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Background and purpose: Magnetic Resonance (MR)-only radiotherapy requires geometrically accurate MR images over the full scanner Field of View (FoV). This study aimed to investigate the repeatability of distortion measurements made using a commercial large FoV phantom and analysis software and the sensitivity of these measurements to small set-up errors. Materials and methods: Geometric distortion was measured using a commercial phantom and software with 2D and 3D acquisition sequences on three different MR scanners. Two sets of repeatability measurements were made: three scans acquired without moving the phantom between scans (single set-up) and five scans acquired with the phantom re-set up in between each scan (repeated set-up). The set-up sensitivity was assessed by scanning the phantom with an intentional 1 mm lateral offset and independently an intentional 1° rotation. Results: The mean standard deviation of distortion for all phantom markers for the repeated set-up scans was

Magnetic resonance imaging (MRI) offers superior soft-tissue contrast as compared with computed tomography (CT), which is conventionally used for radiation therapy treatment planning (RTP) and patient positioning verification, resulting in improved target definition. The 2 modalities are co-registered for RTP; however, this introduces a systematic error. Implementing an MRI-only radiation therapy workflow would be advantageous because this error would be eliminated, the patient pathway simplified, and patient dose reduced. Unlike CT, in MRI there is no direct relationship between signal intensity and electron density; however, various methodologies for MRI-only RTP have been reported. A systematic review of these methods was undertaken. The PRISMA guidelines were followed. Embase and Medline databases were searched (1996 to March, 2017) for studies that generated synthetic CT scans (sCT)s for MRI-only radiation therapy. Sixty-one articles met the inclusion criteria. This review showed that MRI-only RTP techniques could be grouped into 3 categories: (1) bulk density override; (2) atlas-based; and (3) voxel-based techniques, which all produce an sCT scan from MR images. Bulk density override techniques either used a single homogeneous or multiple tissue override. The former produced large dosimetric errors (>2%) in some cases and the latter frequently required manual bone contouring. Atlas-based techniques used both single and multiple atlases and included methods incorporating pattern recognition techniques. Clinically acceptable sCTs were reported, but atypical anatomy led to erroneous results in some cases. Voxel-based techniques included methods using routine and specialized MRI sequences, namely ultra-short echo time imaging. High-quality sCTs were produced; however, use of multiple sequences led to long scanning times increasing the chances of patient movement. Using nonroutine sequences would currently be problematic in most radiation therapy centers. Atlas-based and voxel-based techniques were found to be the most clinically useful methods, with some studies reporting dosimetric differences of

Aims The increasing use of highly conformal radiation techniques to treat meningioma confers a greater need for accurate targeting. Several groups have shown that positron emission tomography/computed tomography (PET/CT) information alters meningioma targets contoured by single observers, but whether this translates into improved accuracy has not been defined. As magnetic resonance imaging (MRI) is the cornerstone of meningioma target contouring, simultaneous PET/MRI may be superior to PET/CT. We assessed whether 68 Ga DOTATATE PET imaging (from PET/CT and PET/MRI) reduced interobserver variability (IOV) in meningioma target volume contouring. Materials and methods Ten patients with meningioma underwent simultaneous 68 Ga DOTATATE PET/MRI followed by PET/CT. They were selected as it was anticipated that target volume definition in their cases would be particularly challenging. Three radiation oncologists contoured target volumes according to an agreed protocol: gross tumour volume (GTV) and clinical target volume (CTV) on CT/MRI alone, CT/MRI+PET(CT) and CT/MRI+PET(MRI). GTV/CTV Kouwenhoven conformity levels (KCL), regions of contour variation and qualitative differences between PET(CT) and PET(MRI) were evaluated. Results There was substantial IOV in contouring. GTV mean KCL: CT/MRI 0.34, CT/MRI+PET(CT) 0.38, CT/MRI+PET(MRI) 0.39 ( P = 0.06). CTV mean KCL: CT/MRI 0.31, CT/MRI+PET(CT) 0.35, CT/MRI+PET(MRI) 0.35 ( P = 0.04 for all groups; P > 0.05 for individual pairs). One observer consistently contoured largest and one smallest. Observers rarely decreased volumes in relation to PET. Most IOV occurred in bone followed by dural tail, postoperative bed and venous sinuses. Tumour edges were qualitatively clearer on PET(MRI) versus PET(CT), but this did not affect contouring. Conclusion IOV in contouring challenging meningioma cases was large and only slightly improved with the addition of 68 Ga DOTATATE PET. Simultaneous PET/MRI for meningioma contouring is feasible, but did not improve IOV versus PET/CT. Whether volumes can be safely reduced according to PET requires evaluation.

The treatment of primary brain tumours remains a significant clinical challenge and developing novel treatment approaches is a major unmet need. The results from recent studies investigating novel molecular targeting agents have been disappointing and this is thought to reflect significant intra-tumoral heterogeneity, tumour cell plasticity and redundancy in targetable pathways. Improved understanding of the underlying biology that drives hallmarks of this disease including angiogenesis, invasion and stem-like behaviour is necessary to identify new approaches to intervention. The identification of prognostic and predictive biomarkers that reflect this biology is also an unmet need in progress towards individualised treatment.

Background: The EGF-receptor variant III (EGFRvIII) is expressed in approximately 30% of all primary glioblastoma (GBM). Although several anti-EGFRvIII strategies have already been tested, the importance of EGFRvIII expression on treatment response is still under debate. Our aim was to clarify the relevance of EGFRvIII for GBM treatment using uni- and multivariate analysis of clinical data and preclinical studies. Methods: We performed retrospective analysis of 338 IDH1 wild type GBM patients treated either at the University of Pennsylvania or North Bristol NHS Trust and included data from the TCGA database. Survival was stratified according to MGMT promoter methylation status, EGFRvIII expression and EGFR gene amplification. The effect of EGFRvIII expression was also analyzed at the cellular and tumor level using isogenic pairs of EGFRvIII-negative and -positive GBM cells and xenograft tumors. Findings: EGFRvIII expression was associated with a significantly prolonged median overall survival but only for GBM patients with MGMT promoter methylated tumors. Importantly, this effect was independent of EGFR gene amplification. We also observed increased temozolomide (TMZ) sensitivity of EGFRvIII positive cells, which translated into improved survival in xenograft experiments. This increase in TMZ sensitivity was associated with an elevated DNA damage induction accompanied by an increased expression of DNA mismatch repair (MMR) proteins. In line with this finding, knock down of MMR proteins or EGFRvIII restored TMZ resistance. Interpretation: EGFRvIII expression is of high relevance for the prediction of GBM therapy outcome. Due to EGFRvIII-dependent upregulation of MMR standard of care treatment is most efficient for GBM displaying both MGMT promoter methylation and EGFRvIII expression. Funding Statement: This work was supported by the Brigitte and Dr. Konstanze Wegener-Stiftung (M.K.), Wilhelm-Sander-Stiftung (M.K.), Forschungsforderungsfonds des Fachbereichs Medizin des Universitatsklinikums Hamburg-Eppendorf (N.S.) and the Federal Ministry of Education and Research (BMBF grant 02NUK032; M.K. K.R.), Cancer Research UK (CRUK/21600; S.C.S, T.B.), The Brain Tumour Charity (TBTC13/192; S.C.S., T.B.), Medical Research Council (MR/K015214/1; S.C.S., T.B.), University of Leeds Academic Fellowship (L.F.S), The Templeton Family Research Fund (Z.A.B) and the National Institutes of Health (NIH 2R01-NS042645-11A1; D.O.R.). U.S. is supported by the Fordergemeinschaft Kinderkrebs-Zentrum Hamburg Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: Animal Use: All work was performed in accordance with the United Kingdom Animals (Scientific Procedures) Act (1986), under the authority of project licence 70/7340.

Purpose: Despite aggressive therapy comprising radical radiation and temozolomide (TMZ) chemotherapy, the prognosis for patients with glioblastoma multiforme (GBM) remains poor, particularly if tumors express O{sup 6}-methylguanine-DNA-methyltransferase (MGMT). The interactions between radiation and TMZ remain unclear and have important implications for scheduling and for developing strategies to improve outcomes. Methods and Materials: Factors determining the effects of combination therapy on clonogenic survival, cell-cycle checkpoint signaling and DNA repair were investigated in four human glioma cell lines (T98G, U373-MG, UVW, U87-MG). Results: Combining TMZ and radiation yielded additive cytotoxicity, but only when TMZ was delivered 72 h before radiation. Radiosensitization was not observed. TMZ induced G2/M cell-cycle arrest at 48-72 h, coincident with phosphorylation of Chk1 and Chk2. Additive G2/M arrest and Chk1/Chk2 phosphorylation was only observed when TMZ preceded radiation by 72 h. The ataxia-telangiectasia mutated (ATM) inhibitor KU-55933 increased radiation sensitivity and delayed repair of radiation-induced DNA breaks, but did not influence TMZ effects. The multiple kinase inhibitor caffeine enhanced the cytotoxicity of chemoradiation and exacerbated DNA damage. Conclusions: TMZ is not a radiosensitizing agent but yields additive cytotoxicity in combination with radiation. Our data indicate that TMZ treatment should commence at least 3 days before radiation to achievemore » maximum benefit. Activation of G2/M checkpoint signaling by TMZ and radiation has a cytoprotective effect that can be overcome by dual inhibition of ATM and ATR. More specific inhibition of checkpoint signaling will be required to increase treatment efficacy without exacerbating toxicity.« less

Introduction The laboratory phenomenon of low dose hyper-radiosensitivity (LDHRS) describes excess cell kill at doses below 1 Gy relative to that predicted by the linear quadratic model. These data have stimulated the investigation of whether LDHRS can be exploited clinically. Methods Patients with metastatic tumor nodules to skin were recruited. The nodules were measured in three dimensions, consecutively numbered according to volume, and randomized, in matched pairs, to receive either conventionally fractionated radiotherapy (1.5 Gy/day) or ultrafractionated radiotherapy (0.5 Gy TDS: 4-h gap). Both groups were treated for 12 days. Measurements were taken Days 0, 5, 8, 12, and 26 and monthly until regrowth occurred. Tumor volumes were normalized to those on Day 0 and plotted against time from the start of treatment. Time to regrowth to original volume was calculated and compared between groups using the Wilcoxon signed rank test. Results Eight patients with a total of 40 paired nodules were analyzed; 36 nodules have regrown and are therefore evaluable. Analysis of the whole data set demonstrates a two-tailed p-value of 0.14 in favor of the “ultrafractionated” treatment. Analysis of the tumors generally accepted as being radioresistant and known to show LDHRS in vitro demonstrates a two-tailed p value of 0.009. Conclusions LDHRS can be demonstrated in tumors clinically. An “ultrafractionated” radiotherapy regime produces significantly increased growth delay in radioresistant malignant tumors.

We report the case of a 54-year-old man with primary central nervous system lymphoma (PCNSL) who achieved a radiological complete response to high-dose methotrexate and 6 months later had a simultaneous local and testicular relapse.

7 patients (5%) experienced DF. On univariate analysis, only GTR was predictive of LF (HR Z 0.55, p Z 0.028). Extent of resection was not predictive of OS (HR Z 0.53, p Z 0.10). Among all patients, adjuvant radiation therapy did not improve LF (HR Z 0.79, p Z 0.53). Among patients with Simpson grade 4 or 5 resection, adjuvant RT significantly reduced LF (HRZ 0.38, pZ 0.036). Median time to LF in this subset was significantly prolonged by adjuvant RT (25 to 63 months). Adjuvant RT was not associated with time to local failure in patients who underwent GTR. Conclusions: Adjuvant RT improves time to local failure in patients with atypical meningiomas who undergo upfront Simpson grade 4 or 5 resection but not in patients who undergo upfront GTR. Author Disclosure: J. Kittel: None. J. Lee: None. N.M. Woody: None. Z. Amy: None. E.S. Murphy: None. G. Barnett: None. V. Michael: None. G. Stevens: None. J.H. Suh: K. Advisory Board; Varian Medical Systems. S.T. Chao: None.

Lymphangioma circumscriptum is a rare disorder of lymphatic channels, the cause of which is poorly understood. It is an unpleasant, but benign, condition conventionally managed by wide local excision, which provides symptom control and often prevents recurrence. No long term complications and no association with squamous cell carcinoma have been previously documented. We present a 20-year-old patient with lymphangioma circumscriptum involving the vulval and perianal areas, which recurred after surgery and seems to have predisposed to squamous cell carcinoma 11 years after presentation.