Objective
There is a paucity of level-one evidence comparing STN and GPi DBS. Our aim in this prospective blinded randomized trial was to compare the cognitive and mood effects of unilateral subthalamic nucleus (STN) vs. unilateral globus pallidus interna (GPi) deep brain stimulation (DBS) in patients with Parkinson disease (PD).
Methods
Fifty-two subjects with moderate-to-advanced PD were randomized to either unilateral STN or GPi DBS. Right or alternatively left sided stimulation was chosen to address the side of the body with the most bothersome symptoms. The co-primary outcome measures were the change in the 8 subscales of the Visual Analog Mood Scale (VAMS), and the change in the 2 versions of verbal fluency (i.e. semantic and letter), at 7 months post-DBS in the optimal setting compared to the pre-DBS state. In addition, at 7 months post-DBS, after subjects underwent initial evaluation off medications and on optimized DBS therapy, they were tested in four randomized and counterbalanced conditions (optimal DBS, ventral DBS, dorsal DBS, and off DBS) while remaining off medication. Secondary outcome measures then compared the differences in the VAMS items and verbal fluency subscales within the 4 DBS conditions at 7 months, and the change in the VAMS items and verbal fluency subscales from the pre-DBS state to the other 3 DBS conditions (ventral, dorsal and off ) at 7 months.
Results
Forty-five subjects (23 GPi and 22 STN) completed the protocol. The study revealed no significant difference between STN and GPi DBS in the change of co-primary mood and cognitive outcomes from pre- to post-DBS in the optimal setting (Hotelling's T2 test: p=0.16 and 0.08 respectively). When comparing the 4 DBS conditions at 7 months, subjects in both targets were less “happy”, less “energetic” and more “confused” when stimulated ventrally to the optimal stimulation site. When comparing the other 3 DBS conditions (ventral, dorsal and off DBS) to the pre-DBS state, the STN group showed a larger deterioration of letter verbal fluency scores than the GPi group, especially in the off DBS state. A 12-point mean improvement in the UPDRS motor subscale was seen post DBS, but there was no significant difference between targets.
Interpretations
There were no significant differences in in the co-primary outcome measures of mood and cognition between STN and GPi in the optimal DBS state.. However, adverse mood effects were noted when stimulating ventrally to the optimal site in both targets. Furthermore, a worsening for letter verbal fluency was noted in the 3 non-optimal post-DBS states in the STN target only. The persistence of deterioration in verbal fluency in the off DBS state at 7 months is, suggestive of a surgical rather than a stimulation-induced effect at the STN target. STN and GPi DBS resulted in similar motor improvement.
Chimeric antigen receptor (CAR) T-cell therapy targeting solid tumors has stagnated as a result of tumor heterogeneity, immunosuppressive microenvironments, and inadequate intratumoral T cell trafficking and persistence. Early (≤3 days) intratumoral presentation of CAR T cells post-treatment is a superior predictor of survival than peripheral persistence. Therefore, we have co-opted IL-8 release from tumors to enhance intratumoral T-cell trafficking through a CAR design for maximal antitumor activity in solid tumors. Here, we demonstrate that IL-8 receptor, CXCR1 or CXCR2, modified CARs markedly enhance migration and persistence of T cells in the tumor, which induce complete tumor regression and long-lasting immunologic memory in pre-clinical models of aggressive tumors such as glioblastoma, ovarian and pancreatic cancer.
Between May, 1988 and August, 1993, 158 patients with arteriovenous malformations (AVMs) were treated radiosurgically at the University of Florida. A mean dose of 1560 cGy was directed to the periphery of the lesions, which had a mean volume of 9 cc (0.5 to 45.3 cc). One hundred thirty-nine of these individuals were treated with one isocenter. The mean follow-up interval was 33 months with clinical information available on 153 of these patients. Patients were followed until magnetic resonance (MR) studies suggested complete AVM thrombosis. An arteriogram was then performed, if possible, to verify occlusion status. If arteriography revealed any persistent nidus at 36 months posttreatment, the residual nidus was re-treated. Outcome categories of AVMs analyzed included the following possibilities: 1) angiographic cure; 2) angiographic failure; 3) re-treatment; 4) MR image suggested cure; 5) MR image suggested failure; 6) patient refused follow-up evaluation; 7) patient lost to follow-up study; or 8) patient deceased. The endpoints for success or failure of radiosurgery were as follows: angiographic occlusion (success), re-treatment (failure), and death due to AVM hemorrhage (failure). Fifty-six patients in this series reached one of the endpoints. Successful endpoints were seen in 91% of AVMs between 1 and 4 cc in volume, 100% of AVMs 4 to 10 cc in volume, and 79% of AVMs greater than 10 cc in volume. The more traditional measure of radiosurgical success, percentage of angiograms showing complete obliteration, was obtained in 81% of AVMs between 1 and 4 cc in volume, 89% of AVMs between 4 and 10 cc in volume, and 69% of AVMs greater than 10 cc in volume. A detailed analysis of the relationship of all outcome categories to size is presented.
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