CTIM-32. FIRST-IN-CHILDREN PHASE 1 TRIAL OF INDOXIMOD-BASED CHEMO-IMMUNOTHERAPY FOR PATIENTS WITH PEDIATRIC BRAIN TUMORS: ANALYSIS OF SAFETY, TOLERABILITY, AND 5-YEAR OUTCOME

alexandrossfakianakis shared this article with you from Inoreader CTIM-32. FIRST-IN-CHILDREN PHASE 1 TRIAL OF INDOXIMOD-BASED CHEMO-IMMUNOTHERAPY FOR PATIENTS WITH PEDIATRIC BRAIN TUMORS: ANALYSIS OF SAFETY, TOLERABILITY, AND 5-YEAR OUTCOME via # Neuro-Oncology Current Issue Abstract BACKGROUND Recurrent brain tumors are the leading cause of cancer death in children. We conducted a first-in-children, two-institution, Phase 1 open-label dose-confirmation study using a 3 + 3 design, with expansion cohorts, to determine the recommended pediatric dose of the IDO pathway-inhibitor indoximod (NCT02502708). DESIGN/ METHODS Eligible patients were 3-22 years old with either recurrent malignant brain tumor or newly-diagnosed diffuse intrinsic pontine glioma (DIPG). Palliative radiation, surgery or dexamethasone were allowed as needed for patient management. Separate dose-finding arms were performed for indoximod plus temozolomide (200 mg/m2/day orally for 5 days of each 28-day cycle) and for indoximod plus conformal radiation (in patients for whom re-irradiation was planned as standard-of-care). At progression, patients who were otherwise clinically stable were offered crossover to indoximod plus a second-line chemot herapy regimen (cyclophosphamide 2.5 mg/kg/day orally and etoposide 50 mg/m2/day orally for 21 days of each 28-day cycle). RESULTS Between December 2015 and January 2019, the study enrolled 81 brain tumor patients, including newly-diagnosed DIPG (n = 13) or recurrent ependymoma (n = 27), glioblastoma/high-grade glioma (n = 19), medulloblastoma (n = 13), or other CNS tumors ( n= 9). Median follow-up was 52 months (range 39-77 months). No dose-limiting toxicities were observed, and the pediatric indoximod dose was determined (19.2 mg/kg/dose, given twice daily). Indoximod was well tolerated and did not affect the ability to deliver chemotherapy or radiation as planned. Median overall survival was 13.6 months (n = 81). Median overall survival was 34.7 months for the subset of patients who continued indoximod with second-line chemotherapy after progression on indoximod plus temozolomide (n = 18). CONCLUSIONS Indoximod was well tolerated and could be combined with a var iety of standard treatments for pediatric brain tumors. Preliminary anti-tumor activity and overall survival suggest that indoximod with standard therapy should be further evaluated in pediatric brain tumors, and potentially other pediatric solid tumors. View on Web

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NCMP-10. NEURO-OPHTHALMOLOGICAL FINDINGS IN CHILDREN AND ADOLESCENTS WITH MEDULLOBLASTOMA - A RETROSPECTIVE ANALYSIS

alexandrossfakianakis shared this article with you from Inoreader NCMP-10. NEURO-OPHTHALMOLOGICAL FINDINGS IN CHILDREN AND ADOLESCENTS WITH MEDULLOBLASTOMA - A RETROSPECTIVE ANALYSIS via # Neuro-Oncology Current Issue Abstract BACKGROUND Medulloblastoma represents the most common malignant pediatric brain tumor. Ophthalmic complications are possible sequelae. METHODS Pediatric medulloblastoma (MB) patients treated at the Medical University of Vienna from January 2012 to August 2021 were analyzed and their last ophthalmic assessment was reviewed. RESULTS Fifty-six MB patients could be included (71.4% non-WNT/non-SHH, 16.1% SHH-activated, 8.9% WNT-activated, 3.6% non-specified). Mean age at diagnosis was 7.2 years (range 0-19). Median follow-up to last ophthalmological assessment was 19.7 months (range 0.1-93.2). Thirty-four children underwent tumor resection at our hospital, their tumor localizations were: vermis (55.9%), floor of the 4th ventricle (26.5%), cerebellar hemispheres (11.8%), lateral recess (5.9%). Symptoms at presentation were evaluable for 51 children: 92.2% had symptoms of elevated intracranial pressure, 76.5% ataxi a and 21.6% visual disturbances. Postoperative posterior fossa syndrome was observed in 11.1% of 54 children. 98.2% had chemotherapy as part of their initial treatment and all children older than four years (85.7%) received postoperative irradiation of the posterior fossa. In 13 (23.2%) intraventricular chemotherapy was applied. At the last follow-up 21 patients experienced relapse after primary treatment. At the final assessment, frequent neuro-ophthalmological abnormalities included: oculomotor disturbance (75%), esotropia (35.7%) including abducens palsy (12.5%), other cranial nerve palsies (21.4%), horizontal gaze-evoked nystagmus (51.8%), spontaneous nystagmus (16.1%), ocular tilt reaction (21.4%), and optic disc abnormalities (14.3%). Good visual acuity (≥20/25) was maintained in 62.5% patients. Visual field and optical coherence tomography was successfully performed in 75% and 66.1% of patients, respectively. Optic pathway lesions were detected in 4 patients (7.1%), includi ng two cases with occipital metastases, one with optic nerve metastasis and one with leptomeningeal carcinomatosis. Orthoptic treatment with prisms and strabismus surgery was required in 14.3% and 7.7% of children, respectively. CONCLUSION Children with MB frequently suffer from neuro-ophthalmological late-effects. Regular monitoring is warranted to initiate appropriate management. View on Web

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TMIC-32. TUMOR CELL CILIA ASSOCIATE WITH SPECIFIC IMMUNE CELL POPULATIONS IN HUMAN AND MOUSE MODELS OF GBM

alexandrossfakianakis shared this article with you from Inoreader TMIC-32. TUMOR CELL CILIA ASSOCIATE WITH SPECIFIC IMMUNE CELL POPULATIONS IN HUMAN AND MOUSE MODELS OF GBM via # Neuro-Oncology Current Issue Abstract INTRODUCTION Glioblastoma (GBM) typically recurs after standard of care therapies. A major obstacle is that GBMs employ various mechanisms to suppress the host immune system, preventing destruction and removal of cancer cells. A better understanding of the crosstalk mechanisms between tumor and immune cell types is needed to advance immunotherapeutic approaches against GBM. GBMs contain primary cilia, organelles likened to both cellular 'antennae' and transmitters, and their presence is associated with more aggressive and treatment resistant tumors. OBJECTIVE To explore whether ciliated GBM cells associate with infiltrating immune cells and to determine if these interactions are specific for certain immune cell populations. METHODS We immunostained GBM patient specimens and sections from syngeneic mouse models of GBM for markers of cilia (ARL13B and gTub) together with various immune cell markers (CD45, CD11b, Ly-6 B.1, CD3). Cilia were also examined in brain tumors generated in CCR2+/rfp/CX3CR1+/gfp mice, to evaluate the proximity of glioma cell cilia to CCR2- and CX3CR1-expressing myeloid cell subpopulations (brain resident microglia as well as peripheral-derived macrophages and monocyctic- MDSCs (M-MDSCs). Proximity of tumor cell cilia to different markers or cell types was quantified using nearest neighbor analyses. RESULTS In patient samples, CD45+ cells extended processes that contacted the tumor cilia and cilia tip. Similar observations were made in intracranial GBM-bearing mice where we detected juxtaposition of cilia with recruited immune cells (i.e. CD45, CD11b and Ly-6B.1). Notably, cilia predominately associated with immune-suppressive M-MDSCs. Further, CD3+ T cells rarely juxtaposed tumor cilia and maintained greater distances away from ciliated tumor cells compared to M-MDSCs. CONCLUSION Our data suggest specific interactions between ciliat ed tumor cells and select immune-suppressive cell types, raising the possibility immunologically cold tumors may contain more ciliated cells. Ongoing studies are examining how the tumor immune cell landscape develops depending on the presence of tumor cilia. View on Web

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BIOM-34. MULTIPLEX PHENOTYPING OF EXTRACELLULAR VESICLES FOR ANALYSIS OF POTENTIAL BIOMARKERS IN GLIOBLASTOMA PATIENTS

alexandrossfakianakis shared this article with you from Inoreader BIOM-34. MULTIPLEX PHENOTYPING OF EXTRACELLULAR VESICLES FOR ANALYSIS OF POTENTIAL BIOMARKERS IN GLIOBLASTOMA PATIENTS via # Neuro-Oncology Current Issue Abstract INTRODUCTION Extracellular vesicles (EVs) carry biological information from their cell of origin that is useful for non-invasive detection of tumor biomarkers and disease monitoring. In glioblastoma (GBM), blood circulating EVs are elevated and carry GBM-associated proteins. However, it is still challenging to analyze tumor derived EVs for translational purposes. Here, we used imaging flow cytometry (IFCM) as a robust strategy to perform phenotyping of EVs with GBM related surface markers in human plasma. METHODS EVs were isolated via differential ultracentrifugation from plasma of (a) 40 GBM patients, pre- and post-surgery, (b) 11matched GBM relapses and (c) 12 healthy donors (HD). EV sizes and concentrations were evaluated by NTA. EV markers (CD9,CD63 and CD81) together with glioma-related markers (integrin beta-1 [ITGB1], tenascin C [TNC], Profilin-1 [PFN1], CD44,GPNMB, SPARC, HLA-II or CD133) were analyzed by IFCM. EV perce ntages and objects/mL plasma were compared among the groups and correlated with clinical parameters. RESULTS CD9 was the predominant tetraspanin in all groups (15-96%), while CD63 had the lowest levels (0-33%) and the strongestdecrease in GBM patients after surgery (fold change [FC]=-5.4, p<0.01). Among the glioma-related markers, ITGB1 and TNC displayed the most significant differences between the analyzed groups, especially the double positives ITGB1+/CD63+and TNC+/CD63+, which decreased in patients after tumor removal (FC=-3.5 and -12, respectively; p<0.001). Meanwhile,ITGB1+/CD9+and TNC+/CD9+EVs exhibited the highest levels in GBM when compared to HD subjects (FC=8.6 and 17.4;p<0.001) and upon tumor recurrence (FC=3.7 and 10.9, respectively; p<0.01). SUMMARY/CONCLUSION We identified EV surface antigens with potential clinical utility as GBM biomarkers. Among them, we highlight ITGB1 and TNC as the most promising markers. View on Web

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EPCO-33. DIFFERENTIAL EXPRESSION OF AN ENDOGENOUS RETROVIRAL ELEMENT [HERV-K(HML-6)] IS ASSOCIATED WITH REDUCED SURVIVAL IN GLIOBLASTOMA PATIENTS

alexandrossfakianakis shared this article with you from Inoreader EPCO-33. DIFFERENTIAL EXPRESSION OF AN ENDOGENOUS RETROVIRAL ELEMENT [HERV-K(HML-6)] IS ASSOCIATED WITH REDUCED SURVIVAL IN GLIOBLASTOMA PATIENTS via # Neuro-Oncology Current Issue Abstract INTRODUCTION Comprising approximately 8% of our genome, Human Endogenous RetroViruses (HERVs) represent a class of germline retroviral infections that are regulated through epigenetic modifications. In cancer cells, which often have epigenetic dysregulation, HERVs have been implicated as potential oncogenic drivers. However, their role in gliomas is not known.Given the link between HERV expression in cancer cell lines and the distinct epigenetic dysregulation in gliomas, we utilized a tailored bioinformatic pipeline to characterize and validate the glioma retrotranscriptome and correlate HERV expression with locus-specific epigenetic modifications.Method:A custom workflow was used to quantify HERV expression in our cell lines of interest. Cell-line methylation was quantified using a custom script. We generated primers specific for the Human endogenous Mouse mammary tumor (MMTV)-Like virus 6 (HML-6 ). Visualization of RNA transcripts was performed using RNA-scope. Clinical data was obtained using the R package, TCGABiolinks. RESULTS The A172 cell line had significantly higher mean overall HERV expression relative to the M059J and H4 cell lines (p< 0.0001 for both). A172 cells had significantly lower mean number of CpG islands relative to M059J cells and H4 cells (p< 0.0001 for both). There was a significant inverse correlation between mean beta value and FC HERV expression (R=-0.57, p=0.01). qPCR confirmed robust expression of the HML-6 locus in cell culture and neurospheres. Elevated ERVK3-1 expression was associated reduced survival among IDHwt GBM patients (18.3 vs. 15.1 months, p=0.039). This was preserved among IDH mutant (IDHm) GBM as well (17.9 months vs. 14.0 months, p=0.0088). CONCLUSION In gliomas, HERV expression correlates with loss of DNA methylation at HERV loci. HML- 6 is overexpressed in highly invasive glioblastoma cell lines and patient-derived neurospheres. We have demonstrated a potential survival detriment associated with elevated expression of the HML-6 product, ERVK3-1. View on Web

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TMIC-78. CIRCADIAN REGULATOR CLOCK DRIVES IMMUNOSUPPRESSION IN GLIOBLASTOMA

alexandrossfakianakis shared this article with you from Inoreader TMIC-78. CIRCADIAN REGULATOR CLOCK DRIVES IMMUNOSUPPRESSION IN GLIOBLASTOMA via # Neuro-Oncology Current Issue Abstract The symbiotic interactions between cancer stem cells and the tumor microenvironment (TME) are critical for tumor progression. However, the molecular mechanism underlying this symbiosis in glioblastoma (GBM) remains enigmatic. Here, we show that circadian locomotor output cycles kaput (CLOCK) and its heterodimeric partner brain and muscle ARNT-like 1 (BMAL1) in glioma stem cells (GSCs) drive immunosuppression in GBM. Integrated analyses of the data from transcriptome profiling, single-cell RNA sequencing, and TCGA datasets, coupled with functional studies, identified legumain (LGMN) as a direct transcriptional target of the CLOCK–BMAL1 complex in GSCs. Moreover, CLOCK-directed olfactomedin-like 3 (OLFML3) upregulates LGMN in GSCs via the hypoxia-inducible factor 1-alpha (HIF1A) signaling. Consequently, LGMN promotes microglial infiltration into the GBM TME via upregulating CD162, and polarizes infiltrating microglia towards an immune-suppressive phenotype. In GBM mouse models, inhibition of the CLOCK–OLFML3–HIF1A–LGMN–CD162 axis reduces intratumoral immune-suppressive microglia, increases CD8+ T cell infiltration, activation and cytotoxicity, and synergizes with anti-PD1 therapy. In human GBM, the CLOCK-regulated LGMN signaling correlates positively with microglial level and poor prognosis. Together, these findings uncover the CLOCK–OLFML3–HIF1A–LGMN axis as a molecular switch that controls microglial biology and immunosuppression, thus revealing potential new therapeutic targets for GBM patients. View on Web

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CSIG-19. THE PI3K/AKT/MTOR SIGNALING CASCADE MAY CONTRIBUTE TO SEX DIFFERENCES IN GLIOBLASTOMA

alexandrossfakianakis shared this article with you from Inoreader CSIG-19. THE PI3K/AKT/MTOR SIGNALING CASCADE MAY CONTRIBUTE TO SEX DIFFERENCES IN GLIOBLASTOMA via # Neuro-Oncology Current Issue Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. It is more prevalent in males and female patients exhibit a survival advantage. Understanding the molecular mechanisms that underlie those sex differences could support novel treatment strategies. The PI3K/Akt/mTOR signaling cascade plays a crucial role in GBM development and progression as it is involved in the regulation of cellular growth, survival, nutrient sensing, and metabolic activity. To investigate whether the PI3K/Akt/mTOR signaling cascade may differ in male and female GBM patients, we first assessed survival data of male and female GBM patients using the TCGA RPPA phosphoproteome data set and found that changes in protein phosphorylation of components of the PI3K/Akt/mTOR pathway, including mTOR phosphorylation, worsen the outcome of male but not female GBM patients in a dose-dependent fashion. This was supported by in vitro experiments of murine tran sformed astrocytes where pathway stimulation via treatment with insulin, IGF-1, or EGF significantly increased pathway activity in male but not female cells. Furthermore, pathway inhibition via serum deprivation resulted in a significant decrease in pathway activity in male but not female cells, indicating that male transformed astrocytes exhibit higher sensitivity to inhibitory conditions (serum deprivation) and stimulatory conditions (insulin, IGF-1, or EGF treatment). Together, these data suggest that (i) the PI3K/Akt/mTOR pathway activity may affect male and female GBM outcome differently, and (ii) there are sex differences in the regulation of the PI3K/Akt/mTOR signaling cascade in GBM which may contribute to the sex disparity in GBM. Our data add to the growing body of literature regarding the presence of sex differences in PI3K/Akt/mTOR signaling in health and disease and provide important insight for the development of translatable approaches to treatment for male and female GBM patients. View on Web

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Varicella Zoster Virus Reactivation Following COVID‐19 Vaccination in patients with autoimmune inflammatory rheumatic diseases: A cross‐sectional Chinese study of 318 cases

alexandrossfakianakis shared this article with you from Inoreader Varicella Zoster Virus Reactivation Following COVID‐19 Vaccination in patients with autoimmune inflammatory rheumatic diseases: A cross‐sectional Chinese study of 318 cases via Journal of Medical Virology Abstract Recently, varicella-zoster virus (VZV) reactivation has been observed after the administration of coronavirus disease 2019 (COVID-19) vaccines. Autoimmune inflammatory rheumatic diseases (AIIRDs) patients are at a higher risk for VZV reactivation for immunocompromised status. The study aimed to investigate the adverse events (AEs), especially VZV reactivation, following vaccination against SARS-CoV-2 in a Chinese cohort of AIIRD patients. A cross-sectional survey using an online questionnaire was conducted among AIIRD patients and healthy controls (HCs). Multivariate logistic regression was used to identify potential factors associated with VZV reactivation. 318 AIIRD patients and 318 age and sex-matched HCs who got COVID-19 inactivated vaccines were recruited. The main AIIRDs are rheumatoid arthritis (31.8%) and systemic lupus erythematous (23.9%). Most of patients (85.5%) had stable disease and 13.2% of them had aggravation after vaccination. Compared to H Cs, patients had higher rates of rash (p=0.001), arthralgia (p<0.001) and insomnia (p=0.007). In addition, there were 6 (1.9%) AIIRD patients and 5 (1.6%) HCs reported VZV reactivation after the COVID-19 vaccination (p=0.761). Multivariate logistic regression analysis illustrated that diabetes mellitus (OR, 20.69; 95%CI, 1.08-396.79; p=0.044), chronic hepatitis B virus infection (OR, 24.34; 95%CI, 1.27-466.74; p=0.034), and mycophenolate mofetil (OR, 40.61; 95%CI, 3.33-496.15; p=0.004) independently identified patients with VZV reactivation. Our findings showed that the inactivated COVID-19 vaccination was safe for AIIRD patients though some patients could suffer from VZV reactivation. This article is protected by copyright. All rights reserved. View on Web

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Low intensity near-infrared light promotes bone regeneration via circadian clock protein cryptochrome 1

alexandrossfakianakis shared this article with you from Inoreader Low intensity near-infrared light promotes bone regeneration via circadian clock protein cryptochrome 1 via International Journal of Oral Science - Issue International Journal of Oral Science, Published online: 14 November 2022; doi:10.1038/s41368-022-00207-y Low intensity near-infrared light promotes bone regeneration via circadian clock protein cryptochrome 1 View on Web

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