bluuebunny/crossref_metadata_2025 huggingface dataset:
Threading between Scylla and Charybdis: developing a framework for arbitrating investor-state tax disputes
Authors: Bhukya Kanishka
Published: August 2024

Tax disputes have traditionally been considered non-arbitrable, but the rise of investment treaties allowing investors to bring arbitration claims against states has raised difficult questions about reconciling fiscal sovereignty with investor rights. In that context, this article tackles the complex issue of determining when investor-state tax disputes can be appropriately arbitrated without impinging on state prerogatives. It builds on the nascent distinction made in Cairn v India between non-arbitrable ‘pure tax disputes’ and treaty-based ‘tax-related investment disputes’ alleging unfair tax treatment. The article explains why the consent-based nature of investment arbitration renders the latter category of disputes arbitrable, before developing a multi-faceted framework to guide arbitral tribunals in exercising jurisdiction despite sovereignty objections. Grounded in treaty interpretation, tax policy space, and proportionality analysis, this principled approach carefully balances states’ regulatory autonomy in tax matters with investment disciplines they voluntarily assumed. Overall, by resolving tensions between sovereign prerogatives and investor rights, the proposed structured framework charts a sovereignty-respecting course for arbitrating tax-related investment disputes.
The utility of interleukin-23 intraclass switching in the treatment of plaque psoriasis: a retrospective review of 43 cases
Authors: Hren M Grace , Miriyala Sreekar , Khattri Saakshi
Published: August 2024

Interleukin (IL)-23 inhibitors are a class of injectable biologics, which include risankizumab, tildrakizumab and guselkumab, used for the treatment of moderate-to-severe psoriasis. This retrospective review sought to determine the value of IL-23 inhibitor intraclass switching among patients with psoriasis after they experienced loss of efficacy to any IL-23 inhibitor. We conducted a retrospective chart review, including 43 patients who underwent any of 6 potential iterations of IL-23 intraclass switching between November 2017 and November 2023. Most commonly, patients switched from guselkumab or tildrakizumab to risankizumab (84%). On average, patients failed 2.3 biologic treatments (SD 1.3) prior to switching. Postswitching, 81% of patients achieved an affected body surface area (BSA) < 1% after 248.8 days (SD 126.5). BSA immediately prior to intraclass switch was 13.1 (SD 8.9) [95% confidence interval (CI) 10.4–15.8] and at most recent follow-up was 2.9 (SD 5.2) (95% CI 2.3–5.5). This research adds to a growing body of literature demonstrating the potential of IL-23 intraclass switching in the treatment of moderate-to-severe plaque psoriasis.
‘Mankind Dame’: John Studley’s early modern Clytemnestra
Authors: Spinelli Elena
Published: August 2024

John Studley’s Agamemnon (1566) explores women’s rule and how it can combine feminine and masculine elements to achieve and maintain political power. To do so, Studley employs the character of Clytemnestra, who simultaneously retains elements of her previous dramatic versions and is shaped to resonate with early modern English audiences. This process is twofold, taking into consideration linguistic and character traits. Clytemnestra’s language is expanded from the Latin through masculine-coded tropes characteristic of vernacular lyric. Moreover, she possesses traits traditionally considered masculine (martial courage, determination, bold speech and skill in weaponry). In Studley’s Clytemnestra, then, endurance and action combined create a gender hybridity in speech and behaviour. In turn, her portrayal resonates with discourses surrounding early modern women rulers, from Elizabeth Tudor to Mary Stuart. Ultimately, Agamemnon reshapes the treacherous queen of Mycenae to function as a commentary on how a woman in power could appear, speak and behave.
The cost-effectiveness of semaglutide in reducing cardiovascular risk among people with overweight and obesity and existing cardiovascular disease, but without diabetes
Authors: Zomer Ella , Zhou Jennifer , Nelson Adam J , Sumithran Priya , Nanayakkara Shane , Ball Jocasta , Kaye David , Liew Danny , Nicholls Stephen J , Stub Dion , Zoungas Sophia
Published: August 2024

Background and aims

The Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) trial demonstrated significant reductions in cardiovascular outcomes in people with cardiovascular disease (CVD) and overweight or obesity (but without diabetes). However, the cost of the medication has raised concerns about its financial viability and accessibility within healthcare systems. This study explored whether the use of semaglutide for the secondary prevention of CVD in overweight or obesity is cost-effective from the Australian healthcare perspective.

Methods and results

A Markov model was developed based on the SELECT trial to model the clinical outcomes and costs of a hypothetical population treated with semaglutide vs. placebo, in addition to standard care, and followed up over 20 years. With each annual cycle, subjects were at risk of having non-fatal CVD events or dying. Model inputs were derived from SELECT and published literature. Costs were obtained from Australian sources. All outcomes were discounted by 5% annually. The main outcome of interest was the incremental cost-effectiveness ratio (ICER) in terms of cost per year of life saved (YoLS) and cost per quality-adjusted life year (QALY) gained. With an annual estimated cost of semaglutide of A$4175, the model resulted in ICERs of A$99 853 (US$143 504; £40 873) per YoLS and A$96 055 (US$138 046; £39 318) per QALY gained.

Conclusion

Assuming a willingness-to-pay threshold of A$50 000, semaglutide is not considered cost-effective at the current price. A price of ≤A$2000 per year or more targeted use in high-risk patients would be needed for it to be considered cost-effective in the Australian setting.
Lifestyle, Cognitive, and Psychological Factors Associated With a Resilience Phenotype in Aging: A Multidimensional Approach on a Population-Based Sample of Oldest-Old (80+)
Authors: Rolandi Elena , Rossi Michele , Colombo Mauro , Pettinato Laura , Del Signore Federica , Aglieri Virginia , Bottini Gabriella , Guaita Antonio
Published: August 2024

Objectives

To investigate the determinants of resilience phenotype in aging, operationalized as the maintenance of cognitive, physical, and psychological health in very old individuals (80+), we investigated the structure and interrelated impact of the main resilience-enhancing factors, which are usually studied in separate research fields.

Methods

Participants were older adults without dementia recruited for the fifth wave of the InveCe.Ab population-based cohort study (aged 83–87 years). Multidimensional evaluation comprised blood sampling, social and lifestyle survey, and geriatric and neuropsychological assessment. We classified resilient individuals as displaying normal cognition, functional independence, and mental health. First, we performed exploratory factor analysis (EFA) to examine the underlying structure of the relevant cognitive, lifestyle, physical, and psychological resilience-enhancing factors. The factors obtained were included as predictors of the resilience phenotype in the logistic regression model, controlling for sociodemographic and cumulative exposure to physical and psychosocial stressors, including COVID-19 infection.

Results

Among the 404 enrolled participants, 153 (38%) exhibited the resilience phenotype. EFA resulted in the identification of six factors (59% of variance): cognitive reserve, affective reserve, insecure attachment, current lifestyle, physical reserve, and avoidant attachment. Among these factors, cognitive reserve, affective reserve, and current lifestyle significantly and independently predicted resilience status, controlling for cumulative exposure to age-related stressors and COVID-19 infection.

Discussion

Our findings showed that, even in very old age, both early and late life modifiable factors affect individuals’ ability to adapt to the aging process, thus confirming the importance of a life-course approach to improve health outcomes in the aged population.

Clinical Trials Registration Number

NCT01345110
Topic Clusters of Successful Aging Studies: Results of a Topic Modeling Approach
Authors: Kim Ha-Neul , Freddolino Paul P
Published: August 2024

Background and Objectives

Literature regarding successful aging reflects a wide variety of fields and perspectives. Given the range of definitions and approaches found in published literature, it is important to investigate clusters of topics studied over time. This study aimed to show the change of topic clusters within successful aging studies.

Research Design and Methods

The study used topic modeling methodology to analyze vast amounts of abstract data. Among publications collected from Scopus (4,458) and Web of Science (5,187), 5,610 publications were analyzed. Topic clusters were analyzed in 2 ways: by (a) division of time (1960s–1990s, 2000s, 2010s, 2020s) and (b) all years combined.

Results

In the 1960s–1990s, 11 topic clusters ranging from health to emotional well-being emerged without any dominant domain. In the 2000s, 2 clusters related to social support and health appeared as major clusters. In the 2010s, 1 topic cluster that included words related to health and social participation was the biggest. In the 2020s, emotional health and social participation appeared again as one of the major clusters and health-related topics started to diverge into subgroups like physical health and mental health. In all years of publications combined, the major cluster involved words that are related to either health or social domains.

Discussion and Implications

Results revealed that successful aging has been studied in many fields using multidimensional perspectives. The dominant categories were health and social domains. These findings suggest interprofessional practice, an interdisciplinary approach in research, and multisector involvement in policy.
O-glycosylation of IgA1 and the pathogenesis of an autoimmune disease IgA nephropathy
Authors: Novak Jan , King R Glenn , Yother Janet , Renfrow Matthew B , Green Todd J
Published: August 2024

IgA nephropathy is a kidney disease characterized by deposition of immune complexes containing abnormally O-glycosylated IgA1 in the glomeruli. Specifically, some O-glycans are missing galactose that is normally β1,3-linked to N-acetylgalactosamine of the core 1 glycans. These galactose-deficient IgA1 glycoforms are produced by IgA1-secreting cells due to a dysregulated expression and activity of several glycosyltransferases. Galactose-deficient IgA1 in the circulation of patients with IgA nephropathy is bound by IgG autoantibodies and the resultant immune complexes can contain additional proteins, such as complement C3. These complexes, if not removed from the circulation, can enter the glomerular mesangium, activate the resident mesangial cells, and induce glomerular injury. In this review, we briefly summarize clinical and pathological features of IgA nephropathy, review normal and aberrant IgA1 O-glycosylation pathways, and discuss the origins and potential significance of natural anti-glycan antibodies, namely those recognizing N-acetylgalactosamine. We also discuss the features of autoantibodies specific for galactose-deficient IgA1 and the characteristics of pathogenic immune complexes containing IgA1 and IgG. In IgA nephropathy, kidneys are injured by IgA1-containing immune complexes as innocent bystanders. Most patients with IgA nephropathy progress to kidney failure and require dialysis or transplantation. Moreover, most patients after transplantation experience a recurrent disease. Thus, a better understanding of the pathogenetic mechanisms is needed to develop new disease-specific treatments.
MYO5B and the Polygenic Landscape of Very Early-Onset Inflammatory Bowel Disease in an Ethnically Diverse Population
Authors: Watson Ashleigh , Harris R Alan , Engevik Amy C , Oezguen Numan , Nicholson Maribeth R , Dooley Sarah , Stubler Rachel , Satter Lisa Forbes , Karam Lina B , Kellermayer Richard
Published: August 2024

Background

Genetic discovery in very early-onset inflammatory bowel disease (VEO-IBD) can elucidate not only the origins of VEO-IBD, but also later-onset inflammatory bowel disease. We aimed to investigate the polygenic origins of VEO-IBD in a cohort with a high proportion of Hispanic patients.

Methods

Patients with VEO-IBD who underwent whole exome sequencing at our center were included. Genes were categorized as genes of interest (GOIs) (129 genes previously described to be associated with VEO-IBD) or non-GOIs. VEO-IBD “susceptibility” single nucleotide variants (SNVs) were identified through enrichment compared with gnomAD (Genome Aggregation Database) and ALFA (Allele Frequency Aggregator) and were scored by Combined Annotation Dependent Depletion for deleteriousness. Gene networks carrying susceptibility SNVs were created. Myosin 5b immunofluorescence was also studied.

Results

Fifty-six patients met inclusion criteria, and 32.1% identified as Hispanic. Monogenic disease was infrequent (8.9%). Significant enrichment of GOI susceptibility SNVs was observed, notably in MYO5B, especially in Hispanics. MEFV, TNFAIP3, SH3TC2, and NCF2 were also central participants in the GOI networks. Myosin 5b immunofluorescence in colonic mucosa was significantly reduced in those with MYO5B susceptibility SNVs compared with control subjects. Seven genes (ESRRA, HLA-DQ1, RETSAT, PABPC1, PARP4, CCDC102A, and SUSD2) were central participants in the non-GOI networks.

Conclusions

Our results support the polygenic nature of VEO-IBD, in which key participants, like MYO5B, were identified through network analytics. Rare variant load within susceptibility genes may be relevant not only for the genetic origins of inflammatory bowel disease, but also for the age of disease onset. Our findings could guide future work in precision medicine.
Evaluating the protective effect of dapsone on experimental osteoarthritis models induced by MIA in male rats
Authors: Nazari Kimia , Hosseindoost Saereh , Dehpour Ahmad Reza , Kheirandish Yasaman , Shafaroodi Hamed
Published: August 2024

Objectives

Osteoarthritis, a degenerative condition that results in significant morbidity, is typically managed with treatments aimed at symptom relief rather than addressing the underlying degeneration. Dapsone, recognized for its anti-inflammatory, antioxidant, antiexcitotoxic, and antiapoptotic properties, has demonstrated promising effects in various neurodegenerative diseases. This study explores the potential of dapsone to mitigate articular destruction, inflammation, and pain in rat models of osteoarthritis.

Methods

Osteoarthritis was induced in rats by injecting MIA into the right knee joint. Dapsone was then administered intraperitoneally at 5, 10, or 20 mg/kg every 2 days for 2 weeks. Behavioural tests were done on days 0, 7, and 14. On day 14, the articular cartilage was histologically analysed using H&E staining. Serum levels of NF-kB, IL-1β, and TNF-α were evaluated by ELISA.

Results

Dapsone effectively reduces pain, inflammation, and articular cartilage damage in osteoarthritis. Specifically, it improves mechanical allodynia and thermal hyperalgesia, reduces inflammatory markers (TNF-α, IL-1β, and NF-κB), and protects against cartilage destruction and chondrocyte loss, with the most significant effects at 20 mg/kg.

Conclusions

Dapsone effectively prevents pain, inflammation, and cartilage damage in osteoarthritis rats, suggesting its potential as a therapeutic option for managing osteoarthritis.
Extrarenal manifestations in inherited kidney diseases
Authors: Hoefele Julia , Eble Julian , Hermle Tobias , Wuttke Matthias , Schultheiss Ulla T
Published: August 2024

Monogenic kidney diseases result from an abundance of potential genes carrying pathogenic variants. These conditions are primarily recognized for manifesting as kidney disorders, defined as an impairment of the structure and/or function of the kidneys. However, the impact of these genetic disorders extends far beyond the kidneys, giving rise to a diverse spectrum of extrarenal manifestations. These manifestations can affect any organ system throughout the body, leading to a complex clinical presentation that demands a comprehensive understanding and interdisciplinary management of affected persons. The intricate interplay between genetic variants, molecular pathways, and systemic interactions underscores the importance of exploring the extrarenal aspects of inherited kidney diseases. This exploration not only deepens our comprehension of the diseases themselves but also opens avenues for more holistic diagnostics, treatment strategies, and improved interdisciplinary patient care. This article delves into the intricate realm of extrarenal manifestations in inherited kidney diseases, shedding light on the far-reaching effects that these genetic conditions can exert beyond the confines of the kidney system.
BSBM-02 SIRPΑ INTRACELLULAR SIGNALING MEDIATED MITOCHONDRIAL FISSION IN TRIPLE-NEGATIVE BREAST CANCER CELLS IS ASSOCIATED WITH BREAST-TO-BRAIN METASTASIS
Authors: Tsai Yu-Ting , Wilson Adam , Miller Lance , Cook Katherine , Zhao Dawen , Lesser Glenn , Soto-Pantoja David
Published: August 2024

Triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype, often leads to brain metastasis (35%). Current need for standard treatment requires the development of new therapies. The CD47/SIRPα interaction drives immune escape. However, SIRPα’s expression and role in cancer cells remain poorly understood. Single-cell RNA-Seq data reveals SIRPα upregulation in TNBC, supported by strong immunoreactivity in patient biopsies and a 3.5-fold increase in breast-to-brain metastatic lesions. (n=9-19; p<0.01). Consistently, the protein expression of SIRPα TNBC 4T1 and EO771 brain-tropic cells (4T1Br3/EO771Br4) is significantly higher than the parental cells (n=3; p<0.05). Stably overexpressed SIRPα and knockout TNBC cell lines show that SIRPα regulates SHP2 phosphorylation in cancer cells, and SIRPα/SHP2 axis regulates TNBC cell migration. According to the gene ontology from Bulk RNA-Seq data on orthotopic tumors, anti-SIRPα treatment affects the genes related to mitochondria and organelle membrane clusters, correlating to mitochondrial fission and fusion dynamics. Our data shows a doubling in Drp1 (mitochondria fission) protein expression in TNBC brain-tropic cells compared to parental, whereas MFN2 (mitochondria fusion) has a 50% decrease in expression. Moreover, SIRPα knockout cell line also downregulates mitochondria fission with decreased Drp1 and increased MFN2 expression. Allosteric SHP2 inhibitor treatment on TNBC brain-tropic cells also shows a dose-dependent inhibition of Drp1 (n=3, p<0.001) and MFN2 enhancement (n=3, p=0.0184) with Erk signaling inhibition. SIRPα/SHP2/Erk axis shifts mitochondria fusion to fission, leading to cancer metastasis. SIRPα blockade by antibody reduced metastatic brain lesion formation in two in vivo models by approximately 90% (n=4-7; p <0.05). Spatial proteomics revealed changes in adaptive and innate suppressive and inflammatory signaling that may be associated with the observed changes in SIRPα intracellular signaling. This was associated with shift in ECM proteins that may influence mitochondrial function to influence metastasis., thus providing a potential mechanism for how SIRPα promotes TNBC brain metastasis.
BSBM-10 GENETIC DELETION OF ERΑ OR ERΒ IN REACTIVE ASTROCYTES DECREASES REACTIVE GLIOSIS AND PROMOTES BRAIN METASTASIS
Authors: Koliavas Stella , Contreras-Zárate Maria J , Jaramillo-Gomez Jenny A , Fox Morgan , Nguyen Alicia , Cittelly Diana M
Published: August 2024

Astrocytes surround brain metastasis (BM) and play both anti-metastatic and pro-metastatic roles throughout BM progression. We have shown that pre-menopausal levels of 17-β-Estradiol (E2) promotes BM of estrogen receptor (ER) negative breast cancer (BC), in part by stimulating ER+ astrocytes to secrete factors that promote proliferation, migration, and invasion of ER-BC cells. E2 exert its function through activation of ERα or ERb, and astrocytic ERα and ERβ play diverse and often interdependent roles modulating neuroinflammatory responses in the brain. Yet, how ERs impact astrocytic function in the context of BM remains unknown. We hypothesize that genetic deletion of astrocytic ERs modulates their function during BM progression and blocks E2-dependent BM. Using a Cre-loxP system, we selectively deleted ERα or ERβ in GFAP+ reactive astrocytes (GFAPCre/+), and measured BM progression after intracardiac injection of E0771 GFPLuc+ cells in ovariectomized (OVX) female mice treated or not with E2. While E2 increased BM in control GFAP+/+ERαfl/fl and GFAP+/+ERbfl/fl mice compared to OVX mice, OVX mice with ERα or ERβ deletion in reactive astrocytes (GFAPCre/+ERαfl/fl or GFAPCre/+ERbfl/fl) showed increased BM with levels comparable to those of E2-treated control mice. Thus, genetic deletion of ERs in GFAP+ reactive astrocytes promoted E2-independent growth of BM. Immunofluorescence staining showed that BM- associated stroma of mice with ERα and ERb deletion contained significantly less reactive astrocytes (GFAP+) than control mice, suggesting that loss of ERs decreases reactive gliosis. Brain immune profiling of BM- bearing mice showed loss of ERα or ERb had a significantly increased fraction of pro-inflammatory microglia compared to OVX-control mice, suggesting that loss of astrocytic ERα and ERb promotes a neuroinflammatory TME. Together, these data suggest that loss of astrocytic ERs promotes E2-independent BM by suppressing the ability of astrocytes to become reactive and exert their anti-metastatic role through BM progression.
BSBM-13 DISTINCT UPTAKE AND ELIMINATION PROFILES FOR TRASTUZUMAB, HUMAN IGG AND BIOCYTIN-TMR IN EXPERIMENTAL HER2+ BRAIN METASTASES OF BREAST CANCER
Authors: Silvestri Vanesa , Tran Andy , Chung Monika , Chung Natalie , Gril Brunilde , Robinson Christina , Difilippantonio Simone , Wei Debbie , Kruhlak Michael , Peer Cody , Figg W Douglas , Khan Imran , Steeg Patricia
Published: August 2024

The aim of this study is an improved understanding of drug distribution in brain metastases. Rather than single point snapshots, we analyzed the time course and route of drug/probe elimination (clearance), focusing on the intramural periarterial drainage (IPAD) pathway. Mice with JIMT1-BR HER2+ experimental brain metastases were injected with biocytin-TMR and either trastuzumab or human IgG. Drugs/probes circulated for 5 min to 48 h, followed by perfusion. Brain sections were stained for human IgG, vascular basement membrane proteins laminin or collagen IV, and periarterial α-SMA. A machine learning algorithm was developed to identify metastases, metastatic microenvironment, and uninvolved brain in confocally scanned brain sections. Drug/probe intensity over time and total imaged drug exposure (iAUC) were calculated for 27,249 lesions and co-immunofluorescence with IPAD-vascular matrix analyzed in 11,668 metastases. In metastases, peak trastuzumab levels were 5-fold higher than human IgG but 4-fold less than biocytin-TMR. The elimination phase constituted 85–93% of total iAUC for all drugs/probes tested. For trastuzumab, total iAUC during uptake was similar to the small molecule drug probe biocytin-TMR, but slower trastuzumab elimination resulted in a 1.7-fold higher total iAUC. During elimination trastuzumab and IgG were preferentially enriched in the α-SMA+ periarterial vascular matrix, consistent with the IPAD clearance route; biocytin-TMR showed heterogeneous elimination pathways. Drug/probe elimination is an important component of drug development for brain metastases. We identified a prolonged elimination pathway for systemically administered antibodies through the periarterial vascular matrix that may contribute to the sustained presence and efficacy of large antibody therapeutics.
BSLM-12 IDENTIFICATION OF THE GDNF: NCAM SIGNALING AXIS AS A NOVEL TARGET AGAINST BREAST CANCER LEPTOMENINGEAL METASTASIS
Authors: Ma Danhui , Wang Lihua , Yu Seok-Yeong , Cui Xiuyu , Fecci Peter , Jeck William , Neff Jadee , Sipkins Dorothy
Published: August 2024

The molecular mechanisms that regulate breast cancer cell (BCC) metastasis within the leptomeninges (LM), and the adaptive mechanisms that allow tumors to thrive under cellular stressors within the nutrient-poor LM niche are poorly understood, limiting the development of effective therapies. Macrophages are well-described to play pro-tumoral roles in many tissues, yet how BCCs might subvert meningeal macrophages to enhance their survival in this unique microenvironment are only beginning to be investigated. Utilizing mouse models of BCC LM metastasis, we find that BCC cross-talk with meningeal macrophages provides significant pro-survival signaling through the hijacking of macrophage glial-derived neurotrophic factor (GDNF) signaling. GDNF is minimally expressed in the healthy adult brain and LM but is secreted by reactive CNS microglia and macrophages in response to stroke and other brain injury, where it serves to block apoptotic neuronal stress responses. We found that GDNF could protect BCCs expressing the GDNF receptor, neural cell adhesion molecule (NCAM), from cell death induced by nutrient deprivation in vitro, upregulating numerous genes involved in cell survival and proliferation. Flow cytometry of meningeal cell isolates from tumored mice revealed that border-associated macrophages (BAMs) and monocyte-derived macrophages (MDMs) were the predominant sources of GDNF in the meningeal microenvironment. In vivo studies in mice demonstrated that intrathecal anti-GDNF antibody blockade, macrophage-specific GDNF ablation, or deletion of NCAM from BCCs inhibited their growth within LM. Lastly, immunohistochemical analysis of meningeal-based tumor patient samples showed that these metastases were highly enriched for BCC-NCAM and stromal-GDNF expression. These findings highlight novel roles for macrophages and the GDNF: NCAM signaling axis in BCC LM disease development.
BSLM-13 EXTRACTION AND WHOLE TRANSCRIPTOME SEQUENCING OF CELL FREE RNA FROM HUMAN CEREBROSPINAL FLUID: A METHOD TO IDENTIFY BIOMARKERS OF BRAIN HEALTH AND DISEASE
Authors: Garcia Maxine Umeh , Taiwo Rukayat , Barisano Giuseppe , Spiliotopoulos Elias , Herrick Daniel , Godfrey Bryanna , Trinh Thy , Lee Seunghyun , Perez Pablo Nunez , Ngo Thuy , Gephart Melanie Hayden
Published: August 2024

BACKGROUND

Brain biopsy carries a morbidity risk of ~5%, which has significantly limited samples available for research, hindering our understanding and treatment of brain metastases (BrM) and Leptomeningeal Disease (LMD). However, cerebrospinal fluid (CSF) – which circulates the CNS, significantly interfacing with brain tumor tissues and carries tumor cell-free nucleic acids and LMD cells – provides a critically understudied biospecimen to understand BrM/LMD biology. We previously found brain tumor-specific cell-free DNA (cfDNA) in CSF, even when not detectable in blood; and showed that the mutant fraction of cfDNA mirrored treatment response and disease progression. Expanding to study CSF cell-free mRNA (cfRNA) allowed us to extend from mutation-driven cancers (e.g., BRAF/melanoma, EGFR/lung cancer) to investigate the transcriptional profiles of not only cancer, but also brain-resident cells.

METHODS

We have banked, and have ready-access to, 300+ CSF samples from patients with brain tumors and LMD, many of whom were treated at Stanford Hospital (2012 – 2023). We then leveraged a combination of total RNA extraction and whole transcriptome RNA sequencing to interrogate gene expression patterns present in CSF cfRNA. A method we term CSF-Seq.

RESULTS

CSF-Seq has revealed expression profiles in LMD CSF not found in CSF of non-LMD cancers, like gliomas, and non-cancer controls, like hydrocephalous. Importantly, CSF-Seq accurately recapitulates our previous panel-based qPCR method, demonstrating upregulated cancer-associated genes like CEACAM6 and MUC1 in breast and lung LMD, and ubiquitous expression of brain-associated genes, like MBP, across all CSF samples. This demonstrates our ability to retrieve well-established, validated target genes, while positioning us to discover novel gene signatures in LMD.

CONCLUSION

These results serve as a starting point for identifying key gene expression signatures associated with development of LMD and BrM progression. Further investigation focused on tumor-brain crosstalk, and gene signatures associated with response to treatment, will provide promising targets for therapeutic advancement.
BMRK-02 PROGNOSTIC VALUE OF CEREBROSPINAL FLUID TUMOR CELL COUNT IN LEPTOMENINGEAL DISEASE FROM SOLID TUMORS
Authors: Barbour Andrew , Blouw Barbara , Taylor Lynne , Graber Jerome , McGranahan Tresa , Blau Molly , Halasz Lia , Lo Simon , Tseng Yolanda , Venur Vyshak , Yang Jonathan
Published: August 2024

Leptomeningeal disease (LMD) affects 5-10% of patients with solid tumors. Treatment decisions for LMD rely on patient risk stratification, since clinicians lack objective prognostic tools. The introduction of rare cell capture technology for identification of cerebrospinal fluid tumor cells (CSF-TCs) improved the sensitivity of LMD diagnosis, but the prognostic value of CSF-TCs is unclear. This study assessed the prognostic value of CSF-TC density in patients with LMD from solid tumors, while determining an optimal CSF-TC density cutpoint for clinical-risk stratification. We conducted a single institution, retrospective cohort study of patients with newly diagnosed or previously treated LMD who had CNSide assay testing for CSF-TCs from 2020 to 2023. Univariable and multivariable survival analyses were conducted with Cox proportional-hazards modeling. Maximally-selected rank statistics were used to determine an optimal cutpoint for CSF-TC density and survival. Of 31 patients, 29 had CSF-TCs detected on CNSide. Median CSF-TC density was 67.8 (interquartile range [IQR] = 4.7-639) TCs/mL. CSF cytology was positive in 16 of 29 patients with positive CNSide, and 0 of 2 patients with negative CNSide (CNSide diagnostic sensitivity = 93.5%, negative predictive value = 85.7%). Median survival from time of CSF-TC detection was 176 (IQR = 89-481) days. On univariable and multivariable analysis, CSF-TC density was significantly associated with survival (univariable hazard ratio [HR] = 1.39, 95% CI = 1.01-1.90, P =.04; multivariable HR = 1.50, 95% CI = 1.02-2.21, P =.04). An optimal cutpoint for dichotomizing survival by CSF-TC density was 19.34 TCs/mL. The time-dependent sensitivity and specificity for survival using this stratification were 76% and 67% at 6 months and 65% and 67% at 1 year, respectively. CSF-TC density may carry prognostic value in patients with LMD from solid tumors. Integrating CSF-TC density into LMD patient risk-stratification may help guide treatment decisions.
BMRK-11 REAL-WORLD EXPERIENCE WITH CIRCULATING TUMOR DNA IN CEREBROSPINAL FLUID IN PATIENTS WITH CENTRAL NERVOUS SYSTEM TUMORS
Authors: Hickman Richard , Miller Alexandra M , Holle Bridget M , Jee Justin , Liu Si-Yang , Ross Dara , Yu Helena , Riley Gregory J , Ombres Christina , Gewirtz Alexandra , Reiner Anne S , Nandakumar Subhiksha , Price Adam , Kaley Thomas J , Graham Maya S , Vanderbilt Chad , Rana Satshil , Hill Katherine , Chabot Kiana , Campos Carl , Nafa Khedoudja , Shukla Neerav , Karajannis Matthias , Li Bob , Berger Michael , Ladanyi Marc , Pentsova Elena , Boire Adrienne , Brannon A Rose , Bale Tejus , Mellinghoff Ingo K , Arcila Maria E
Published: August 2024

Next generation sequencing (NGS) of circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF) offers a minimally invasive approach to identify somatic alterations for individuals with central nervous system (CNS) cancers. Here, we review our ‘real world’ experience using a clinically validated, FDA-authorized platform, MSK-IMPACTTM, to comprehensively profile ctDNA from CSF samples with and without clinically documented CNS involvement by cancer (1007 samples, 711 patients). The patient cohort included patients with over 90 distinct tumor types of primary CNS and metastatic origin, with lung cancer (n = 188), breast cancer (n = 150), and glioma (n = 148) representing the most common broad categories. We identified genetic alterations (ctDNA-positive) in 489/922 (53.0%) CSF samples from patients with clinically documented CNS cancer. Over half of these ctDNA-positive samples (248, 50.7%) possessed a biomarker that was predictive of response to an FDA-approved drug (OncoKB level 1). Furthermore, the distribution of clinically actionable somatic alterations was consistent with tumor-type specific alterations across the AACR GENIE cohort. Of patients without clinical documentation of CNS cancer, none of these 85 CSF samples were ctDNA-positive (specificity = 100%). Successive CSF sequencing over time identified clonal evolution and the emergence of resistance mechanisms to therapies. ctDNA positivity corresponded with shortened overall survival after CSF collection (HR: 3.23, 95% CI: 2.58-4.05, P < 0.001). NGS of CSF cfDNA can detect clinically actionable somatic alterations in a large subset of CNS cancer patients and allows tracking of tumor evolution. Detection of somatic alterations in CSF may be a useful prognostic biomarker for survival in cancer patients.
DSAI-06 TECHNICAL AND ADMINISTRATIVE CHALLENGES FOR OPEN SCIENCE; REAL-LIFE EXPERIENCE FROM ASNR-MICCAI-BRATS-METS 2023 SEGMENTATION CHALLENGE DATASET
Authors: Tahon Nourel hoda , Ashraf Nader , Moawad Ahmed , Janas Anastasia , Baid Ujjwal , Saluja Rachit , Velichko Yuri , Ramakrishnan Divya , Krantchev Kiril , Rudie Jeffrey , Bakas Spyridon , Aboian Mariam
Published: August 2024

PURPOSE

1-Highlighting the Brain Tumor Segmentation (BraTS) challenge; the past, present and the future. 2- Emergence of ASNR-MICCAI BraTS-METS 2023 challenge with discussing our experience. 3-Discussing BraTS-METS 2023 challenge and how to overcome it. 4- Highlighting administrative and technical challenges for sharing data.4- Reviewing educational initiatives for the challenge.

CLINICAL RELEVANCE/APPLICATION

Brain Tumor Segmentation (BraTS) challenge: History of BraTS challenge and evolution of its opensource datasets, The challenge and its components. The challenge workflow. How we used the cumulative experience to run the brain metastasis challenge with > 2000 subjects. Administrative challenges in managing large multi-institutional dataset: Paperwork acquisition, including Data transfer agreement, IRB, and Licensing. Organizing > 2000 MRI scans from 12 different institutions and forming a pipeline for receiving and assigning data. Recruiting trainees, medical students, attendings by ASNR call for volunteers. Mentoring ~ 150 trainees and medical students and providing incentives and awards. Communication with ~ 50 neuroradiology experts. Educational effort to increase training and confidence level of trainees and medical students. Technical challenges for ASNR-MICCAI BraTS 2023 brain metastasis challenge: Inconsistent data extraction workflow. Availability of computational power for preprocessing large high-resolution MR images.Using tailored segmentation algorithms for automated pre-segmentation. Performance of publicly available algorithms and their problems, including tiny, hemorrhagic, and post-therapy cases. Educational initiative for medical students and trainees: Lectures and workshops for segmentation software and dealing with common mistakes. Segmentation Hackathon for any difficult cases. Live lectures by experts about different appearances of brain metastasis and post-treatment changes. Future vision of BraTS-METS 2023: Building a consortium of brain metastasis cases. Recruiting more institutions with diverse patient populations and more diverse vendors. Stay tuned for BraTS-METS 2024 challenge.
DSAI-08 MIXED-EFFECTS DEEP-LEARNING BASED QUANTITATIVE RADIOMIC ANALYSIS OF LONGITUDINAL MAGNETIC RESONANCE IMAGING OF BRAIN METASTASES PREDICT PRIMARY TUMOR ORIGIN
Authors: Panchawagh Suhrud
Published: August 2024

BACKGROUND

Brain metastases, secondary brain tumors originating from cancers elsewhere in the body, can present with focal neurologic deficits without systemic symptoms and are usually evaluated using magnetic resonance imaging (MRI). Multimodal imaging methods are usually used to determine the primary cancer source. Radiomic analysis involves extracting quantitative features from medical images using data-characterization algorithms. Recent advances in deep learning and radiomics, which quantitatively analyze imaging data, offer the potential for improved prediction of primary tumor origin through MR imaging analysis. Using longitudinal MRI data, we developed and validated a mixed-effects neural network model for predicting the primary origin of brain metastases.

METHODS

We used the open-source dataset from 5 different institutions made available by Ocaña-Tienda et al. (2023) to build the model. Radiomic feature selection was performed, followed by building a novel quantitative radiomic approach that uses mixed-effects deep learning to analyze longitudinal radiomic data of brain metastases from MRI scans. Model performance was evaluated using receiver operating characteristic curve (ROC) analysis.

RESULTS

Our mixed-effects model demonstrated high accuracy (90.5%), precision (92.7%), recall (87.8%), and F1 score (90.2%), with an area under the ROC (AUC-ROC) curve of 0.944 in identifying the primary tumor site. The nested mixed-effects model was superior to the fixed-effects model with an AUC-ROC of 0.719.

CONCLUSIONS

Our mixed-effects neural network model accurately predicts the primary origin of brain metastases with high internal and external validity. Using advanced radiomic feature selection and deep learning techniques. Our model achieved high-performance metrics, thus providing a promising tool for enhancing diagnostic capability and tailoring patient-specific management strategies. Further research could explore adding more data from other institutions and studying the effect of integrating this model in clinical workflows to optimize patient care.
DSAI-09 APPLYING CONSENSUS QUALITY OF CARE MEASURES FOR BRAIN METASTASES (BMETS-QC) TO PATIENT EHR DATA, A PILOT STUDY
Authors: Anderson Roger , Bonilla Gloribel , Fadul Camilo
Published: August 2024

PURPOSE

Optimal management of patients with brain metastases requires coordinated, interprofessional care, that is well-documented in their electronic health record (EHR). There are unquantified inconsistencies and gaps in the care for this complex medical diagnosis. We explored the feasibility of applying a peer-reviewed set of 29 quality of care (QOC) consensus measures to commercially available aggregated, limited EHR data. These measures address care planning, treatment timing, assessment of QoL, referrals to palliative care and hospice, and survival.

METHODS

Patients with BMETS were selected (N=43) from a an EHR data warehouse sourced from IQVIA’s collaboration with the Guardian Research Network (GRN). Data extraction followed curation rules developed by the study team and performed by GRN. Patients’ EHR data was manually reviewed by trained staff. Both structured data and unstructured text notes were reviewed and coded. Dates of diagnosis, medical services, and death were masked by indexing to birth date. For each indicator, a patient’s EHR data was coded as done (+), not done(-), or inconclusive (missing).

RESULTS

Of 29 indicators, 23 could be ascertained in > 85% of cases. Instances of lower ascertainment occurred for patients lost to follow-up, missing dates of service, no information on planned or actual dose, or missing prognostic scores. BMETS-QC processes ascertained as not performed (-) mostly involved a lack of documented patient-centered care (i.e., shared decision-making, patient education, and psychosocial support). Finally, 12 indicators required the use of unstructured data and required data curation with manual review or NLP.

CONCLUSION

Most BMETS-QC indicators appear feasible to collect in EHR data with curation processes. An important finding is that providers may fail to document key elements of patient-centered care or timely prognostic information. To handle missing data, patients must have their BMETS care recorded within a single EHR system.
MMOD-13 PREVALENCE, TREATMENT PATTERNS, AND SURVIVAL OUTCOMES OF PATIENTS WITH BRAIN METASTASES FROM SMALL CELL LUNG CANCER: A RETROSPECTIVE COHORT STUDY FROM 2013-2023 USING THE TRINETX ONCOLOGY DATABASE
Authors: Parker Megan , Kalluri Anita , Jiang Kelly , Materi Joshua , Azad Tej D , Murray Joseph , Ha Jinny Suk , Kamson David O , Kleinberg Lawrence R , Redmond Kristin J , Brahmer Julie R , Hann Christine , Ye Xiaobu , Bettegowda Chetan , Rincon-Torroella Jordina
Published: August 2024

Brain metastases (BM) portend increased morbidity and mortality in patients with small cell lung cancer (SCLC), yet nationwide reporting of BM is lacking. We aimed to characterize the prevalence, timing, treatment patterns, and survival outcomes of BM associated with SCLC over the past decade. Data from 4,014 patients with histologically confirmed SCLC were extracted from the TrinetX Oncology database. Clinical and demographic variables were compared between patients with and without BM using and Chi-squared and t-tests. Kaplan-Meier and Cox regression analyses were used to evaluate overall survival (OS), after propensity score matching cohorts for age at diagnosis of lung/bronchus cancer, sex, cancer stage at diagnosis, extracranial metastases, and cancer-directed therapy. Among 4,014 patients with SCLC, 34.98% had BM (9.89% synchronous, 21.18% metachronous, 3.91% precocious) At SCLC diagnosis, 0.75% had stage 0, 5.78% stage 1, 3.69% had stage 2, 20.35% had stage 3 cancer, and 48.75% had stage 4 cancer. Patients who developed BM were younger (p<0.001) at diagnosis of SCLC, more likely Black/African American (p= 0.0068), and presented with more advanced cancer stages (p<0.001) than patients who did not develop BM. The median BM-free survival from the time of SCLC diagnoses was 27.9 months. Patients with BM received significantly higher rates of cancer-directed therapies compared to those without BM. Synchronous BM were associated with lower OS than metachronous BM after the diagnosis of SCLC (HR[95%CI] = 1.56[1.32-1.83]), but there was no difference in OS after the BM diagnosis. OS did not differ significantly between patients with BM and patients with extracranial metastases only, following the diagnosis of BM or extracranial metastases, respectively. Our findings underscore the ongoing challenges in treating SCLC patients with BM and support routine intracranial screening as well as the development of interventions to prevent the development of BM in this population.
MMOD-14 IMPACT OF SYSTEMIC THERAPY ACTIVITY ON BRAIN METASTASIS OUTCOMES IN A FEMALE AND HISPANIC-DOMINANT LUNG CANCER COHORT TREATED WITH STEREOTACTIC RADIOSURGERY
Authors: La Rosa Alonso , Yarlagadda Sreenija , Kutuk Tugce , Akdemir Eyub Y , Gal Omer , Albretch Federico , Kaywin Paul , Press Robert H , Hall Matthew D , Mehta Minesh P , Kotecha Rupesh
Published: August 2024

We analyzed the impact of systemic therapy on lung cancer (LC) patients treated with stereotactic radiosurgery (SRS) for brain metastasis (BM) in terms of objective response, intracranial progression-free survival (iPFS), and overall survival (OS). Response was calculated using chi-square analysis with adjusted residuals, while iPFS and OS were computed using the Kaplan-Meier method. A total of 426 BMs in 91 LC patients from 01/2017-07/2022 were included. The median age was 66 years (interquartile range [IQR] 58-73), in our predominantly female (57.1%) and Hispanic (76.9%) population. The median number of BMs was 4 (IQR: 2-8). Systemic therapy was grouped as no switch (no change; 15 patients, 34 BMs) or switch (change from pre- to post-SRS), with the latter classified as a switch-up (increased CNS activity; 76 patients, 392 BMs) or switch-down (decreased CNS activity; 0 patients). At first radiographic evaluation, rates of complete response, partial response, stable disease, or progressive disease were similar (switch-up [%]/no switch [%]) in 32.7%/50.0%, 23.0%/11.8%, 38.3%/32.4%, and 6.1%/5.9%, p<0.05). With a median follow-up of 18 months (IQR: 5-28), the estimated iPFS (95% CI) for the switch-up group was 7.0 months (4.5-9.5), and the no switch group was 10.0 months (2.5-17.5) (p=0.37). However, the estimated OS for the switch-up group was 21.0 months (18.5-23.5) vs. 19.0 months (15.0-23.0), for no switch (p=0.04). Multivariate analysis identified KPS, lesion number, burden of disease, and prescription dose as predictors for iPFS, and age, lesion number, KPS, and disease status (p<0.05) for OS. In conclusion, upgrading systemic therapy based on intracranial activity combined with SRS for BMs from LC is associated with a statistically significant improvement in OS, without impacting iPFS or first response, implying considerable potential for developing next-generation agents with better intracranial activity.
MMOD-15 SURGICAL RESECTION AND STEREOTACTIC RADIOSURGERY IN COMBINATION FOR LOCAL THERAPY OF BRAIN METASTASES
Authors: Fadrus Pavel , Vybihal Vaclav , Juran Vilem , Pukova Andrea Sprlakova , Kerkovsky Milos , Kren Leos , Lakomy Radek , Kazda Tomas , Hynkova Ludmila , Vecera Marek , Hermanova Marketa , Jancalek Radim , Sana Jiri , Slaby Ondrej , Slampa Pavel , Smrcka Martin
Published: August 2024

OBJECTIVES

Complex local treatment of BM combining surgical resection and radiosurgery provides the possibility of adequate local control while maintaining a satisfactory quality of life.

METHODS

Patients after surgical resection and postoperative radiotherapy treated between 2007-2023 were evaluated. Local control was assessed separately at the site of the operated MM (localPFS) and separately in other parts of the brain (distalPFS).

RESULTS

A total of 158 patients were enrolled (70 with WBRT), 56% were women, the median age was 61 years, the median performance status Karnofsky 78%. The most common primary tumor was lung carcinoma (39/118, 33%). Targeted stereotactic radiotherapy was significantly more often indicated in operations performed after 2016 (p <0.001). In the period 2013-2019, gross total resection was achieved significantly more often (88 vs 64%; p = 0.061). The median follow-up is 51 months. The median overall survival (OS) is 9,5 months (6.2 - 12), the median localPFS 24 months (14 - unattainable), median distPFS 12 months (6.8 - 27 months), median extracranialPFS 13 months (5.9 - 15). Stratification of patients according to the prognostic index brainmetgpa.com led to significant separation of patients for OS (p = 0.00017). In a multivariate analysis, stereotactic radiotherapy was statistically significant positive prognostic factor for OS compared to WBRT (median OS 18 vs. 6,1 months, HR 0.59, p = 0.018) with no effect on localPFS.

CONCLUSION

Our results of comprehensive local treatment of BM are comparable with the results presented by important foreign studies from prestigious oncology centers. We described targeted stereotactic postoperative radiotherapy as an independent positive prognostic factor after brain metastasectomy. The study was supported by Ministry of Health, Czech Republic-conceptual development of research organization (FNBr, 65269705).