Imipridones inhibit tumor growth and improve survival in an orthotopic liver metastasis mouse model of human uveal melanoma.

BACKGROUND: Uveal melanoma (UM) is a highly aggressive disease with very few treatment options. We previously demonstrated that mUM is characterized by high oxidative phosphorylation (OXPHOS). Here we tested the anti-tumor, signaling and metabolic effects of imipridones, which are CLPP activators, which inhibit OXPHOS indirectly and have demonstrated safety in patients. METHODS: We assessed CLPP expression in UM patient samples. We tested the effects of imipridones (ONC201 and ONC212) on the growth, survival, signaling and metabolism of UM cell lines in vitro, and for therapeutic efficacy in vivo in UM liver metastasis models. RESULTS: CLPP expression was detected in primary and mUM patient samples. ONC201 and 212 decreased OXPHOS effectors, inhibited cell growth and migration, and induced apoptosis in human UM cell lines in vitro. ONC212 inhibited OXPHOS, increased metabolic stress and apoptotic pathways, inhibited amino acid metabolism, and induced cell death-related lipids. ONC212 also decreased tumor burden and increased survival in vivo in two UM liver metastasis models. CONCLUSIONS: Imipridones are a promising strategy for further testing and development in mUM.

Getting to effective housing policy for health: a thematic synthesis of policy development and implementation.

Impacts of housing on health are well-recognised. Despite this, housing standards have been neglected and there are gaps in healthy housing policies, particularly in low and middle-income countries. Given the recent publication of the WHO Housing and health guidelines, and the need to implement these into policy at all scales, we carried out a focused search and thematic synthesis of available literature on the barriers and enablers to recent housing and health policy. We aimed to generate lessons of what works to support healthy housing policy development and implementation elsewhere. Twenty-three studies representing four countries were eligible for inclusion and covered housing-related risks of air quality, lead, accessible design, and housing conditions. Findings demonstrated that policy development and implementation were facilitated through awareness of housing and health, evidence of existing housing conditions and health impacts, collaborations across sectors and between residents and decision-makers and effective enforcement systems that employed incentives, tools such as certificates for compliance, and housing inspections. Concerns about economic viability and tensions between housing rights and responsibilities limited healthy housing policy for the 'common good'. Despite limitations in the diversity of available evidence, this thematic synthesis provides a starting point for healthy and equitable housing for all.

Mapping of oxidative modifications on the alpha-keto glutarate dehydrogenase complex induced by singlet oxygen: Effects on structure and activity.

The large multi-subunit mitochondrial alpha-keto glutarate dehydrogenase (KGDH) complex plays a key, rate-determining, role in the tricarboxylic acid (Krebs) cycle, catalyzing the conversion of alpha-keto glutarate to succinyl-CoA. This complex is both a source and target of oxidants, but the sites of modification and association with structural changes and activity loss are poorly understood. We report here oxidative modifications induced by Rose Bengal (RB) in the presence of O2, a source of singlet oxygen (1O2). A rapid loss of activity was detected, with this being dependent on light exposure, illumination time, and the presence of RB and O2. Activity loss was enhanced by D2O (consistent with 1O2 involvement), but diminished by both pre- and (to a lesser extent) post-illumination addition of lipoic acid and lipoamide. Aggregates containing all three KGDH subunits were detected on photooxidation. LC-MS experiments provided evidence for oxidation at 45 sites, including specific Met, His, Trp, Tyr residues and the lipoyllysine active-site cofactor. Products include mono- and di-oxygenated species, and kynurenine from Trp. Mapping of the modifications to the 3-D structure showed that these are localized to both the inner channel and the external surface, consistent with reactions of free 1O2, however the sites and extent of modification do not correlate with their solvent accessibility. These products are generated concurrently with loss of activity, indicative of strong links between these events. These data provide evidence for the impairment of KGDH activity by 1O2 via the oxidation of specific residues on the protein subunits of the complex.

Virulence of Burkholderia pseudomallei ATS2021 Unintentionally Imported to United States in Aromatherapy Spray.

In the United States in 2021, an outbreak of 4 cases of Burkholderia pseudomallei, the etiologic agent of melioidosis and a Tier One Select Agent (potential for deliberate misuse and subsequent harm), resulted in 2 deaths. The causative strain, B. pseudomallei ATS2021, was unintentionally imported into the United States in an aromatherapy spray manufactured in India. We established that ATS2021 represents a virulent strain of B. pseudomallei capable of robust formation of biofilm at physiologic temperatures that may contribute to virulence. By using mouse melioidosis models, we determined median lethal dose estimates and analyzed the bacteriologic and histopathologic characteristics of the organism, particularly the potential neurologic pathogenesis that is probably associated with the bimABm allele identified in B. pseudomallei strain ATS2021. Our data, combined with previous case reports and the identification of endemic B. pseudomallei strains in Mississippi, support the concept that melioidosis is emerging in the United States.

Concurrent use of hormonal long-acting reversible contraception by women of reproductive age dispensed teratogenic medications, Australia, 2013-2021: a retrospective cohort study.

OBJECTIVES: To examine patterns in the dispensing of category X medications (Therapeutic Goods Administration categorisation system for prescribing medicines in pregnancy) to women aged 15-49 years in Australia during 2008-2021, and patterns of concurrent use of hormonal long-acting reversible contraception (LARC) and other hormonal contraception. STUDY DESIGN: Retrospective cohort study; analysis of 10% random sample of national Pharmaceutical Benefits Scheme dispensing data. PARTICIPANTS, SETTING: Women aged 15-49 years dispensed category X medications, Australia, 1 January 2013 - 31 December 2021. MAIN OUTCOME MEASURES: Incident and prevalent dispensing of category X medications, by medication class, age group, and year; contraceptive overlap (proportions of women dispensed hormonal LARC or other hormonal contraception that overlapped the first dispensing of category X medications), by medication class. RESULTS: Among 15 627 women aged 15-49 years dispensed category X medications during 2013-2021, the prevalence of dispensing increased from 4.6 in 2013 to 8.7 per 1000 women aged 15-49 years in 2021; the largest increase was for the dispensing of dermatological agents, from 3.9 to 7.9 per 1000 women aged 15-49 years. LARC overlap was inferred for 2059 women at the time of first dispensing of category X medications (13.2%); 3441 had been dispensed any type of hormonal contraception (22.1%). The proportion with LARC overlap was smallest for those dispensed dermatological agents (1806 of 14 331 women, 12.6%); for this drug class, both LARC overlap (adjusted odds ratio [aOR], 0.17; 95% confidence interval [CI], 0.14-0.20) and any hormonal contraception overlap (aOR, 0.28; 95% CI, 0.25-0.32) were less likely for those aged 15-19 years than for women aged 25-29 years. CONCLUSIONS: Concurrent use of highly effective hormonal contraception at the time of first dispensing of category X medications is low in Australia, raising concerns about potential fetal harms during unintended pregnancies. Awareness of the importance of hormonal contraception and its uptake by women prescribed category X medications should be increased.

A protein expression atlas on tissue samples and cell lines from cancer patients provides insights into tumor heterogeneity and dependencies.

The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE) are foundational resources in cancer research, providing extensive molecular and phenotypic data. However, large-scale proteomic data across various cancer types for these cohorts remain limited. Here, we expand upon our previous work to generate high-quality protein expression data for approximately 8,000 TCGA patient samples and around 900 CCLE cell line samples, covering 447 clinically relevant proteins, using reverse-phase protein arrays. These protein expression profiles offer profound insights into intertumor heterogeneity and cancer dependency and serve as sensitive functional readouts for somatic alterations. We develop a systematic protein-centered strategy for identifying synthetic lethality pairs and experimentally validate an interaction between protein kinase A subunit α and epidermal growth factor receptor. We also identify metastasis-related protein markers with clinical relevance. This dataset represents a valuable resource for advancing our understanding of cancer mechanisms, discovering protein biomarkers and developing innovative therapeutic strategies.

Effects of Sotagliflozin on Health Status in Patients With Worsening Heart Failure: Results From SOLOIST-WHF.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve health status in heart failure (HF) across the left ejection fraction ejection spectrum. However, the effects of SGLT1 and SGLT2 inhibition on health status are unknown. OBJECTIVES: These prespecified analyses of the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure) trial examined the effects of sotagliflozin vs placebo on HF-related health status. METHODS: SOLOIST-WHF randomized patients hospitalized or recently discharged after a worsening HF episode to receive sotagliflozin or placebo. The primary endpoint was total number of HF hospitalizations, urgent HF visits, and cardiovascular death. Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) score was a prespecified secondary endpoint. This analysis evaluated change in the KCCQ-12 score from baseline to month 4. RESULTS: Of 1,222 patients randomized, 1,113 (91%) had complete KCCQ-12 data at baseline and 4 months. The baseline KCCQ-12 score was low overall (median: 41.7; Q1-Q3: 27.1-58.3) and improved by 4 months in both groups. Sotagliflozin vs placebo reduced the risk of the primary endpoint consistently across KCCQ-12 tertiles (Ptrend = 0.54). Sotagliflozin-treated patients vs those receiving placebo experienced modest improvement in KCCQ-12 at 4 months (adjusted mean change: 4.1 points; 95% CI: 1.3-7.0 points; P = 0.005). KCCQ-12 improvements were consistent across prespecified subgroups, including left ventricular ejection fraction <50% or ≥50%. More patients receiving sotagliflozin vs those receiving placebo had at least small (≥5 points) improvements in KCCQ-12 at 4 months (OR: 1.38; 95% CI: 1.06-1.80; P = 0.017). CONCLUSIONS: Sotagliflozin improved symptoms, physical limitations, and quality of life within 4 months after worsening HF, with consistent benefits across baseline demographic and clinical characteristics. (Effect of Sotagliflozin on Cardiovascular Events in Participants With Type 2 Diabetes Post Worsening Heart Failure [SOLOIST-WHF]; NCT03521934).

Unveiling common transcriptomic features between melanoma brain metastases and neurodegenerative diseases.

Melanoma represents a critical clinical challenge due to its unfavorable outcomes. This type of skin cancer exhibits unique adaptability to the brain microenvironment, but its underlying molecular mechanisms are poorly understood. Recent findings have suggested that melanoma brain metastases (MBM) may share biological processes similar to those found in various neurodegenerative diseases. To further characterize MBM development, we explore the relationship between the transcriptional profiles of MBM and the neurodegenerative diseases Alzheimer's disease, Parkinson's disease, and multiple sclerosis. We take an in silico approach to unveil a neurodegenerative signature of MBM when compared to melanoma non-brain metastasis (53 dysregulated genes enriched in 11 functional terms, such as associated terms to the extracellular matrix and development) and to non tumor-bearing brain controls (195 dysregulated genes, mostly involved in development and cell differentiation, chromatin remodeling and nucleosome organization, and translation). Two genes, ITGA10 and DNAJC6, emerged as key potential markers being dysregulated in both scenarios. Lastly, we developed an open source, user-friendly web tool (https://bioinfo.cipf.es/metafun-mbm/) that allows interactive exploration of the complete results.

Tumour-intrinsic endomembrane trafficking by ARF6 shapes an immunosuppressive microenvironment that drives melanomagenesis and response to checkpoint blockade therapy.

Tumour-host immune interactions lead to complex changes in the tumour microenvironment (TME), impacting progression, metastasis and response to therapy. While it is clear that cancer cells can have the capacity to alter immune landscapes, our understanding of this process is incomplete. Herein we show that endocytic trafficking at the plasma membrane, mediated by the small GTPase ARF6, enables melanoma cells to impose an immunosuppressive TME that accelerates tumour development. This ARF6-dependent TME is vulnerable to immune checkpoint blockade therapy (ICB) but in murine melanoma, loss of Arf6 causes resistance to ICB. Likewise, downregulation of ARF6 in patient tumours correlates with inferior overall survival after ICB. Mechanistically, these phenotypes are at least partially explained by ARF6-dependent recycling, which controls plasma membrane density of the interferon-gamma receptor. Collectively, our findings reveal the importance of endomembrane trafficking in outfitting tumour cells with the ability to shape their immune microenvironment and respond to immunotherapy.

Loss of HD-PTP function results in lipodystrophy, defective cellular signaling and altered lipid homeostasis.

His domain protein tyrosine phosphatase (HD-PTP; also known as PTPN23) facilitates function of the endosomal sorting complexes required for transport (ESCRTs) during multivesicular body (MVB) formation. To uncover its role in physiological homeostasis, embryonic lethality caused by a complete lack of HD-PTP was bypassed through generation of hypomorphic mice expressing reduced protein, resulting in animals that are viable into adulthood. These mice exhibited marked lipodystrophy and decreased receptor-mediated signaling within white adipose tissue (WAT), involving multiple prominent pathways including RAS/MAPK, phosphoinositide 3-kinase (PI3K)/AKT and receptor tyrosine kinases (RTKs), such as EGFR. EGFR signaling was dissected in vitro to assess the nature of defective signaling, revealing decreased trans-autophosphorylation and downstream effector activation, despite normal EGF binding. This corresponds to decreased plasma membrane cholesterol and increased lysosomal cholesterol, likely resulting from defective endosomal maturation necessary for cholesterol trafficking and homeostasis. The ESCRT components Vps4 and Hrs have previously been implicated in cholesterol homeostasis; thus, these findings expand knowledge on which ESCRT subunits are involved in cholesterol homeostasis and highlight a non-canonical role for HD-PTP in signal regulation and adipose tissue homeostasis.

Association of Preoperative Shoulder Osteoarthritis Severity Score With Change in American Shoulder and Elbow Surgeons Score at 2 Years After Rotator Cuff Repair.

Background: The impact of early glenohumeral osteoarthritis (GHOA) on clinical outcomes after rotator cuff repair (RCR) remains unclear. The magnetic resonance imaging (MRI)-based Shoulder Osteoarthritis Severity (SOAS) score is a comprehensive approach to quantifying glenohumeral degeneration. Purpose: To investigate the association between SOAS scores and changes in American Shoulder and Elbow Surgeons (ASES) scores in patients who underwent RCR. Study Design: Cohort study; Level of evidence, 3. Methods: Two reviewers independently analyzed the preoperative MRI scans of 116 shoulders and assigned SOAS scores. Spearman correlation was used to calculate the association of mean SOAS scores with patient demographic characteristics and change in ASES scores over the 2-year follow-up period (ΔASES). Multivariate regression analysis was performed between the independent variables of patient age, sex, body mass index, and significant SOAS score components as determined by univariate analysis, with the dependent variable being ΔASES. Significance was defined as P < .05 for univariate analysis and P < .0125 after application of the Bonferroni correction for multivariate analysis. Results: The mean ASES scores were 55.8 ± 18.6 preoperatively and 92.1 ± 12.1 at 2 years postoperatively. The mean preoperative SOAS score was 15.2 ± 7.1. On univariate analysis, the total SOAS score was positively correlated with patient age (r S = 0.41; P < .001), whereas ΔASES was negatively correlated with patient age (r S = -0.27; P = .0032). Increasing SOAS subscores for supraspinatus/infraspinatus tear size (r S = -0.28; P = .024), tendon retraction (r S = -0.23; P = .015), muscle atrophy (r S = -0.20; P = .034), paralabral ganglia (r S = -0.23; P = .015), and cartilage degeneration (r S = -0.21; P = .024) were negatively correlated with ΔASES. A negative correlation was found between increasing total SOAS score and ΔASES (r S = -0.22; P = .016). On multivariate analysis, increasing supraspinatus/infraspinatus tear size was significantly and negatively correlated with ΔASES (ß = -3.3; P = .010). Conclusion: Increasing the total SOAS score was predictive of less improvement in ASES scores at 2 years postoperatively. On univariate analysis, SOAS subscores with the strongest negative correlations with ΔASES scores included tear size, muscle atrophy, tendon retraction, paralabral ganglia, and cartilage wear. On multivariate analysis, only tear size was significantly associated with a lower change in the ASES score.

On the informative value of community-based indoor radon values in relation to lung cancer.

BACKGROUND: Radon is a radioactive gas and a major risk factor for lung cancer (LC). METHODS: We investigated the dose-response relationship between radon and LC risk in the International Lung Cancer Consortium with 8927 cases and 5562 controls from Europe, North America, and Israel, conducted between 1992 and 2016. Spatial indoor radon exposure in the residential area (sIR) obtained from national surveys was linked to the participants' residential geolocation. Parametric linear and spline functions were fitted within a logistic regression framework. RESULTS: We observed a non-linear spatial-dose response relationship for sIR < 200 Bq/m3. The lowest risk was observed for areas of mean exposure of 58 Bq/m3 (95% CI: 56.1-59.2 Bq/m3). The relative risk of lung cancer increased to the same degree in areas averaging 25 Bq/m3 (OR = 1.31, 95% CI: 1.01-1.59) as in areas with a mean of 100 Bq/m3 (OR = 1.34, 95% CI: 1.20-1.45). The strongest association was observed for small cell lung cancer and the weakest for squamous cell carcinoma. A stronger association was also observed in men, but only at higher exposure levels. The non-linear association is primarily observed among the younger population (age < 69 years), but not in the older population, which can potentially represent different biological radiation responses. CONCLUSIONS: The sIR is useful as proxy of individual radon exposure in epidemiological studies on lung cancer. The usual assumption of a linear, no-threshold dose-response relationship, as can be made for individual radon exposures, may not be optimal for sIR values of less than 200 Bq/m3.

Maternal modifiable factors and risk of congenital heart defects: systematic review and causality assessment.

OBJECTIVE: Primary prevention strategies are critical to reduce the global burden of congenital heart defects (CHDs); this requires robust knowledge of causal agents. We aimed to review associations between CHDs and maternal advanced age, obesity, diabetes, hypertension, smoking and alcohol consumption and assess the causal nature of the associations. DESIGN: Systematic review of reviews with application of a Bradford Hill criteria score-based causal assessment system. DATA SOURCES: We searched PubMed, Embase and Episteminokos (January 1990-April 2023). ELIGIBILITY CRITERIA: Systematic reviews of original epidemiological studies reporting association (relative risk) between one or more of the above maternal factors and CHDs overall (any type) in subsequent offspring. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers selected eligible reviews, assessed the risk of bias and assigned the strength of evidence for causality. RESULTS: There was strong evidence of a causal relationship between CHDs and maternal obesity (prepregnancy and early pregnancy) and pre-existing diabetes (six of seven Bradford Hill criteria met). For pre-existing hypertension (strength and biological gradient not met), and advanced age (strength, consistency and biological gradient not met), causal evidence was moderate. Evidence for the causal contribution of gestational diabetes, gestational hypertension, smoking and alcohol consumption was weak (strength, consistency, temporality and biological gradient not met). CONCLUSIONS: CHDs can be reduced with stronger action to reduce maternal obesity and pre-existing diabetes prevalence. Investigating environmental exposures that have received limited attention, such as air pollutants and chemical exposures, is important to further inform prevention.

Systemic inequalities in heat risk for greater London.

The temperature rise and increases in extreme heat events related to global climate change is a growing public health threat. Populations in temperate climates, including the UK, must urgently adapt to increased hot weather as current infrastructure primarily focusses on resilience to cold. As we adapt, care should be taken to ensure existing health inequalities are reduced. Lessons can be learned from regions that experience warmer climates and applied to adaptation in the UK. We identified known indicators of heat-health risk and explored their distribution across area level income for London. Understanding these indicators and their distributions across populations can support the development of interventions that have the dual aim of improving health and reducing inequalities. An exploratory analysis was conducted for each indicator at neighbourhood level to assess existence of disparities in their distributions across London. A systems-thinking approach was employed to deduce if these amount to systemic inequalities in heat risk, whereby those most exposed to heat are more susceptible and less able to adapt. Using this information, we proposed interventions and made recommendations for their implementation. We find inequalities across indicators relating to exposure, vulnerability, and adaptive capacity. Including inequalities in urban greening and access to greenspace, physical and mental health and access to communication and support. Through a system diagram we demonstrate how these indicators interact and suggest that systemic inequalities in risk exist and will become more evident as exposure increases with rising temperatures, depending on how we adapt. We use this information to identify barriers to the effective implementation of adaptation strategies and make recommendations on the implementation of interventions. This includes effective and wide-reaching communication considering the various channels and accessibility requirements of the population and consideration of all dwelling tenures when implementing policies relating to home improvements in the context of heat.

A Pan-Cancer Patient-Derived Xenograft Histology Image Repository with Genomic and Pathologic Annotations Enables Deep Learning Analysis.

Patient-derived xenografts (PDX) model human intra- and intertumoral heterogeneity in the context of the intact tissue of immunocompromised mice. Histologic imaging via hematoxylin and eosin (H&E) staining is routinely performed on PDX samples, which could be harnessed for computational analysis. Prior studies of large clinical H&E image repositories have shown that deep learning analysis can identify intercellular and morphologic signals correlated with disease phenotype and therapeutic response. In this study, we developed an extensive, pan-cancer repository of >1,000 PDX and paired parental tumor H&E images. These images, curated from the PDX Development and Trial Centers Research Network Consortium, had a range of associated genomic and transcriptomic data, clinical metadata, pathologic assessments of cell composition, and, in several cases, detailed pathologic annotations of neoplastic, stromal, and necrotic regions. The amenability of these images to deep learning was highlighted through three applications: (i) development of a classifier for neoplastic, stromal, and necrotic regions; (ii) development of a predictor of xenograft-transplant lymphoproliferative disorder; and (iii) application of a published predictor of microsatellite instability. Together, this PDX Development and Trial Centers Research Network image repository provides a valuable resource for controlled digital pathology analysis, both for the evaluation of technical issues and for the development of computational image-based methods that make clinical predictions based on PDX treatment studies. Significance: A pan-cancer repository of >1,000 patient-derived xenograft hematoxylin and eosin-stained images will facilitate cancer biology investigations through histopathologic analysis and contributes important model system data that expand existing human histology repositories.

Expected Pass Turnovers (xPT) - a model to analyse turnovers from passing events in football.

The aim of this study was to create a novel metric, Expected Pass Turnovers (xPT), that could evaluate possession retention from player-passing events in football. Event and positional data were analysed from all 380 matches in the 2020/21 English Premier League season, which encompassed 256,433 passes in the final dataset. A logistic mixed-effects model was implemented to attribute the probability of each pass getting turned over. The use of positional data enabled the identification of a) opposition players present in radii surrounding the ball carrier and b) availability of teammates with respect to the ball carrier. The addition of these positional features improved the accuracy (+6.1 AUC Score) of the model. xPT serves as a practitioner Key Performance Indicator, as analysts can identify players that lose possession more often or not than expected, given the situational context of each pass, from game to game. Future work may include modelling the turnover probability of dribble and carry actions, as this would lead to a more comprehensive understanding of turnover events in football.

The use of venous blood gas in assessing arterial acid-base and oxygenation status - an analysis of aggregated data from multiple studies evaluating the venous to arterial conversion (v-TAC) method.

BACKGROUND: Several methods exist to reduce the number of arterial blood gases (ABGs). One method, Roche v-TAC, has been evaluated in different patient groups. This paper aggregates data from these studies, in different patient categories using common analysis criteria. RESEARCH DESIGN AND METHODS: We included studies evaluating v-TAC based on paired arterial and peripheral venous blood samples. Bland-Altman analysis compared measured and calculated arterial values of pH, PCO2, and PO2. Subgroup analyses were performed for normal, chronic hypercapnia and chronic base excess, acute hyper- and hypocapnia, and acute and chronic base deficits. RESULTS: 811 samples from 12 studies were included. Bias and limits of agreement for measured and calculated values: pH 0.001 (-0.029 to 0.031), PCO2 -0.08 (-0.65 to 0.49) kPa, and PO2 0.04 (-1.71 to 1.78) kPa, with similar values for all sub-group analyses. CONCLUSION: These data suggest that v-TAC analysis may have a role in replacing ABGs, avoiding arterial puncture. Substantial data exist in patients with chronic hypercapnia and chronic base excess, acute hyper- and hypocapnia, and in patients with relatively normal acid-base status, with similar bias and precision across groups and across study data. Limited data exist for patients with acute and chronic base deficits.

Tumoral Interferon Beta Induces an Immune-Stimulatory Phenotype in Tumor-Associated Macrophages in Melanoma Brain Metastases.

Type I interferons (IFN) are immune-stimulatory cytokines involved in antiviral and antitumor immune responses. They enhance the efficacy of immunogenic anticancer therapies such as radiotherapy by activating both innate and adaptive immune cells. Macrophages are one of the most abundant innate immune cells in the immune microenvironment of melanoma brain metastases (MBM) and can exert potent immune-suppressive functions. Here, we investigate the potential of tumoral type I IFNs to repolarize tumor-associated macrophages (TAM) in two murine MBM models and assess the effects of radiotherapy-induced type I IFN on TAMs in a transcriptomic MBM patient dataset. In mice, we describe a proinflammatory M1-like TAM phenotype induced by tumoral IFNß and identify a myeloid type I IFN-response signature associated with a high M1/M2-like TAM ratio. Following irradiation, patients with MBM displaying a myeloid type I IFN-response signature showed increased overall survival, providing evidence that tumoral IFNß supports an effective antitumor immune response by re-educating immune-regulatory TAM. These findings uncover type I IFN-inducing therapies as a potential macrophage-targeting therapeutic approach and provide a rationale for combining radiotherapy with concomitant immunotherapy to improve treatment response in patients with MBM. SIGNIFICANCE: Our study shows that re-education of tumor-associated macrophages by tumoral IFNß translates into improved clinical outcome in patients with melanoma brain metastases, providing pathomechanistic insights into synergistic type I interferon-inducing therapies with immunotherapies and warranting investigation of IFNß as a predictive biomarker for combined radioimmunotherapy.

Survival and treatment outcomes in patients with leptomeningeal disease from metastatic melanoma.

Background: Melanoma leptomeningeal disease (LMD) has a poor prognosis. However, the management of patients with advanced melanoma has evolved with time, including those with LMD. We reviewed a large cohort of melanoma LMD patients to assess factors associated with survival. Methods: Retrospective clinical data was collected on patients diagnosed with LMD at MD Anderson Cancer Center from 2015 to 2020. Overall survival (OS) was determined from LMD diagnosis to date of death or last follow-up. The Kaplan-Meier method and log-rank test were used to estimate OS and to assess univariate group differences, respectively. Multivariable associations of survival with variables of interest were determined using Cox proportional hazards regression models. Results: A total of 172 patients were identified. The median age at LMD diagnosis was 53 (range 20-79) years, and all patients had radiographic evidence of LMD on magnetic resonance imaging of either brain or spine. In total 143 patients previously received systemic therapy (83%), with a median of 2 prior treatments (range 0-5). 81 patients (47%) had concurrent uncontrolled systemic disease and 80 patients (53%) had elevated serum LDH at the time of diagnosis. With a median follow-up of 4.0 months (range 0.1-65.3 months), median OS for all patients from LMD diagnosis was 4.9 months. Patients (n = 45) who received intrathecal therapy or systemic immunotherapy for LMD had a median OS of 8.0 months and 10.2 months, respectively. On multivariable analysis, decreased performance status, positive CSF cytology, elevated LDH, and whole brain radiation were associated with worse OS. Conclusions: Despite many advances in therapeutic options, the outcomes of melanoma patients with LMD remains poor. However, a subset of patients appears to derive benefit from LMD-directed treatment.