogenic factor in CRC and an attractive therapeutic target.
The ambition of the RADIOTRANSNET network, launched by the INCa at the end of 2018, is to create a French research consortium dedicated to preclinical radiotherapy to foster scientific and clinical ...interactions at the interface of radiotherapy and radiobiology, and to identify research priorities dedicated to innovation in radiotherapy. The activities of the network are organized around four major axes that are target definition, normal tissue, combined treatments and dose modelling. Under the supervision of the Scientific Council, headed by a coordinator designated by the SFRO and a co-coordinator designated by the SFPM, three leaders coordinate each axis: a radiation-oncologist, a medical physicist and a biologist, who are responsible for organizing a scientific meeting based on the consensus conference methodology to identify priority issues. The selected themes will be the basis for the establishment of a strategic research agenda and a roadmap to help coordinate national basic and translational research efforts in oncological radiotherapy. This work will be published and will be transmitted to the funding institutions and bodies with the aim of opening dedicated calls to finance the necessary human and technical resources. Structuration of a preclinical research network will allow coordinating the efforts of all the actors in the field and thus promoting innovation in radiotherapy.
PDF
