Epigenetics to clinicopathological features: a bibliometric analysis of H3 G34-mutant diffuse hemispheric glioma literature.

PURPOSE: Pediatric-type diffuse high-grade gliomas are the leading cause of cancer-related morbidity and mortality in children. More than 30% of diffuse hemispheric gliomas (DHG) in adolescents harbor histone H3 G34 mutations and are recognized by the World Health Organization as a distinct tumor entity. By reporting bibliometric characteristics of the most cited publications on H3 G34-mutant DHG (H3 G34 DHG), we provide an overview of emerging literature and speculate where future research efforts may lead. METHODS: One hundred fourteen publications discussing H3 G34 DHG were identified, categorized as basic science (BSc), clinical (CL), or review (R), and ranked by citation number. Various bibliometric parameters were summarized, and a comparison between article types was performed. RESULTS: Articles within this study represent principal investigators from 15 countries and were published across 63 journals between 2012 and 2024, with 36.84% of articles originating in the United States. Overall median values were as follows: citation count, 20 (range, 0-2591), number of authors, 9 (range, 2-78), and year of publication, 2020 (range, 2012-2024). Among the top ten most cited articles, BSc articles accounted for all ten reports. Compared to CL and R articles, BSc articles were published in journals with higher impact factors. CONCLUSION: We establish variability in bibliometric parameters for the most cited publications on H3 G34 DHG. Our findings demonstrate a paucity of high-impact and highly cited CL reports and acknowledge an unmet need to intersect basic mechanism with clinical data to inform novel therapeutic approaches.

The longitudinal risk of hemorrhage of melanoma brain metastases after Gamma Knife radiosurgery.

OBJECTIVE: The objective of this study was to analyze the hemorrhagic risk of melanoma brain metastases after Gamma Knife radiosurgery (GKRS). METHODS: A prospective institutional database was retrospectively queried to identify patients who underwent GKRS for melanoma brain metastases between 1990 and 2021. Lesional hemorrhage was defined as definite or possible based on radiologists' readings, and severity was graded according to Common Terminology Criteria for Adverse Events. RESULTS: Two hundred ninety-one patients with 1083 lesions treated in 419 sessions were identified. The mean (± SD) patient age was 60 ± 15 years, and 61% were male. The median follow-up period for overall survival (OS) was 11 (range 0-214) months with 581 patient-years. Definite/possible lesional hemorrhages occurred in 13% of lesions, with grade 3 hemorrhages observed in 4% of lesions. Surgical intervention was required in 2% of cases (5% of patients), and all resected lesions were pathologically consistent with melanoma. A decreased risk of definite/possible lesional hemorrhage was associated with a later time period between 2015 and 2021 (OR 0.45, 95% CI 0.266-0.75, p = 0.0021), increased marginal dose (OR 0.91, 95% CI 0.83-0.99, p = 0.037), antiplatelet use post-GKRS (OR 0.195, 95% CI 0.083-0.46, p < 0.001), and whole-brain radiotherapy (WBRT; OR 0.53, 95% CI 0.344-0.82, p = 0.0042). After 2015, more patients received anticoagulation, B-Raf proto-oncogene inhibitors, and immune checkpoint inhibitors, and fewer received bevacizumab (p < 0.001). The cumulative risk of lesional hemorrhage was 17%-20% at 36 months from GKRS, with 95%-96% of cases occurring within 12 months. The median patient OS was 11 (95% CI 9-13) months, and multivariate Cox regression analysis revealed that antiplatelet agents (hazard ratio [HR] 0.66, 95% CI 0.45-0.96, p = 0.031) and immune checkpoint inhibitors (HR 0.35, 95% CI 0.26-0.48, p < 0.001) were associated with longer OS, while WBRT (HR 1.36, 95% CI 1.02-1.81, p = 0.037) and definite/possible hemorrhage (HR 1.39, 95% CI 1.04-1.85, p = 0.024) were associated with shorter OS. CONCLUSIONS: The definite hemorrhage risk of melanoma brain metastases after GKRS was 17% in the first 3 years and 95% of the lesional hemorrhage occurred within the 1st year. Surgical intervention was needed in 5% of patients. Antiplatelet agents and immune checkpoint inhibitors were associated with improved OS, while definite/possible hemorrhage was associated with worse OS.

Methodological and analytical considerations for intra-operative microdialysis.

BACKGROUND: Microdialysis is a technique that can be utilized to sample the interstitial fluid of the central nervous system (CNS), including in primary malignant brain tumors known as gliomas. Gliomas are mainly accessible at the time of surgery, but have rarely been analyzed via interstitial fluid collected via microdialysis. To that end, we obtained an investigational device exemption for high molecular weight catheters (HMW, 100 kDa) and a variable flow rate pump to perform microdialysis at flow rates amenable to an intra-operative setting. We herein report on the lessons and insights obtained during our intra-operative HMW microdialysis trial, both in regard to methodological and analytical considerations. METHODS: Intra-operative HMW microdialysis was performed during 15 clinically indicated glioma resections in fourteen patients, across three radiographically diverse regions in each patient. Microdialysates were analyzed via targeted and untargeted metabolomics via ultra-performance liquid chromatography tandem mass spectrometry. RESULTS: Use of albumin and lactate-containing perfusates impacted subsets of metabolites evaluated via global metabolomics. Additionally, focal delivery of lactate via a lactate-containing perfusate, induced local metabolic changes, suggesting the potential for intra-operative pharmacodynamic studies via reverse microdialysis of candidate drugs. Multiple peri-operatively administered drugs, including levetiracetam, cefazolin, caffeine, mannitol and acetaminophen, could be detected from one microdialysate aliquot representing 10 min worth of intra-operative sampling. Moreover, clinical, radiographic, and methodological considerations for performing intra-operative microdialysis are discussed. CONCLUSIONS: Intra-operative HMW microdialysis can feasibly be utilized to sample the live human CNS microenvironment, including both metabolites and drugs, within one surgery. Certain variables, such as perfusate type, must be considered during and after analysis. Trial registration NCT04047264.

Plasma exchange as a tool for removal of bevacizumab: Highlighting application for urgent surgery.

Background: Bevacizumab is commonly used to manage cerebral edema associated with brain tumors. However, its long half-life poses challenges for patients requiring urgent surgery due to wound complications. We present a case of utilizing therapeutic plasma exchange (TPE) to remove bevacizumab in a patient with recurrent glioblastoma requiring urgent surgery. Methods: A 58-year-old male with recurrent glioblastoma, IDH-wildtype, presented with clinical and radiographic concern for ventriculitis requiring urgent wound washout only 4 days after his last bevacizumab infusion. TPE was performed for 3 sessions after surgery using a centrifugation-based cell separator. Replacement fluids included normal serum albumin, normal saline, and fresh frozen plasma. Bevacizumab levels were quantified using an enzyme-linked immunoabsorbent assay before and after each TPE session. Results: TPE effectively removed bevacizumab, enabling safe surgery without new complications. Plasma bevacizumab levels decreased from 1087.63 to 145.35 ng/mL (13.4% of original) by the end of the last TPE session. This decline is consistent with nearly 3 half-lives, which compares favorably to the expected timeline of natural decline given the 21-day half-life. Conclusions: We report a complex clinical scenario of a patient requiring urgent wound washout 4 days after last bevacizumab infusion for CNS infection. Surgery was successfully performed without new complications with use of TPE to remove bevacizumab immediately following surgery. This case highlights the feasibility of this approach, which may be utilized effectively in patients requiring surgery after having recently received bevacizumab.

An untapped window of opportunity for glioma: targeting therapy-induced senescence prior to recurrence.

High-grade gliomas are primary brain tumors that are incredibly refractory long-term to surgery and chemoradiation, with no proven durable salvage therapies for patients that have failed conventional treatments. Post-treatment, the latent glioma and its microenvironment are characterized by a senescent-like state of mitotic arrest and a senescence-associated secretory phenotype (SASP) induced by prior chemoradiation. Although senescence was once thought to be irreversible, recent evidence has demonstrated that cells may escape this state and re-enter the cell cycle, contributing to tumor recurrence. Moreover, senescent tumor cells could spur the growth of their non-senescent counterparts, thereby accelerating recurrence. In this review, we highlight emerging evidence supporting the use of senolytic agents to ablate latent, senescent-like cells that could contribute to tumor recurrence. We also discuss how senescent cell clearance can decrease the SASP within the tumor microenvironment thereby reducing tumor aggressiveness at recurrence. Finally, senolytics could improve the long-term sequelae of prior therapy on cognition and bone marrow function. We critically review the senolytic drugs currently under preclinical and clinical investigation and the potential challenges that may be associated with deploying senolytics against latent glioma. In conclusion, senescence in glioma and the microenvironment are critical and potential targets for delaying or preventing tumor recurrence and improving patient functional outcomes through senotherapeutics.

Calcifying Pseudoneoplasm of the Neuraxis: An Institutional Series of Ten Cases and Review of the Literature to Date.

BACKGROUND: Calcified pseudoneoplasms of the neuraxis (CAPNONs) are rare, fibro-osseous lesions with an unknown cause that may present anywhere along the neuroaxis. Little is known about how intracranial CAPNONs present and about patients' long-term outcomes. METHODS: A retrospective institutional review of intracranial pathology-confirmed CAPNONs was performed. Presenting clinical features, management, and clinical outcomes are highlighted. A literature review of intracranial CAPNON lesions was also performed to build on our series. RESULTS: Ten patients were identified who met the inclusion criteria. Most patients presented with headaches (n = 6; 60%), seizures (n = 5; 50.0%), and neck and facial pain (n = 3; 30.0%). Most lesions were supratentorial (n = 7; 70.0%), with 3 infratentorial origins. Surgical resection was the most common initial management undertaken (n = 7; 70.0%). No new permanent postoperative neurologic deficits were identified. The median clinical and/or radiographic follow-up for all patients was 6.8 years (range, 0.7-23.3 years), with no recurrence of disease for 5 patients who underwent gross total resection. Four of 5 patients with residual or nonresectable lesions showed no interval growth on radiographic follow-up; 1 patient showed progression and worsening of presenting symptoms 2 months after resection. Resection substantially improved seizures and headaches in patients presenting with these symptoms (80% and 83.3%, respectively). CONCLUSIONS: Intracranial CAPNONs may present with a wide variety of symptoms characteristic of the site of origin. The outcomes of these symptoms regarding survival and disease control are generally favorable, although resection does not always yield complete resolution of presenting deficits in certain patients, particularly those presenting with headaches or neck/facial pain.

Blood-brain barrier disruption defines the extracellular metabolome of live human high-grade gliomas.

The extracellular microenvironment modulates glioma behaviour. It remains unknown if blood-brain barrier disruption merely reflects or functionally supports glioma aggressiveness. We utilised intra-operative microdialysis to sample the extracellular metabolome of radiographically diverse regions of gliomas and evaluated the global extracellular metabolome via ultra-performance liquid chromatography tandem mass spectrometry. Among 162 named metabolites, guanidinoacetate (GAA) was 126.32x higher in enhancing tumour than in adjacent brain. 48 additional metabolites were 2.05-10.18x more abundant in enhancing tumour than brain. With exception of GAA, and 2-hydroxyglutarate in IDH-mutant gliomas, differences between non-enhancing tumour and brain microdialysate were modest and less consistent. The enhancing, but not the non-enhancing glioma metabolome, was significantly enriched for plasma-associated metabolites largely comprising amino acids and carnitines. Our findings suggest that metabolite diffusion through a disrupted blood-brain barrier may largely define the enhancing extracellular glioma metabolome. Future studies will determine how the altered extracellular metabolome impacts glioma behaviour.

Glioma Metabolic Feedback In Situ: A First-In-Human Pharmacodynamic Trial of Difluoromethylornithine + AMXT-1501 Through High-Molecular Weight Microdialysis.

BACKGROUND AND OBJECTIVES: No new drug has improved survival for glioblastoma since temozolomide in 2005, due in part to the relative inaccessibility of each patient's individualized tumor biology and its response to therapy. We have identified a conserved extracellular metabolic signature of enhancing high-grade gliomas enriched for guanidinoacetate (GAA). GAA is coproduced with ornithine, the precursor to protumorigenic polyamines through ornithine decarboxylase (ODC). AMXT-1501 is a polyamine transporter inhibitor that can overcome tumoral resistance to the ODC inhibitor, difluoromethylornithine (DFMO). We will use DFMO with or without AMXT-1501 to identify candidate pharmacodynamic biomarkers of polyamine depletion in patients with high-grade gliomas in situ . We aim to determine (1) how blocking polyamine production affects intratumoral extracellular guanidinoacetate abundance and (2) the impact of polyamine depletion on the global extracellular metabolome within live human gliomas in situ. METHODS: DFMO, with or without AMXT-1501, will be administered postoperatively in 15 patients after clinically indicated subtotal resection for high-grade glioma. High-molecular weight microdialysis catheters implanted into residual tumor and adjacent brain will be used for postoperative monitoring of extracellular GAA and polyamines throughout therapeutic intervention from postoperative day (POD) 1 to POD5. Catheters will be removed on POD5 before discharge. EXPECTED OUTCOMES: We anticipate that GAA will be elevated in tumor relative to adjacent brain although it will decrease within 24 hours of ODC inhibition with DFMO. If AMXT-1501 effectively increases the cytotoxic impact of ODC inhibition, we expect an increase in biomarkers of cytotoxicity including glutamate with DFMO + AMXT-1501 treatment when compared with DFMO alone. DISCUSSION: Limited mechanistic feedback from individual patients' gliomas hampers clinical translation of novel therapies. This pilot Phase 0 study will provide in situ feedback during DFMO + AMXT-1501 treatment to determine how high-grade gliomas respond to polyamine depletion.

Cerebrospinal fluid 2-hydroxyglutarate (2-HG) as a monitoring biomarker for IDH-mutant gliomas.

D-2-hydroxyglutarate (D-2-HG) is a well-established oncometabolite of isocitrate dehydrogenase (IDH) mutant gliomas. While prior studies have demonstrated that D-2-HG is elevated in the cerebrospinal fluid (CSF) of patients with IDH-mutant gliomas 1,2 , no study has determined if CSF D-2-HG can provide a plausible method to evaluate therapeutic response. We are obtaining CSF samples from consenting patients during their disease course via intra-operative collection and Ommaya reservoirs. D-2-HG and D/L-2-HG consistently decreased following tumor resection and throughout chemoradiation in patients monitored longitudinally. Our early experience with this strategy demonstrates the potential for intracranial CSF D-2-HG as a monitoring biomarker for IDH-mutant gliomas.

Clinical manifestation, management and prognosis of clear cell meningioma: an evidence-based review.

Clear cell meningioma (CCM) is an uncommon histologic subtype of meningioma classified as a WHO grade II tumor and accounting for less than 1% of all meningiomas. Demographically, younger patients are commonly affected without any remarkable gender preference. Moreover, CCM shows a unique anatomical site of involvement. It tends to occur in the cranium than the spine, whereas the basilar skull, posterior fossa and lumbar spine have been the most frequently affected area. Although most cases present as typical the mass effect by the tumor, CCM exhibits characteristic imaging and histologic patterns. Even though surgical resection is the treatment of choice, recurrence-free survival is the biggest challenge and has been attempting to improve by adjuvant therapy. There is still debate about its management, outcome and factors defining it. Herein, we aimed to summarize natural history, radiographic characteristics, histological features, treatment strategies to guide the best possible individualized care for the most favorable outcome.

The LazyBox Educational Intervention Trial: Can Longitudinal Practice on a Low-Fidelity Microsurgery Simulator Improve Microsurgical Skills?

Introduction Every surgical trainee must acquire microsurgical skills within a limited timeframe. Therefore, identifying effective educational strategies to help learners attain these skills is crucial. Objective Establish the effectiveness of a low-fidelity microsurgery simulator to improve the execution and one's perception of the difficulty of basic surgical techniques. Methods From 2021 to 2022, 24 medical students were randomized to either (1) a treatment group (n=12) that engaged in longitudinal practice on a low-fidelity microsurgery simulator (the LazyBox) or (2) a control group (n=12) that did not practice. Students performed vessel loop ligation, catheter macroanastomosis, and synthetic vessel microanastomosis prior to and six weeks after intervention. Both objective metrics and subjective metrics (Swedish Occupational Fatigue Inventory (SOFI) and Surgery Task Load Index (SURG-TLX)) were obtained. Results The treatment and control arms had 1.2 (SD = 2.6) and 2.1 (SD = 2.4) points increase in the vessel loop ligation, respectively (p = 0.39). The treatment and control arms had a 3.4 (SD = 4.1) and 2.9 (SD = 3.6) points increase in the macroanastomosis task, respectively (p = 0.74). In the synthetic vessel microanastomosis task training, the experimental and control arms showed a 5.4 (SD = 8.3) and a 2.9 (SD = 5.6) points increase, respectively (p = 0.30). No differences were found between the groups regarding survey metrics of mental (p = 0.82), temporal (p = 0.23), and physical demands (p = 0.48). Conclusion In our randomized educational intervention, we found no significant difference in objective and subjective metrics of microsurgical task performance between learners who did and did not use the LazyBox simulator.

The Early Bird Gets the Worm: Introducing Medical Students to Microsurgical Technique via a Low-Cost, User-Friendly, Reusable Simulation System.

BACKGROUND: Mastery of microsurgical technique requires thousands of hours of deliberate practice, often with equipment that is not accessible to medical students. This study aimed to develop, test, and report a novel simulation system for providing medical students with early access to microsurgical technique. METHODS: Low-cost, user-friendly, reusable microsurgery kits were iteratively developed using excess surgical supplies, such as catheter tubing and vessel loops. Students were tested on 2 separate tasks, with grading via a standardized performance scale incorporating aspects of alignment, leak, and anastomotic patency. RESULTS: Twelve medical students were tested on standardized microsurgery kits at 2 different time points 6 weeks apart with no additional training received in between. Median change in total score on the vessel loop suturing task after 6 weeks was +2.6 points (range, -1.7 to +5 points); median change in completion time was -1.9 minutes (range, -3.5 to +2.7 minutes). Median change in total score on the red rubber anastomosis task was +5.8 points (range, -2.6 to +9.6 points) with a median improvement of -4.3 minutes (range, -9.6 to +2.6 minutes). CONCLUSIONS: Reusable microsurgery kits designed with excess surgical supplies are educationally impactful tools that introduce medical students to microsurgical techniques early in their training, while also providing objective measures for skills acquisition over time.

The role of CCR5 in HIV-associated neurocognitive disorders.

While combination antiretroviral therapy (cART) has successfully increased the lifespan of individuals infected with HIV, a significant portion of this population remains affected by HIV-associated neurocognitive disorder (HAND). C-C chemokine receptor 5 (CCR5) has been well studied in immune response and as a co-receptor for HIV infection. HIV-infected (HIV+) patients experienced mild to significant amelioration of cognitive function when treated with different CCR5 antagonists, including maraviroc and cenicriviroc. Consistent with clinical results, Ccr5 knockout or knockdown rescued cognitive deficits in HIV animal models, with mechanisms of reduced microgliosis and neuroinflammation. Pharmacologic inhibition of CCR5 directly improved cerebral and hippocampal neuronal plasticity and cognitive function. By summarizing the animal and human studies of CCR5 in HIV-associated cognitive deficits, this review aims to provide an overview of the mechanistic role of CCR5 in HAND pathophysiology. This review also discusses the addition of CCR5 antagonists, such as maraviroc, to cART for targeted prevention and treatment of cognitive impairments in patients infected with HIV.

Outcomes and Principles of Patient Selection for Laser Interstitial Thermal Therapy for Metastatic Brain Tumor Management: A Multisite Institutional Case Series.

BACKGROUND: Laser interstitial thermal therapy (LITT) is an emerging treatment modality for both primary brain tumors and metastases. We report initial outcomes after LITT for metastatic brain tumors across 3 sites at our institution and discuss potential strategies for optimal patient selection and outcomes. METHODS: International Classification of Diseases, Ninth Revision and Tenth Revision codes were used to identify patients with malignant brain tumors treated via LITT across all 3 Mayo Clinic sites with at least 6 months follow-up. Local control was based on radiologic and clinical evidence. Overall survival was measured from time of receiving LITT until death or end of the study period. RESULTS: Twenty-three patients were treated for progression of a single (n = 21) or multiple (n = 2) previously radiated metastatic lesions and/or radiation necrosis. Median age was 56 years (interquartile range, 47-66.5 years). LITT achieved local control of the lesion in most patients with metastatic tumors or radiation necrosis (n = 18; 81.8%) for the duration of follow-up. One patient did not have local control data available. Thirteen (56.5%) patients remained alive at the end of the study period. No other patients died of their treated disease during the study period; 5 of 10 deaths were attributable to central nervous system progression outside the treated lesion. Although median survival for this cohort has not yet been reached, the current median survival is 16 months (interquartile range, 12-48.5 months) after LITT for metastatic/radiation necrosis lesions. CONCLUSIONS: LITT was associated with sustained local control in 81.8% of patients treated for radiographic progression of metastatic central nervous system disease.

Ultra-early therapeutic anticoagulation after craniotomy - A single institution experience.

There is a paucity of information regarding the optimal timing of initiation or re-initiation of therapeutic anticoagulation after intracranial surgery. Anticoagulation that is started too soon after surgery may increase the risk of catastrophic intracranial bleeding. However, there are scenarios that necessitate the use of anticoagulation in the immediate post-operative period despite the increased risk of hemorrhage. Therefore, we sought to report our experience with ultra-early therapeutic anticoagulation after craniotomy. Retrospective chart review of patients from a single institution between 1/1/2010 and 10/1/2021 who were treated with therapeutic anticoagulation for venous thromboembolism on or before 7-days after a craniotomy or craniectomy. The primary endpoint was intracranial hemorrhage resulting in death or return to the operating room for hematoma evacuation. Secondary endpoints included extra-cranial hemorrhage, length of hospital stay, and 90-day readmission rate. Eighteen patients were included for analysis. The median time that therapeutic anticoagulation was started was post-operative day 5 (range 1-7 days). One patient (5.6%) met the primary endpoint as they experienced an intracranial hemorrhage 5 days after starting anticoagulation, which required surgical evacuation. No patients experienced an extra-cranial hemorrhage. The median length of hospitalization was 13 days (range 4-89 days). No patients were readmitted within 90 days. The 90-day survival rate was 100%. Ultra-early anticoagulation after craniotomy resulted in a 5.6% risk of intracranial hemorrhage. Thus, ultra-early anticoagulation can be performed safely but it does carry a substantial risk of intracranial bleeding that may require emergent hematoma evacuation or result in permeant neurologic deficits or death.

Management strategies for pediatric patients with tectal gliomas: a systematic review.

Pediatric tectal gliomas generally have a benign clinical course with the majority of these observed radiologically. However, patients often need treatment for obstructive hydrocephalus and occasionally require cytotoxic therapy. Given the lack of level I data, there is a need to further characterize management strategies for these rare tumors. We have therefore performed the first systematic review comparing various management strategies. The literature was systematically searched from January 1, 2000, to July 30, 2020, to identify studies reporting treatment strategies for pediatric tectal gliomas. The systematic review included 355 patients from 14 studies. Abnormal ocular findings-including gaze palsies, papilledema, diplopia, and visual field changes-were a common presentation with between 13.6 and 88.9% of patients experiencing such findings. CSF diversion was the most performed procedure, occurring in 317 patients (89.3%). In individual studies, use of CSF diversion ranged from 73.1 to 100.0%. For management options, 232 patients were radiologically monitored (65.4%), 69 received resection (19.4%), 30 received radiotherapy (8.4%), and 19 received chemotherapy (5.4%). When examining frequencies within individual studies, chemotherapy ranged from 2.5 to 29.6% and radiotherapy ranged from 2.5 to 28.6%. Resection was the most variable treatment option between individual studies, ranging from 2.3 to 100.0%. Most tectal gliomas in the pediatric population can be observed through radiographic surveillance and CSF diversion. Other forms of management (i.e., chemotherapy and radiotherapy) are warranted for more aggressive tumors demonstrating radiological progression. Surgical resection should be reserved for large tumors and/or those that are refractory to other treatment modalities.