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Kaposiform lymphangiomatosis (KLA) is a rare lymphatic anomaly primarily affecting the mediastinum with high mortality rate. We present a patient with KLA and significant disease burden harboring a somatic point mutation in the Casitas B lineage lymphoma ( CBL ) gene. She was treated with MEK inhibition with complete resolution of symptoms, near‐complete resolution of lymphatic fluid burden, and remodeling of her lymphatic system. While patients with KLA have been reported to harbor mutations in NRAS , here we report for the first time a causative mutation in the CBL gene in a patient with KLA, successfully treated with Ras pathway inhibition. Synopsis Report of a patient with the rare lymphatic anomaly, Kaposiform lymphangiomatosis (KLA). CBL proto‐oncogene mutation was identified and she was successfully treated by targeting the MAP kinase pathway. Identification of CBL mutation driving KLA. Patient successfully treated with MEK inhibition. Graphical Abstract Report of a patient with the rare lymphatic anomaly, Kaposiform lymphangiomatosis (KLA). CBL proto‐oncogene mutation was identified and she was successfully treated by targeting the MAP kinase pathway.

Purpose of ReviewGiven the invasive and high-risk nature of brain surgery, the need for non-invasive biomarkers obtained from the peripheral blood is greatest in tumors of the central nervous system (CNS). In this comprehensive review, we highlight recent advances in blood biomarker development for adult and pediatric brain tumors.Recent FindingsWe summarize recent blood biomarker development for CNS tumors across multiple key analytes, including peripheral blood mononuclear cells, cell-free DNA, cell-free RNA, proteomics, circulating tumor cells, and tumor-educated platelets. We also discuss methods for enhancing blood biomarker detection through transient opening of the blood-brain barrier.SummaryAlthough blood-based biomarkers are not yet used in routine neuro-oncology practice, this field is advancing rapidly and holds great promise for improved and non-invasive management of patients with brain tumors. Prospective and adequately powered studies are needed to confirm the clinical utility of any blood biomarker prior to widespread clinical implementation.

Pediatric low-grade gliomas (pLGGs) exhibit heterogeneous prognoses and variable responses to treatment, leading to tumor progression and adverse outcomes in cases where complete resection is unachievable. Early prediction of treatment responsiveness and suitability for immunotherapy has the potential to improve clinical management and outcomes. Here, we present a radiogenomic analysis of pLGGs, integrating MRI and RNA sequencing data. We identify three immunologically distinct clusters, with one group characterized by increased immune activity and poorer prognosis, indicating potential benefit from immunotherapies. We develop a radiomic signature that predicts these immune profiles with over 80% accuracy. Furthermore, our clinicoradiomic model predicts progression-free survival and correlates with treatment response. We also identify genetic variants and transcriptomic pathways associated with progression risk, highlighting links to tumor growth and immune response. This radiogenomic study in pLGGs provides a framework for the identification of high-risk patients who may benefit from targeted therapies. Understanding the molecular and pathological features of paediatric low-grade glioma (pLGG) is crucial to develop targeted therapies. Here, the authors perform a radiogenomic analysis of pLGGs combining treatment-naïve multiparametric MRI and RNA sequencing, enabling prognostication based on immune profiles as well as prediction of treatment response.

Diffuse intrinsic pontine glioma (DIPG) is a fatal brainstem tumor desperately in need of better treatments. Chimeric antigen receptor (CAR) T cell therapies for DIPG have demonstrated clinical tolerability and bioactivity, but not universal benefit. A major obstacle is insufficient CAR T cell trafficking to the tumor. As our recent clinical trials have demonstrated locoregional elevation of CXCL10, a ligand of the chemokine receptor CXCR3, here we aim to leverage this CXCL10 upregulation to enhance cell trafficking by engineering our B7-H3-targeting CAR T cells to overexpress CXCR3 variants. We demonstrate that, compared to unmodified B7-H3 CAR T cells, CXCR3-A-modified CAR T cells migrate more efficiently toward CXCR3 ligands in vitro, and when delivered intracerebroventricularly in orthotopic DIPG mouse models, CXCR3-A-modified CAR T cells show enhanced trafficking into the tumor and improved therapeutic efficacy. Overall, our data support the potential for engineering CXCR3-A expression to enhance CAR T cell trafficking and efficacy against DIPG. CAR T cell therapies have been developed to treat paediatric diffuse intrinsic pontine glioma (DIPG), however, clinical efficacy remains limited. Here, the authors report that engineering B7-H3-targeting CAR T cells to express the chemokine receptor CXCR3-A enhances their trafficking and efficacy in DIPG preclinical models.

Uterine glands are essential for pregnancy establishment. By employing forkhead box A2 (FOXA2)-deficient mouse models coupled with leukemia inhibitory factor (LIF) repletion, we reveal definitive roles of uterine glands in embryo implantation and stromal cell decidualization. Here we report that LIF from the uterine glands initiates embryo-uterine communication, leading to embryo attachment and stromal cell decidualization. Detailed histological and molecular analyses discovered that implantation crypt formation does not involve uterine glands, but removal of the luminal epithelium is delayed and subsequent decidualization fails in LIF-replaced glandless but not gland-containing FOXA2-deficient mice. Adverse ripple effects of those dysregulated events in the glandless uterus result in embryo resorption and pregnancy failure. These studies provide evidence that uterine glands synchronize embryo-endometrial interactions, coordinate on-time embryo implantation, and impact stromal cell decidualization, thereby ensuring embryo viability, placental growth, and pregnancy success. The transcription factor FOXA2 is specifically expressed in uterine glands. Here, using two conditional FOXA2 knockout mouse models, the authors show that glandular epithelia of the endometrium are required for timely embryo implantation and subsequent endometrial decidualization during successful pregnancy establishment.

Several model plants are known to respond to bacterial quorum sensing molecules with altered root growth and gene expression patterns and induced resistance to plant pathogens. These compounds may represent novel elicitors that could be applied as seed primers to enhance cereal crop resistance to pathogens and abiotic stress and to improve yields. We investigated whether the acyl-homoserine lactone N-hexanoyl-L-homoserine lactone (C6-HSL) impacted winter wheat (Triticum aestivum L.) seed germination, plant development and productivity, using two Ukrainian varieties, Volodarka and Yatran 60, in both in vitro experiments and field trials. In vitro germination experiments indicated that C6-HSL seed priming had a small but significant positive impact on germination levels (1.2x increase, p < 0.0001), coleoptile and radicle development (1.4x increase, p < 0.0001). Field trials over two growing seasons (2015-16 and 2016-17) also demonstrated significant improvements in biomass at the tillering stage (1.4x increase, p < 0.0001), and crop structure and productivity at maturity including grain yield (1.4-1.5x increase, p < 0.0007) and quality (1.3x increase in good grain, p < 0.0001). In some cases variety effects were observed (p ≤ 0.05) suggesting that the effect of C6-HSL seed priming might depend on plant genetics, and some benefits of priming were also evident in F1 plants grown from seeds collected the previous season (p ≤ 0.05). These field-scale findings suggest that bacterial acyl-homoserine lactones such as C6-HSL could be used to improve cereal crop growth and yield and reduce reliance on fungicides and fertilisers to combat pathogens and stress.

BackgroundPediatric brain tumors are the leading cause of cancer death in children with an urgent need for innovative therapies. Glypican 2 (GPC2) is a cell surface oncoprotein expressed in neuroblastoma for which targeted immunotherapies have been developed. This work aimed to characterize GPC2 expression in pediatric brain tumors and develop an mRNA CAR T cell approach against this target.MethodsWe investigated GPC2 expression across a cohort of primary pediatric brain tumor samples and cell lines using RNA sequencing, immunohistochemistry, and flow cytometry. To target GPC2 in the brain with adoptive cellular therapies and mitigate potential inflammatory neurotoxicity, we used optimized mRNA to create transient chimeric antigen receptor (CAR) T cells. We developed four mRNA CAR T cell constructs using the highly GPC2-specific fully human D3 single chain variable fragment for preclinical testing.ResultsWe identified high GPC2 expression across multiple pediatric brain tumor types including medulloblastomas, embryonal tumors with multilayered rosettes, other central nervous system embryonal tumors, as well as definable subsets of highly malignant gliomas. We next validated and prioritized CAR configurations using in vitro cytotoxicity assays with GPC2-expressing neuroblastoma cells, where the light-to-heavy single chain variable fragment configurations proved to be superior. We expanded the testing of the two most potent GPC2-directed CAR constructs to GPC2-expressing medulloblastoma and high-grade glioma cell lines, showing significant GPC2-specific cell death in multiple models. Finally, biweekly locoregional delivery of 2–4 million GPC2-directed mRNA CAR T cells induced significant tumor regression in an orthotopic medulloblastoma model and significantly prolonged survival in an aggressive orthotopic thalamic diffuse midline glioma xenograft model. No GPC2-directed CAR T cell related neurologic or systemic toxicity was observed.ConclusionTaken together, these data show that GPC2 is a highly differentially expressed cell surface protein on multiple malignant pediatric brain tumors that can be targeted safely with local delivery of mRNA CAR T cells, laying the framework for the clinical translation of GPC2-directed immunotherapies for pediatric brain tumors.

Aims: Preconception planning is an essential component of improving maternal and child health, particularly for individuals with mental health conditions. Within this population those with severe and enduring mental illnesses face significant barriers to accessing preconception care and are at higher risk of unplanned pregnancy, leading to suboptimal outcomes for both mothers and babies. This poster outlines the establishment of a preconception planning clinic for individuals within a mental health rehabilitation setting, developed through a collaborative initiative between the Rehabilitation and Recovery Service, Perinatal Mental Health Service, All Wales Psychiatric Genomics Service and Sexual Health services. The clinic aims to provide personalised, multidisciplinary support to women with severe and enduring mental health conditions who are of childbearing age, ensuring that their mental health, medical, and social needs are addressed in a holistic and coordinated manner. Key components include individualised care planning, medication review, counselling on genetic risk to the baby, and psychosocial support, as well as the provision of education on reproductive health, contraception, and healthy relationships. Risks and impact to both mother and baby will be central to all discussions. Methods: Through close collaboration between the Rehabilitation and Recovery Service, Perinatal Mental Health Service, All Wales Psychiatric Genomics Service and Sexual Health services, the clinic will foster an integrated approach to care, promoting early intervention and prevention of adverse outcomes. This initiative also supports service users in navigating the complexities of mental health during pregnancy, enhancing their confidence in planning for a safe and supported conception. Results: The hope is that this clinic will promote proactive discussion of reproduction and sexual health within a population that have historically been overlooked in this aspect and reduce associated stigma and inequity. Conclusion: The poster will showcase the clinic’s design, key challenges encountered, strategies for team integration, and initial outcomes from service users, with the aim of providing a model for other settings seeking to improve preconception care for individuals with severe and enduring mental illness.

Increasing evidence suggests that besides mutational and molecular alterations, the immune component of the tumor microenvironment also substantially impacts tumor behavior and complicates treatment response, particularly to immunotherapies. Although the standard method for characterizing tumor immune profile is through performing integrated genomic analysis on tissue biopsies, the dynamic change in the immune composition of the tumor microenvironment makes this approach not feasible, especially for brain tumors. Radiomics is a rapidly growing field that uses advanced imaging techniques and computational algorithms to extract numerous quantitative features from medical images. Recent advances in machine learning methods are facilitating biological validation of radiomic signatures and allowing them to “mine” for a variety of significant correlates, including genetic, immunologic, and histologic data. Radiomics has the potential to be used as a non-invasive approach to predict the presence and density of immune cells within the microenvironment, as well as to assess the expression of immune-related genes and pathways. This information can be essential for patient stratification, informing treatment decisions and predicting patients’ response to immunotherapies. This is particularly important for tumors with difficult surgical access such as gliomas. In this review, we provide an overview of the glioma microenvironment, describe novel approaches for clustering patients based on their tumor immune profile, and discuss the latest progress on utilization of radiomics for immune profiling of glioma based on current literature.

Background The aim of the present study was to investigate microglia activation over time following traumatic brain injury (TBI) and to relate these findings to glutamate release. Procedures Sequential dynamic (R) -[ 11 C]PK11195 PET scans were performed in rats 24 hours before (baseline), and one and ten days after TBI using controlled cortical impact, or a sham procedure. Extracellular fluid (ECF) glutamate concentrations were measured using cerebral microdialysis. Brains were processed for histopathology and (immuno)-histochemistry. Results Ten days after TBI, (R) -[ 11 C]PK11195 binding was significantly increased in TBI rats compared with both baseline values and sham controls (p < 0.05). ECF glutamate values were increased immediately after TBI (27.6 ± 14.0 μmol·L -1 ) as compared with the sham procedure (6.4 ± 3.6 μmol·L -1 ). Significant differences were found between TBI and sham for ED-1, OX-6, GFAP, Perl's, and Fluoro-Jade B. Conclusions Increased cerebral uptake of (R) -[ 11 C]PK11195 ten days after TBI points to prolonged and ongoing activation of microglia. This activation followed a significant acute posttraumatic increase in ECF glutamate levels.