Ali Reza Tafreshi

Clinical efficacy of deep brain stimulation (DBS) for obsessive–compulsive disorder (OCD) remains limited by the absence of objective neural biomarkers to guide targeting, programming, and longitudinal optimization of therapy. Using sensing-enabled DBS devices, we analyzed intracranial local field potentials recorded longitudinally from thirteen patients with treatment-refractory OCD implanted in the ventral capsule/ventral striatum (VC/VS). We identify the periodic component of alpha-band activity (7–14 Hz) as a robust electrophysiological correlate of OCD symptom severity. At the initial clinical evaluation, periodic alpha power explained inter-individual variance in symptom severity, and within individuals it tracked longitudinal symptom fluctuations during chronic treatment. Spatial mapping localized the source of this periodic alpha activity to the anterior external globus pallidus (GPe), aligning with stimulation contacts selected as therapeutically optimal during clinical monopolar review. Together, these findings identify anterior GPe alpha oscillations as a state-dependent and spatially specific biomarker of OCD severity, with direct implications for electrophysiology-informed DBS programming and the development of adaptive neuromodulation strategies.

OBJECTIVE: Tranexamic acid (TXA) is an antifibrinolytic agent associated with reduced blood loss and mortality in a wide range of procedures, including spine surgery, traumatic brain injury, and craniosynostosis. Despite this wide use, the safety and efficacy of TXA in spine surgery has been considered controversial due to a relative scarcity of literature and lack of statistical power in reported studies. However, if TXA can be shown to reduce blood loss in laminectomy with fusion and posterior instrumentation, more surgeons may include it in their armamentarium. The authors aimed to conduct an up-to-date systematic review and meta-analysis of the efficacy of TXA in reducing blood loss in laminectomy and fusion with posterior instrumentation. METHODS: A systematic review and meta-analysis, abiding by PRISMA guidelines, was performed by searching the databases of PubMed, Web of Science, and Cochrane. These platforms were queried for all studies reporting the use of TXA in laminectomy and fusion with posterior instrumentation. Variables retrieved included patient demographics, surgical indications, involved spinal levels, type of laminectomy performed, TXA administration dose, TXA route of administration, operative duration, blood loss, blood transfusion rate, postoperative hemoglobin level, and perioperative complications. Heterogeneity across studies was evaluated using a chi-square test, Cochran’s Q test, and I² test performed with R statistical programming software. RESULTS: A total of 7 articles were included in the qualitative study, while 6 articles featuring 411 patients underwent statistical analysis. The most common route of administration for TXA was intravenous with 15 mg/kg administered preoperatively. After the beginning of surgery, TXA administration patterns were varied among studies. Blood transfusions were increased in non-TXA cohorts compared to TXA cohorts. Patients administered TXA demonstrated a significant reduction in blood loss (mean difference −218.44 mL; 95% CI −379.34 to −57.53; p = 0.018). TXA administration was not associated with statistically significant reductions in operative durations. There were no adverse events reported in either the TXA or non-TXA patient cohorts. CONCLUSIONS: TXA can significantly reduce perioperative blood loss in cervical, thoracic, and lumbar laminectomy and fusion procedures, while demonstrating a minimal complication profile.

OBJECTIVE: Global neurosurgery is a rapidly emerging field that aims to address the worldwide shortages in neurosurgical care. Many published outreach efforts and initiatives exist to address the global disparity in neurosurgical care; however, there is no centralized report detailing these efforts. This scoping review aims to characterize the field of global neurosurgery by identifying partnerships between high-income countries (HICs) and low- and/or middle-income countries (LMICs) that seek to increase neurosurgical capacity. METHODS: A scoping review was conducted using the Arksey and O’Malley framework. A search was conducted in five electronic databases and the gray literature, defined as literature not published through traditional commercial or academic means, to identify studies describing global neurosurgery partnerships. Study selection and data extraction were performed by four independent reviewers, and any disagreements were settled by the team and ultimately the team lead. RESULTS: The original database search produced 2221 articles, which was reduced to 183 final articles after applying inclusion and exclusion criteria. These final articles, along with 9 additional gray literature references, captured 169 unique global neurosurgery collaborations between HICs and LMICs. Of this total, 103 (61%) collaborations involved surgical intervention, while local training of medical personnel, research, and education were done in 48%, 38%, and 30% of efforts, respectively. Many of the collaborations (100 [59%]) are ongoing, and 93 (55%) of them resulted in an increase in capacity within the LMIC involved. The largest proportion of efforts began between 2005–2009 (28%) and 2010–2014 (17%). The most frequently involved HICs were the United States, Canada, and France, whereas the most frequently involved LMICs were Uganda, Tanzania, and Kenya. CONCLUSIONS: This review provides a detailed overview of current global neurosurgery efforts, elucidates gaps in the existing literature, and identifies the LMICs that may benefit from further efforts to improve accessibility to essential neurosurgical care worldwide.

Objective. Characterize the role of the beta-band (13–30 Hz) in the human hippocampus during the execution of voluntary movement. Approach. We recorded electrophysiological activity in human hippocampus during a reach task using stereotactic electroencephalography (SEEG). SEEG has previously been utilized to study the theta band (3–8 Hz) in conflict processing and spatial navigation, but most studies of hippocampal activity during movement have used noninvasive measures such as fMRI. We analyzed modulation in the beta band (13–30 Hz), which is known to play a prominent role throughout the motor system including the cerebral cortex and basal ganglia. We conducted the classic ‘center-out’ direct-reach experiment with nine patients undergoing surgical treatment for medically refractory epilepsy. Main results. In seven of the nine patients, power spectral analysis showed a statistically significant decrease in power within the beta band (13–30 Hz) during the response phase, compared to the fixation phase, of the center-out direct-reach task using the Wilcoxon signed-rank hypothesis test (p < 0.05). Significance. This finding is consistent with previous literature suggesting that the hippocampus may be involved in the execution of movement, and it is the first time that changes in beta-band power have been demonstrated in the hippocampus using human electrophysiology. Our findings suggest that beta-band modulation in the human hippocampus may play a role in the execution of voluntary movement.

5544 Background: Pembro + olaparib has shown antitumor activity and acceptable safety in docetaxel-pretreated pts with mCRPC enrolled in cohort A of the phase I/II KEYNOTE-365 study (NCT02861573). Updated results with new biomarker data are reported. Methods: Pts with docetaxel-pretreated mCRPC who progressed within 6 mo of screening received pembro 200 mg IV Q3W + olaparib 400-mg capsule or 300-mg tablet PO BID. Pts might have received 1 other chemotherapy and ≤2 second-generation androgen-receptor targeted therapies. Primary end points: PSA response rate (decrease ≥50% from baseline, confirmed by a second value ≥3 wks later), ORR per RECIST v1.1, and safety. Key secondary end points: DCR, DOR, rPFS, and OS. Biospecimens (eg, blood, tissue) were collected for biomarker analysis (tissue PD-L1 expression, androgen receptor variant 7 [AR-v7] expression in circulating tumor cells [CTCs], and a T-cell–inflamed gene expression profile [GEP]). ctDNA was analyzed by Guardant Health 360 (GH360) and Omni (GH Omni) assays. FFPE tissue was analyzed by FoundationOne CDx (F1CDx) assay. Results: 84 of 87 enrolled pts were treated; 48/84 (57.1%) had measurable disease. Median (range) time from enrollment to data cutoff was 3.6 mo (0.0-29.2) for all pts and 26.7 mo (21.2-29.2) for 41 pts with ≥27 wks’ follow-up. Confirmed PSA response rate was 9% (95% CI, 3.5-16.8) in 82 pts with a baseline PSA assessment. Median time to PSA progression: 3.8 mo (95% CI, 2.9-4.4). In 24 pts with measurable disease and ≥27 wks’ follow-up, ORR was 8.3% (95% CI, 1.0-27.0; 2 PRs) and DCR ≥6 mo was 20.8% (95% CI, 7.1-42.2). Median (range) DOR was NR (12.0+ to 21.4+ mo); 2 pts had DOR ≥12 mo. In all pts, median rPFS was 4.3 mo (95% CI, 3.4-7.7) and median OS was 14.4 mo (95% CI, 8.1-18.5). Grade ≥3 TRAEs occurred in 29 pts (35%); 2 pts died of TRAEs (1 myocardial infarction, 1 unknown). Overall, 26% had PD-L1⁺ tumors (combined positive score ≥1). Of 31 pts with CTC data, 12.9% were AR-v7⁺. No BRCA1/2 mutation was detected by GH360 (n=42). Of 57 pts analyzed by GH Omni, 2 had BRCA2 mutations, 1 had a BRCA1 mutation, 4 had ATM mutations, 1 had a CHEK1 mutation, and 6 had CDK12 mutations. Of 49 pts analyzed by F1CDx, 4 had BRCA mutations; 1 pt had a copy number loss mutation not detected by ctDNA analysis. GEP was not associated with ORR or PSA response. Conclusions: Pembro + olaparib continued to show activity and acceptable safety in pts with docetaxel-pretreated mCRPC. A phase III study of this combination is ongoing (KEYLYNK-010, NCT03834519). Clinical trial information: NCT02861573 .

In the randomized KEYNOTE-407 study (NCT02775435), pembro + carboplatin and paclitaxel/nab-paclitaxel (chemo) significantly improved OS, PFS, and ORR compared with placebo + chemo in patients (pts) with previously untreated metastatic squamous NSCLC. Benefit was observed irrespective of PD-L1 TPS. We report updated OS from the protocol-specified final analysis and, for the first time, PFS2. Eligible pts were randomized 1:1 to pembro (n = 278) or placebo (n = 281) + 4 cycles of carboplatin and paclitaxel/nab-paclitaxel. Randomization was stratified by PD-L1 TPS (≥1%/<1%), choice of taxane (paclitaxel/nab-paclitaxel), and region (East Asia/rest of world). Pts in the placebo + chemo arm could crossover to pembro monotherapy at the time of confirmed PD. After positive results from IA2, pts on the placebo arm were unblinded to stop placebo. Response was assessed by RECIST v1.1 by blinded central review. Primary endpoints were OS and PFS. PFS2 was an exploratory endpoint and defined as time from randomization to time of PD per investigator or death after start of 2L therapy, whichever occurred first. With median follow-up of 14.3 mo (range, 0.1–31.3) and 365 total deaths, pembro + chemo continued to improve OS (median [95% CI], 17.1 [14.4–19.9] vs 11.6 [10.1–13.7] mo), PFS (median [95% CI], 8.0 [6.3–8.4] vs 5.1 [4.3–6.0]; Table) and ORR (62.6% vs 38.4%). 2L+ therapy was received by 32.0% in the pembro + chemo arm and 59.4% (49.1% 2L+ antiPD[L]1) in the placebo + chemo arm. PFS2 was longer for 1L pembro + chemo (median [95% CI], 13.8 [12.2–15.9] mo vs 9.1 [8.2–10.2] mo), with no difference by PD-L1 TPS. LBA82 LBA82 Pembro + chemo continued to demonstrate improved outcomes, including OS, PFS, ORR and PFS2, compared with placebo + chemo for previously untreated metastatic squamous NSCLC, with a manageable safety profile. These results support first-line pembro + chemo in pts with metastatic squamous NSCLC. NCT02775435. Writing support was provided by Sheri Arndt, PharmD, of C4 MedSolutions, LLC (Yardley, PA, USA), a CHC Group company, funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. L. Paz-Ares: Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Roche; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Lilly; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Boehringer Ingelheim; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: AstraZeneca; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Novartis; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Pfizer; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Amgen; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: BMS; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: MSD; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Merck; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Sanofi; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: PharmaMar; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Servier; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Sysmex; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Incyte; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Ipsen; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Adacap; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Bayer; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Blueprint Medicines; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Celgene; Honoraria to self/spouse for scientific advice or as a speaker for Roche, Lilly, Boehringer Ingelheim, AstraZeneca, Novartis, Pfizer, Amgen, BMS, MSD, Merck, Sanofi, PharmaMar, Servier, Sysmex, Incyte, Ipsen, Adacap, Bayer, Blueprint Medicines, and Celgene; board member for Genómica; grants to institution from MSD, BMS, AstraZeneca, and Pfizer. D. Vicente: Honoraria (self), Self/spouse for scientific advice or as a speaker: Boehringer Ingelheim, AstraZeneca, Pfizer, BMS, and MSD . A. Robinson: Research grant / Funding (institution), funding for clinical trials: Merck, AstraZeneca, Roche, and Pfizer; Advisory / Consultancy: Merck. H. Soto Parra: Advisory / Consultancy: AstraZeneca, MSD, BMS, Roche, and Eli Lilly. J. Mazières: Honoraria (institution): Roche, AstraZeneca, Boehringer Ingelheim, Pfizer, BMS, MSD, Merck, Pierre Fabre, PharmaMar, Bayer, and Blueprint; Research grant / Funding (institution): Roche, MSD, BMS, and AstraZeneca. B. Hermes: Travel / Accommodation / Expenses: PharmaMar and Eli Lilly; Honoraria (institution), honoraria for lectures: BMS and Pfizer; Research grant / Funding (institution): MSD, Novartis, BMS, Bayer, Roche, Eli Lilly, and...

E12554 Background: Triple-negative breast cancer is a biologically aggressive disease that accounts for 15% of all breast cancers, of which around 4-5% are metastatic (mTNBC) at diagnosis. Notably, there is no standard of care for mTNBC in the first line (1L) setting. This, in addition to higher relapse rates and poor long-term survival, warrants evaluation of real-world treatment patterns, especially in the 1L setting, to better inform on clinical outcomes. Methods: This observational, retrospective, chart review study included a cohort of twenty-six mTNBC patients from six different sites Australia, who commenced 1L treatment between July 1, 2012 and June 30, 2015. Medical records of eligible patients were abstracted using electronic case report forms after gaining relevant ethics approvals. Data on treatment patterns and clinical outcomes in the 1L setting were then collected from the index date until the end of data abstraction or death. The index date is defined as the date of initiation of 1L systemic therapy for mTNBC. Results: In the 1L setting, patients that received combination (52%) chemotherapy was slightly higher than single-agent (48%) chemotherapy. The commonest combination used was Carboplatin-Gemcitabine (12%), and the most common monotherapy was Nab-Paclitaxel (24%). The overall response rate and disease control rate were estimated to be 32% and 60% in the 1L setting. The median duration of treatment and the median time to next line of therapy were calculated to be 98 days and 12.45 (95% CI 2.79, 20.30) months respectively. Importantly, the median progression free survival (sensitivity analysis) and the median overall survival were estimated to be 3.17 (95% CI 1.91, 5.09) and 10.41 (95% CI 5.36, 16.53) months respectively. Conclusions: Chemotherapy is currently the mainstay of treatment for mTNBC. However, disease progression and chemo-related toxicities warrant stratified use of more efficacious and tolerable treatment options, especially in the 1L setting. Results from this study could be useful in comparing the efficacy and cost effectiveness of these emerging targeted and immuno-therapies outside the clinical trial setting.