Selective DNA-PK Inhibition Enhances Chemotherapy and Ionizing Radiation Activity in Soft-Tissue Sarcomas.

PURPOSE: Patients with advanced soft-tissue sarcomas (STS) exhibit a poor prognosis and have few therapeutic options. DNA-dependent protein kinase (DNA-PK) catalytic subunit is a multifunctional serine-threonine protein kinase that plays a crucial role in DNA double-strand damage repair via nonhomologous end joining. EXPERIMENTAL DESIGN: To investigate the therapeutic potential of DNA-PK targeting in STS, we first evaluated the prognostic value of DNA-PK expression in two large cohorts of patients with STS. We then used the potent and selective DNA-PK inhibitor AZD7648 compound to investigate the antitumor effect of the pharmacologic inhibition of DNA-PK in vitro via MTT, apoptosis, cell cycle, and proliferation assays. In vivo studies were performed with patient-derived xenograft models to evaluate the effects of AZD7648 in combination with chemotherapy or ionizing radiation on tumor growth. The mechanisms of sensitivity and resistance to DNA-PK inhibition were investigated by using a genome-wide CRISPR-Cas9 positive screen. RESULTS: DNA-PK overexpression is significantly associated with poor prognosis in patients with sarcomas. Selective pharmacologic inhibition of DNA-PK strongly synergizes with radiation- and doxorubicin-based regimen in sarcoma models. By using a genome-wide CRISPR-Cas9 positive screen, we identified genes involved in sensitivity to DNA-PK inhibition. CONCLUSIONS: DNA-PK inhibition deserves clinical investigation to improve response to current therapies in patients with sarcoma.

Highly hypofractionated schedules for localized prostate cancer: Recommendations of the GETUG radiation oncology group.

Stereotactic body radiotherapy (SBRT) has become treatment option for localized prostate cancer but the evidence base remains incomplete. Several clinical studies, both prospective and retrospective, have been published. However, treatment techniques, target volumes and dose constraints lack consistency between studies. Based on the current available literature, the French Genito-Urinary Group (GETUG) suggests that.

Recommendations for planning and delivery of radical radiotherapy for localized urothelial carcinoma of the bladder.

PURPOSE: Curative radio-chemotherapy is recognized as a standard treatment option for muscle-invasive bladder cancer (MIBC). Nevertheless, the technical aspects for MIBC radiotherapy are heterogeneous with a lack of practical recommendations. METHODS AND MATERIALS: In 2018, a workshop identified the need for two cooperative groups to develop consistent, evidence-based guidelines for irradiation technique in the delivery of curative radiotherapy. Two radiation oncologists performed a review of the literature addressing several topics relative to radical bladder radiotherapy: planning computed tomography acquisition, target volume delineation, radiation schedules (total dose and fractionation) and dose delivery (including radiotherapy techniques, image-guided radiotherapy (IGRT) and adaptive treatment modalities). Searches for original and review articles in the PubMed and Google Scholar databases were conducted from January 1990 until March 2020. During a meeting conducted in October 2020, results on 32 topics were presented and discussed with a working group involving 15 radiation oncologists, 3 urologists and one medical oncologist. We applied the American Urological Association guideline development's method to define a consensus strategy. RESULTS: A consensus was obtained for all 34 except 4 items. The group did not obtain an agreement on CT enhancement added value for planning, PTV margins definition for empty bladder and full bladder protocols, and for pelvic lymph-nodes irradiation. High quality evidence was shown in 6 items; 8 items were considered as low quality of evidence. CONCLUSION: The current recommendations propose a homogenized modality of treatment both for routine clinical practice and for future clinical trials, following the best evidence to date, analyzed with a robust methodology. The XXX group formulates practical guidelines for the implementation of innovative techniques such as adaptive radiotherapy.

Detectors assessment for stereotactic radiosurgery with cones.

The purpose of this work is to assess eight detectors performance for output factor (OF), percent depth dose (PDD), and beam profiles in a 6-MV Clinac stereotactic radiosurgery mode for cone irradiation using Monte Carlo simulation as reference. Cones with diameters comprised between 30 and 4 mm have been studied. The evaluated detectors were ionization chambers: pinpoint and pinpoint 3D, diodes: SRS, P and E, Edge, MicroDiamond and EBT3 radiochromic films. The results showed that pinpoints underestimate OF up to -2.3% for cone diameters ≥10 mm and down to -12% for smaller cones. Both nonshielded (SRS and E) and shielded diodes (P and Edge) overestimate the OF respectively up to 3.3% and 5.2% for cone diameters ≥10 mm and in both cases more than 7% for smaller cones. MicroDiamond slightly overestimates the OF, 3.7% for all the cones and EBT3 film is the closest to Monte Carlo with maximum difference of ±1% whatever the cone size is. For the profiles and the PDD, particularly for the small cones, the size of the detector predominates. All diodes and EBT3 agree with the simulation within ±0.2 mm for beam profiles determination. For PDD curve all the active detectors response agree with simulation up to 1% for all the cones. EBT3 is the more accurate detector for beam profiles and OF determinations of stereotactic cones but it is restrictive to use. Due to respectively inappropriate size of the sensitive volume and composition, pinpoints and diodes do not seem appropriate without OF corrective factors below 10 mm diameter cone. MicroDiamond appears to be the best detector for OF determination regardless all cones. For off-axis measurements, the size of the detector predominates and for PDD all detectors give promising results.

Manual vs. automated implantation of seeds in prostate brachytherapy: Oncologic results from a single-center study.

PURPOSE: The objective of this study was to study survival and tolerance of prostate cancer patients treated with 125I permanent interstitial brachytherapy by automated vs. manual implantation of seeds. METHODS AND MATERIALS: Between 2002 and 2010, 349 selected patients were treated with 125I brachytherapy by the same team: from 2002 to April 2005, 65 patients with linked seeds and then 284 patients treated using Nucletron First System automated implantation. We analyzed biochemical recurrence-free survival (bRFS) rates and toxicities (univariate and multivariate analyses). RESULTS: Two hundred seventy-seven (79.4%) and 69 patients (19.8%) with low- and intermediate-risk disease were treated, respectively (median follow-up: 64 months). The 5-year bRFS rate was 93.1% (95% confidence interval 89.3-95.6) for the entire cohort. The 5-year bRFS rates were 93.4% and 91.7% for patients with low- and intermediate-risk disease, respectively (p = 0.42). In univariate and multivariate analyses, there was no statistically significant difference in the 5-year bRFS rate depending on the implantation technique (93.1% vs. 91.8%, respectively, for automated and linked seeds; p = 0.53). In univariate analysis, only D90 prostate (dose delivered to 90% of the prostate) <140 Gy (p = 0.01), lack of prostate-specific antigen bounce (p = 0.008), and nadir prostate-specific antigen >0.11 (p = 0.01) were predictive factors for bRFS. We observed Grade 3 urethritis in 7 patients (2%), urinary incontinence in 2 patients (0.7%), and Grade 4 proctitis in 2 patients (0.7%). CONCLUSIONS: In this large single-center series, brachytherapy for selected localized prostate cancer achieved excellent rates of biochemical control at 5 years (93.1%) with an acceptable toxicity profile, irrespective of the implantation technique used.