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Over the past few years, studies have focused on the development of targeted radiosensitizers such as poly(ADP-ribose) polymerase inhibitors. We performed an in vivo study and a whole-transcriptome analysis to determine whether PARP inhibition enhanced gemcitabine-based chemoradiosensitization of pancreatic cancer xenografts, combined with either proton or photon irradiation. NMRI mice bearing MIA PaCa-2 xenografts were treated with olaparib and/or gemcitabine and irradiated with 10 Gy photon or proton. First, a significant growth inhibition was obtained after 10 Gy proton irradiation compared to 10 Gy photon irradiation (p = 0.046). Moreover, the combination of olaparib, gemcitabine and proton therapy significantly sensitized tumor xenografts, compared to gemcitabine (p = 0.05), olaparib (p = 0.034) or proton therapy (p &lt, 0.0001) alone or to the association of olaparib, gemcitabine and radiotherapy (p = 0.024). Simultaneously, whole RNA sequencing profiling showed differentially expressed genes implicated in categories such as DNA repair, type I interferon signaling and cell cycle. Moreover, a large amount of lncRNA was dysregulated after proton therapy, gemcitabine and olaparib. This is the first study showing that addition of olaparib to gemcitabine-based chemoradiotherapy improved significantly local control in vivo, especially after proton therapy. RNA sequencing profiling analysis presented dynamic alteration of transcriptome after chemoradiation and identified a classifier of gemcitabine response.

Background Current research that combines radiation with targeted therapy may dramatically improve prognosis of pancreatic ductal adenocarcinoma (PDAC). We investigated preclinical outcomes of DNA repair inhibitor targeted therapy associated with radiotherapy. Methods We searched Pubmed database to identify publications assessing DNA damage targeted therapies in preclinical models of PDACin vitro and in vivo. Standard enhancement ratio, median survival and growth delay were extracted. Results We identified fourteen publications using DNA repair targeted therapies in preclinical models of PDAC. Ten publications comprising twenty-eight experiments evaluated radiosensitization with different DNA repair inhibitors in vitro and displayed cell killing by a factor of 1.35 ± 0.047. Moreover, 86 % (24/28) of in vitro experiments showed radiosensitization with DNA damage response inhibitor. However, only 60 % (9/15) of the in vivo experiments presented radiosensitization effects. Conclusion DNA repair targeted therapies use promising radiosensitizers for PDAC and could successfully be translated into clinical trials.

International audience; Background: Poly-(ADP-Ribose)-Polymerase (PARP) inhibitors are becoming important actors of anti-neoplasic agents landscape, with recent but narrow FDA's approvals for ovarian BRCA mutated cancers and prostatic cancer. Nevertheless, PARP inhibitors are also promising drugs for combined treatments particularly with radiotherapy. More than seven PARP inhibitors have been currently developed. Central Role of PARP in DNA repair, makes consider PARP inhibitor as potential radiosensitizers, especially for tumors with DNA repair defects, such as BRCA mutation, because of synthetic lethality. Furthermore the replication-dependent activity of PARP inhibitor helps to maintain the differential effect between tumoral and healthy tissues. Inhibition of chromatin remodeling, G2/M arrest, vasodilatory effect induced by PARP inhibitor, also participate to their radio-sensitization effect. Materials and Methods: Here, after highlighting mechanisms of PARP inhibitors radiosensitization we methodically searched PubMed, Google Scholar, Cochrane Databases and meeting proceedings for human pre-clinical and clinical studies that evaluated PARP inhibitor radiosensitizing effect. Enhancement ratio, when available, was systematically reported. Results: Sixty four studies finally met our selection criteria and were included in the analysis. Only three pre-clinical studies didn't find any radiosensitizing effect. Median enhancement ratio vary from 1,3 for prostate tumors to 1,5 for lung cancers. Nine phase I or II trials assessed safety data. Conclusion: PARP inhibitors are promising radiosensitizers, but need more clinical investigation. The next ten years will be determining for judging their real potential.

Hematologic malignancies may require, at one point during their treatment, allogeneic bone marrow transplantation. Total body irradiation combined with chemotherapy or radiomimetic used in allogeneic bone marrow transplantation is known to be very toxic. Total body irradiation (TBI) induces immunosuppression to prevent the rejection of donor marrow. TBI is also used to eradicate malignant cells and is in sanctuary organs that are not reached by chemotherapy drugs. TBI has evolved since its introduction in the late fifties, but acute and late toxicities remain. Helical tomotherapy, which is widely used for some solid tumors, is a path for the improvement of outcomes and toxicities in TBI because of its sparing capacities. In this article, we first review the practical aspects of TBI with patient positioning, radiobiological considerations and total dose and fractionation prescriptions. Second, we review the use of intensity modulated radiation therapy in bone marrow transplantation with a focus on helical tomotherapy TBI, helical tomotherapy total marrow irradiation (TMI) and total marrow and lymphoid irradiation (TMLI) and their dosimetric and clinical outcomes. Finally, we review the perspective of dose escalation and the extension to older patients and patients with comorbidity who do not benefit from a standard bone marrow transplantation conditioning regimen.

Background: Surgery for anal canal cancer (ACC) and anal margin cancer (AMC) is the only curative option after failure of chemoradiotherapy (CRT). This study aimed to determine the efficacy of surgery for ACC or AMC after failed CRT. Methods: This was a single-centre, retrospective study of 161 patients initially treated with CRT. We compared the survival rates of patients successfully treated by CRT with those of patients whose CRT failed (both surgically salvaged and treated palliatively). Results: Thirty-one patients underwent surgery with curative intent, 20 received palliative treatment after failure of CRT, and 110 had effective CRT. The 5-year overall survival (OS) rate was significantly higher among patients with successful CRT than among patients who underwent surgery with curative intent (86 vs. 66%, p < 0.001). On the other hand, the 5-year OS of patients treated with curative surgery was significantly better than that of patients who underwent palliative treatment (66 vs. 13.5%, p < 0.001). The postoperative morbidity and mortality rates were 32 and 3%, respectively. Considering patients with failed CRT, curative surgery was the only factor prognostic of favourable OS in the multivariate analysis. Conclusion: Curative surgery after failure of CRT for ACC or AMC remains an effective treatment to improve survival in two-thirds of cases, resulting in high but manageable morbidity.

TomoDirect (TD) can only operate in free-breathing. The purpose of this study is to compare TD with breath-hold 3D conformal radiotherapy (3DCRT) and intensity modulated radiotherapy (IMRT) techniques for left breast treatments, and to determine if the lack of respiratory gating is a handicap for cardiac sparing.15 patients treated for left breast had two computed tomography simulation, in free breathing (FB) and in deep-inspiration breath-hold (DIBH). Four treatments were planned: TD-FB, 3DCRT-FB, 3DCRT-DIBH and IMRT-DIBH. Dose to PTV, heart, lungs, right breast and patient were compared.A slightly lower cardiac mean dose is found for 3DCRT-DIBH than for TD-FB group (1.99Gy Vs 2.89Gy, p=0.0462), while no statistical difference is found for heart V20. TD-FB plans show the best PTV dose homogeneity (0.053, p0.001) and the lowest left lung mean dose (5.16Gy, p0.001). No major differences are found for the other organs.TomoDirect and breath-hold 3DCRT are complementary techniques for left breast treatments: for a minority of patients, respiratory gating is mandatory to lower cardiac dose; for the remaining majority of patients, TomoDirect achieves better PTV homogeneity and reduced left lung dose, with cardiac dose equivalent to 3DCRT-DIBH.

Aim: The purpose of this study was to investigate prospectively the predictive value of positron emission tomography with proton magnetic resonance spectroscopic imaging (MRSI) and 18F-fluorodeoxyglucose (FDG-PET) performed the 1st month after surgery and before radio- chemotherapy in 43 patients with glioblastoma (GBM). Patients and methods: Metabolite concentrations were quantified using LCModel. Overall survival (OS) and progression free survival (PFS) were calculated including all 43 patients using Kaplan-Meier curves, and the Cox proportional hazard model was used to calculate the predictor of survival. Results: At the end of the follow-up period, all patients died within a period of 1–70.2 months. In 32 patients (74.4%), increased FDG-uptake was seen around the resection cavity and abnormal metabolic profiles on MRSI, indicative of residual disease, were present in all patients. There was no significant difference between the median OS in patients with hypometabolic FDG lesions compared to patients with hypermetabolic FDG lesions. On univariate analysis, normalized choline-containing compounds/creatine (nCho/Cr) and normalized lactate/creatine (nLac/Cr) were significantly predictive of OS and nLac/Cr and normalized N-Acetylaspartylglutamate and NAcetylaspartate/ creatine (NAA/Cr) were significantly predictive of PFS. Conclusions: nCho/Cr and nLac/Cr ratio after surgery and before radio-chemotherapy were independent metabolic predictive factors of OS times in newly diagnosed patients with GBM.

Meningiomas represent the most common tumours of the central nervous system in adults. Risk factors include ionizing radiation, female hormones exposure, head trauma, cell phone use, breast cancer and family history of meningioma. Despite complete surgical resection, natural history of meningiomas often includes local recurrence but very few metastatic meningiomas have been reported. Here, we report the case of a metastatic meningioma. A 43-year-old woman was firstly treated for a symptomatic parietal meningioma WHO grade II by surgical resection followed by an irradiation of the surgical bed. After surgical resection and irradiation, the patient recovered incompletely. Two months after the end of the radiation treatment, the patient presented at the emergency unit for sciatic pain revealing bone metastases that has been histologically confirmed. Moreover, imaging led to the diagnosis of liver and lungs metastasis. Despite lack of guidelines for metastatic meningioma, few treatments have been used and published for recurrent and multiple meningioma management. In case studies, some partial responses have been seen with mifepristone and improved progression-free survival rates have been obtained with hydroxyurea and sunitinib. Metastasis in meningioma is very uncommon and no specific management has been described. Hydroxyurea, sunitinib and mifepristone could be options if no clinical trial data is available.