Antiretroviral Drug Repositioning for Glioblastoma.

Outcomes for glioblastoma (GBM) remain poor despite standard-of-care treatments including surgical resection, radiation, and chemotherapy. Intratumoral heterogeneity contributes to treatment resistance and poor prognosis, thus demanding novel therapeutic approaches. Drug repositioning studies on antiretroviral therapy (ART) have shown promising potent antineoplastic effects in multiple cancers; however, its efficacy in GBM remains unclear. To better understand the pleiotropic anticancer effects of ART on GBM, we conducted a comprehensive drug repurposing analysis of ART in GBM to highlight its utility in translational neuro-oncology. To uncover the anticancer role of ART in GBM, we conducted a comprehensive bioinformatic and in vitro screen of antiretrovirals against glioblastoma. Using the DepMap repository and reversal of gene expression score, we conducted an unbiased screen of 16 antiretrovirals in 40 glioma cell lines to identify promising candidates for GBM drug repositioning. We utilized patient-derived neurospheres and glioma cell lines to assess neurosphere viability, proliferation, and stemness. Our in silico screen revealed that several ART drugs including reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs) demonstrated marked anti-glioma activity with the capability of reversing the GBM disease signature. RTIs effectively decreased cell viability, GBM stem cell markers, and proliferation. Our study provides mechanistic and functional insight into the utility of ART repurposing for malignant gliomas, which supports the current literature. Given their safety profile, preclinical efficacy, and neuropenetrance, ARTs may be a promising adjuvant treatment for GBM.

Laser Interstitial Thermal Therapy Induces Robust Local Immune Response for Newly Diagnosed Glioblastoma With Long-term Survival and Disease Control.

Laser interstitial thermal therapy (LITT) is a minimally invasive neurosurgical technique used to ablate intra-axial brain tumors. The impact of LITT on the tumor microenvironment is scarcely reported. Nonablative LITT-induced hyperthermia (33-43˚C) increases intra-tumoral mutational burden and neoantigen production, promoting immunogenic cell death. To understand the local immune response post-LITT, we performed longitudinal molecular profiling in a newly diagnosed glioblastoma and conducted a systematic review of anti-tumoral immune responses after LITT. A 51-year-old male presented after a fall with progressive dizziness, ataxia, and worsening headaches with a small, frontal ring-enhancing lesion. After clinical and radiographic progression, the patient underwent stereotactic needle biopsy, confirming an IDH-WT World Health Organization Grade IV Glioblastoma, followed by LITT. The patient was subsequently started on adjuvant temozolomide, and 60 Gy fractionated radiotherapy to the post-LITT tumor volume. After 3 months, surgical debulking was conducted due to perilesional vasogenic edema and cognitive decline, with H&E staining demonstrating perivascular lymphocytic infiltration. Postoperative serial imaging over 3 years showed no evidence of tumor recurrence. The patient is currently alive 9 years after diagnosis. Multiplex immunofluorescence imaging of pre-LITT and post-LITT biopsies showed increased CD8 and activated macrophage infiltration and programmed death ligand 1 expression. This is the first depiction of the in-situ immune response to LITT and the first human clinical presentation of increased CD8 infiltration and programmed death ligand 1 expression in post-LITT tissue. Our findings point to LITT as a treatment approach with the potential for long-term delay of recurrence and improving response to immunotherapy.

Outcomes of HSV-1 encephalitis infection in glioblastoma: An integrated systematic analysis.

INTRODUCTION: Herpes Simplex Virus-1 (HSV-1) is a neurotropic DNA virus with neural latency and stereotypic viral encephalitis. It has been reported to conceal underlying glioblastoma (GBM) due to similar radiographic imaging and clinical presentation. Limited data exist on the co-occurrence of GBM and HSV-1. To better describe the pathophysiology of HSV-1 superinfections in GBM, we performed a comprehensive review of GBM cases with superimposed HSV-1. METHODS: A comprehensive literature search of six electronic databases with apriori search criteria was performed to identify eligible cases of GBM with HSV-1. Relevant clinic-radiographic data were collected, Kaplan-Meier estimates, Fisher's exact test, and logistic regression analyses were used. RESULTS: We identified 20 cases of HSE in GBM with an overall survival (OS) of 8.0 months. The median age of presentation was 63 years (range: 24-78 years) and the median interval between GBM or HSE diagnosis was 2 months (range: 0.05-25 months). HSE diagnosis before GBM diagnosis was a predictor for improved survival (HR: 0.06; 95% CI: [0.01-0.54]; p < 0.01). There is a significant reduction in OS in patients with concomitant HSE and GBM compared to the cancer genome atlas (TCGA) cohort (median OS: 8 months vs. 14.2 months; p < 0.05). Finally, HSV does not directly infect GBM cells but indirectly activates a local immune response in the tumor microenvironment. CONCLUSIONS: Superimposed HSE in GBM may contribute to a significant reduction in OS compared to uninfected controls, potentially activating proto-oncogenes during active infection and latency. Preoperative HSE may induce an antiviral immune response, which may serve as a positive prognostic factor. Prompt antiviral treatment upon co-occurrence is necessary.

Predicting Academic Career Placement via Development of Novel Intra-residency Metrics.

OBJECTIVE: Increasing centralization of high-level neurosurgical practice at academic centers has increased the need for academic neurosurgeons. The lack of systematic metrics-based analyses among neurosurgery trainees and the recent pass/fail U.S. Medical Licensing Examination system necessitates a multiparametric approach to assess academic success among trainees. METHODS: We conducted a comprehensive analysis of the University of Miami residency program using 2 data sets, one containing applicants' pre-residency metrics and a second containing trainees' intra-residency metrics. Intra-residency metrics were subjectively and anonymously assessed by faculty. Univariate and multivariate logistic regression analyses were performed to determine differences among academic and non-academic neurosurgeons and identify predictors of academic careers. RESULTS: Academic neurosurgeons had a significantly higher median Step 1 percentile relative to non-academic neurosurgeons (P = 0.015), and medical school ranking had no significant impact on career (P > 0.05). Among intra-residency metrics, academic neurosurgeons demonstrated higher mean rating of leadership skills (mean difference [MD] 0.46, P = 0.0011), technical skill (MD 0.42, P = 0.006), and other intra-residency metrics. Higher administrative and leadership skills were significantly associated with increased likelihood of pursuing an academic career (odds ratio [OR] 9.03, 95% CI [2.296 to 49.88], P = 0.0044). Clinical judgment and clinical knowledge were strongly associated with pursuit of an academic career (OR 9.33 and OR 9.32, respectively, with P = 0.0060 and P = 0.0010, respectively). CONCLUSIONS: Pre-residency metrics had little predictive value in determining academic careers. Furthermore, medical school ranking does not play a significant role in determining a career in academic neurosurgery. Intra-residency judgment appears to play a significant role in career placement, as academic neurosurgeons were rated consistently higher than their non-academic peers in multiple key parameters by their attending physicians.

Outcomes of laparoscopic versus open resection of pediatric choledochal cyst.

BACKGROUND: Untreated pediatric choledochal cyst (CC) is associated with complications including cholangitis, pancreatitis, and risk of malignancy. Therefore, CC is typically treated by surgical excision with biliary reconstruction. Both open and laparoscopic (lap) surgical approaches are regularly used, but outcomes have not been compared on a national level. METHODS: The Nationwide Readmissions Database was used to identify pediatric patients (age 0-21 years, excluding newborns) with choledochal cyst from 2016 to 2018 based on ICD-10 codes. Patients were stratified by operative approach (open vs. lap). Demographics, operative management, and complications were compared using standard statistical tests. Results were weighted for national estimates. RESULTS: Choledochal cyst excision was performed in 577 children (75% female) via lap (28%) and open (72%) surgical approaches. Patients undergoing an open resection experienced longer index hospital length of stay (LOS), higher total cost, and more complications. Anastomotic technique differed by approach, with Roux-en-Y hepaticojejunostomy (RYHJ) more often utilized with open cases (86% vs. 29%) and hepaticoduodenostomy (HD) more common with laparoscopic procedures (71% vs. 15%), both p < 0.001. There was no significant difference in post-operative cholangitis or mortality. CONCLUSIONS: Although utilized less frequently than an open approach, laparoscopic choledochal cyst resection is safe in pediatric patients and is associated with shorter LOS, lower costs, and fewer complications. HD anastomosis is more commonly performed during laparoscopic procedures, whereas RYHJ more commonly used with the open approach. While HD is associated with more short-term gastrointestinal dysfunction than RYHJ, the latter is more commonly associated with sepsis, wound infection, and respiratory dysfunction. LEVEL OF EVIDENCE: Level III: Retrospective Comparative Study.

Combined Heart-Lung Transplantation Outcomes in Asian Populations: National Database Analysis.

Background: Heart-lung transplantation (HLTx) is a definitive surgical procedure for end-stage cardiopulmonary failure. Studies to understand the relationship between ethnicity and race and outcomes after HLTx are needed to uphold equitable HLTx access to the increasingly diverse U.S. population facing advanced cardiopulmonary failure. Objectives: This study sought to examine the outcomes of HLTx recipients of Asian origin, with emphasis on the ethnic and racial disparities in the outcomes. Methods: We analyzed data from the United Network for Organ Sharing (UNOS) for patients of ≥18 years of age who underwent HLTx between 1987 and 2021. Propensity-score matching was performed between Asian and non-Hispanic Whites (NHWs), with a 1:3 matching ratio based on the propensity score of each patient estimated by multivariable logistic regression. Results: We identified 42 Asian and Asian American heart-lung transplant recipients and 834 NHW recipients. In the pre-matched cohort, the median survival was 1,459 days (IQR: 1,080-2,692 days) in Asian recipients after transplantation, whereas it was 1,521 days (IQR: 1,262-1,841 days) in White recipients. Of the 876 recipients, 156 transplants were successfully matched (Asian, n = 36; NHW, n = 108). Among the post-transplantation outcomes, there were no significant differences in morbidity and mortality between Asian and NHW cohorts. Conclusions: This large-scale analysis in Asian patients will have important implications in Asian countries that have relatively fewer HLTx surgeries. An outcome equivalent to NHW in Asian patients, as demonstrated in our study, could be the driving force for further expansion of HLTx surgeries in Asian countries.

Initial experience with SOFIA as an intermediate catheter in mechanical thrombectomy for acute ischemic stroke.

BACKGROUND: The benefits of mechanical thrombectomy for emergent large vessel occlusion (ELVO) have been established. Combined mechanical/aspiration (Solumbra) and a direct aspiration as a first pass technique (ADAPT) are valid procedures requiring an intermediate catheter for clot suction. Recently, SOFIA (Soft torqueable catheter Optimized For Intracranial Access) was developed as a single lumen flexible catheter with coil and braid reinforcement, but its suitability for mechanical thrombectomy had not been evaluated. OBJECTIVE: To describe our initial experience with SOFIA in acute stroke intervention and evaluate its efficacy and safety. METHODS: All patients with ELVO undergoing endovascular stroke intervention with SOFIA were identified. Demographic, presentation, treatment, and complication data were recorded. Primary outcome was Thrombolysis in Cerebral Infarction (TICI) 2b/3 revascularization rate and the number of passes required. Secondary outcomes included complication rates and discharge National Institute of Health Stroke Scale (NIHSS) score. RESULTS: 33 patients with a mean age of 72 years were treated for ELVO with SOFIA and IV tissue plasminogen activator was administered in 67%. Vessel occlusion involved the internal carotid artery (15.2%), M1 (48.5%), and M2 (24.2%) segments, and posterior circulation (12.1%). Median presentation NIHSS score was 14 (IQR 11-19) and discharge NIHSS 4 (IQR 2-14). The Solumbra technique represented 94% of treatments and ADAPT 3%. The TICI 2b/3 revascularization rate was 94%, including 48.5% TICI 3 with an average of 1.6 passes. The symptomatic reperfusion hemorrhage rate was 6%. Procedural complications occurred in four patients, but were unrelated to SOFIA. Mortality was 21%, secondary to failed revascularization, hemorrhagic transformation, and baseline medical condition. CONCLUSIONS: Mechanical and aspiration thrombectomy with SOFIA is safe and effective with high revascularization rates. Its trackability, stability, and luminal size make SOFIA suitable for stroke intervention.