Simultaneous multi-region detection of GABA+ and Glx using 3D spatially resolved SLOW-editing and EPSI-readout at 7T.

GABA+ and Glx (glutamate and glutamine) are widely studied metabolites, yet the commonly used magnetic resonance spectroscopy (MRS) techniques have significant limitations, including sensitivity to B0 and B1+-inhomogeneities, limited bandwidth of MEGA-pulses, high SAR which is accentuated at 7T. To address these limitations, we propose SLOW-EPSI method, employing a large 3D MRSI coverage and achieving a high resolution down to 0.26 ml. Simulation results demonstrate the robustness of SLOW-editing for both GABA+ and Glx against B0 and B1+-inhomogeneities within the range of [-0.3, +0.3] ppm and [40 %, 250 %], respectively. Two protocols, both utilizing a 70 mm thick FOV slab, were employed to target distinct brain regions in vivo, differentiated by their orientation: transverse and tilted. Protocol 1 (n = 11) encompassed 5 locations (cortical gray matter, white matter, frontal lobe, parietal lobe, and cingulate gyrus). Protocol 2 (n = 5) involved 9 locations (cortical gray matter, white matter, frontal lobe, occipital lobe, cingulate gyrus, caudate nucleus, hippocampus, putamen, and inferior thalamus). Quantitative analysis of GABA+ and Glx was conducted in a stepwise manner. First, B1+/B1--inhomogeneities were corrected using water reference data. Next, GABA+ and Glx values were calculated employing spectral fitting. Finally, the GABA+ level for each selected region was compared to the global Glx within the same subject, generating the GABA+/Glx_global ratio. Our findings from two protocols indicate that the GABA+/Glx_global level in cortical gray matter was approximately 16 % higher than in white matter. Elevated GABA+/Glx_global levels acquired with protocol 2 were observed in specific regions such as the caudate nucleus (0.118±0.067), putamen (0.108±0.023), thalamus (0.092±0.036), and occipital cortex (0.091±0.010), when compared to the cortical gray matter (0.079±0.012). Overall, our results highlight the effectiveness of SLOW-EPSI as a robust and efficient technique for accurate measurements of GABA+ and Glx at 7T. In contrast to previous SVS and 2D-MRSI based editing sequences with which only one or a limited number of brain regions can be measured simultaneously, the method presented here measures GABA+ and Glx from any brain area and any arbitrarily shaped volume that can be flexibly selected after the examination. Quantification of GABA+ and Glx across multiple brain regions through spectral fitting is achievable with a 9-minute acquisition. Additionally, acquisition times of 18-27 min (GABA+) and 9-18 min (Glx) are required to generate 3D maps, which are constructed using Gaussian fitting and peak integration.

Radiosurgery of vestibular schwannoma: prognostic factors for hearing outcome using 3D-constructive interference in steady state (3D-CISS).

PURPOSE: Stereotactic radiosurgery (SRS) is an effective treatment for vestibular schwannoma (VS). Three-dimensional (3D) constructive interference in steady state (CISS) is the preferred magnetic resonance imaging (MRI) sequence for evaluating signal changes in the inner ear endolymph. Previous studies demonstrated a correlation between pretreatment cochlear signal intensity in 3D-CISS and posttherapeutic hearing outcomes. The purpose of our study was to compare 3D-CISS sequences before and after primary SRS of unilateral VSs to evaluate the effect of radiosurgery on the 3D-CISS signal intensities of cochlea and sacculus/utriculus. METHODS: We retrospectively reviewed 47 patients with unilateral VS treated with SRS. The neuroradiological MRI datasets were analysed to evaluate the signal intensity of the inner ear structure, tumour size, Koos grade, tumour volume, and infiltration of the cochlear aperture before therapy and at follow-up. The differences in these signal intensities before SRS and at follow-up were correlated with clinical symptoms, cochlear radiation dose, tumour volume and infiltration of the cochlear aperture. RESULTS: No differences were found between signal intensities in cochlea and utriculus/sacculus before and after SRS and no correlation with clinical symptoms, cochlear radiation dose, tumour volume, Koos grade or infiltration of the cochlear aperture (all p > 0.05). CONCLUSION: Our study supports the theory of a complex interaction causing alteration of the endolymph protein concentration and not a direct dependency on the SRS. Use of modern dosing schemes will have a positive impact on clinical outcome with preservation of hearing in patients with VS.

Triggered episodic vestibular syndrome and transient loss of consciousness due to a retrostyloidal vagal schwannoma: a case report.

Background: Various conditions may trigger episodic vertigo or dizziness, with positional changes being the most frequently identified condition. In this study, we describe a rare case of triggered episodic vestibular syndrome (EVS) accompanied by transient loss of consciousness (TLOC) linked to retrostyloidal vagal schwannoma. Case description: A 27-year woman with known vestibular migraine presented with a 19-month history of nausea, dysphagia, and odynophagia triggered by swallowing food and followed by recurrent TLOC. These symptoms occurred independently of her body position, resulting in a weight loss of 10 kg within 1 year and in an inability to work. An extensive cardiologic diagnostic work-up undertaken before she presented to the neurologic department was normal. On the fiberoptic endoscopic evaluation of swallowing, she showed a decreased sensitivity, a slight bulging of the right lateral pharyngeal wall, and a pathological pharyngeal squeeze maneuver without any further functional deficits. Quantitative vestibular testing revealed an intact peripheral-vestibular function, and electroencephalography was read as normal. On the brain MRI, a 16 x 15 x 12 mm lesion in the right retrostyloidal space suspicious of a vagal schwannoma was detected. Radiosurgery was preferred over surgical resection, as resection of tumors in the retrostyloid space bears the risk of intraoperative complications and may result in significant morbidity. A single radiosurgical procedure (stereotactic CyberKnife radiosurgery, 1 x 13Gy) accompanied by oral steroids was performed. On follow-up, a cessation of (pre)syncopes was noted 6 months after treatment. Only residual infrequent episodes of mild nausea were triggered by swallowing solid food remained. Brain MRI after 6 months demonstrated no progression of the lesion. In contrast, migraine headaches associated with dizziness remained frequent. Discussion: Distinguishing triggered and spontaneous EVS is important, and identifying specific triggers by structured history-taking is essential. Episodes being elicited by swallowing solid foods and accompanied by (near) TLOC should initiate a thorough search for vagal schwannoma, as symptoms are often disabling, and targeted treatment is available. In the case presented here, cessation of (pre)syncopes and significant reduction of nausea triggered by swallowing was noted with a 6-month delay, illustrating the advantages (no surgical complications) and disadvantages (delayed treatment response) of first-line radiotherapy in vagal schwannoma treatment.

ASTRA: Atomic Surface Transformations for Radiotherapy Quality Assurance.

Treatment for glioblastoma, an aggressive brain tumour usually relies on radiotherapy. This involves planning how to achieve the desired radiation dose distribution, which is known as treatment planning. Treatment planning is impacted by human errors, inter-expert variability in segmenting (or outlining) the tumor target and organs-at-risk, and differences in segmentation protocols. Erroneous segmentations translate to erroneous dose distributions, and hence sub-optimal clinical outcomes. Reviewing segmentations is time-intensive, significantly reduces the efficiency of radiation oncology teams, and hence restricts timely radiotherapy interventions to limit tumor growth. Moreover, to date, radiation oncologists review and correct segmentations without information on how potential corrections might affect radiation dose distributions, leading to an ineffective and suboptimal segmentation correction workflow. In this paper, we introduce an automated deep-learning based method: atomic surface transformations for radiotherapy quality assurance (ASTRA), that predicts the potential impact of local segmentation variations on radiotherapy dose predictions, thereby serving as an effective dose-aware sensitivity map of segmentation variations. On a dataset of 100 glioblastoma patients, we show how the proposed approach enables assessment and visualization of areas of organs-at-risk being most susceptible to dose changes, providing clinicians with a dose-informed mechanism to review and correct segmentations for radiation therapy planning. These initial results suggest strong potential for employing such methods within a broader automated quality assurance system in the radiotherapy planning workflow. Code to reproduce this is available at https://github.com/amithjkamath/astraClinical Relevance: ASTRA shows promise in indicating what regions of the OARs are more likely to impact the distribution of radiation dose.

PyRaDiSe: A Python package for DICOM-RT-based auto-segmentation pipeline construction and DICOM-RT data conversion.

BACKGROUND AND OBJECTIVE: Despite fast evolution cycles in deep learning methodologies for medical imaging in radiotherapy, auto-segmentation solutions rarely run in clinics due to the lack of open-source frameworks feasible for processing DICOM RT Structure Sets. Besides this shortage, available open-source DICOM RT Structure Set converters rely exclusively on 2D reconstruction approaches leading to pixelated contours with potentially low acceptance by healthcare professionals. PyRaDiSe, an open-source, deep learning framework independent Python package, addresses these issues by providing a framework for building auto-segmentation solutions feasible to operate directly on DICOM data. In addition, PyRaDiSe provides profound DICOM RT Structure Set conversion and processing capabilities; thus, it applies also to auto-segmentation-related tasks, such as dataset construction for deep learning model training. METHODS: The PyRaDiSe package follows a holistic approach and provides DICOM data handling, deep learning model inference, pre-processing, and post-processing functionalities. The DICOM data handling allows for highly automated and flexible handling of DICOM image series, DICOM RT Structure Sets, and DICOM registrations, including 2D-based and 3D-based conversion from and to DICOM RT Structure Sets. For deep learning model inference, extending given skeleton classes is straightforwardly achieved, allowing for employing any deep learning framework. Furthermore, a profound set of pre-processing and post-processing routines is included that incorporate partial invertibility for restoring spatial properties, such as image origin or orientation. RESULTS: The PyRaDiSe package, characterized by its flexibility and automated routines, allows for fast deployment and prototyping, reducing efforts for auto-segmentation pipeline implementation. Furthermore, while deep learning model inference is independent of the deep learning framework, it can easily be integrated into famous deep learning frameworks such as PyTorch or Tensorflow. The developed package has successfully demonstrated its capabilities in a research project at our institution for organs-at-risk segmentation in brain tumor patients. Furthermore, PyRaDiSe has shown its conversion performance for dataset construction. CONCLUSIONS: The PyRaDiSe package closes the gap between data science and clinical radiotherapy by enabling deep learning segmentation models to be easily transferred into clinical research practice. PyRaDiSe is available on https://github.com/ubern-mia/pyradise and can be installed directly from the Python Package Index using pip install pyradise.

Accurate prediction of isocitrate dehydrogenase -mutation status of gliomas using SLOW-editing magnetic resonance spectroscopic imaging at 7 T MR.

Background: 2-hydroxy-glutarate (2HG) is a metabolite that accumulates in isocitrate dehydrogenase (IDH)-mutated gliomas and can be detected noninvasively using MR spectroscopy. However, due to the low concentration of 2HG, established magnetic resonance spectroscopic imaging (MRSI) techniques at the low field have limitations with respect to signal-to-noise and to the spatial resolution that can be obtained within clinically acceptable measurement times. Recently a tailored editing method for 2HG detection at 7 Tesla (7 T) named SLOW-EPSI was developed. The underlying prospective study aimed to compare SLOW-EPSI to established techniques at 7 T and 3 T for IDH-mutation status determination. Methods: The applied sequences were MEGA-SVS and MEGA-CSI at both field strengths and SLOW-EPSI at 7 T only. Measurements were performed on a MAGNETOM-Terra 7 T MR-scanner in clinical mode using a Nova 1Tx32Rx head coil and on a 3 T MAGNETOM-Prisma scanner with a standard 32-channel head coil. Results: Fourteen patients with suspected glioma were enrolled. Histopathological confirmation was available in 12 patients. IDH mutation was confirmed in 9 out of 12 cases and 3 cases were characterized as IDH wildtype. SLOW-EPSI at 7 T showed the highest accuracy for IDH-status prediction (91.7% accuracy, 11 of the 12 predictions correct with 1 false negative case). At 7 T, MEGA-CSI had an accuracy of 58.3% and MEGA-SVS had an accuracy of 75%. At 3 T, MEGA-CSI showed an accuracy of 63.6% and MEGA-SVS of 33.3%. The co-edited cystathionine was detected in 2 out of 3 oligodendroglioma cases with 1p/19q codeletion. Conclusions: Depending on the pulse sequence, spectral editing can be a powerful tool for the noninvasive determination of the IDH status. SLOW-editing EPSI sequence is the preferable pulse sequence when used at 7 T for IDH-status characterization.

Therapy Resistance of Glioblastoma in Relation to the Subventricular Zone: What Is the Role of Radiotherapy?

Glioblastoma is a highly heterogeneous primary malignant brain tumor with marked inter-/intratumoral diversity and a poor prognosis. It may contain a population of neural stem cells (NSC) and glioblastoma stem cells that have the capacity for migration, self-renewal and differentiation. While both may contribute to resistance to therapy, NSCs may also play a role in brain tissue repair. The subventricular zone (SVZ) is the main reservoir of NSCs. This study investigated the impact of bilateral SVZ radiation doses on patient outcomes. We included 147 patients. SVZs were delineated and the dose administered was extracted from dose-volume histograms. Tumors were classified based on their spatial relationship to the SVZ. The dose and outcome correlations were analyzed using the Kaplan-Meier and Cox proportional hazards regression methods. Median progression-free survival (PFS) was 7 months (range: 4-11 months) and median overall survival (OS) was 14 months (range: 9-23 months). Patients with an ipsilateral SVZ who received ≥50 Gy showed significantly better PFS (8 versus 6 months; p < 0.001) and OS (16 versus 11 months; p < 0.001). Furthermore, lower doses (<32 Gy) to the contralateral SVZ were associated with improved PFS (8 versus 6 months; p = 0.030) and OS (15 versus 11 months; p = 0.001). Targeting the potential tumorigenic cells in the ipsilateral SVZ while sparing contralateral NSCs correlated with an improved outcome. Further studies should address the optimization of dose distribution with modern radiotherapy techniques for the areas surrounding infiltrated and healthy SVZs.

Deep-Learning-Based Dose Predictor for Glioblastoma-Assessing the Sensitivity and Robustness for Dose Awareness in Contouring.

External beam radiation therapy requires a sophisticated and laborious planning procedure. To improve the efficiency and quality of this procedure, machine-learning models that predict these dose distributions were introduced. The most recent dose prediction models are based on deep-learning architectures called 3D U-Nets that give good approximations of the dose in 3D almost instantly. Our purpose was to train such a 3D dose prediction model for glioblastoma VMAT treatment and test its robustness and sensitivity for the purpose of quality assurance of automatic contouring. From a cohort of 125 glioblastoma (GBM) patients, VMAT plans were created according to a clinical protocol. The initial model was trained on a cascaded 3D U-Net. A total of 60 cases were used for training, 15 for validation and 20 for testing. The prediction model was tested for sensitivity to dose changes when subject to realistic contour variations. Additionally, the model was tested for robustness by exposing it to a worst-case test set containing out-of-distribution cases. The initially trained prediction model had a dose score of 0.94 Gy and a mean DVH (dose volume histograms) score for all structures of 1.95 Gy. In terms of sensitivity, the model was able to predict the dose changes that occurred due to the contour variations with a mean error of 1.38 Gy. We obtained a 3D VMAT dose prediction model for GBM with limited data, providing good sensitivity to realistic contour variations. We tested and improved the model's robustness by targeted updates to the training set, making it a useful technique for introducing dose awareness in the contouring evaluation and quality assurance process.

Vestibular Schwannoma: Long-term Outcome of the Vestibular Function After Stereotactic Radiosurgery.

Objective: Evaluation at long term of the impact of the stereotactic surgery (SRS) on the vestibular function in vestibular schwannoma (VS) patients. Study design and setting: Retrospective study in a tertiary referral center. Patients: Fifty-one VS patients were included (34 females;17 males), aged from 41 to 78 years treated exclusively with SRS. Intervention: Vestibular function was assessed before SRS and with median time interval of 14 (FU1) and 25 (FU2) months after treatment. Vestibular evaluation included: history, clinical vestibular examination, videonystagmography, head impulse test (v-HIT) and cervical vestibular evoked myogenic potentials (c-VEMPS). Results: Before SRS, caloric testing (Caloric) was impaired in 77%; after treatment, in 92% (FU1) and 77% (FU2). Lateral HIT was decreased in 22% before SRS, in 39% at FU1 and FU2. C-VEMPS were absent in 50% before SRS, in 76% at FU1 and, FU2. Before SRS, no statistically significant association was found between asymptomatic and symptomatic patients with respect to the results of Caloric, v-HIT and c-VEMPS. This lack of association was also seen after SRS, at FU1 and FU2. Conclusion: Our study showed that the impairment of the vestibular function might be attributed to the VS itself as well as to the radiation of the inner ear during SRS. The lateral SSC at low frequencies and the saccular function seem to be more involved with the time.

Response assessment after stereotactic body radiation therapy for spine and non-spine bone metastases: results from a single institutional study.

BACKGROUND: The use of stereotactic body radiation therapy (SBRT) for tumor and pain control in patients with bone metastases is increasing. We report response assessment after bone SBRT using radiological changes through time and clinical examination of patients. METHODS: We analyzed retrospectively oligo-metastatic/progressive patients with bony lesions treated with SBRT between 12/2008 and 10/2018, without in-field re-irradiation, in our institution. Radiological data were obtained from imaging modalities used for SBRT planning and follow-up purposes in picture archiving and communication system and assessed by two independent radiologists blind to the time of treatment. Several radiological changes were described. Radiographic response assessment was classified according to University of Texas MD Anderson Cancer Center criteria. Pain response and the neurological deficit were captured before and at least 6 months after SBRT. RESULTS: A total of 35 of the 74 reviewed patients were eligible, presenting 43 bone metastases, with 51.2% (n = 22) located in the vertebral column. Median age at the time of SBRT was 66 years (range 38-84) and 77.1% (n = 27) were male. Histology was mainly prostate (51.4%, n = 18) and breast cancer (14.3%, n = 5). Median total radiation dose delivered was 24 Gy (range 24-42), in three fractions (range 2-7), prescribed to 70-90% isodose-line. After a median follow-up of 1.8 years (range < 1-8.2) for survivors, complete or partial response, stable, and progressive disease occurred in 0%, 11.4% (n = 4), 68.6% (n = 24), and 20.0% (n = 7) of the patients, respectively. Twenty patients (57.1%) died during the follow-up time, all from disease progression, yet 70% (n = 14) from this population with local stable disease after SBRT. From patients who were symptomatic and available for follow-up, almost half (44.4%) reported pain reduction after SBRT. CONCLUSIONS: Eighty percent of the patients showed local control after SBRT for bone metastases. Pain response was favorable. For more accurate response assessment, comparing current imaging modalities with advanced imaging techniques such as functional MRI and PET/CT, in a prospective and standardized way is warranted. Trial registration Retrospectively registered.

Programmed Death-Ligand 1 Expression in Lung Cancer and Paired Brain Metastases-a Single-Center Study in 190 Patients.

Introduction: Expression of programmed death-ligand 1 (PD-L1) is the only routinely used tissue biomarker for predicting response to programmed cell death protein 1/PD-L1 inhibitors. It is to date unclear whether PD-L1 expression is preserved in brain metastases (BMs). Methods: In this single-center, retrospective study, we evaluated PD-L1 expression using the SP263 assay in consecutively resected BMs of lung carcinomas and paired primary tumors, diagnosed from 2000 to 2015, with correlation to clinicopathological and molecular tumor and patient characteristics. Results: PD-L1 tumor proportional score (TPS) could be evaluated on whole tissue slides in 191 BMs and 84 paired primary lung carcinomas. PD-L1 TPS was less than 1% in 113 of 191 (59.2%), 1% to 49% in 34 of 191 (17.8%), and greater than or equal to 50% in 44 of 191 (23.0%) BMs. TPS was concordant between BMs and paired primary lung carcinomas in most cases, with discordance regarding the clinically relevant cutoffs at 1% and 50% in 18 of 84 patients (21.4%). Four of 18 discordant cases had no shared mutations between the primary lung carcinoma and BM. Intratumoral heterogeneity, as assessed using tissue microarray cores, was only significant at the primary site (p Wilcoxon signed rank = 0.002) with higher PD-L1 TPS at the infiltration front (mean = 40.4%, interquartile range: 0%-90%). Neither TPS greater than or equal to 1% nor TPS greater than or equal to 50% nor discordance between the primary lung carcinoma and BMs had prognostic significance regarding overall survival or BM-specific overall survival. Conclusions: PD-L1 expression was mostly concordant between primary lung carcinoma and its BM and between resections of BM and stereotactic biopsies, mirrored by tissue microarray cores. Differences in PD-L1 TPS existed primarily in cases with TPS greater than 10%, for which also human assessment tends to be most error prone.

Impact of random outliers in auto-segmented targets on radiotherapy treatment plans for glioblastoma.

AIMS: To save time and have more consistent contours, fully automatic segmentation of targets and organs at risk (OAR) is a valuable asset in radiotherapy. Though current deep learning (DL) based models are on par with manual contouring, they are not perfect and typical errors, as false positives, occur frequently and unpredictably. While it is possible to solve this for OARs, it is far from straightforward for target structures. In order to tackle this problem, in this study, we analyzed the occurrence and the possible dose effects of automated delineation outliers. METHODS: First, a set of controlled experiments on synthetically generated outliers on the CT of a glioblastoma (GBM) patient was performed. We analyzed the dosimetric impact on outliers with different location, shape, absolute size and relative size to the main target, resulting in 61 simulated scenarios. Second, multiple segmentation models where trained on a U-Net network based on 80 training sets consisting of GBM cases with annotated gross tumor volume (GTV) and edema structures. On 20 test cases, 5 different trained models and a majority voting method were used to predict the GTV and edema. The amount of outliers on the predictions were determined, as well as their size and distance from the actual target. RESULTS: We found that plans containing outliers result in an increased dose to healthy brain tissue. The extent of the dose effect is dependent on the relative size, location and the distance to the main targets and involved OARs. Generally, the larger the absolute outlier volume and the distance to the target the higher the potential dose effect. For 120 predicted GTV and edema structures, we found 1887 outliers. After construction of the planning treatment volume (PTV), 137 outliers remained with a mean distance to the target of 38.5 ± 5.0 mm and a mean size of 1010.8 ± 95.6 mm3. We also found that majority voting of DL results is capable to reduce outliers. CONCLUSIONS: This study shows that there is a severe risk of false positive outliers in current DL predictions of target structures. Additionally, these errors will have an evident detrimental impact on the dose and therefore could affect treatment outcome.

Feasibility of postoperative spine stereotactic body radiation therapy in proximity of carbon and titanium hybrid implants using a robotic radiotherapy device.

BACKGROUND AND PURPOSE: To assess the feasibility of postoperative stereotactic body radiation therapy (SBRT) for patients with hybrid implants consisting of carbon fiber reinforced polyetheretherketone and titanium (CFP-T) using CyberKnife. MATERIALS AND METHODS: All essential steps within a radiation therapy (RT) workflow were evaluated. First, the contouring process of target volumes and organs at risk (OAR) was done for patients with CFP-T implants. Second, after RT-planning, the accuracy of the calculated dose distributions was tested in a slab phantom and an anthropomorphic phantom using film dosimetry. As a third step, the accuracy of the mandatory image guided radiation therapy (IGRT) including automatic matching was assessed using the anthropomorphic phantom. For this goal, a standard quality assurance (QA) test was modified to carry out its IGRT part in presence of CFP-T implants. RESULTS: Using CFP-T implants, target volumes could precisely delineated. There was no need for compromising the contours to overcome artifact obstacles. Differences between measured and calculated dose values were below 11% for the slab phantom, and at least 95% of the voxels were within 5% dose difference. The comparisons for the anthropomorphic phantom showed a gamma-passing rate (5%, 1 mm) of at least 97%. Additionally the test results with and without CFP-T implants were comparable. No issues concerning the IGRT were detected. The modified machine QA test resulted in a targeting error of 0.71 mm, which corresponds to the results of the unmodified standard tests. CONCLUSION: Dose calculation and delivery of postoperative spine SBRT is feasible in proximity of CFP-T implants using a CyberKnife system.

Stereotactic body radiotherapy as a boost after external beam radiotherapy for high-risk prostate cancer patients.

BACKGROUND: The effect of high-dose-rate (HDR) brachytherapy after external radiation in high-risk prostate cancer patients has been proven. Stereotactic body radiotherapy as a less invasive method has similar dosimetric results with HDR brachytherapy. This study aims to evaluate the prostate-specific antigen (PSA) response, acute side effects, and quality of life of patients who underwent stereotactic body radiotherapy (SBRT) as a boost after pelvic radiotherapy (RT). METHODS: A total of 34 patients diagnosed with high-risk prostate cancer treated with SBRT boost (21 Gy in three fractions) combined with whole pelvic RT (50 Gy in 25 fractions) were evaluated. Biochemical control has been evaluated with PSA before, and after treatment, acute adverse events were evaluated with radiation therapy oncology group (RTOG) grading scale and quality of life with the Expanded Prostate Cancer Index Composite (EPIC) scoring system. RESULTS: The mean follow-up of 34 patients was 41.2 months (range 7-52). The mean initial PSA level was 22.4 ng/mL. None of the patients had experienced a biochemical or clinical relapse of the disease. Grade 2 and higher acute gastrointestinal (GI) was observed in 14%, and genitourinary (GU) toxicity was observed in 29%. None of the patients had grade 3-4 late toxicity. CONCLUSIONS: SBRT boost treatment after pelvic irradiation has been used with a good biochemical control and acceptable toxicity in high-risk prostate cancer patients. More extensive randomized trial results are needed on the subject.

Mutational profiles of primary pulmonary adenocarcinoma and paired brain metastases disclose the importance of KRAS mutations.

BACKGROUND: Brain metastases present a significant complication in lung cancer with an unmet therapeutic need. METHODS: In this single-centre, retrospective study, we genotyped a clinico-pathologically well-annotated cohort of consecutively resected brain metastases of lung adenocarcinomas and paired primary tumours, diagnosed from 2000 to 2015, using the Ion Torrent Oncomine Comprehensive Cancer Panel v3. RESULTS: Among 444 consecutive brain metastases, 210 (49%) originated from lung cancer. Analysis was successful in 111 samples, including 54 pairs of brain metastasis and primary tumour. Most driver alterations were preserved in brain metastases. Private alterations exclusive to primary tumours, brain metastases or both sites (intersecting cases) were present in 22%, 26% and 26% of cases, respectively. Seven percent had no shared mutations. KRAS mutations were more frequent in primary tumours metastasised to the brain (32/55, 58%) compared to TCGA (33%, p < 0.005) and own data from routine diagnostics, independent from clinical or pathological characteristics. Fourteen cases showed alterations in the EGFR signalling pathway including additional KRAS alterations that were private to brain metastases. KRAS G12C was detected most frequently (26% of patients) and KRAS G12C and G13C variants were significantly enriched in brain metastases. Synchronous and metachronous cases had a similar mutation profile. CONCLUSIONS: Our results suggest an important role of KRAS alterations in the pathobiology of brain metastases from lung adenocarcinomas. This has direct therapeutic implications as inhibitors selectively targeting KRAS G12C are entering the clinics.

Assessment of Tumor Volume Dynamics and Outcome After Radiosurgery for the Treatment of Vestibular Schwannoma: A Single-Center Experience.

OBJECTIVE: To assess the factors affecting early local and audiometric outcomes in vestibular schwannoma (VS) patients treated with stereotactic radiosurgery (SRS). STUDY DESIGN: A retrospective review of medical records. SETTING: Tertiary referral center. PATIENTS: Records of all adult patients who underwent SRS between 2010 and 2016 for the treatment of VS were retrospectively reviewed. Patients treated with microsurgery or multi-fractionation schemes, and those who had neurofibromatosis type 2, were excluded. INTERVENTION: SRS, tumor volume/size measurements. MAIN OUTCOME MEASURES: The impact of tumor volume dynamics on the early local and hearing-related outcomes, together with the factors that influence them following SRS, and comparison of different tumor size measurement methods. RESULTS: From 2010 to 2016, 53 patients underwent single fraction SRS of 12 Gy. Median follow-up time was 32 months (range, 6-79). At the last follow-up, only one patient had clinical progression. Age less than or equal to 65 years (p = 0.04; odds ratio [OR]: 0.17; 95% confidence interval [CI]: 0.03-0.93) and baseline pure-tone average (PTA) level less than or equal to 30 dB (p = 0.03; OR: 0.90; 95% CI: 0.84-0.96) were associated with maintenance of serviceable hearing. On multivariate analysis, PTA remained significant (p = 0.01; OR: 0.04; 95% CI: 0.003-0.45). In patients with a loss of serviceable hearing, the mean volume increase tended to be higher than in the patients whose hearing was maintained. The linear measurement method underestimated, and the A × B × C/2 equation overestimated, the radiological progression compared with 3D-volumetric delineations. CONCLUSION: During the median observation period of almost 3 years, we reported our early outcome results. Tumor volume increase may have an impact on serviceable hearing loss after SRS. Currently there is no widely accepted method for the evaluation of post-SRS response. Linear measurement and the A × B × C/2 equation produce less reliable estimates of radiological progression compared with 3D-volumetric delineations. Accurate volume measurements with 3D delineations should be considered as part of clinical routine for assessing progression and deciding on salvage therapies.

Vestibular dose correlates with dizziness after radiosurgery for the treatment of vestibular schwannoma.

BACKGROUND: Stereotactic radiosurgery (SRS) has been recognized as a first-line treatment option for small to moderate sized vestibular schwannoma (VS). Our aim is to evaluate the impact of SRS doses and other patient and disease characteristics on vestibular function in patients with VS. METHODS: Data on VS patients treated with single-fraction SRS to 12 Gy were retrospectively reviewed. No dose constraints were given to the vestibule during optimization in treatment planning. Patient and tumor characteristics, pre- and post-SRS vestibular examination results and patient-reported dizziness were assessed from patient records. RESULTS: Fifty-three patients were analyzed. Median follow-up was 32 months (range, 6-79). The median minimum, mean and maximum vestibular doses were 2.6 ± 1.6 Gy, 6.7 ± 2.8 Gy, and 11 ± 3.6 Gy, respectively. On univariate analysis, Koos grade (p = 0.04; OR: 3.45; 95% CI 1.01-11.81), tumor volume (median 6.1 cm3; range, 0.8-38; p = 0.01; OR: 4.85; 95% CI 1.43-16.49), presence of pre-SRS dizziness (p = 0.02; OR: 3.98; 95% CI 1.19-13.24) and minimum vestibular dose (p = 0.033; OR: 1.55; 95% CI 1.03-2.32) showed a significant association with patient-reported dizziness. On multivariate analysis, minimum vestibular dose remained significant (p = 0.02; OR: 1.75; 95% CI 1.05-2.89). Patients with improved caloric function had received significantly lower mean (1.5 ± 0.7 Gy, p = 0.01) and maximum doses (4 ± 1.5 Gy, p = 0.01) to the vestibule. CONCLUSIONS: Our results reveal that 5 Gy and above minimum vestibular doses significantly worsened dizziness. Additionally, mean and maximum doses received by the vestibule were significantly lower in patients who had improved caloric function. Further investigations are needed to determine dose-volume parameters and their effects on vestibular toxicity.

Fully automated brain resection cavity delineation for radiation target volume definition in glioblastoma patients using deep learning.

BACKGROUND: Automated brain tumor segmentation methods are computational algorithms that yield tumor delineation from, in this case, multimodal magnetic resonance imaging (MRI). We present an automated segmentation method and its results for resection cavity (RC) in glioblastoma multiforme (GBM) patients using deep learning (DL) technologies. METHODS: Post-operative, T1w with and without contrast, T2w and fluid attenuated inversion recovery MRI studies of 30 GBM patients were included. Three radiation oncologists manually delineated the RC to obtain a reference segmentation. We developed a DL cavity segmentation method, which utilizes all four MRI sequences and the reference segmentation to learn to perform RC delineations. We evaluated the segmentation method in terms of Dice coefficient (DC) and estimated volume measurements. RESULTS: Median DC of the three radiation oncologist were 0.85 (interquartile range [IQR]: 0.08), 0.84 (IQR: 0.07), and 0.86 (IQR: 0.07). The results of the automatic segmentation compared to the three different raters were 0.83 (IQR: 0.14), 0.81 (IQR: 0.12), and 0.81 (IQR: 0.13) which was significantly lower compared to the DC among raters (chi-square = 11.63, p = 0.04). We did not detect a statistically significant difference of the measured RC volumes for the different raters and the automated method (Kruskal-Wallis test: chi-square = 1.46, p = 0.69). The main sources of error were due to signal inhomogeneity and similar intensity patterns between cavity and brain tissues. CONCLUSIONS: The proposed DL approach yields promising results for automated RC segmentation in this proof of concept study. Compared to human experts, the DC are still subpar.

Evaluation of a new software prototype for frameless radiosurgery of arteriovenous malformations.

BACKGROUND: In order to locate an arteriovenous malformation, typically, a digital subtraction angiography (DSA) is carried out. To use the DSA for target definition an accurate image registration between CT and DSA is required. Carrying out a non-invasive, frameless procedure, registration of the 2D-DSA images with the CT is critical. A new software prototype is enabling this frameless procedure. The aim of this work was to evaluate the prototype in terms of targeting accuracy and reliability based on phantom measurements as well as with the aid of patient data. In addition, the user's ability to recognize registration mismatches and quality was assessed. METHODS: Targeting accuracy was measured with a simple cubic, as well as with an anthropomorphic head phantom. Clearly defined academic targets within the phantoms were contoured on the CT. These reference structures were compared with the structures generated within the prototype. A similar approach was used with patient data, where the clinically contoured target served as the reference structure. An important error source decreasing the target accuracy comes from registration errors between CT and 2D-DSA. For that reason, the tools in BC provided to the user to check these registrations are very important. In order to check if the user is able to recognize registration errors, a set of different registration errors was introduced to the correctly registered CT and 2D-DSA image data sets of three different patients. Each of six different users rated the whole set of registrations within the prototype. RESULTS: The target accuracy of the prototype was found to be below 0.04 cm for the cubic phantom and below 0.05 cm for the anthropomorphic head phantom. The mean target accuracy for the 15 patient cases was found to be below 0.3 cm. In the registration verification part, almost all introduced registration errors above 1° or 0.1 cm were detected by the six users. Nevertheless, in order to quantify and categorize the possibility to detect mismatches in the registration process more data needs to be evaluated. CONCLUSION: Our study shows, that the prototype is a useful tool that has the potential to fill the gap towards a frameless procedure when treating AVMs with the aid of 2D-DSA images in radiosurgery. The target accuracy of the prototype is similar to other systems already established in clinical routine.

Influencing Factors on Radiotherapy Outcome in Stage I-II Glottic Larynx Cancer-A Multicenter Study.

Background and Purpose: Larynx cancer represents one of the most frequently diagnosed head and neck malignancies, which is most often confined to the glottic area. The aim of this study was to report the oncological outcome and identify prognostic factors in early-stage glottic squamous cell carcinoma treated with radiotherapy. Material and Methods: Patients (n = 761) diagnosed and treated in 10 centers between 1990 and 2015 were retrospectively analyzed. Probabilities of loco-regional control (LRC) and overall survival (OS) were calculated and possible prognostic factors were analyzed using Cox proportional hazards models. Results: The median follow-up was 63 months (range: 2-243). Three hundred and sixty-four, 148 and 249 patients had cT1a, cT1b, and cT2 stage I-II disease, respectively. Five and 10-years LRC/OS rates in the whole cohort were 83/82% and 80/68%, respectively. Three patients developed distant recurrences. In univariate analysis, male sex (HR: 3.49; 95% CI: 1.47-11.37; p < 0.01), T2 vs. T1a (HR: 1.62; 95% CI: 1.08-2.43; p = 0.02) and anterior commissure involvement (ACI) (HR: 1.66; 95% CI: 1.38-2.45; p < 0.01) were associated with impaired LRC. In multivariate analysis, male sex (HR: 3.42; 95% CI: 1.44-11.17; p < 0.01) and ACI (HR: 1.51; 95% CI: 1.01-2.28; p = 0.047) remained poor prognostic factors. No relation of treatment technique and biologically equivalent dose (BED) to oncological outcome was identified except for higher BED10(L = 25; T = 1) yielding better LRC in T1a tumors (p = 0.04) in univariate analyses. Conclusion: Our results highlight the negative impact of ACI on tumor control. A less-expected finding was the impact of sex on tumor control. Further research is needed to validate its prognostic value and investigate any related biologic or behavioral factors, which may be modified to improve oncologic outcome.