Relationship between apparent diffusion coefficient and survival as a function of distance from gross tumor volume on radiation planning MRI in newly diagnosed glioblastoma.

PURPOSE: To investigate the changes in apparent diffusion coefficient (ADC) within incrementally-increased margins beyond the gross tumor volume (GTV) on post-operative radiation planning MRI and their prognostic utility in glioblastoma. METHODS: Radiation planning MRIs of adult patients with newly diagnosed glioblastoma from 2017 to 2020 were assessed. The ADC values were normalized to contralateral normal white matter (nADC). Using 1 mm isotropic incremental margin increases from the GTV, the nADC values were calculated at each increment. Age, ECOG performance status, extent of resection and MGMT promoter methylation status were obtained from medical records. Using univariate and multivariable Cox regression analysis, association of nADC to progression-free and overall survival (PFS, OS) was assessed at each increment. RESULTS: Seventy consecutive patients with mean age of 53.6 ± 10.3 years, were evaluated. The MGMT promoter was methylated in 31 (44.3%), unmethylated in 36 (51.6%) and unknown in 3 (4.3%) patients. 11 (16%) underwent biopsy, 41 (44%) subtotal resection and 18 (26%) gross total resection. For each 1 mm increase in distance from GTV, the nADC decreased by 0.16% (p < 0.0001). At 1-5 mm increment, the nADC was associated with OS (p < 0.01). From 6 to 11 mm increment the nADC was associated with OS with the p-value gradually increasing from 0.018 to 0.046. nADC was not associated with PFS. CONCLUSION: The nADC values at 1-11 mm increments from the GTV margin were associated with OS. Future prospective multicenter studies are needed to validate the findings and to pave the way for the utilization of ADC for margin reduction in radiation planning.

Hypofractionated stereotactic radiosurgery (HSRS) as a salvage treatment for brain metastases failing prior stereotactic radiosurgery (SRS).

INTRODUCTION: Various treatment options exist to salvage stereotactic radiosurgery (SRS) failures for brain metastases, including repeat SRS and hypofractionated SRS (HSRS). Our objective was to report outcomes specific to salvage HSRS for brain metastases that failed prior HSRS/SRS. METHODS: Patients treated with HSRS to salvage local failures (LF) following initial HSRS/SRS, between July 2010 and April 2020, were retrospectively reviewed. The primary outcomes were the rates of LF, radiation necrosis (RN), and symptomatic radiation necrosis (SRN). Univariable (UVA) and multivariable (MVA) analyses using competing risk regression were performed to identify predictive factors for each endpoint. RESULTS: 120 Metastases in 91 patients were identified. The median clinical follow up was 13.4 months (range 1.1-111.1), and the median interval between SRS courses was 13.1 months (range 3.0-56.5). 115 metastases were salvaged with 20-35 Gy in 5 fractions and the remaining five with a total dose ranging from 20 to 24 Gy in 3-fractions. 67 targets (56%) were postoperative cavities. The median re-treatment target volume and biological effective dose (BED10) was 9.5 cc and 37.5 Gy, respectively. The 6- and 12- month LF rates were 18.9% and 27.7%, for RN 13% and 15.6%, and for SRN were 6.1% and 7.0%, respectively. MVA identified larger re-irradiation volume (hazard ratio [HR] 1.02, p = 0.04) and shorter interval between radiosurgery courses (HR 0.93, p < 0.001) as predictors of LF. Treatment of an intact target was associated with a higher risk of RN (HR 2.29, p = 0.04). CONCLUSION: Salvage HSRS results in high local control rates and toxicity rates that compare favorably to those single fraction SRS re-irradiation experiences reported in the literature.

Detection of solid and subsolid pulmonary nodules with lung MRI: performance of UTE, T1 gradient-echo, and single-shot T2 fast spin echo.

BACKGROUND: Although MRI is a radiation-free imaging modality, it has historically been limited in lung imaging due to inherent technical restrictions. The aim of this study is to explore the performance of lung MRI in detecting solid and subsolid pulmonary nodules using T1 gradient-echo (GRE) (VIBE, Volumetric interpolated breath-hold examination), ultrashort time echo (UTE) and T2 Fast Spin Echo (HASTE, Half fourier Single-shot Turbo spin-Echo). METHODS: Patients underwent a lung MRI in a 3 T scanner as part of a prospective research project. A baseline Chest CT was obtained as part of their standard of care. Nodules were identified and measured on the baseline CT and categorized according to their density (solid and subsolid) and size (> 4 mm/ ≤ 4 mm). Nodules seen on the baseline CT were classified as present or absent on the different MRI sequences by two thoracic radiologists independently. Interobserver agreement was determined using the simple Kappa coefficient. Paired differences were compared using nonparametric Mann-Whitney U tests. The McNemar test was used to evaluate paired differences in nodule detection between MRI sequences. RESULTS: Thirty-six patients were prospectively enrolled. One hundred forty-nine nodules (100 solid/49 subsolid) with mean size 10.8 mm (SD = 9.4) were included in the analysis. There was substantial interobserver agreement (k = 0.7, p = 0.05). Detection for all nodules, solid and subsolid nodules was respectively; UTE: 71.8%/71.0%/73.5%; VIBE: 61.6%/65%/55.1%; HASTE 72.4%/72.2%/72.7%. Detection rate was higher for nodules > 4 mm in all groups: UTE 90.2%/93.4%/85.4%, VIBE 78.4%/88.5%/63.4%, HASTE 89.4%/93.8%/83.8%. Detection of lesions ≤4 mm was low for all sequences. UTE and HASTE performed significantly better than VIBE for detection of all nodules and subsolid nodules (diff = 18.4 and 17.6%, p = < 0.01 and p = 0.03, respectively). There was no significant difference between UTE and HASTE. There were no significant differences amongst MRI sequences for solid nodules. CONCLUSIONS: Lung MRI shows adequate performance for the detection of solid and subsolid pulmonary nodules larger than 4 mm and can serve as a promising radiation-free alternative to CT.

High grade glioma radiation therapy on a high field 1.5 Tesla MR-Linac - workflow and initial experience with daily adapt-to-position (ATP) MR guidance: A first report.

Purpose: This study reports the workflow and initial clinical experience of high grade glioma (HGG) radiotherapy on the 1.5 T MR-Linac (MRL), with a focus on the temporal variations of the tumor and feasibility of multi-parametric image (mpMRI) acquisition during routine treatment workflow. Materials and methods: Ten HGG patients treated with radiation within the first year of the MRL's clinical operation, between October 2019 and August 2020, were identified from a prospective database. Workflow timings were recorded and online adaptive plans were generated using the Adapt-To-Position (ATP) workflow. Temporal variation within the FLAIR hyperintense region (FHR) was assessed by the relative FHR volumes (n = 281 contours) and migration distances (maximum linear displacement of the volume). Research mpMRIs were acquired on the MRL during radiation and changes in selected functional parameters were investigated within the FHR. Results: All patients completed radiotherapy to a median dose of 60 Gy (range, 54-60 Gy) in 30 fractions (range, 30-33), receiving a total of 287 fractions on the MRL. The mean in-room time per fraction with or without post-beam research imaging was 42.9 minutes (range, 25.0-69.0 minutes) and 37.3 minutes (range, 24.0-51.0 minutes), respectively. Three patients (30%) required re-planning between fractions 9 to 12 due to progression of tumor and/or edema identified on daily MRL imaging. At the 10, 20, and 30-day post-first fraction time points 3, 3, and 4 patients, respectively, had a FHR volume that changed by at least 20% relative to the first fraction. Research mpMRIs were successfully acquired on the MRL. The median apparent diffusion coefficient (ADC) within the FHR and the volumes of FLAIR were significantly correlated when data from all patients and time points were pooled (R=0.68, p<.001). Conclusion: We report the first clinical series of HGG patients treated with radiotherapy on the MRL. The ATP workflow and treatment times were clinically acceptable, and daily online MRL imaging triggered adaptive re-planning for selected patients. Acquisition of mpMRIs was feasible on the MRL during routine treatment workflow. Prospective clinical outcomes data is anticipated from the ongoing UNITED phase 2 trial to further refine the role of MR-guided adaptive radiotherapy.

Proposing a quantitative MRI-based linear measurement framework for response assessment following stereotactic body radiation therapy in patients with spinal metastasis.

PURPOSE: To provide evidence towards a quantitative response assessment framework incorporating MRI-based linear measurements for spinal metastasis that predicts outcome following stereotactic body radiation therapy (SBRT). METHODS: Adult patients with de novo spinal metastases treated with SBRT between 2008 and 2018 were retrospectively assessed. The metastatic lesions involving the pedicles, articular processes, lamina, transverse process, spinous process and vertebral body at leach level were measured separately using linear measurements on pre- and all post-SBRT MRIs. The outcome was segment-specific progression (SSP) using SPINO guidelines which was dated to the first clinical documentation of progression, or the date of the associated MRI if imaging was the reason for progression. Random forest analysis for variable selection and recursive partitioning analysis for SSP probability prediction were used. RESULTS: Five Hundred Ninety-three spinal levels (323 patients) from 4081 MRIs were evaluated. The appearance of new T1 hypointensity and increase in Bilsky grade had an odds ratio (OR) of 33.5 and 15.5 for SSP, respectively. Compared to baseline, an increase of > 3 mm in any lesion dimension, combined with a 1.67-fold increase in area, had an OR of 4.6 for SSP. The sensitivity, specificity, positive predictive value, negative predictive value, balanced accuracy and area under the curve of the training model were 96.7%, 89.6%, 28.6%, 99.8%, 93.2% and 0.905 and of the test model were 91.3%, 89.3%, 27.1% 99.6%, 90.3% and 0.933, respectively. CONCLUSION: With further refinement and validation in prospective multicentre studies, MRI-based linear measurements can help predict response assessment in SBRT-treated spinal metastases.

Gamma knife icon based hypofractionated stereotactic radiosurgery (GKI-HSRS) for brain metastases: impact of dose and volume.

OBJECTIVE: Gamma Knife Icon-based hypofractionated stereotactic radiosurgery (GKI-HSRS) is a novel technical paradigm in the treatment of brain metastases that allows for both the dosimetric benefits of the GKI stereotactic radiosurgery (SRS) platform as well as the biologic benefits of fractionation. We report mature local control and adverse radiation effect (ARE) outcomes following 5 fraction GKI-HSRS for intact brain metastases. METHODS: Patients with intact brain metastases treated with 5-fraction GKI-HSRS were retrospectively reviewed. Survival, local control, and adverse radiation effect rates were determined. Univariable and multivariable regression (MVA) were performed on potential predictive factors. RESULTS: Two hundred and ninety-nine metastases in 146 patients were identified. The median clinical follow-up was 10.7 months (range 0.5-47.6). The median total dose and prescription isodose was 27.5 Gy (range, 20-27.5) in 5 daily fractions and 52% (range, 45-93), respectively. The median overall survival (OS) was 12.7 months, and the 1-year local failure rate was 15.2%. MVA identified a total dose of 27.5 Gy vs. ≤ 25 Gy (hazard ratio [HR] 0.59, p = 0.042), and prior chemotherapy exposure (HR 1.99, p = 0.015), as significant predictors of LC. The 1-year ARE rate was 10.8% and the symptomatic ARE rate was 1.8%. MVA identified a gross tumor volume of ≥ 4.5 cc (HR 7.29, p < 0.001) as a significant predictor of symptomatic ARE. CONCLUSION: Moderate total doses in 5 daily fractions of GKI-HSRS were associated with high rates of LC and a low incidence of symptomatic ARE.

MR-guided focused ultrasound liquid biopsy enriches circulating biomarkers in patients with brain tumors.

BACKGROUND: Liquid biopsy is promising for early detection, monitoring of response, and recurrence of cancer. The blood-brain barrier (BBB) limits the shedding of biomarker, such as cell-free DNA (cfDNA), into the blood from brain tumors, and their detection by conventional assays. Transcranial MR-guided focused ultrasound (MRgFUS) can safely and transiently open the BBB, providing an opportunity for less-invasive access to brain pathology. We hypothesized that MRgFUS can enrich the signal of circulating brain-derived biomarkers to aid in liquid biopsy. METHODS: Nine patients were treated in a prospective single-arm, open-label trial to investigate serial MRgFUS and adjuvant temozolomide combination in patients with glioblastoma (NCT03616860). Blood samples were collected as an exploratory measure within the hours before and after sonication, with control samples from non-brain tumor patients undergoing BBB opening (BBBO) alone (NCT03739905). RESULTS: Brain regions averaging 7.8 ± 6.0 cm3 (range 0.8-23.1 cm3) were successfully treated within 111 ± 39 minutes without any serious adverse events. We found MRgFUS acutely enhanced plasma cfDNA (2.6 ± 1.2-fold, P < .01, Wilcoxon signed-rank test), neuron-derived extracellular vesicles (3.2 ± 1.9-fold, P < .01), and brain-specific protein S100b (1.4 ± 0.2-fold, P < .01). Further comparison of the cfDNA methylation profiles suggests a signature that is disease- and post-BBBO-specific, in keeping with our hypothesis. We also found cfDNA-mutant copies of isocitrate dehydrogenase 1 (IDH1) increased, although this was in only one patient known to harbor the tumor mutation. CONCLUSIONS: This first-in-human proof-of-concept study shows MRgFUS enriches the signal of circulating brain-derived biomarkers, demonstrating the potential of the technology to support liquid biopsy for the brain.

Glioma consensus contouring recommendations from a MR-Linac International Consortium Research Group and evaluation of a CT-MRI and MRI-only workflow.

INTRODUCTION: This study proposes contouring recommendations for radiation treatment planning target volumes and organs-at-risk (OARs) for both low grade and high grade gliomas. METHODS: Ten cases consisting of 5 glioblastomas and 5 grade II or III gliomas, including their respective gross tumor volume (GTV), clinical target volume (CTV), and OARs were each contoured by 6 experienced neuro-radiation oncologists from 5 international institutions. Each case was first contoured using only MRI sequences (MRI-only), and then re-contoured with the addition of a fused planning CT (CT-MRI). The level of agreement among all contours was assessed using simultaneous truth and performance level estimation (STAPLE) with the kappa statistic and Dice similarity coefficient. RESULTS: A high level of agreement was observed between the GTV and CTV contours in the MRI-only workflow with a mean kappa of 0.88 and 0.89, respectively, with no statistically significant differences compared to the CT-MRI workflow (p = 0.88 and p = 0.82 for GTV and CTV, respectively). Agreement in cochlea contours improved from a mean kappa of 0.39 to 0.41, to 0.69 to 0.71 with the addition of CT information (p < 0.0001 for both cochleae). Substantial to near perfect level of agreement was observed in all other contoured OARs with a mean kappa range of 0.60 to 0.90 in both MRI-only and CT-MRI workflows. CONCLUSIONS: Consensus contouring recommendations for low grade and high grade gliomas were established using the results from the consensus STAPLE contours, which will serve as a basis for further study and clinical trials by the MR-Linac Consortium.

Minimally Invasive Approach for the Removal of a Ruptured Radiculomedullary Artery Aneurysm: Case Report and Literature Review.

BACKGROUND: Radiculomedullary arteries aneurysms are rare, with only few cases so far reported. CASE DESCRIPTION: We report the case of a 54-year-old woman with sudden onset of upper thoracic back pain. Magnetic resonance imaging/magnetic resonance angiography of the spine showed a cervico-thoraco-lumbar hematoma, with no evidence of underlying vascular malformations. Using Phantom retractors, a unilateral laminectomy was performed at the level of T3, in proximity of the thickest part of the epidural hematoma. No epidural blood was detected. The dura was opened, and subdural and subarachnoid blood was found. After its removal, a fusiform aneurysm of the right radiculomedullary artery was found. The parental vessel was temporarily clipped and the aneurysm removed after ligation of both proximal and distal vessels. No postoperative complications occurred. CONCLUSIONS: Rupture of radiculomedullary artery aneurysm always should be considered as differential diagnosis in patients with sudden onset of isolated back pain, headache, and spinal epidural/subdural bleeding. Among different possible treatments, surgery represents a valid option. The use of microsurgical techniques is crucial to achieve a good clinical outcome. A minimally invasive approach can be used to minimize muscle disruption, with minimal blood loss, and faster recovery.

Blood-Brain Barrier Opening in Primary Brain Tumors with Non-invasive MR-Guided Focused Ultrasound: A Clinical Safety and Feasibility Study.

The blood-brain barrier (BBB) has long limited therapeutic access to brain tumor and peritumoral tissue. In animals, MR-guided focused ultrasound (MRgFUS) with intravenously injected microbubbles can temporarily and repeatedly disrupt the BBB in a targeted fashion, without open surgery. Our objective is to demonstrate safety and feasibility of MRgFUS BBB opening with systemically administered chemotherapy in patients with glioma in a phase I, single-arm, open-label study. Five patients with previously confirmed or suspected high-grade glioma based on imaging underwent the MRgFUS in conjunction with administration of chemotherapy (n = 1 liposomal doxorubicin, n = 4 temozolomide) one day prior to their scheduled surgical resection. Samples of "sonicated" and "unsonicated" tissue were measured for the chemotherapy by liquid-chromatography-mass spectrometry. Complete follow-up was three months. The procedure was well-tolerated, with no adverse clinical or radiologic events related to the procedure. The BBB within the target volume showed radiographic evidence of opening with an immediate 15-50% increased contrast enhancement on T1-weighted MRI, and resolution approximately 20 hours after. Biochemical analysis of sonicated versus unsonicated tissue suggest chemotherapy delivery is feasible. In this study, we demonstrated transient BBB opening in tumor and peritumor tissue using non-invasive low-intensity MRgFUS with systemically administered chemotherapy was safe and feasible. The characterization of therapeutic delivery and clinical response to this treatment paradigm requires further investigation.

Incidence and Time of Onset of Osseous Pseudoprogression in Patients With Metastatic Spine Disease From Renal Cell or Prostate Carcinoma After Treatment With Stereotactic Body Radiation Therapy.

BACKGROUND: Tumor osseous pseudoprogression (PP), defined as an imaging-based transient increase in tumor size following treatment, was recently described in patients with spinal metastases following stereotactic body radiation therapy. Distinguishing PP from true tumor progression is critical. OBJECTIVE: To describe the incidence, time of onset, and time range of PP following stereotactic body radiation therapy in patients treated for spinal metastases from either prostate cancer (PC) or renal cell carcinoma (RCC), and associated predictive factors. METHODS: A retrospective study was conducted on our institution's cancer database from 2009 to 2015. Selection was based on single level, no prior radiation or surgery, ≥2 follow-up spine magnetic resonance imaging (MRI), and metastases arising from either PC or RCC. Gross tumor volume was contoured on pre- and up to 5 posttreatment MRIs. Patients were sorted into groups depending on gross tumor volume response: PP, non-PP, or progressive disease. Clinical and dosimetric variables were compared using either Fisher's exact test or Kruskal-Wallis analyses. RESULTS: Forty-three spinal segments from 31 patients were analyzed. RCC and PC patients showed similar incidence of PP (∼37%). Whether the primary was lytic or sclerotic was a significant predictive factor with more PP in the lytic group (P = .0208). There was a trend of earlier PP onset in RCC (within 6-18 mo) as compared to PC; however, PC segments showed more time-confined presentation of PP (9-12 mo). CONCLUSION: There was a higher incidence of PP in lytic compared to sclerotic primary tumor type. PP in spinal metastatic sites may have variable presentations depending on the primary cancer.

Differentiating radiation necrosis from tumor progression in brain metastases treated with stereotactic radiotherapy: utility of intravoxel incoherent motion perfusion MRI and correlation with histopathology.

Radiation necrosis is a serious potential adverse event of stereotactic radiosurgery that cannot be reliably differentiated from recurrent tumor using conventional imaging techniques. Intravoxel incoherent motion (IVIM) is a magnetic resonance imaging (MRI) based method that uses a diffusion-weighted sequence to estimate quantitative perfusion and diffusion parameters. This study evaluated the IVIM-derived apparent diffusion coefficient (ADC) and perfusion fraction (f), and compared the results to the gold standard histopathological-defined outcomes of radiation necrosis or recurrent tumor. Nine patients with ten lesions were included in this study; all lesions exhibited radiographic progression after stereotactic radiosurgery for brain metastases that subsequently underwent surgical resection due to uncertainty regarding the presence of radiation necrosis versus recurrent tumor. Pre-surgical IVIM was performed to obtain f and ADC values and the results were compared to histopathology. Five lesions exhibited pathological radiation necrosis and five had predominantly recurrent tumor. The IVIM perfusion fraction reliably differentiated tumor recurrence from radiation necrosis (fmean = 10.1 ± 0.7 vs. 8.3 ± 1.2, p = 0.02; cutoff value of 9.0 yielding a sensitivity/specificity of 100%/80%) while the ADC did not distinguish between the two (ADCmean = 1.1 ± 0.2 vs. 1.2 ± 0.4, p = 0.6). IVIM shows promise in differentiating recurrent tumor from radiation necrosis for brain metastases treated with radiosurgery, but needs to be validated in a larger cohort.

Temporal evolution of perfusion parameters in brain metastases treated with stereotactic radiosurgery: comparison of intravoxel incoherent motion and dynamic contrast enhanced MRI.

Intravoxel incoherent motion (IVIM) is a magnetic resonance imaging (MRI) technique that is seeing increasing use in neuro-oncology and offers an alternative to contrast-enhanced perfusion techniques for evaluation of tumor blood volume after stereotactic radiosurgery (SRS). To date, IVIM has not been validated against contrast enhanced techniques for brain metastases after SRS. In the present study, we measure blood volume for 20 brain metastases (15 patients) at baseline, 1 week and 1 month after SRS using IVIM and dynamic contrast enhanced (DCE)-MRI. Correlation between blood volume measurements made with IVIM and DCE-MRI show poor correlation at baseline, 1 week, and 1 month post SRS (r = 0.33, 0.14 and 0.30 respectively). At 1 week after treatment, no significant change in tumor blood volume was found using IVIM or DCE-MRI (p = 0.81 and 0.41 respectively). At 1 month, DCE-MRI showed a significant decrease in blood volume (p = 0.0002). IVIM, on the other hand, demonstrated the opposite effect and showed a significant increase in blood volume at 1 month (p = 0.03). The results of this study indicate that blood volume measured with IVIM and DCE-MRI are not equivalent. While this may relate to differences in the type of perfusion information each technique is providing, it could also reflect a limitation of tumor blood volume measurements made with IVIM after SRS. IVIM measurements of tumor blood volume in the month after SRS should therefore be interpreted with caution.

Spinal metastases: multimodality imaging in diagnosis and stereotactic body radiation therapy planning.

Due to increased effectiveness of cancer treatments and increasing survival rates, metastatic disease has become more frequent compared to the past, with the spine being the most common site of bony metastases. Diagnostic imaging is an integral part of screening, diagnosis and follow-up of spinal metastases. In this article, we review the principles of multimodality imaging for tumor detection with respect to their value for diagnosis and stereotactic body radiation therapy planning for spinal metastases. We will also review the current international consensus agreement for stereotactic body radiation therapy planning, and the role of imaging in achieving the best possible treatment plan.