Αρχειοθήκη ιστολογίου

Δευτέρα 14 Νοεμβρίου 2022

DDEL-02. LUMBAR OMMAYA RESERVOIR- A COST EFFECTIVE ALTERNATIVE TO INTRAVENTRICULAR OMMAYA RESERVOIR FOR TREATMENT OF LEPTOMENINGEAL DISEASE

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Abstract
Introduction
Lumbar puncture (LP) is a well-established approach for intrathecal (IT) delivery of chemotherapeutics for leptomeningeal disease (LMD). Intraventricular Ommaya reservoir (OR) has supplanted LPs as an easier and safer route for IT administration. Radiotherapy for treatment of LMD must be delayed in order for surgical wound healing following OR placement. Furthermore, prior cranial radiation can thin the scalp, predisposing to wound breakdown. Placement of lumbar Ommaya reservoir (LOR) provides an alternative to IT delivery, but this has not reached a wide-spread acceptance. Objective Provide cost-analysis and report patient outcomes after placement of LOR.
METHODS
Following IRB approval, all patients undergoing LOR placement between 2018 and 2020 were retrospectively reviewed. Patients age, primary tumor, survival lengths and complications were reviewed. Average procedure-related treatment cost was obtained from an uncomplicated representative case excluding the surgeon's fee.
RESULTS
Fourteen patients (mean age 46.35 years) were identified. The mean follow-up was 440.7 (25-1003) days post-surgery. Acute lymphoblastic leukemia (n = 4), acute myeloblastic leukemia (n = 3), breast carcinoma (n = 3), ependymoma (n = 3), lymphoma (n = 2) and lung adenocarcinoma (n = 1) were identified as underlying malignancy. LMD was diagnosed on average after 581.1 days after the diagnosis of the underlying malignancy. 8 patients succumbed to their malignancy on average after 463.9 and 314.6 days after the diagnosis of LMD and LOR surgery, respectively. There were 2 complications – pain at the site of the LOR and a fractured catheter caused by inadvertent puncture of the catheter. No infections or wound healing complications were noted. Typical cost for placement of LOR and OR was – 17,350 USD and 29,052 USD, respectively. Placement of the LOR proved to be more cost-effective in this cohort by ap proximately 40% cost reduction.
CONCLUSION
Placement of LOR is a cost effective alternative to cranial OR with low complication profile, and well tolerated by patients.
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TMIC-19. NEURODEVELOPMENTAL SUBTYPES SHAPE LIPID METABOLIC REPROGRAMMING IN GLIOMAS

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Abstract
Gliomas have been classified into molecular (proneural, classical, mesenchymal) and neurodevelopmental (astrocyte, mesenchymal, neural progenitor cell (NPC), oligodendrocyte progenitor cell (OPC)) subtypes describing inter- and intra-tumoral heterogeneity; however, the functional outcomes and therapeutic implications of these subtypes has yet to be fully described. Metabolic reprogramming is a hallmark of cancer, and malignant cells, including gliomas, acquire metabolic adaptations in response to a multitude of intrinsic (oncogenotype, mutations) and extrinsic (tumor microenvironment) factors to fuel neoplastic progression. Altered metabolism in glioma is of particular interest given the extensive molecular heterogeneity of tumors, while also developing in the brain microenvironment, a tissue known for its unique metabolic milieu. It is unknown whether neurodevelopmental subtypes influence metabolism in gliomas. Preliminary comprehensive lipidomi c and transcriptomic analysis of over 200 patient-derived glioma samples revealed that distinct lipid signatures were linked to neurodevelopmental subtypes. Specifically, proneural-like gliomas (OPC, NPC, Neuron) had a lipid metabolic profile enriched in ether lipids. Conversely, mesenchymal-like gliomas (radial glia, MES.progenitor, vascular) have a lipid metabolic profile enriched in triacylglycerides (TAGs). Intriguingly, these differences in lipid metabolic programs between subtypes were associated with environmental dependencies; in contrast to more mesenchymal like gliomas, which could grow irrespective of tumor microenvironment (brain or in vitro cell culture), the proneural-like gliomas required features of the brain microenvironment to accumulate complex fatty acids and grow. Collectively, these data emphasize the metabolic heterogeneity within gliomas, and reveal a subset of gliomas that lack metabolic plasticity in fatty acid biosynthetic programs, indicating a potential brain-microenvironment specific metabolic dependency linked to transcriptional identity that may be targeted for therapy.
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NCMP-10. NEURO-OPHTHALMOLOGICAL FINDINGS IN CHILDREN AND ADOLESCENTS WITH MEDULLOBLASTOMA - A RETROSPECTIVE ANALYSIS

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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.
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CTIM-13. LOCAL ADOPTIVE CELLULAR IMMUNOTHERAPY WITH CYTOKINE-INDUCED KILLER (CIK) CELLS FOR HIGH GRADE GLIOMAS: A PILOT STUDY WITH LONG-TERM FOLLOW-UP AND POTENTIAL FACTORS FOR SURVIVAL BENEFITS

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Abstract
BACKGROUND
Immunotherapy is emerging as a promising approach for the treatment of high grade gliomas (HGGs). We reported the long-term follow-up of 6 HGG patients treated by local administration of autologous cytokine-induced killer (CIK) cells through Ommaya reservoirs implanted into the tumor cavity following operation. Meanwhile, Gene expression profiles and immune microenvironments of tumors were further compared between the long-term and short -term survivors.
METHODS
Clinicopathological characteristics and outcomes of patients were reviewed and updated. Gene expression profiles, expressions of cytokines and infiltrations of immune cells in tumors were investigated by RNA sequencing, an electrochemiluminescence assay and immunohistochemistry staining, respectively
RESULTS
Fever and symptoms of encephaledema occurred in 5 patients after local administration of CIK cells, and could be efficiently relieved by mannito l and dexamethasone. Four patients died from progressive disease during follow-up, and their overall survival ranged from 6 to 26 months. Remarkably, 2 patients have survived more than 200 months without evidence of recurrence. Comparing with the tumors of the short-term survivors, 353 genes which were highly associated with tumor microenvironment immune were differentially expressed (false discovery rate (FDR) < 0.05 and log2 fold change (FC) ≥ 1) in the tumor of the long-term survivor. Higher expressions of cytokines, especially IL-8 and IL-10, were observed in the tumor of the long-term survivor, while the infiltrations of M2 polarized macrophages were significantly higher in the tumors of short-term survivors.
CONCLUSION
Long-term survival of HGG patients could achieve after local administration of CIK cells into tumor cavity postoperatively. High expressions of cytokines and low infiltrations of M2 polarized macrophages in the tumors potentially benefited the CIK cell therapy.
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TMIC-32. TUMOR CELL CILIA ASSOCIATE WITH SPECIFIC IMMUNE CELL POPULATIONS IN HUMAN AND MOUSE MODELS OF GBM

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

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

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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.
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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

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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.

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

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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
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