The ERK inhibitor LY3214996 augments anti-PD-1 immunotherapy in preclinical mouse models of BRAFV600E melanoma brain metastasis.

BACKGROUND: Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment; however, only a subset of patients with brain metastasis (BM) respond to ICI. Activating mutations in the mitogen-activated protein kinase signaling pathway are frequent in BM. The objective of this study was to evaluate whether therapeutic inhibition of extracellular signal-regulated kinase (ERK) can improve the efficacy of ICI for BM. METHODS: We used immunotypical mouse models of BM bearing dual extracranial/intracranial tumors to evaluate the efficacy of single-agent and dual-agent treatment with selective ERK inhibitor LY3214996 (LY321) and anti-programmed death receptor 1 (PD-1) antibody. We verified target inhibition and drug delivery, then investigated treatment effects on T-cell response and tumor-immune microenvironment using high-parameter flow cytometry, multiplex immunoassays, and T-cell receptor profiling. RESULTS: We found that dual treatment with LY321 and anti-PD-1 significantly improved overall survival in 2 BRAFV600E-mutant murine melanoma models but not in KRAS-mutant murine lung adenocarcinoma. We demonstrate that although LY321 has limited blood-brain barrier (BBB) permeability, combined LY321 and anti-PD-1 therapy increases tumor-infiltrating CD8+ effector T cells, broadens the T-cell receptor repertoire in the extracranial tumor, enriches T-cell clones shared by the periphery and brain, and reduces immunosuppressive cytokines and cell populations in tumors. CONCLUSIONS: Despite the limited BBB permeability of LY321, combined LY321 and anti-PD-1 treatment can improve intracranial disease control by amplifying extracranial immune responses, highlighting the role of extracranial tumors in driving intracranial response to treatment. Combined ERK and PD-1 inhibition is a promising therapeutic approach, worthy of further investigation for patients with melanoma BM.

Leveraging translational insights toward precision medicine approaches for brain metastases.

Due to increasing incidence and limited treatments, brain metastases (BM) are an emerging unmet need in modern oncology. Development of effective therapeutics has been hindered by unique challenges. Individual steps of the brain metastatic cascade are driven by distinctive biological processes, suggesting that BM possess intrinsic biological differences compared to primary tumors. Here, we discuss the unique physiology and metabolic constraints specific to BM as well as emerging treatment strategies that leverage potential vulnerabilities.

A Systematic Review of Recent and Ongoing Clinical Trials in Patients With the Neurofibromatoses.

INTRODUCTION: The neurofibromatoses comprise three different genetic conditions causing considerable morbidity and mortality: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN). This review summarizes recent and ongoing clinical trials involving patients with neurofibromatoses to better understand the current state of clinical trial research centered around these conditions and inform areas of need. METHODS: A search was conducted using the Cochrane Central Register of Controlled Trials and clinicaltrials.gov databases. Inclusion and exclusion criteria were designed to identify clinical trials focused on patients with NF1, NF2, or SWN completed in or after 2010 and in process as of December 31, 2021. Information was collected using standardized guidelines. RESULTS: A total of 134 clinical trials were included, with 75 (56%) completed and 59 (44%) in process. For completed trials, 74% (n = 56) involved patients with NF1, and of those based on specific tumors (n = 26, 46%), the majority focused on plexiform neurofibromas (PNs) (n = 12, 46%). For ongoing trials, 79% (n = 47) involve patients with NF1, and of those based on specific tumors (n = 29, 61%), the majority are focused on PNs (n = 13, 45%). CONCLUSION: Both recent and ongoing clinical trials have primarily focused on patients with NF1 and the treatment of PNs. This research has led to the first FDA-approved drug for NF1-PN and has changed management of these tumors, allowing for systemic therapy rather than reliance on only a surgical modality. Trials evaluating comorbid psychiatric conditions and quality of life among patients with any of the neurofibromatoses appear less common. These areas may warrant focus in future studies to improve clinical management.

Emerging Systemic Treatment Perspectives on Brain Metastases: Moving Toward a Better Outlook for Patients.

The diagnosis of brain metastases has historically been a dreaded, end-stage complication of systemic disease. Additionally, with the increasing effectiveness of systemic therapies that prolong life expectancy and improved imaging tools, the incidence of intracranial progression is becoming more common. Within this context, there has been increasing attention directed at understanding the molecular underpinnings of intracranial progression. Exploring the unique features of brain metastases compared with their extracranial counterparts to identify aberrant signaling pathways, which can be targeted pharmacologically, may help lead to new treatments for this patient population. Additionally, critical discoveries outside the sphere of the central nervous system are increasingly being applied to brain metastases with the emergence of immune checkpoint inhibition, becoming a prevalent treatment option for patients with brain metastases across multiple histologies. As novel treatment strategies are considered, they require thoughtful incorporation of agents that can cross the blood-brain barrier and can synergize with pre-existing agents through rational combinations. Lastly, as clinicians and scientists continue to understand key molecular features of these tumors, they will continue to influence the treatment algorithms that are developing for the management of these patients. Due to the complexity of treatment decisions for patients with brain metastases, an emerging tool is the utilization of multidisciplinary brain metastasis tumor boards to ensure optimal treatment decisions are made and that patients are provided access to applicable clinical trials. Looking to the future, the collective effort to understand the various tumor-intrinsic and tumor-extrinsic factors that promote central nervous system seeding and propagation will have the potential to change the clinical trajectory for these patients.

Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer.

PURPOSE: Patients with KRAS-mutant non-small cell lung cancer (NSCLC) with brain metastases (BM) have a poor prognosis. Adagrasib (MRTX849), a potent oral small-molecule KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib has been optimized for favorable pharmacokinetic properties, including long half-life (∼24 hours), extensive tissue distribution, dose-dependent pharmacokinetics, and central nervous system penetration; however, BM-specific antitumor activity of KRASG12C inhibitors remains to be fully characterized. EXPERIMENTAL DESIGN: A retrospective database query identified patients with KRAS-mutant NSCLC to understand their propensity to develop BM. Preclinical studies assessed physiochemical and pharmacokinetic properties of adagrasib. Mice bearing intracranial KRASG12C-mutant NSCLC xenografts (LU99-Luc/H23-Luc/LU65-Luc) were treated with clinically relevant adagrasib doses, and levels of adagrasib in plasma, cerebrospinal fluid (CSF), and brain were determined along with antitumor activity. Preliminary clinical data were collected from 2 patients with NSCLC with untreated BM who had received adagrasib 600 mg twice daily in the phase Ib cohort of the KRYSTAL-1 trial; CSF was collected, adagrasib concentrations measured, and antitumor activity in BM evaluated. RESULTS: Patients with KRAS-mutant NSCLC demonstrated high propensity to develop BM (≥40%). Adagrasib penetrated into CSF and demonstrated tumor regression and extended survival in multiple preclinical BM models. In 2 patients with NSCLC and untreated BM, CSF concentrations of adagrasib measured above the target cellular IC50. Both patients demonstrated corresponding BM regression, supporting potential clinical activity of adagrasib in the brain. CONCLUSIONS: These data support further development of adagrasib in patients with KRASG12C-mutant NSCLC with untreated BM. See related commentary by Kommalapati and Mansfield, p. 3179.

Central Nervous System Metastases.

The proportion of patients developing central nervous system (CNS) metastasis is increasing. Most are identified once symptomatic. Surgical resection is indicated for solitary or symptomatic brain metastases, separation surgery for compressive radioresistant spinal metastases, and instrumentation for unstable spinal lesions. Surgical biopsies are performed when histological diagnoses are required. Stereotactic radiosurgery is an option for limited small brain metastases and radioresistant spinal metastases. Whole-brain radiotherapy is reserved for extensive brain metastases and leptomeningeal disease with approaches to reduce cognitive side effects. Radiosensitive and inoperable spinal metastases typically receive external beam radiotherapy. Systemic therapy is increasingly being utilized for CNS metastases.

Racial, ethnic, and gender diversity of applicants and matriculants to neurological surgery residency programs.

OBJECTIVE: The aim of this study was to identify trends in the demographic constitution of applicants and matriculants to neurological surgery based on race, ethnicity, and gender. METHODS: The authors conducted a cross-sectional study using compiled demographic data obtained from the Association of American Medical Colleges. Trends analyzed included proportional changes in race, ethnicity, and gender of applicants and matriculants to neurosurgical residency programs from academic years 2010-2011 to 2018-2019. RESULTS: A total of 5100 applicants and 2104 matriculants to neurosurgical residency programs were analyzed. No significant change in the percentage of overall women applicants (+0.3%, 95% CI -0.7% to 1.3%; p = 0.77) or in the percentage of women matriculants (+0.3%, 95% CI -2.2% to 2.9%; p = 0.71) was observed. For applicants, no change over time was observed in the percentages of American Indian or Alaska Native (AI/AN) men (0.0%, 95% CI -0.3% to 0.3%; p = 0.65); Asian men (-0.1%, 95% CI -1.2% to 1.1%; p = 0.97); Black or African American men (-0.2%, 95% CI -0.7% to 0.4%; p = 0.91); Hispanic, Latino, or of Spanish Origin men (+0.4%, 95% CI -0.8% to 1.7%; p = 0.26); White men (+0.5%, 95% CI -2.1% to 3.0%; p = 0.27); Asian women (+0.1,% 95% CI -0.9% to 1.1%; p = 0.73); Black or African American women (0.0%, 95% CI -0.6% to 0.5%; p = 0.30); Hispanic, Latino, or of Spanish Origin women (0.0%, 95% CI -0.4% to 0.4%; p = 0.71); and White women (+0.3%, 95% CI -1.1% to 1.7%; p = 0.34). For matriculants, no change over time was observed in the percentages of AI/AN men (0.0%, 95% CI -0.6% to 0.6%; p = 0.56); Asian men (0.0%, 95% CI -2.7% to 2.7%; p = 0.45); Black or African American men (-0.3%, 95% CI -1.4% to 0.8%; p = 0.52); Hispanic, Latino, or of Spanish Origin men (+0.6%, 95% CI -0.8 to 2.0%; p = 0.12); White men (-1.0%, 95% CI -5.3% to 3.3%; p = 0.92); Asian women (+0.1%, 95% CI -1.3% to 1.5%; p = 0.85); Black or African American women (0.0%, 95% CI -0.6% to 0.7%; p = 0.38); Hispanic, Latino, or of Spanish Origin women (-0.1%, 95% CI -0.7% to 0.5%; p = 0.46); and White women (+0.3%, 95% CI -2.4% to 3.0%; p = 0.70). CONCLUSIONS: Despite efforts to diversify the demographic constitution of incoming neurosurgical trainees, few significant advances have been made in recent years. This study suggests that improved strategies for recruitment and cultivating early interest in neurological surgery are required to further increase the diversification of future cohorts of neurosurgical trainees.

Prognostic Value of Hemorrhagic Brainstem Injury on Early Computed Tomography: A TRACK-TBI Study.

BACKGROUND: Traumatic brainstem injury has yet to be incorporated into widely used imaging classification systems for traumatic brain injury (TBI), and questions remain regarding prognostic implications for this TBI subgroup. To address this, retrospective data on patients from the multicenter prospective Transforming Research and Clinical Knowledge in TBI study were studied. METHODS: Patients with brainstem and cerebrum injury (BSI+) were matched by age, sex, and admission Glasgow Coma Scale (GCS) score to patients with cerebrum injuries only. All patients had an interpretable head computed tomography (CT) scan from the first 48 hours after injury and a 6-month Glasgow Outcome Scale Extended (GOSE) score. CT scans were reviewed for brainstem lesions and, when present, characterized by location, size, and type (traumatic axonal injury, contusion, or Duret hemorrhage). Clinical, demographic, and outcome data were then compared between the two groups. RESULTS: Mann-Whitney U-tests showed no significant difference in 6-month GOSE scores in patients with BSI+ (mean 2.7) compared with patients with similar but only cerebrum injuries (mean 3.9), although there is a trend (p = 0.10). However, subclassification by brainstem lesion type, traumatic axonal injury (mean 4.0) versus Duret hemorrhage or contusion (mean 1.4), did identify a proportion of BSI+ with significantly less favorable outcome (p = 0.002). The incorporation of brainstem lesion type (traumatic axonal injury vs. contusion/Duret), along with GCS into a multivariate logistic regression model of favorable outcome (GOSE score 4-8) did show a significant contribution to the prognostication of this brainstem injury subgroup (odds ratio 0.08, 95% confidence interval 0.00-0.67, p = 0.01). CONCLUSIONS: These findings suggest two groups of patients with brainstem injuries may exist with divergent recovery potential after TBI. These data support the notion that newer CT imaging classification systems may augment traditional clinical measures, such as GCS in identifying those patients with TBI and brainstem injuries that stand a higher chance of favorable outcome.

United States Medicolegal Progress and Innovation in Telemedicine in the Age of COVID-19: A Primer for Neurosurgeons.

Telemedicine has received increased attention in recent years as a potential solution to expand clinical capability and patient access to care in many fields, including neurosurgery. Although patient and physician attitudes are rapidly shifting toward greater telemedicine use in light of the COVID-19 pandemic, there remains uncertainty about telemedicine's regulatory future. Despite growing evidence of telemedicine's utility, there remain a number of significant medicolegal barriers to its mass adoption and wider implementation. Herein, we examine recent progress in state and federal regulations in the United States governing telemedicine's implementation in quality of care, finance and billing, privacy and confidentiality, risk and liability, and geography and interstate licensure, with special attention to how these concern teleneurosurgical practice. We also review contemporary topics germane to the future of teleneurosurgery, including the continued expansion of reciprocity in interstate licensure, expanded coverage for homecare services for chronic conditions, expansion of Center for Medicare and Medicaid Services reimbursements, and protections of store-and-forward technologies. Additionally, we discuss recent successes in teleneurosurgery, stroke care, and rehabilitation as models for teleneurosurgical best practices. As telemedicine technology continues to mature and its expanse grows, neurosurgeons' familiarity with its benefits, limitations, and controversies will best allow for its successful adoption in our field to maximize patient care and outcomes.

Racial and ethnic disparities among children with primary central nervous system tumors in the US.

INTRODUCTION: Primary central nervous system (CNS) tumors are among the most common and lethal types of cancer in children. However, the existence of health disparities in CNS tumors by race or ethnicity remains poorly understood. This systematic review sought to determine whether racial and ethnic disparities in incidence, healthcare access, and survival exist among pediatric patients diagnosed with CNS tumors. METHODS: A search of MEDLINE, Embase, CINAHL, Web of Science, and Scopus was conducted. Inclusion criteria selected for studies published between January 1, 2005 and July 15, 2020 that focused on pediatric populations in the US, evaluated for potential differences based on racial or ethnic backgrounds, and focused on CNS tumors. A standardized study form was used to collect study information, population of interest, research design, and quality of analysis, sample size, participant demographics, pathology evaluated, and incidence or outcomes observed. RESULTS: A total of 30 studies were inlcuded. Studies suggest White children may be more likely to be diagnosed with a CNS tumor and Hispanic children to present with advanced-stage disease and have worse outcomes. The degree of influence derived from socioeconomic factors is unclear. This review was limited by few available studies that included race and ethnicity as a variable, the overlap in databases used, and unclear categorization of race and ethnicity. CONCLUSIONS: This review identified notable and at times contradicting variations in racial/ethnic disparities among children with CNS tumors, suggesting that the extent of these disparities remains largely unknown and prompts further research to improve health equity.

Emerging Immunotherapies in the Treatment of Brain Metastases.

Brain metastases account for considerable morbidity and mortality in patients with cancer. Despite increasing prevalence, limited therapeutic options exist. Recent advances in our understanding of the molecular and cellular underpinnings of the tumor immune microenvironment and the immune evasive mechanisms employed by tumor cells have shed light on how immunotherapies may provide therapeutic benefit to patients. The development and evolution of immunotherapy continue to show promise for the treatment of brain metastases. Positive outcomes have been observed in several studies evaluating the efficacy and safety of these treatments. However, many challenges persist in the application of immunotherapies to brain metastases. This review discusses the potential benefits and challenges in the development and use of checkpoint inhibitors, chimeric antigen receptor T-cell therapy, and oncolytic viruses for the treatment of brain metastases. Future studies are necessary to further evaluate and assess the potential use of each of these therapies in this setting. As we gain more knowledge regarding the role immunotherapies may play in the treatment of brain metastases, it is important to consider how these treatments may guide clinical decision making for clinicians and the impact they may have on patients. IMPLICATIONS FOR PRACTICE: Immunotherapies have produced clinically significant outcomes in early clinical trials evaluating patients with brain metastases or demonstrated promising results in preclinical models. Checkpoint inhibitors have been the most common immunotherapy studied to date in the setting of brain metastases, but novel approaches that can harness the immune system to contain and eliminate cancer cells are currently under investigation and may soon become more common in the clinical setting. An understanding of these evolving therapies may be useful in determining how the future management and treatment of brain metastases among patients with cancer will continue to advance.

HIF1A signaling selectively supports proliferation of breast cancer in the brain.

Blood-borne metastasis to the brain is a major complication of breast cancer, but cellular pathways that enable cancer cells to selectively grow in the brain microenvironment are poorly understood. We find that cultured circulating tumor cells (CTCs), derived from blood samples of women with advanced breast cancer and directly inoculated into the mouse frontal lobe, exhibit striking differences in proliferative potential in the brain. Derivative cell lines generated by serial intracranial injections acquire selectively increased proliferative competency in the brain, with reduced orthotopic tumor growth. Increased Hypoxia Inducible Factor 1A (HIF1A)-associated signaling correlates with enhanced proliferation in the brain, and shRNA-mediated suppression of HIF1A or drug inhibition of HIF-associated glycolytic pathways selectively impairs brain tumor growth while minimally impacting mammary tumor growth. In clinical specimens, brain metastases have elevated HIF1A protein expression, compared with matched primary breast tumors, and in patients with brain metastases, hypoxic signaling within CTCs predicts decreased overall survival. The selective activation of hypoxic signaling by metastatic breast cancer in the brain may have therapeutic implications.

Trends in Race/Ethnicity Among Applicants and Matriculants to US Surgical Specialties, 2010-2018.

Importance: Surgical programs across the US continue to promote and invest in initiatives aimed at improving racial/ethnic diversity, but whether this translates to changes in the percentage of applicants or matriculants from racial/ethnic minority groups remains unclear. Objective: To examine trends in the percentage of applicants and matriculants to US surgical specialties who identified as part of a racial/ethnic group underrepresented in medicine from the 2010-2011 to 2018-2019 academic years. Design, Setting, and Participants: This cross-sectional study examined trends in self-reported racial/ethnic identity among applicants and matriculants to US residency programs to evaluate demographic changes among surgical programs from 2010 to 2018. Data were obtained from the Association of American Medical Colleges. Results: The study population consisted of a total of 737 034 applicants and 265 365 matriculants to US residency programs, including 134 158 applicants and 41 347 matriculants to surgical programs. A total of 21 369 applicants (15.9%) and 5704 matriculants (13.8%) to surgical specialties identified as underrepresented in medicine. There was no statistically significant difference in the percentage of applicants underrepresented in medicine based on race/ethnicity for all surgical specialties combined in 2010 vs 2018 (15.3% [95% CI, 14.7%-15.9%] vs 17.5% [95% CI, 16.9%-18.1%]; P = .63). Thoracic surgery was the only surgical specialty in which there was a statistically significant change in the percentage of applicants (8.1% [95% CI, 4.9%-13.2%] vs 14.6% [95% CI, 10.2%-20.4%]; P = .02) or matriculants (0% [95% CI, 0%-19.4%] vs 10.0% [95% CI, 4.0%-23.1%]; P = .01) underrepresented in medicine based on race/ethnicity. Obstetrics and gynecology had the highest mean percentage of applicants (20.2%; 95% CI, 19.4%-20.8%) and matriculants (19.0%; 95% CI, 18.2%-19.8%) underrepresented in medicine among surgical specialties. Thoracic surgery had the lowest mean percentage of applicants (12.5%; 95% CI, 9.46%-15.4%) and otolaryngology the lowest mean percentage of matriculants (8.5%; 95% CI, 7.2%-9.9%) underrepresented in medicine. Conclusions and Relevance: In this cross-sectional study, overall US surgical programs had no change in the percentage of applicants or matriculants who self-identified as underrepresented in medicine based on race/ethnicity, but the proportion remained higher than in nonsurgical specialties. Reevaluation of current strategies aimed at increasing racial/ethnic representation appear to be necessary to help close the existing gap in medicine and recruit a more racially/ethnically diverse surgical workforce.

Changing How Race Is Portrayed in Medical Education: Recommendations From Medical Students.

The medical community has been complicit in legitimizing claims of racial difference throughout the history of the United States. Unfortunately, a rigorous examination of the role medicine plays in perpetuating inequity across racial lines is often missing in medical school curricula due to time constraints and other challenges inherent to medical education. The imprecise use of race-a social construct-as a proxy for pathology in medical education is a vestige of institutionalized racism. Recent examples are presented that illustrate how attributing outcomes to race may contribute to bias and unequal care. This paper proposes the following recommendations for guiding efforts to mitigate the adverse effects associated with the use of race in medical education: emphasize the need for incoming students to be familiar with how race can influence health outcomes; provide opportunities to hold open conversations about race in medicine among medical school faculty, students, and staff; craft and implement protocols that address and correct the inappropriate use of race in medical school classes and course materials; and encourage a large cultural shift within the field of medicine. Adoption of an interdisciplinary approach that taps into many fields, including ethics, history, sociology, evolutionary genetics, and public health is a necessary step for cultivating more thoughtful physicians who will be better prepared to care for patients of all racial and ethnic backgrounds.