BIOGUIDE-X: A First-in-Human Study of the Performance of Positron Emission Tomography-Guided Radiation Therapy.

PURPOSE: Positron emission tomography (PET)-guided radiation therapy is a novel tracked dose delivery modality that uses real-time PET to guide radiation therapy beamlets. The BIOGUIDE-X study was performed with sequential cohorts of participants to (1) identify the fluorodeoxyglucose (FDG) dose for PET-guided therapy and (2) confirm that the emulated dose distribution was consistent with a physician-approved radiation therapy plan. METHODS AND MATERIALS: This prospective study included participants with at least 1 FDG-avid targetable primary or metastatic tumor (2-5 cm) in the lung or bone. For cohort I, a modified 3 + 3 design was used to determine the FDG dose that would result in adequate signal for PET-guided therapy. For cohort II, PET imaging data were collected on the X1 system before the first and last fractions among patients undergoing conventional stereotactic body radiation therapy. PET-guided therapy dose distributions were modeled on the patient's computed tomography anatomy using the collected PET data at each fraction as input to an "emulated delivery" and compared with the physician-approved plan. RESULTS: Cohort I demonstrated adequate FDG activity in 6 of 6 evaluable participants (100.0%) with the first injected dose level of 15 mCi FDG. In cohort II, 4 patients with lung tumors and 5 with bone tumors were enrolled, and evaluable emulated delivery data points were collected for 17 treatment fractions. Sixteen of the 17 emulated deliveries resulted in dose distributions that were accurate with respect to the approved PET-guided therapy plan. The 17th data point was just below the 95% threshold for accuracy (dose-volume histogram score = 94.6%). All emulated fluences were physically deliverable. No toxicities were attributed to multiple FDG administrations. CONCLUSIONS: PET-guided therapy is a novel radiation therapy modality in which a radiolabeled tumor can act as its own fiducial for radiation therapy targeting. Emulated therapy dose distributions calculated from continuously acquired real-time PET data were accurate and machine-deliverable in tumors that were 2 to 5 cm in size with adequate FDG signal characteristics.

Cerebral Blood Flow Predicts the Infarct Core: New Insights From Contemporaneous Diffusion and Perfusion Imaging.

Background and Purpose- The aim of this study is to determine the spatial and volumetric accuracy of infarct core estimates from relative cerebral blood flow (rCBF) by comparison with near-contemporaneous diffusion-weighted imaging (DWI), and evaluate whether it is sufficient for patient triage to reperfusion therapies. Methods- One hundred ninety-three patients enrolled in the DEFUSE 2 (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution) and SENSE 3 (Sensitivity Encoding) stroke studies were screened, and 119 who underwent acute magnetic resonance imaging with DWI and perfusion imaging within 24 hours of onset were included. Infarct core was estimated using reduced rCBF at 12 thresholds (<0.20-<0.44) and compared against DWI (apparent diffusion coefficient <620 10-6mm2/s). For each threshold, volumetric agreement between the rCBF and DWI core estimates was assessed using Bland-Altman, correlation, and linear regression analyses; spatial agreement was assessed using receiver operating characteristic analysis. Results- An rCBF threshold of 0.32 yielded the smallest mean absolute volume difference (14.7 mL), best linear regression fit (R2=0.84), and best spatial agreement (Youden index, 0.38; 95% CI, 0.34-0.41) between rCBF and DWI, with high correlation (r=0.91, P<0.05), a small mean volume difference (1.3 mL) and no fixed bias (P<0.05). At this threshold, 110 of 119 (92.4%) patients were correctly triaged when applying 70 mL as the volume limit for thrombectomy. Spatial agreement was better for prediction of large infarcts (>70 mL) than small infarcts (≤70 mL), with Youden indices of 0.53 (95% CI, 0.49-0.56) and 0.34 (95% CI, 0.30-0.37), respectively. Conclusions- Strong correlation and agreement with near-contemporaneous DWI indicate that infarct core estimates obtained using rCBF are sufficiently accurate for patient triage to reperfusion therapies. The identified optimal rCBF threshold of 0.32 closely approximates the threshold currently used in clinical practice.

Development of a Mobile Tool That Semiautomatically Screens Patients for Stroke Clinical Trials.

BACKGROUND AND PURPOSE: Despite several national coordinated research networks, enrollment in many cerebrovascular trials remains challenging. An electronic tool was needed that would improve the efficiency and efficacy of screening for multiple simultaneous acute clinical stroke trials by automating the evaluation of inclusion and exclusion criteria, improving screening procedures and streamlining the communication process between the stroke research coordinators and the stroke clinicians. METHODS: A multidisciplinary group consisting of physicians, study coordinators, and biostatisticians designed and developed an electronic clinical trial screening tool on a HIPAA (Health Insurance Portability and Accountability Act)-compliant platform. RESULTS: A web-based tool was developed that uses branch logic to determine eligibility for simultaneously enrolling clinical trials and automatically notifies the study coordinator teams about eligible patients. After 12 weeks of use, 225 surveys were completed, and 51 patients were enrolled in acute stroke clinical trials. Compared with the 12 weeks before implementation of the tool, there was an increase in enrollment from 16.5% of patients screened to 23.4% of patients screened (P<0.05). Clinicians and coordinators reported increased satisfaction with the process and improved ease of screening. CONCLUSIONS: We created a semiautomated electronic screening tool that uses branch logic to screen patients for stroke clinical trials. The tool has improved efficiency and efficacy of screening, and it could be adapted for use at other sites and in other medical fields.

Prognostic Value of Quantitative Diffusion-Weighted MRI in Patients with Traumatic Brain Injury.

BACKGROUND AND PURPOSE: Data about the predictive value of quantitative diffusion-weighted MRI in traumatic brain injury (TBI) patients is lacking. This study aimed to determine if specific apparent diffusion coefficient (ADC) thresholds could be determined that correlate with outcome in moderate-severe TBI. METHODS: This retrospective observational study investigated patients with moderate-severe TBI. MRIs obtained post-injury days 1-13 were analyzed. MRIs were obtained on a 1.5T scanner; 20-23 contiguous diffusion-weighted imaging (DWI) sections with a spin-echo echo planar imaging DWI 256×256 reconstructed matrix; field of view 24×24 cm; slice thickness/gap of 5/1.5 or 5/2.5 mm. The ADC value of each brain tissue voxel was determined. The percentage of voxels below different ADC thresholds was calculated and correlated with outcome. A good outcome was defined as discharge to home or a rehabilitation facility. RESULTS: Seventy-six patients were analyzed. Thirty-five patients (46%) had a good outcome. The timing of MRI scans did not differ between groups, but the mean age did (42±18 years vs. 56±19 years, p<.01, good vs. poor outcome). Patients with poor outcome had significantly higher percentage of brain volume with ADC < 400×10(-6) mm2 /second (.85±.67% vs. .60±.29%, poor vs. good outcome, p<.05). Using a ROC curve analysis and Youden's index, an ADC <400×10(-6) mm2 /second in ≥.49% of brain was 85% sensitive and 46% specific for poor outcome (p<.05). CONCLUSIONS: Quantitative MRI offers additional prognostic information in acute TBI. A whole brain tissue ADC threshold of <400×10(-6) mm2 /second in ≥.49% of brain may be a novel prognostic biomarker.

Magnetic resonance imaging profile of blood-brain barrier injury in patients with acute intracerebral hemorrhage.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) is associated with blood-brain barrier (BBB) injury, which is a poorly understood factor in ICH pathogenesis, potentially contributing to edema formation and perihematomal tissue injury. We aimed to assess and quantify BBB permeability following human spontaneous ICH using dynamic contrast-enhanced magnetic resonance imaging (DCE MRI). We also investigated whether hematoma size or location affected the amount of BBB leakage. METHODS AND RESULTS: Twenty-five prospectively enrolled patients from the Diagnostic Accuracy of MRI in Spontaneous intracerebral Hemorrhage (DASH) study were examined using DCE MRI at 1 week after symptom onset. Contrast agent dynamics in the brain tissue and general tracer kinetic modeling were used to estimate the forward leakage rate (K(trans)) in regions of interest (ROI) in and surrounding the hematoma and in contralateral mirror-image locations (control ROI). In all patients BBB permeability was significantly increased in the brain tissue immediately adjacent to the hematoma, that is, the hematoma rim, compared to the contralateral mirror ROI (P<0.0001). Large hematomas (>30 mL) had higher K(trans) values than small hematomas (P<0.005). K(trans) values of lobar hemorrhages were significantly higher than the K(trans) values of deep hemorrhages (P<0.005), independent of hematoma volume. Higher K(trans) values were associated with larger edema volumes. CONCLUSIONS: BBB leakage in the brain tissue immediately bordering the hematoma can be measured and quantified by DCE MRI in human ICH. BBB leakage at 1 week is greater in larger hematomas as well as in hematomas in lobar locations and is associated with larger edema volumes.