Subjective feelings associated with expectations and rewards during risky decision-making in impulse control disorder.

Impulse Control Disorder (ICD) in Parkinson's disease is a behavioral addiction induced by dopaminergic therapies, but otherwise unclear etiology. The current study investigates the interaction of reward processing variables, dopaminergic therapy, and risky decision-making and subjective feelings in patients with versus without ICD. Patients with (n = 18) and without (n = 12) ICD performed a risky decision-making task both 'on' and 'off' standard-of-care dopaminergic therapies (the task was performed on 2 different days with the order of on and off visits randomized for each patient). During each trial of the task, participants choose between two options, a gamble or a certain reward, and reported how they felt about decision outcomes. Subjective feelings of 'pleasure' are differentially driven by expectations of possible outcomes in patients with, versus without ICD. While off medication, the influence of expectations about risky-decisions on subjective feelings is reduced in patients with ICD versus without ICD. While on medication, the influence of expected outcomes in patients with ICD versus without ICD becomes similar. Computational modeling of behavior supports the idea that latent decision-making factors drive subjective feelings in patients with Parkinson's disease and that ICD status is associated with a change in the relationship between factors associated with risky behavior and subjective feelings about the experienced outcomes. Our results also suggest that dopaminergic medications modulate the impact expectations have on the participants' subjective reports. Altogether our results suggest that expectations about risky decisions may be decoupled from subjective feelings in patients with ICD, and that dopaminergic medications may reengage these circuits and increase emotional reactivity in patients with ICD.

Developing a hippocampal neural prosthetic to facilitate human memory encoding and recall of stimulus features and categories.

Objective: Here, we demonstrate the first successful use of static neural stimulation patterns for specific information content. These static patterns were derived by a model that was applied to a subject's own hippocampal spatiotemporal neural codes for memory. Approach: We constructed a new model of processes by which the hippocampus encodes specific memory items via spatiotemporal firing of neural ensembles that underlie the successful encoding of targeted content into short-term memory. A memory decoding model (MDM) of hippocampal CA3 and CA1 neural firing was computed which derives a stimulation pattern for CA1 and CA3 neurons to be applied during the encoding (sample) phase of a delayed match-to-sample (DMS) human short-term memory task. Main results: MDM electrical stimulation delivered to the CA1 and CA3 locations in the hippocampus during the sample phase of DMS trials facilitated memory of images from the DMS task during a delayed recognition (DR) task that also included control images that were not from the DMS task. Across all subjects, the stimulated trials exhibited significant changes in performance in 22.4% of patient and category combinations. Changes in performance were a combination of both increased memory performance and decreased memory performance, with increases in performance occurring at almost 2 to 1 relative to decreases in performance. Across patients with impaired memory that received bilateral stimulation, significant changes in over 37.9% of patient and category combinations was seen with the changes in memory performance show a ratio of increased to decreased performance of over 4 to 1. Modification of memory performance was dependent on whether memory function was intact or impaired, and if stimulation was applied bilaterally or unilaterally, with nearly all increase in performance seen in subjects with impaired memory receiving bilateral stimulation. Significance: These results demonstrate that memory encoding in patients with impaired memory function can be facilitated for specific memory content, which offers a stimulation method for a future implantable neural prosthetic to improve human memory.

Sub-second and multi-second dopamine dynamics underlie variability in human time perception.

Timing behaviour and the perception of time are fundamental to cognitive and emotional processes in humans. In non-human model organisms, the neuromodulator dopamine has been associated with variations in timing behaviour, but the connection between variations in dopamine levels and the human experience of time has not been directly assessed. Here, we report how dopamine levels in human striatum, measured with sub-second temporal resolution during awake deep brain stimulation surgery, relate to participants' perceptual judgements of time intervals. Fast, phasic, dopaminergic signals were associated with underestimation of temporal intervals, whereas slower, tonic, decreases in dopamine were associated with poorer temporal precision. Our findings suggest a delicate and complex role for the dynamics and tone of dopaminergic signals in the conscious experience of time in humans.

Brain metastases from renal cell carcinoma: Effects of novel systemic agents on brain metastasis outcomes.

OBJECTIVE: The objective of this study was to examine survival outcomes in 136 patients with renal cell carcinoma with metastases to the brain who were treated with radiation combined with immunotherapy or tyrosine kinase inhibitor compared to those who were treated with radiation therapy alone. METHODS: The Wake Forest Gamma Knife prospective database was searched for all patients with renal cell carcinoma brain metastases. Outcome measurements included overall survival, determined via the Kaplan-Meier Method, and cumulative incidence of local and distant failure, determined using the Fine Gray competing risks analysis with death as a competing risk for the 136 patients included. RESULTS: Overall survival for the entire population at 6 months, 12 months, and 24 months was 67%, 47% and 30%, respectively. For the TKI (non-immunotherapy-treated) population (n = 37), overall survival was 75%, 61%, and 40% at 6 months, 12 months, and 24 months, respectively. For the immunotherapy-treated population (n = 35), overall survival was 85%, 64%, and 50% at 6 months, 12 months, and 24 months, respectively. Overall survival was significantly increased for patients who received radiation with either immunotherapy or TKI (p < 0.0001). CONCLUSION: Prior series of patients with brain metastases of multiple histologies have demonstrated an improvement in the local efficacy of stereotactic radiosurgery when combined with systemic agents. We found that patients treated with targeted agents and patients treated with immunotherapy demonstrated a trend towards improvement over patients treated in the era prior to the advent of either classes of novel therapies.

Delayed Imaging Changes 18 Months or Longer After Stereotactic Radiosurgery for Brain Metastases: Necrosis or Progression.

OBJECTIVE: Imaging changes after stereotactic radiosurgery (SRS) can occur for years after treatment, although the available data on the incidence of tumor progression and adverse radiation effects (ARE) are generally limited to the first 2 years after treatment. METHODS: A single-institution retrospective review was conducted of patients who had >18 months of imaging follow-up available. Patients who had ≥1 metastatic brain lesions treated with Gamma Knife SRS were assessed for the time to radiographic progression. Those with progression ≥18 months after the initial treatment were included in the present study. The lesions that progressed were characterized as either ARE or tumor progression based on the tissue diagnosis or imaging characteristics over time. RESULTS: The cumulative incidence of delayed imaging radiographic progression was 35% at 5 years after the initial SRS. The cumulative incidence curves of the time to radiographic progression for lesions determined to be ARE and lesions determined to be tumor progression were not significantly different statistically. The cumulative incidence of delayed ARE and delayed tumor progression was 17% and 16% at 5 years, respectively. Multivariate analysis indicated that the number of metastatic brain lesions present at the initial SRS was the only factor associated with late radiographic progression. CONCLUSIONS: The timing of late radiographic progression does not differ between ARE and tumor progression. The number of metastatic brain lesions at the initial SRS is a risk factor for late radiographic progression.

Subsecond fluctuations in extracellular dopamine encode reward and punishment prediction errors in humans.

In the mammalian brain, midbrain dopamine neuron activity is hypothesized to encode reward prediction errors that promote learning and guide behavior by causing rapid changes in dopamine levels in target brain regions. This hypothesis (and alternatives regarding dopamine's role in punishment-learning) has limited direct evidence in humans. We report intracranial, subsecond measurements of dopamine release in human striatum measured, while volunteers (i.e., patients undergoing deep brain stimulation surgery) performed a probabilistic reward and punishment learning choice task designed to test whether dopamine release encodes only reward prediction errors or whether dopamine release may also encode adaptive punishment learning signals. Results demonstrate that extracellular dopamine levels can encode both reward and punishment prediction errors within distinct time intervals via independent valence-specific pathways in the human brain.

Sub-second Dopamine Signals during Risky Decision-Making in Patients with Impulse Control Disorder.

Background: Impulse Control Disorder (ICD) in Parkinson's disease is a behavioral addiction arising secondary to dopaminergic therapies, most often dopamine receptor agonists. Prior research implicates changes in striatal function and heightened dopaminergic activity in the dorsal striatum of patients with ICD. However, this prior work does not possess the temporal resolution required to investigate dopaminergic signaling during real-time progression through various stages of decision-making involving anticipation and feedback. Methods: We recorded high-frequency (10Hz) measurements of extracellular dopamine in the striatum of patients with (N=3) and without (N=3) a history of ICD secondary to dopamine receptor agonist therapy for Parkinson's disease symptoms. These measurements were made using carbon fiber microelectrodes during awake DBS neurosurgery and while participants performed a sequential decision-making task involving risky investment decisions and real monetary gains and losses. Per clinical standard-of-care, participants withheld all dopaminergic medications prior to the procedure. Results: Patients with ICD invested significantly more money than patients without ICD. On each trial, patients with ICD made smaller adjustments to their investment levels compared to patients without ICD. In patients with ICD, dopamine levels rose or fell on sub-second timescales in anticipation of investment outcomes consistent with increased or decreased confidence in a positive outcome, respectively; dopamine levels in patients without ICD were significantly more stable during this phase. After outcome revelation, dopamine levels in patients with ICD rose significantly more than in inpatients without ICD for better-than-expected gains. For worse-than-expected losses, dopamine levels in patients with ICD remained level whereas dopamine levels in patients without ICD fell. Conclusion: We report significantly increased risky behavior and exacerbated phasic dopamine signaling, on sub-second timescales, anticipating and following the revelation of the outcomes of risky decisions in patients with ICD. Notably, these results were obtained when patients who had demonstrated ICD in the past but were, at the time of surgery, in an off-medication state. Thus, it is unclear whether observed signals reflect an inherent predisposition for ICD that was revealed when dopamine receptor agonists were introduced or whether these observations were caused by the introduction of dopamine receptor agonists and the patients having experienced ICD symptoms in the past. Regardless, future work investigating dopamine's role in human cognition, behavior, and disease should consider the signals this system generates on sub-second timescales.

Long-term outcomes of mesial temporal laser interstitial thermal therapy for drug-resistant epilepsy and subsequent surgery for seizure recurrence: a multi-centre cohort study.

BACKGROUND: Magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) is a minimally invasive alternative to surgical resection for drug-resistant mesial temporal lobe epilepsy (mTLE). Reported rates of seizure freedom are variable and long-term durability is largely unproven. Anterior temporal lobectomy (ATL) remains an option for patients with MRgLITT treatment failure. However, the safety and efficacy of this staged strategy is unknown. METHODS: This multicentre, retrospective cohort study included 268 patients consecutively treated with mesial temporal MRgLITT at 11 centres between 2012 and 2018. Seizure outcomes and complications of MRgLITT and any subsequent surgery are reported. Predictive value of preoperative variables for seizure outcome was assessed. RESULTS: Engel I seizure freedom was achieved in 55.8% (149/267) at 1 year, 52.5% (126/240) at 2 years and 49.3% (132/268) at the last follow-up ≥1 year (median 47 months). Engel I or II outcomes were achieved in 74.2% (198/267) at 1 year, 75.0% (180/240) at 2 years and 66.0% (177/268) at the last follow-up. Preoperative focal to bilateral tonic-clonic seizures were independently associated with seizure recurrence. Among patients with seizure recurrence, 14/21 (66.7%) became seizure-free after subsequent ATL and 5/10 (50%) after repeat MRgLITT at last follow-up≥1 year. CONCLUSIONS: MRgLITT is a viable treatment with durable outcomes for patients with drug-resistant mTLE evaluated at a comprehensive epilepsy centre. Although seizure freedom rates were lower than reported with ATL, this series represents the early experience of each centre and a heterogeneous cohort. ATL remains a safe and effective treatment for well-selected patients who fail MRgLITT.

Effect of Ventral Intermediate Nucleus Deep Brain Stimulation on Vocal Tremor in Essential Tremor.

Background: There is a paucity of literature examining the effect of Ventral Intermediate Nucleus (VIM) deep brain stimulation (DBS) on voice in patients with vocal tremor (VT). Objective: Investigate the effect of unilateral and bilateral VIM DBS on voice in patients with Essential Tremor (ET) and VT. Methods: All patients receiving VIM DBS surgery underwent voice evaluation pre- and six-months post-operatively. We collected patient-reported quality-of-life outcome measures and acoustic voice measures of sustained phonation and connected speech. Acoustic measures specific to VT included amplitude tremor intensity index (ATRI), frequency tremor intensity index (FTRI), rate and extent of F0 modulation, and rate and extent of intensity modulation. Results: Five patients, age 72.8 ± 2.6 years, 4 female, 1 male with mean disease duration of 29 ± 26.2 years met the inclusion criteria and were included. Two subjects had bilateral procedure and three had unilateral. We observed significant improvements in measures of vocal tremor including ATRI, FTRI, rate of F0 modulation, rate of intensity modulation, and extent of intensity modulation, as well as patient reported voice-related quality of life measured by VHI-10. Bilateral VIM DBS cases showed greater improvement in VT than unilateral cases. Conclusion: Both unilateral and bilateral VIM DBS resulted in significant improvement of VT, with more improvement demonstrated in patients having bilateral as compared to unilateral VIM DBS. In addition, patients also reported significant improvements in voice-related quality of life. If larger studies confirm our results, VIM DBS has the potential to become a treatment specifically for disabling VT.

Efficacy of laser interstitial thermal therapy for biopsy-proven radiation necrosis in radiographically recurrent brain metastases.

Background: Laser interstitial thermal therapy (LITT) in the setting of post-SRS radiation necrosis (RN) for patients with brain metastases has growing evidence for efficacy. However, questions remain regarding hospitalization, local control, symptom control, and concurrent use of therapies. Methods: Demographics, intraprocedural data, safety, Karnofsky performance status (KPS), and survival data were prospectively collected and then analyzed on patients who consented between 2016-2020 and who were undergoing LITT for biopsy-proven RN at one of 14 US centers. Data were monitored for accuracy. Statistical analysis included individual variable summaries, multivariable Fine and Gray analysis, and Kaplan-Meier estimated survival. Results: Ninety patients met the inclusion criteria. Four patients underwent 2 ablations on the same day. Median hospitalization time was 32.5 hours. The median time to corticosteroid cessation after LITT was 13.0 days (0.0, 1229.0) and cumulative incidence of lesional progression was 19% at 1 year. Median post-procedure overall survival was 2.55 years [1.66, infinity] and 77.1% at one year as estimated by KaplanMeier. Median KPS remained at 80 through 2-year follow-up. Seizure prevalence was 12% within 1-month post-LITT and 7.9% at 3 months; down from 34.4% within 60-day prior to procedure. Conclusions: LITT for RN was not only again found to be safe with low patient morbidity but was also a highly effective treatment for RN for both local control and symptom management (including seizures). In addition to averting expected neurological death, LITT facilitates ongoing systemic therapy (in particular immunotherapy) by enabling the rapid cessation of steroids, thereby facilitating maximal possible survival for these patients.

Five-year survivors from brain metastases treated with stereotactic radiosurgery: Biology, improving treatments, or just plain luck?

Background: Improvements in therapies have led to an increasing number of long-term survivors of brain metastases. The present series compares a population of 5-year survivors of brain metastases to a generalized brain metastases population to assess for factors attributable to long-term survival. Methods: A single institution retrospective review was performed to identify 5-year survivors of brain metastases who received stereotactic radiosurgery (SRS). A historical control population of 737 patients with brain metastases was used to assess similarities and differences between the long-term survivor population and the general population treated with SRS. Results: A total of 98 patients with brain metastases were found to have survived over 60 months. No differences between long-term survivors and controls were identified with regards to the age at first SRS (P = .19), primary cancer distribution (P = .80), and the number of metastases at first SRS (P = .90). Cumulative incidence of neurologic death at 6, 8 and 10 years for the long-term survivor cohort was 4.8%, 16%, and 16% respectively. In the historical controls, cumulative incidence of neurologic death reached a plateau at 40% after 4.9 years. A significant difference in the distribution of burden of disease at the time of the first SRS was found between the 5-year survivors and the control (P = .0049). 58% of 5-year survivors showed no evidence of clinical disease at the last follow-up. Conclusion: Five-year survivors of brain metastases represent a diverse histologic population, suggesting a small population of oligometastatic and indolent cancers exist for each cancer type.

Intracranial subsecond dopamine measurements during a "sure bet or gamble" decision-making task in patients with alcohol use disorder suggest diminished dopaminergic signals about relief.

OBJECTIVE: To the authors' knowledge, no data have been reported on dopamine fluctuations on subsecond timescales in humans with alcohol use disorder (AUD). In this study, dopamine release was monitored in 2 patients with and 2 without a history of AUD during a "sure bet or gamble" (SBORG) decision-making task to begin to characterize how subsecond dopamine responses to counterfactual information, related to psychological notions of regret and relief, in AUD may be altered. METHODS: Measurements of extracellular dopamine levels were made once every 100 msec using human voltammetric methods. Measurements were made in the caudate during deep brain stimulation electrode implantation surgeries (for treatment of movement disorders) in patients who did (AUD, n = 2) or did not (non-AUD, n = 2) have a history of AUD. Participants performed an SBORG decision-making task in which they made choices between sure bets and 50%-chance monetary gamble outcomes. RESULTS: Fast changes were found in dopamine levels that appear to be modulated by "what could have been" and by patients' AUD status. Positive counterfactual prediction errors (related to relief) differentiated patients with versus without a history of AUD. CONCLUSIONS: Dopaminergic encoding of counterfactual information appears to differ between patients with and without AUD. The current study has a major limitation of a limited sample size, but these data provide a rare insight into dopaminergic physiology during real-time decision-making in humans with an addiction disorder. The authors hope future work will expand the sample size and determine the generalizability of the current results.

Collagen deposition within brain metastases is associated with leptomeningeal failure after cavity-directed radiosurgery.

Background: Leptomeningeal failure (LMF) represents a devastating progression of disease following resection of brain metastases (BrM). We sought to identify a biomarker at time of BrM resection that predicts for LMF using mass spectrometry-based proteomic analysis of resected BrM and to translate this finding with histochemical assays. Methods: We retrospectively reviewed 39 patients with proteomic data available from resected BrM. We performed an unsupervised analysis with false discovery rate adjustment (FDR) to compare proteomic signature of BrM from patients that developed LMF versus those that did not. Based on proteomic analysis, we applied trichrome stain to a total of 55 patients who specifically underwent resection and adjuvant radiosurgery. We used competing risks regression to assess predictors of LMF. Results: Of 39 patients with proteomic data, FDR revealed type I collagen-alpha-1 (COL1A1, P = .045) was associated with LMF. The degree of trichrome stain in each block correlated with COL1A1 expression (ß = 1.849, P = .001). In a cohort of 55 patients, a higher degree of trichrome staining was associated with an increased hazard of LMF in resected BrM (Hazard Ratio 1.58, 95% CI 1.11-2.26, P = .01). Conclusion: The degree of trichrome staining correlated with COL1A1 and portended a higher risk of LMF in patients with resected brain metastases treated with adjuvant radiosurgery. Collagen deposition and degree of fibrosis may be able to serve as a biomarker for LMF.

A Review on the Surgical Management of Insular Gliomas.

The surgical treatment of insular gliomas requires specialized knowledge. Over the last three decades, increased momentum in surgical resection of insular gliomas shifted the focus from one of expectant management to maximal safe resection to establish a diagnosis, characterize tumor genetics, treat preoperative symptoms (i.e., seizures), and delay malignant transformation through tumor cytoreduction. A comprehensive review of the literature was performed regarding insular glioma classification/genetics, insular anatomy, surgical approaches, and patient outcomes. Modern large, published series of insular resections have reported a median 80% resection, 80% improvement in preoperative seizures, and postsurgical permanent neurologic deficits of less than 10%. Major complication avoidance includes recognition and preservation of eloquent cortex for language and respecting the lateral lenticulostriate arteries.

Outcomes of radiation-induced meningiomas treated with stereotactic radiosurgery.

PURPOSE: Data on the efficacy and safety of stereotactic radiosurgery (SRS) for treatment of radiation-induced meningiomas (RIMs) are limited. METHODS: A single institution database of Cobalt-60 SRS cases from 08/1999 to 10/2020 was reviewed. Radiation-induced meningiomas were identified using Cahan's criteria. Endpoints included overall survival (OS), progression free survival (PFS), local control (LC), treatment failure, and treatment toxicity. Univariate and multivariate analyses were performed using cox proportional hazard models. RESULTS: A total of 29 patients with 86 RIM lesions were identified. Median follow-up after SRS was 59 months. The median dose prescribed to the 50% isodose line was 14 Gy (range 12-20 Gy). The actuarial 5-yr OS and PFS were 96% and 68%, respectively. Patients treated for recurrent RIMs had a significantly lower PFS (45% vs 94% at 3 yr, p < 0.005) than patients treated in the upfront setting. Patients with presumed or WHO grade I RIMs had a significantly greater PFS (3-year PFS 96% vs 20%) than patients with WHO grade II RIMs (p < 0.005). On a per-lesion basis, local control (LC) at 1-, 3-, and 5-yrs was 82%, 76%, 74%, respectively. On multivariate analysis, female gender was associated with improved LC (p < 0.001), while marginal doses > 14 Gy were associated with worse local control (p < 0.001). Grade I-III toxicity following treatment was 9.0%. CONCLUSIONS: Stereotactic radiosurgery is a safe and effective treatment option for radiographic RIMs, WHO grade I RIMs, or lesions treated in the upfront setting. WHO grade II lesions and recurrent lesions are at increased risk for disease progression.

Long term survivors of stereotactic radiosurgery for brain metastases: do distant brain failures reach a plateau and what factors are associated with a brain metastasis velocity of zero?

PURPOSE: Life expectancy continues to increase for patients with brain metastases treated with stereotactic radiosurgery (SRS). The present study sought to retrospectively analyze brain metastasis patients who have survived 2 years or more, and assess for what factors may predict for a final brain metastasis velocity (BMV) of zero. METHODS: This was a single-institution retrospective study of 300 patients treated with SRS from 2001 to 2019 for brain metastases who survived greater than 2 years after first SRS. Final BMV is calculated by summing all metastases through the observed time divided by the total time in years. A BMV of zero is defined as at least 2 years of imaging follow-up without distant brain failure (DBF). RESULTS: Median age at first SRS is 61 (IQR: 53, 70). Kaplan-Meier estimated median overall survival is 4.9 years and time to DBF is 1.5 years (95% CI 1.2, 2.0). Twenty-eight (9.3%) patients underwent subsequent WBRT. One hundred and one (33.7%) patients never had any further brain metastases (BMV = 0) at a median follow-up time of 3.3 years. Median BMV is 0.4 (IQR: 0, 1.4). Distant brain failures reach a plateau at 4 years where the cumulative incidence of DBF is 82%. 70% of first time DBFs have occurred by 2 years. Factors significantly associated with a BMV of zero include fewer brain metastases at first SRS (HR 1.1; p = 0.0004) and Caucasian race (HR 1.5; p = 0.03). CONCLUSION: Approximately one third of brain metastasis patients who live beyond 2 years after initial SRS have a BMV of zero. DBFs appear to reach a plateau at 4 years. Factors significantly associated with a BMV of zero include Caucasian race and having had a single brain metastasis at first SRS.

Immersion bioprinting of hyaluronan and collagen bioink-supported 3D patient-derived brain tumor organoids.

Organoids, and in particular patient-derived organoids, have emerged as crucial tools for cancer research. Our organoid platform, which has supported patient-derived tumor organoids (PTOs) from a variety of tumor types, has been based on the use of hyaluronic acid (HA) and collagen, or gelatin, hydrogel bioinks. One hurdle to high throughput PTO biofabrication is that as high-throughput multi-well plates, bioprinted volumes have increased risk of contacting the sides of wells. When this happens, surface tension causes bioinks to fall flat, resulting in 2D cultures. To address this problem, we developed an organoid immersion bioprinting method-inspired by the FRESH printing method-in which organoids are bioprinted into support baths in well plates. The bath-in this case an HA solution-shields organoids from the well walls, preventing deformation. Here we describe an improvement to our approach, based on rheological assessment of previous gelatin baths versus newer HA support baths, combined with morphological assessment of immersion bioprinted organoids. HA print baths enabled more consistent organoid volumes and geometries. We optimized the printing parameters of this approach using a cell line. Finally, we deployed our optimized immersion bioprinting approach into a drug screening application, using PTOs derived from glioma biospecimens, and a lung adenocarcinoma brain metastasis. In these studies, we showed a general dose dependent response to an experimental p53 activator compound and temozolomide (TMZ), the drug most commonly given to brain tumor patients. Responses to the p53 activator compound were effective across all PTO sets, while TMZ responses were observed, but less pronounced, potentially explained by genetic and epigenetic states of the originating tumors. The studies presented herein showcase a bioprinting methodology that we hope can be used in increased throughput settings to help automate biofabrication of PTOs for drug development-based screening studies and precision medicine applications.

Upfront immunotherapy leads to lower brain metastasis velocity in patients undergoing stereotactic radiosurgery for brain metastases.

Background: While immunotherapy has been shown to improve survival and decrease neurologic death in patients with brain metastases, it remains unclear whether this improvement is due to prevention of new metastasis to the brain. Method: We performed a retrospective review of patients presenting with brain metastases simultaneously with the first diagnosis of metastatic disease and were treated with upfront immunotherapy as part of their treatment regimen and stereotactic radiosurgery (SRS) to the brain metastases. We compared this cohort with a historical control population (prior to the immunotherapy era) who were treated with pre-immunotherapy standard of care systemic therapy and with SRS to the brain metastases. Results: Median overall survival time was improved in the patients receiving upfront immunotherapy compared to the historical cohort (48 months vs 8.4 months, p=0.001). Median time to distant brain failure was statistically equivalent (p=0.3) between the upfront immunotherapy cohort and historical control cohort (10.3 vs 12.6 months). Brain metastasis velocity was lower in the upfront immunotherapy cohort (median 3.72 metastases per year) than in the historical controls (median 9.48 metastases per year, p=0.001). Cumulative incidence of neurologic death at one year was 12% in the upfront immunotherapy cohort and 28% in the historical control cohort (p=0.1). Conclusions: Upfront immunotherapy appears to improve overall survival and decrease BMV compared to historical controls. While these data remain to be validated, they suggest that brain metastasis patients may benefit from concurrent immunotherapy with SRS.

Corrigendum: Patterned hippocampal stimulation facilitates memory in patients with a history of head impact and/or brain injury.

[This corrects the article DOI: 10.3389/fnhum.2022.933401.].

Intensity-modulated radiotherapy with planned Gamma Knife radiosurgery boost for head and neck cancer with extensive disease in proximity to critical structures.

BACKGROUND: To describe intensity-modulated radiotherapy (IMRT) with Gamma Knife Radiosurgery (GKRS) boost for locally advanced head and neck cancer (HNC) with disease near dose-limiting structures. METHODS: Patients with HNC treated with IMRT/GKRS as part of a combined modality approach between 2011 and 2021 were reviewed. Local control, overall survival and disease-specific survival were estimated using the Kaplan Meier method. RESULTS: Twenty patients were included. Nineteen patients had T3-4 tumors. Median follow-up was 26.3 months. GKRS site control was 95%. Two patients progressed at the treated primary site, one patient failed at the edge of the GKRS treatment volume, with no perineural or intracranial failure. 2-year OS was 94.7% (95% CI: 85.2%-100%). Concurrent chemotherapy was given in nine patients (45%). One patient (5%) received induction/concurrent chemotherapy. Brain radionecrosis occurred in three patients, one of which was biopsy-proven. CONCLUSIONS: IMRT plus GKRS boost results in excellent disease control near critical structures with minimal toxicity.