To identify an optimal margin about the gross target volume (GTV) for stereotactic radiosurgery (SRS) of brain metastases, minimizing toxicity and local recurrence.
Adult patients with 1 to 3 brain ...metastases less than 4 cm in greatest dimension, no previous brain radiation therapy, and Karnofsky performance status (KPS) above 70 were eligible for this institutional review board-approved trial. Individual lesions were randomized to 1- or 3- mm uniform expansion of the GTV defined on contrast-enhanced magnetic resonance imaging (MRI). The resulting planning target volume (PTV) was treated to 24, 18, or 15 Gy marginal dose for maximum PTV diameters less than 2, 2 to 2.9, and 3 to 3.9 cm, respectively, using a linear accelerator-based image-guided system. The primary endpoint was local recurrence (LR). Secondary endpoints included neurocognition Mini-Mental State Examination, Trail Making Test Parts A and B, quality of life (Functional Assessment of Cancer Therapy-Brain), radionecrosis (RN), need for salvage radiation therapy, distant failure (DF) in the brain, and overall survival (OS).
Between February 2010 and November 2012, 49 patients with 80 brain metastases were treated. The median age was 61 years, the median KPS was 90, and the predominant histologies were non-small cell lung cancer (25 patients) and melanoma (8). Fifty-five, 19, and 6 lesions were treated to 24, 18, and 15 Gy, respectively. The PTV/GTV ratio, volume receiving 12 Gy or more, and minimum dose to PTV were significantly higher in the 3-mm group (all P<.01), and GTV was similar (P=.76). At a median follow-up time of 32.2 months, 11 patients were alive, with median OS 10.6 months. LR was observed in only 3 lesions (2 in the 1 mm group, P=.51), with 6.7% LR 12 months after SRS. Biopsy-proven RN alone was observed in 6 lesions (5 in the 3-mm group, P=.10). The 12-month DF rate was 45.7%. Three months after SRS, no significant change in neurocognition or quality of life was observed.
SRS was well tolerated, with low rates of LR and RN in both cohorts. However, given the higher potential risk of RN with a 3-mm margin, a 1-mm GTV expansion is more appropriate.
Purpose
This study investigated the prognostic potential of intra‐treatment PET radiomics data in patients undergoing definitive (chemo) radiation therapy for oropharyngeal cancer (OPC) on a ...prospective clinical trial. We hypothesized that the radiomic expression of OPC tumors after 20 Gy is associated with recurrence‐free survival (RFS).
Materials and Methods
Sixty‐four patients undergoing definitive (chemo)radiation for OPC were prospectively enrolled on an IRB‐approved study. Investigational 18F‐FDG‐PET/CT images were acquired prior to treatment and 2 weeks (20 Gy) into a seven‐week course of therapy. Fifty‐five quantitative radiomic features were extracted from the primary tumor as potential biomarkers of early metabolic response. An unsupervised data clustering algorithm was used to partition patients into clusters based only on their radiomic expression. Clustering results were naïvely compared to residual disease and/or subsequent recurrence and used to derive Kaplan‐Meier estimators of RFS. To test whether radiomic expression provides prognostic value beyond conventional clinical features associated with head and neck cancer, multivariable Cox proportional hazards modeling was used to adjust radiomic clusters for T and N stage, HPV status, and change in tumor volume.
Results
While pre‐treatment radiomics were not prognostic, intra‐treatment radiomic expression was intrinsically associated with both residual/recurrent disease (P = 0.0256, χ2 test) and RFS (HR = 7.53, 95% CI = 2.54–22.3; P = 0.0201). On univariate Cox analysis, radiomic cluster was associated with RFS (unadjusted HR = 2.70; 95% CI = 1.26–5.76; P = 0.0104) and maintained significance after adjustment for T, N staging, HPV status, and change in tumor volume after 20 Gy (adjusted HR = 2.69; 95% CI = 1.03–7.04; P = 0.0442). The particular radiomic characteristics associated with outcomes suggest that metabolic spatial heterogeneity after 20 Gy portends complete and durable therapeutic response. This finding is independent of baseline metabolic imaging characteristics and clinical features of head and neck cancer, thus providing prognostic advantages over existing approaches.
Conclusions
Our data illustrate the prognostic value of intra‐treatment metabolic image interrogation, which may potentially guide adaptive therapy strategies for OPC patients and serve as a blueprint for other disease sites. The quality of our study was strengthened by its prospective image acquisition protocol, homogenous patient cohort, relatively long patient follow‐up times, and unsupervised clustering formalism that is less prone to hyper‐parameter tuning and over‐fitting compared to supervised learning.
Collateral circulation plays a pivotal role in acute ischemic stroke due to large vessel occlusion (LVO) and may be affected by multiple variables during sedation for endovascular therapy (EVT). We ...conducted detailed analyses of the GOLIATH trial to identify predictors of collateral circulation grade and infarct growth. We also modified the ASITN collateral grading scale and sought to determine its impact on clinical outcome and infarct growth. Multivariable analysis was used to identify predictors of collaterals and infarct growth. Ordinal analysis demonstrated nominal, but non-significant association between modified ASITN scale and infarct growth. Among all analyzed baseline clinical and procedural variables, the most significant predictors of infarct growth at 24 h were phenylephrine dose (estimate 6.78; p = 0.014) and baseline infarct volume (estimate 0.93; p = 0.03). The most significant predictors of worse collateral grade were mean arterial pressure (MAP) <70 mmHg (OR 0.35; p = 0.048) and baseline infarct volume (OR 0.96; p = 0.003). Hypotension during sedation for EVT for LVO negatively impacts collateral circulation, while higher pressor dose is a strong predictor of infarct growth. Avoidance of anesthesia-induced hypotension and consequent need for pressor therapy may prevent collateral failure and minimize infarct growth.
Angiographic revascularization grading after intra-arterial stroke therapy is limited by poor standardization, making it unclear which scale is optimal for predicting outcome. Using recently ...standardized criteria, we sought to compare the prognostic performance of 2 commonly used reperfusion scales.
Inclusion criteria for this multicenter retrospective study were acute ischemic stroke attributable to middle cerebral artery M1 occlusion, intra-arterial therapy, and 90-day modified Rankin scale score. Post-intra-arterial therapy reperfusion was graded using the Thrombolysis in Myocardial Infarction (TIMI) and Modified Thrombolysis in Cerebral Infarction (mTICI) scales. The scales were compared for prediction of clinical outcome using receiver-operating characteristic analysis.
Of 308 patients, mean age was 65 years, and median National Institutes of Health Stroke Scale score was 17. The mean time from stroke onset to groin puncture was 305 minutes. There was no difference in the time to treatment between patients grouped by final TIMI (ie, 0 versus 1 versus 2 versus 3) or mTICI grades (ie, 0 versus 1 versus 2a versus 2b versus 3). Good outcome (modified Rankin scale, 0-2) was achieved in 32.5% of patients, and mortality rate was 25.3% at 90 days. There was a 6.3% rate of parenchymal hematoma type 2. In receiver-operating characteristic analysis, mTICI was superior to TIMI for predicting 90-day modified Rankin scale 0 to 2 (c-statistic: 0.74 versus 0.68; P<0.0001). The optimal threshold for identifying a good outcome was mTICI 2b to 3 (sensitivity 78.0%; specificity 66.1%).
mTICI is superior to TIMI for predicting clinical outcome after intra-arterial therapy. mTICI 2b to 3 is the optimal biomarker for procedural success.
IMPORTANCE: Brain-computer interface (BCI) implants have previously required craniotomy to deliver penetrating or surface electrodes to the brain. Whether a minimally invasive endovascular technique ...to deliver recording electrodes through the jugular vein to superior sagittal sinus is safe and feasible is unknown. OBJECTIVE: To assess the safety of an endovascular BCI and feasibility of using the system to control a computer by thought. DESIGN, SETTING, AND PARTICIPANTS: The Stentrode With Thought-Controlled Digital Switch (SWITCH) study, a single-center, prospective, first in-human study, evaluated 5 patients with severe bilateral upper-limb paralysis, with a follow-up of 12 months. From a referred sample, 4 patients with amyotrophic lateral sclerosis and 1 with primary lateral sclerosis met inclusion criteria and were enrolled in the study. Surgical procedures and follow-up visits were performed at the Royal Melbourne Hospital, Parkville, Australia. Training sessions were performed at patients’ homes and at a university clinic. The study start date was May 27, 2019, and final follow-up was completed January 9, 2022. INTERVENTIONS: Recording devices were delivered via catheter and connected to subcutaneous electronic units. Devices communicated wirelessly to an external device for personal computer control. MAIN OUTCOMES AND MEASURES: The primary safety end point was device-related serious adverse events resulting in death or permanent increased disability. Secondary end points were blood vessel occlusion and device migration. Exploratory end points were signal fidelity and stability over 12 months, number of distinct commands created by neuronal activity, and use of system for digital device control. RESULTS: Of 4 patients included in analyses, all were male, and the mean (SD) age was 61 (17) years. Patients with preserved motor cortex activity and suitable venous anatomy were implanted. Each completed 12-month follow-up with no serious adverse events and no vessel occlusion or device migration. Mean (SD) signal bandwidth was 233 (16) Hz and was stable throughout study in all 4 patients (SD range across all sessions, 7-32 Hz). At least 5 attempted movement types were decoded offline, and each patient successfully controlled a computer with the BCI. CONCLUSIONS AND RELEVANCE: Endovascular access to the sensorimotor cortex is an alternative to placing BCI electrodes in or on the dura by open-brain surgery. These final safety and feasibility data from the first in-human SWITCH study indicate that it is possible to record neural signals from a blood vessel. The favorable safety profile could promote wider and more rapid translation of BCI to people with paralysis. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03834857
Abstract
In this multicenter, open-label, single-arm, Phase II study with Simon two-stage optimum design (NCT04361370), we investigate the efficacy and safety of triplet maintenance (olaparib, ...pembrolizumab, bevacizumab) in patients with platinum-sensitive recurrent ovarian cancer who are wild-type for
BRCA
1/2. A total of 44 patients were enrolled, and the median follow-up duration was 22.9 months (interquartile range: 17.4–24.7). The primary outcome was 6-months progression-free survival (PFS), which was 88.6% (95% confidence interval CI 75.4–96.2), meeting the pre-specified primary endpoint. The secondary outcomes reported here include median PFS, 12-months PFS, and overall survival and safety. The median PFS was 22.4 months (20.4–∞), with a 12-months PFS rate of 84.0% (95% CI 69.3–92.0). The median overall survival was 28.6 months (27.3–∞). The combination demonstrated tolerable toxicity with manageable side effects. Other secondary outcomes include time-to-progression, time to subsequent treatment, time to second treatment and PFS2; however, this data is not reported, as treatment is still ongoing in a majority of patients. Exploratory analysis shows that patients who were homologous recombination deficiency-positive or had a programmed death-ligand 1 combined positive score ≥1 showed a favorable response (
P
= 0.043 and
P
< 0.001, respectively). Thus, triplet maintenance shows durable efficacy with tolerable safety in patients with platinum-sensitive recurrence.
Digital computing is nearing its physical limits as computing needs and energy consumption rapidly increase. Analogue‐memory‐based neuromorphic computing can be orders of magnitude more energy ...efficient at data‐intensive tasks like deep neural networks, but has been limited by the inaccurate and unpredictable switching of analogue resistive memory. Filamentary resistive random access memory (RRAM) suffers from stochastic switching due to the random kinetic motion of discrete defects in the nanometer‐sized filament. In this work, this stochasticity is overcome by incorporating a solid electrolyte interlayer, in this case, yttria‐stabilized zirconia (YSZ), toward eliminating filaments. Filament‐free, bulk‐RRAM cells instead store analogue states using the bulk point defect concentration, yielding predictable switching because the statistical ensemble behavior of oxygen vacancy defects is deterministic even when individual defects are stochastic. Both experiments and modeling show bulk‐RRAM devices using TiO2‐X switching layers and YSZ electrolytes yield deterministic and linear analogue switching for efficient inference and training. Bulk‐RRAM solves many outstanding issues with memristor unpredictability that have inhibited commercialization, and can, therefore, enable unprecedented new applications for energy‐efficient neuromorphic computing. Beyond RRAM, this work shows how harnessing bulk point defects in ionic materials can be used to engineer deterministic nanoelectronic materials and devices.
A resistive memory cell based on the electrochemical migration of oxygen vacancies for in‐memory neuromorphic computing is presented. By using the average statistical behavior of all oxygen vacancies to store analogue information states, this cell overcomes the stochastic and unpredictable switching plaguing filament‐forming memristors, and instead achieves linear, predictable, and deterministic switching.
The purpose of this study was to investigate the relationship between hyperperfusion and hemorrhagic transformation (HT) in acute ischemic stroke (AIS). Pseudo-continuous arterial spin labeling (ASL) ...with background suppressed 3D GRASE was performed during routine clinical magnetic resonance imaging (MRI) on AIS patients at various time points. Arterial spin labeling cerebral blood flow (CBF) maps were visually inspected for the presence of hyperperfusion. Hemorrhagic transformation was followed during hospitalization and was graded on gradient recalled echo (GRE) scans into hemorrhagic infarction (HI) and parenchymal hematoma (PH). A total of 361 ASL scans were collected from 221 consecutive patients with middle cerebral artery stroke from May 2010 to September 2013. Hyperperfusion was more frequently detected posttreatment (odds ratio (OR)=4.8, 95% confidence interval (CI) 2.5 to 8.9, P<0.001) and with high National Institutes of Health Stroke Scale (NIHSS) scores at admission (P<0.001). There was a significant association between having hyperperfusion at any time point and HT (OR=3.5, 95% CI 2.0 to 6.3, P<0.001). There was a positive relationship between the grade of HT and time—hyperperfusion with the Spearman's rank correlation of 0.44 (P=0.003). Arterial spin labeling hyperperfusion may provide an imaging marker of HT, which may guide the management of AIS patients post tissue-type plasminogen activator (tPA) and/or endovascular treatments. Late hyperperfusion should be given more attention to prevent high-grade HT.
Background and Purpose:
End-of-procedure substantial reperfusion modified Treatment in Cerebral Ischemia (mTICI) 2b-3, the leading endpoint for thrombectomy studies, has several limitations including ...a ceiling effect, with recent achieved rates of ~90%. We aimed to identify a more optimal definition of angiographic success along two dimensions: (1) the extent of tissue reperfusion, and (2) the speed of revascularization.
Methods:
Core-lab adjudicated TICI scores for the first three passes of EmboTrap and the final all-procedures result were analyzed in the ARISE II multicenter study. The clinical impact of extent of reperfusion and speed of reperfusion (first-pass vs. later-pass) were evaluated. Clinical outcomes included 90-day functional independence modified Rankin Scale (mRS) 0–2, 90-day freedom-from-disability (mRS 0–1), and dramatic early improvement 24-h National Institutes of Health Stroke Scale (NIHSS) improvement ≥ 8 points.
Results:
Among 161 ARISE II subjects with ICA or MCA M1 occlusions, reperfusion results at procedure end showed substantial reperfusion in 149 (92.5%), excellent reperfusion in 121 (75.2%), and complete reperfusion in 79 (49.1%). Reperfusion rates on first pass were substantial in 81 (50.3%), excellent reperfusion in 62 (38.5%), and complete reperfusion in 44 (27.3%). First-pass excellent reperfusion (first-pass TICI 2c-3) had the greatest nominal predictive value for 90-day mRS 0–2 (sensitivity 58.5%, specificity 68.6%). There was a progressive worsening of outcomes with each additional pass required to achieve TICI 2c-3.
Conclusions:
First-pass excellent reperfusion (TICI 2c-3), reflecting rapid achievement of extensive reperfusion, is the technical revascularization endpoint that best predicted functional independence in this international multicenter trial and is an attractive candidate for a lead angiographic endpoint for future trials.
Clinical Trial Registration:
http://www.clinicaltrials.gov
, identifier NCT02488915.
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