A Review of the Molecular Determinants of Therapeutic Response in Non-Small Cell Lung Cancer Brain Metastases.

Lung cancer is a leading cause of cancer-related morbidity and mortality worldwide. Metastases in the brain are a common hallmark of advanced stages of the disease, contributing to a dismal prognosis. Lung cancer can be broadly classified as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). NSCLC represents the most predominant histology subtype of lung cancer, accounting for the majority of lung cancer cases. Recent advances in molecular genetics, coupled with innovations in small molecule drug discovery strategies, have facilitated both the molecular classification and precision targeting of NSCLC based on oncogenic driver mutations. Furthermore, these precision-based strategies have demonstrable efficacy across the blood-brain barrier, leading to positive outcomes in patients with brain metastases. This review provides an overview of the clinical features of lung cancer brain metastases, as well as the molecular mechanisms that drive NSCLC oncogenesis. We also explore how precision medicine-based strategies can be leveraged to improve NSCLC brain metastases.

Flexible Learning in Nursing in the Philippines as a Response to the Restrictions of the COVID-19 Pandemic: An Educational Case Report.

The COVID-19 pandemic, coupled with societal and technological changes around the globe, demanded adaptations to nursing education. This educational case report is an idiographic narrative of an institution's experience of shifting to flexible learning in nursing education in the Philippines during the COVID-19 pandemic. Various subjects, involving foundation, intervention, and intensive nursing courses, were implemented in flexible learning modes during the Academic Year 2020 to 2021. This case report identified how curricular integration and curricular redesign were carried out to ensure the achievement of BSN Program Outcomes. Faculty development on flexible learning was implemented with training outcomes to include the application of key concepts and instructional design principles toward flexible learning. Training outcomes were evaluated through embedded activities on course package development by the faculty participants. This case report also identified various teaching-learning strategies, and how they addressed emerging issues, including differences in technological competence and accessibility. The report highlighted how the college transitioned to flexible learning through curriculum integration and course redesign which has been effective and efficient in the achievement of educational outcomes. Appropriate training and guidance of the faculty to enable them to integrate and redesign courses, and address emerging issues and challenges, could help in the transition to flexible learning. Flexible learning is an effective pedagogical approach to implementing nursing education. Timely implementation of measures must be taken to ensure relevant and appropriate curricular integration and redesign of courses, and consequently, the nursing program.

Status of Interprofessional Education (IPE) Implementation in Asian Nursing Schools.

Background and Objective: Interprofessional Education (IPE) is a necessary step in preparing a collaborative practice-ready health workforce that is better prepared to respond to local and global health needs. This study examined the status of IPE implementation in Asian nursing schools in the World Health Organization (WHO) Western Pacific Region (WPR). Methods: Descriptive online survey research design was utilized, supplemented by online interviews. Purposive sampling was done wherein nursing schools, colleges, and universities were invited to nominate a representative to serve as respondent in this study. Descriptive approach was used to analyze both quantitative and qualitative data. Results: A total of 29 Asian nursing schools participated in the survey. Majority (82.76%) of them stated that they have an IPE program or a similar activity. Interviews with the respondents revealed that not all IPE opportunities were part of a formal IPE program, but were embedded in the different learning activities of nursing students. A clear program focus served as one of the facilitators of IPE implementation. Identified barriers included insufficient administrative support and lack of trained faculty to implement IPE and related activities. Conclusions: IPE is present in most Asian nursing schools in WPR. They may not exactly be called or recognized as IPE, but there is the existence of programs and activities that bring together health and non-health science students to learn from, about, and with each other to enable effective collaboration and improve health outcomes. It is recommended that massive formal training should be conducted so that educational institutions and their faculty will be equipped in developing more formal programs, facilitate activities, and monitor implementation and progress.

Characterization of cellulose nanocrystals from Zhombwe (Neorautanenia brachypus (harms) CA Sm.) bagasse.

Increased awareness of environmental pollution has changed focus to the use of biodegradable materials because they lack persistence in the environment. This article focused on the production of cellulose nanocrystals from Zhombwe, Neorautanenia brachypus (Harms) CA Sm. bagasse using steam explosion, alkaline treatment, bleaching, purification, and acid hydrolysis. The chemical composition after the treatments was determined using TAPPI standards. Further characterization was done using x-ray Diffraction (XRD), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and thermogravimetric analysis (TGA). The nanoscale dimensions and morphology of the extracted nanocrystals was determined through field emission scanning electron microscopy (FE-SEM). FTIR spectroscopy and DSC confirmed the removal of noncellulosic compounds. XRD revealed that N. brachypus bagasse contained cellulose type I, which partly endured morphological change to polymorph II after purification and hydrolysis. FE-SEM revealed elliptical to rod-shaped structures after acid hydrolysis, which had a mean length and width of 1103 nm and 597 nm respectively. TAPPI tests revealed that successive chemical treatments increased crystallinity by 29.7%, enriched cellulose content by 74.2%, reduced lignin content by 21.7%, and reduced hemicellulose to less than 1%. The semicrystalline nature of the material produced in our work is a promising candidate for swelling hydrogel applications in areas such as wound dressing, heavy metal removal, controlled drug delivery, agriculture, and sanitary products. Future studies may focus on surface modification of nanocrystals to improve their thermal stability and therefore expand their range for potential industrial applications.

The Role of Mesenchymal Reprogramming in Malignant Clonal Evolution and Intra-Tumoral Heterogeneity in Glioblastoma.

Glioblastoma (GBM) is the most common yet uniformly fatal adult brain cancer. Intra-tumoral molecular and cellular heterogeneities are major contributory factors to therapeutic refractoriness and futility in GBM. Molecular heterogeneity is represented through molecular subtype clusters whereby the proneural (PN) subtype is associated with significantly increased long-term survival compared to the highly resistant mesenchymal (MES) subtype. Furthermore, it is universally recognized that a small subset of GBM cells known as GBM stem cells (GSCs) serve as reservoirs for tumor recurrence and progression. The clonal evolution of GSC molecular subtypes in response to therapy drives intra-tumoral heterogeneity and remains a critical determinant of GBM outcomes. In particular, the intra-tumoral MES reprogramming of GSCs using current GBM therapies has emerged as a leading hypothesis for therapeutic refractoriness. Preventing the intra-tumoral divergent evolution of GBM toward the MES subtype via new treatments would dramatically improve long-term survival for GBM patients and have a significant impact on GBM outcomes. In this review, we examine the challenges of the role of MES reprogramming in the malignant clonal evolution of glioblastoma and provide future perspectives for addressing the unmet therapeutic need to overcome resistance in GBM.

Job demands-resources theory: Frequently asked questions.

Job demands-resources (JD-R) theory is commonly used to predict employee well-being, work behaviors, and performance. This article provides a short description of JD-R theory and discusses issues and questions that have been raised regarding the theory. These issues include the differences between conservation of resources theory and JD-R theory, whether a job resource can be a job demand, the impact of job resources on strain and health, the role of hindrance and challenge job demands in JD-R theory, the relationship between job demands and resources, and the likelihood of work engagement being a redundant concept. We also discuss whether JD-R theory can be falsified, the role of personality in the theory, within- and between-person effects in JD-R theory, the question whether there is a standard JD-R questionnaire, and the existence of loss and gain spirals. Finally, we discuss the use of JD-R theory in domains other than work and answer the question whether JD-R theory is universally applicable. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma.

Immunosuppressive macrophages restrict anti-cancer immunity in glioblastoma (GBM). Here, we studied the contribution of microglia (MGs) and monocyte-derived macrophages (MDMs) to immunosuppression and mechanisms underlying their regulatory function. MDMs outnumbered MGs at late tumor stages and suppressed T cell activity. Molecular and functional analysis identified a population of glycolytic MDM expressing GLUT1 with potent immunosuppressive activity. GBM-derived factors promoted high glycolysis, lactate, and interleukin-10 (IL-10) production in MDMs. Inhibition of glycolysis or lactate production in MDMs impaired IL-10 expression and T cell suppression. Mechanistically, intracellular lactate-driven histone lactylation promoted IL-10 expression, which was required to suppress T cell activity. GLUT1 expression on MDMs was induced downstream of tumor-derived factors that activated the PERK-ATF4 axis. PERK deletion in MDM abrogated histone lactylation, led to the accumulation of intratumoral T cells and tumor growth delay, and, in combination with immunotherapy, blocked GBM progression. Thus, PERK-driven glucose metabolism promotes MDM immunosuppressive activity via histone lactylation.

[Curriculum "Tracheostomy management in dysphagia therapy"]. / Curriculum "Trachealkanülenmanagement in der Dysphagietherapie".

The number of tracheotomized patients with dysphagia and their need for treatment are continuously increasing in clinical and community settings. The revised version of the directive on home care and community-based intensive care of the Federal Joint Committee (G-BA) requires that tracheotomized patients are regularly evaluated with the aim of identifying and promoting the therapeutic potential after hospital discharge. Dysphagia treatment plays a crucial role as without improvement of severe dysphagia there is practically no possibility for decannulation. Tracheotomized patients with dysphagia are treated by speech and language therapists (SLT); however, the contents of tracheostomy management (TM) are not obligatory in the speech and language therapeutic training curricula, so that there is a need for further education and treatment standards must be secured. Therefore, the German Interdisciplinary Society for Dysphagia (DGD) in cooperation with the participating German medical and therapeutic societies developed a postgraduate curriculum for TM. This should serve as the basis for contents in TM and qualification of therapists within the framework of the delegation of medical services. The goals of the TM curriculum are the definition of theoretical and practical contents of TM, the qualification to perform TM according to current standards of care and quality assurance. The curriculum defines two qualification levels (user and trainer), entry requirements, curricular contents, examination and qualification criteria as well as transitional regulations for SLTs already experienced in TM.

Sustained type I interferon signaling after human immunodeficiency virus type 1 infection of human iPSC derived microglia and cerebral organoids.

Human immunodeficiency virus type-1 (HIV-1)-associated neurocognitive disorder (HAND) affects up to half of people living with HIV-1 and causes long term neurological consequences. The pathophysiology of HIV-1-induced glial and neuronal functional deficits in humans remains enigmatic. To bridge this gap, we established a model simulating HIV-1 infection in the central nervous system using human induced pluripotent stem cell (iPSC)-derived microglia combined with sliced neocortical organoids. Incubation of microglia with two replication-competent macrophage-tropic HIV-1 strains (JRFL and YU2) elicited productive infection and inflammatory activation. RNA sequencing revealed significant and sustained activation of type I interferon signaling pathways. Incorporating microglia into sliced neocortical organoids extended the effects of aberrant type I interferon signaling in a human neural context. Collectively, our results illuminate a role for persistent type I interferon signaling in HIV-1-infected microglia in a human neural model, suggesting its potential significance in the pathogenesis of HAND.

[Curriculum "Tracheostomy management in dysphagia therapy"]. / Curriculum "Trachealkanülenmanagement in der Dysphagietherapie".

The number of tracheotomized patients with dysphagia and their need for treatment are continuously increasing in clinical and community settings. The revised version of the directive on home care and community-based intensive care of the Federal Joint Committee (G-BA) requires that tracheotomized patients are regularly evaluated with the aim of identifying and promoting the therapeutic potential after hospital discharge. Dysphagia treatment plays a crucial role as without improvement of severe dysphagia there is practically no possibility for decannulation. Tracheotomized patients with dysphagia are treated by speech and language therapists (SLT); however, the contents of tracheostomy management (TM) are not obligatory in the speech and language therapeutic training curricula, so that there is a need for further education and treatment standards must be secured. Therefore, the German Interdisciplinary Society for Dysphagia (DGD) in cooperation with the participating German medical and therapeutic societies developed a postgraduate curriculum for TM. This should serve as the basis for contents in TM and qualification of therapists within the framework of the delegation of medical services. The goals of the TM curriculum are the definition of theoretical and practical contents of TM, the qualification to perform TM according to current standards of care and quality assurance. The curriculum defines two qualification levels (user and trainer), entry requirements, curricular contents, examination and qualification criteria as well as transitional regulations for SLTs already experienced in TM.

Status of Interprofessional Education (IPE) implementation in Asian Nursing Schools

@#<strong>BACKGROUND AND OBJECTIVE</strong><p style="text-align: justify;" data-mce-style="text-align: justify;">Interprofessional Education (IPE) is a necessary step in preparing a collaborative practice- ready health workforce that is better prepared to respond to local and global health needs. This study examined the status of IPE implementation in Asian nursing schools in the World Health Organization (WHO) Western Pacific Region (WPR).</p><strong>METHODS</strong><p style="text-align: justify;" data-mce-style="text-align: justify;">Descriptive online survey research design was utilized, supplemented by online interviews. Purposive sampling was done wherein nursing schools, colleges, and universities were invited to nominate a representative to serve as respondent in this study. Descriptive approach was used to analyze both quantitative and qualitative data.</p><strong>RESULTS</strong><p style="text-align: justify;" data-mce-style="text-align: justify;">A total of 29 Asian nursing schools participated in the survey. Majority (82.76%) of them stated that they have an IPE program or a similar activity. Interviews with the respondents revealed that not all IPE opportunities were part of a formal IPE program, but were embedded in the different learning activities of nursing students. A clear program focus served as one of the facilitators of IPE implementation. Identified barriers included insufficient administrative support and lack of trained faculty to implement IPE and related activities.</p><strong>CONCLUSION</strong><p style="text-align: justify;" data-mce-style="text-align: justify;">IPE is present in most Asian nursing schools in WPR. They may not exactly be called or recognized as IPE, but there is the existence of programs and activities that bring together health and non-health science students to learn from, about, and with each other to enable effective collaboration and improve health outcomes. It is recommended that massive formal training should be conducted so that educational institutions and their faculty will be equipped in developing more formal programs, facilitate activities, and monitor implementation and progress.</p>

Flexible learning in nursing in the Philippines as a response to the restrictions of the COVID-19 pandemic: An educational case report

@#<p style="text-align: justify;" data-mce-style="text-align: justify;">The COVID-19 pandemic, coupled with societal and technological changes around the globe, demanded adaptations to nursing education. This educational case report is an idiographic narrative of an institution’s experience of shifting to flexible learning in nursing education in the Philippines during the COVID-19 pandemic. Various subjects, involving foundation, intervention, and intensive nursing courses, were implemented in flexible learning modes during the Academic Year 2020 to 2021. This case report identified how curricular integration and curricular redesign were carried out to ensure the achievement of BSN Program Outcomes. Faculty development on flexible learning was implemented with training outcomes to include the application of key concepts and instructional design principles toward flexible learning. Training outcomes were evaluated through embedded activities on course package development by the faculty participants. This case report also identified various teaching-learning strategies, and how they addressed emerging issues, including differences in technological competence and accessibility. The report highlighted how the college transitioned to flexible learning through curriculum integration and course redesign which has been effective and efficient in the achievement of educational outcomes. Appropriate training and guidance of the faculty to enable them to integrate and redesign courses, and address emerging issues and challenges, could help in the transition to flexible learning. Flexible learning is an effective pedagogical approach to implementing nursing education. Timely implementation of measures must be taken to ensure relevant and appropriate curricular integration and redesign of courses, and consequently, the nursing program.<br></p>

Daily interpersonal conflicts and daily negative and positive affect: exploring the moderating role of neuroticism.

BACKGROUND AND OBJECTIVES: Drawing on affective events theory, the present study investigates relationships between daily interpersonal conflicts and negative and positive affective reactions, and tested whether trait neuroticism moderates immediate (same day) and persisting (next-day) affective reactions. DESIGN AND METHODS: A sample of 53 Norwegian naval cadets completed a diary questionnaire for 30 consecutive days (total N = 1590). RESULTS: As predicted, the findings showed that cadets reported more negative affect (but not less positive affect) on days they were confronted with affective events that were of a conflicting nature. In addition, the proposed interaction effects between daily conflict and neuroticism were significant for both negative and positive affect. Specifically, the immediate and persistent effects of daily conflicts on negative affect were strongest for individuals high (vs. low) in neuroticism. Moreover, individuals high in neuroticism reported less positive affect on days with conflicts, whereas individuals low in neuroticism reported more positive affect the two days following interpersonal conflicts. CONCLUSIONS: The findings contribute to affective events theory with important knowledge about the role of trait neuroticism in dealing with interpersonal conflicts in a natural work setting.

La Teoría de las Demandas y Recursos Laborales: Nuevos Desarrollos en la Última Década / [Job Demands-Resources theory: New developments over the last decade]

Este artículo realiza una descripción general de la teoría de las demandas y recursos laborales (DRL). Se describen los supuestos básicos y se destacan los nuevos hallazgos empíricos e innovaciones teóricas en relación con la teoría. Se analizan cuatro innovaciones principales de la última década, a saber: (a) el enfoque persona × situación de la DRL, (b) la teoría DRL multinivel, (c) nuevos enfoques proactivos en dicha teoría y (d) el modelo de recursos trabajo-hogar. Después de examinar las implicaciones prácticas, se profundiza en las posibles investigaciones futuras que incluyan intervenciones desde la teoría DRL, enfoques de equipo y demandas y recursos de otros ámbitos de la vida.(AU)

This article gives an overview of Job Demands-Resources (JD-R) theory. We outline the basic propositions and highlight new empirical findings and theoretical innovations in relation to the theory. We discuss four major innovations of the past decade, namely (a) the person × situation approach of JD-R, (b) multilevel JD-R theory, (c) new proactive approaches in JD-R theory, and (d) the Work-Home Resources model. After discussing practical implications, we elaborate on opportunities for future research, including JD-R interventions, team-level approaches, and demands and resources from other life domains.(AU)

Dysregulated neuroimmune interactions and sustained type I interferon signaling after human immunodeficiency virus type 1 infection of human iPSC derived microglia and cerebral organoids.

Human immunodeficiency virus type-1 (HIV-1) associated neurocognitive disorder (HAND) affects up to half of HIV-1 positive patients with long term neurological consequences, including dementia. There are no effective therapeutics for HAND because the pathophysiology of HIV-1 induced glial and neuronal functional deficits in humans remains enigmatic. To bridge this knowledge gap, we established a model simulating HIV-1 infection in the central nervous system using human induced pluripotent stem cell (iPSC) derived microglia combined with sliced neocortical organoids. Upon incubation with two replication-competent macrophage-tropic HIV-1 strains (JRFL and YU2), we observed that microglia not only became productively infected but also exhibited inflammatory activation. RNA sequencing revealed a significant and sustained activation of type I interferon signaling pathways. Incorporating microglia into sliced neocortical organoids extended the effects of aberrant type I interferon signaling in a human neural context. Collectively, our results illuminate the role of persistent type I interferon signaling in HIV-1 infected microglial in a human neural model, suggesting its potential significance in the pathogenesis of HAND.

Development of a "Geo-Tagged" tumor sample registry: intra-operative linkage of sample location to imaging.

PURPOSE: There is a growing body of literature documenting glioma heterogeneity in terms of radiographic, histologic, molecular, and genetic characteristics. Incomplete spatial specification of intraoperative tumor samples may contribute to variability in the results of pathological and biological investigations. We have developed a system, termed geo-tagging, for routine intraoperative linkage of each tumor sample to its location via neuronavigation. METHODS: This is a single-institution, IRB approved, prospective database of undergoing clinically indicated surgery. We evaluated relevant factors affecting data collection by this registry, including tumor and surgical factors (e.g. tumor volume, location, grade and surgeon). RESULTS: Over a 2-year period, 487 patients underwent craniotomy for an intra-axial tumor. Of those, 214 underwent surgery for a newly diagnosed or recurrent glioma. There was significant variation in the average number of samples collected per registered case, with a range of samples from 2.53 to 4.75 per tumor type. Histology and grade impacted on sampling with a range of 2.0 samples per tumor in Grade four, IDH-WT gliomas to 4.5 samples in grade four, IDH-mutant gliomas. The range of cases with sampling per surgeon was 6 to 99 with a mean of 47.6 cases and there was a statistically significant differences between surgeons. Tumor grade did not have a statistically significant impact on number of samples per case. No significant correlation was found between the number of samples collected and enhancing tumor volume, EOR, or volume of tumor resected. CONCLUSION: We are using the results of this analysis to develop a prospective sample collection protocol.

Epigenetic Activation of TUSC3 Sensitizes Glioblastoma to Temozolomide Independent of MGMT Promoter Methylation Status.

Temozolomide (TMZ) is an important first-line treatment for glioblastoma (GBM), but there are limitations to TMZ response in terms of durability and dependence on the promoter methylation status of the DNA repair gene O6-methylguanine DNA methyltransferase (MGMT). MGMT-promoter-hypermethylated (MGMT-M) GBMs are more sensitive to TMZ than MGMT-promoter-hypomethylated (MGMT-UM) GBMs. Moreover, TMZ resistance is inevitable even in TMZ-sensitive MGMT-M GBMs. Hence, epigenetic reprogramming strategies are desperately needed in order to enhance TMZ response in both MGMT-M and MGMT-UM GBMs. In this study, we present novel evidence that the epigenetic reactivation of Tumor Suppressor Candidate 3 (TUSC3) can reprogram sensitivity of GBM stem cells (GSCs) to TMZ irrespective of MGMT promoter methylation status. Interrogation of TCGA patient GBM datasets confirmed TUSC3 promoter regulation of TUSC3 expression and also revealed a strong positive correlation between TUSC3 expression and GBM patient survival. Using a combination of loss-of-function, gain-of-function and rescue studies, we demonstrate that TUSC3 reactivation is associated with enhanced TMZ response in both MGMT-M and MGMT-UM GSCs. Further, we provide novel evidence that the demethylating agent 5-Azacitidine (5-Aza) reactivates TUSC3 expression in MGMT-M GSCs, whereas the combination of 5-Aza and MGMT inhibitor Lomeguatrib is necessary for TUSC3 reactivation in MGMT-UM GSCs. Lastly, we propose a pharmacological epigenetic reactivation strategy involving TUSC3 that leads to significantly prolonged survival in MGMT-M and MGMT-UM orthotopic GSCs models. Collectively, our findings provide a framework and rationale to further explore TUSC3-mediated epigenetic reprogramming strategies that could enhance TMZ sensitivity and outcomes in GBM. Mechanistic and translational evidence gained from such studies could contribute towards optimal design of impactful trials for MGMT-UM GBMs that currently do not have good treatment options.

Care Needs of Parents of Children With Cancer in a Low-Middle-Income Country.

Background: Mapping out actual supportive care needs assists nurses in providing holistic individualized care. This study aimed to explore the care needs of parents of children with cancer in the Philippines. Method: Guided by the Supportive Care Needs Framework (SCNF), this study used an embedded mixed-method design with the quantitative revised Cancer Patient Needs Questionnaire and qualitative semistructured interviews to describe parents' care needs and priorities. Results: Filipino parents (N = 156) of children with cancer have various care needs which could be classified along the SCNF categories-practical, informational, spiritual, physical, emotional, and physical needs as ranked from highest to lowest. A number of variables were significantly associated with care needs. Solid tumor diagnosis was associated with greater practical, emotional, and psychosocial care needs; having a child who had undergone surgery was associated with more practical and spiritual care needs; and being within one year of the child's diagnosis was associated with practical, psychosocial, and spiritual care needs. Parent priority needs included (a) addressing financial needs; (b) access to temporary housing to minimize treatment-related costs; (c) support groups among parents of children with cancer as a source of information; (d) financial and social support between members of family and partners of parents of children with cancer; and (e) using prayer to facilitate acceptance. Conclusions: Supportive care needs of parents of children with cancer are important components of care that should be given recognition to enhance holistic individualized care throughout the childhood cancer experience.

Characterization of Immune Infiltrates Associated With Radiation Necrosis in the Setting of Brain Metastases Following Stereotactic Radiosurgery and Immunotherapy: A Retrospective Cohort Analysis.

INTRODUCTION: Radiation necrosis (RN) is caused by vascular damage and brain parenchymal injury resulting in inflammation following radiotherapy (RT) for brain metastases. The impact of immunotherapy (IO) on the immune cellular microenvironment in patients' brain metastases is unknown. The objective of this study was to characterize the inflammatory microenvironment in the setting of RN compared to recurrent metastasis and determine whether IO treatment affects the cellular infiltrates. METHODS: Adult patients with brain metastases from solid tumors who received both systemic IO and RT prior to resection of intracranial lesions were retrospectively analyzed. The resection either showed biopsy-proven RN or recurrent tumor. A group of patients who developed RN and were not on IO was reviewed as well. A total of 18 patients were categorized into one of three groups: necrosis, IO+RT; tumor, IO+RT; and necrosis, RT. Surgical specimens were stained for immune and inflammatory components and reviewed by a neuro-pathologist who remained blinded during the analysis. The presence or absence of lymphocytes, perivascular cuffs, plasma cells, macrophages, and fibrinoid vascular changes was characterized in a semiquantitative manner. RESULTS: The median age was 61.5 years (range 37-82 years). Seventy-seven percent of primary cancers were melanoma. Patients with RN were more likely to exhibit immune infiltrates compared to patients with recurrent metastasis. Limited analysis showed 100% of patients in "necrosis, IO+RT" had quantifiable cell counts; conversely, 83.3% of patients in "tumor, IO+RT" lacked quantifiable cell counts. Additionally, 83.3% of patients in "necrosis, RT" showed immune cells, including lymphocytes, macrophages, plasma cells, and cuffing. CONCLUSION: The immune microenvironment of brain metastasis following RT and IO showed higher levels of cell infiltrates in the RN setting versus the recurrent tumor setting. Patients who received prior IO compared to those with no IO had similar immune cell infiltrates adjacent to RN. Lower levels of immune cells in tumor recurrence following IO and RT raise the possibility that an environment lacking primed immune cells may decrease the efficacy of IO.

Stereotactic radiosurgery and anti-PD-1 + CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitors, or conventional chemotherapy for the management of melanoma brain metastases.

BACKGROUND: Immunotherapy and targeted BRAF/MEK inhibitors (i) have revolutionised the systemic management of advanced melanoma. Given the role of stereotactic radiosurgery (SRS) in the local management of brain metastases, we sought to evaluate clinical outcomes in patients with melanoma brain metastases (MBM) treated with SRS and various systemic therapies. METHODS: Patients were included if MBM were diagnosed and treated with SRS within 3 months of receiving anti-PD-1+CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK-i, BRAF-i, or conventional chemotherapy. Comparisons between groups were made for overall survival (OS), distant MBM control, local MBM, systemic progression-free survival (sPFS), and neurotoxicity. RESULTS: In total, 257 patients with 1048 MBM treated over 368 SRS sessions between 2011 and 2020 were identified. On MVA, treatment with anti-PD1+anti-CTLA-4, anti-PD-1, and BRAF/MEK-i improved distant intracranial control over conventional chemotherapy. No significant differences were noted in local control (LC) between groups (p = 0.78). Kaplan-Meier OS at 12 months for anti-PD-1 + CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK-i, BRAF-i, and conventional chemotherapy was 68%, 59%, 45%, 62%, 21%, and 15%, respectively (p = <0.0001). The sPFS rates at 12 months were 57%, 53%, 42%, 45%, 14%, and 6% (p = <0.0001). No significant differences were noted in rates of radiation necrosis (p = 0.93). CONCLUSIONS: This is among the largest series evaluating MBM treated with SRS and various systemic therapy regimens. Our analysis noted significant differences in OS, distant MBM control, and sPFS by systemic therapy. No differences in LC or radiation necrosis risk were noted.