julilili42/papers huggingface dataset:
Prevalence of COVID-19 and Psychotropic Drug Treatment in Psychiatric In-patients in Germany in 2020: Results from a Nationwide Pilot Survey
2023-11-01

Abstract Introduction In patients with a pre-existing mental disorder, an increased risk for a first manifestation of a psychiatric disorder in COVID-19 patients, a more severe course of COVID-19 and an increased mortality have been described. Conversely, observations of lower COVID-19 incidences in psychiatric in-patients suggested protective effects of psychiatric treatment and/or psychotropic drugs against COVID-19. Methods A retrospective multi-center study was conducted in 24 German psychiatric university hospitals. Between April and December 2020 (the first and partly second wave of COVID-19), the effects of COVID-19 were assessed on psychiatric in-patient care, the incidence and course of a SARS-CoV-2 infection, and treatment with psychotropic drugs. Results Patients (n=36,322) were admitted to the hospitals. Mandatory SARS-CoV-2 tests before/during admission were reported by 23 hospitals (95.8%), while 18 (75%) conducted regular testing during the hospital stay. Two hundred thirty-two (0.6%) patients were tested SARS-CoV-2-positive. Thirty-seven (16%) patients were receiving medical treatment for COVID-19 at the psychiatric hospital, ten (4.3%) were transferred to an intermediate/intensive care unit, and three (1.3%) died. The most common prescription for SARS-CoV-2-positive patients was for second-generation antipsychotics (n=79, 28.2%) and antidepressants (SSRIs (n=38, 13.5%), mirtazapine (n=36, 12.9%) and SNRIs (n=29, 10.4%)). Discussion Contrary to previous studies, our results showed a low number of infections and mortality in SARS-CoV-2-positive psychiatric patients. Several preventive measures seem effective to protect this vulnerable group. Our observations are compatible with the hypothesis of a protective effect of psychotropic drugs against COVID-19 as the overall mortality and need for specific medical treatment was low.
Intrinsic flat stability of the positive mass theorem for asymptotically hyperbolic graphical manifolds
2023-11-01

Abstract The rigidity of the Riemannian positive mass theorem for asymptotically hyperbolic manifolds states that the total mass of such a manifold is zero if and only if the manifold is isometric to the hyperbolic space. This leads to study the stability of this statement, that is, if the total mass of an asymptotically hyperbolic manifold is almost zero, is this manifold close to the hyperbolic space in any way? Motivated by the work of Huang, Lee and Sormani for asymptotically flat graphical manifolds with respect to intrinsic flat distance, we show the intrinsic flat stability of the positive mass theorem for a class of asymptotically hyperbolic graphical manifolds by adapting the positive answer to this question provided by Huang, Lee and the third named author.
NCOG-29. THE NEURO-ONCOLOGY MAGNITUDE OF CLINICAL BENEFIT SCALE (NEURO-MCBS) AS A COMPREHENSIVE AND CLINICALLY RELEVANT ASSESSMENT TOOL TO DETERMINE CLINICAL BENEFIT FROM TARGETED THERAPIES IN CNS TUMORS
2023-11-01

Abstract BACKGROUND Once first-line therapy options fail, there are no effective therapy options for most neuro-oncological conditions, including glioblastoma, gliomas, and brain metastases, thereby representing a high unmet clinical need. Novel targeted therapy options are often explored in small phase-I studies or are given as off-label therapies. Assessment of treatment efficacy in this setting is challenging and should incorporate outcome measures such as progression-free survival (PFS) or objective response rate (ORR) as well as clinical parameters. To address this, we developed the Neuro-Oncology Magnitude of Clinical Benefit Scale (Neuro-MCBS) as a comprehensive clinical tool to assess treatment efficacy in patients with CNS tumors who receive off-label targeted therapies outside of clinical trials. We prospectively evaluated the feasibility and clinical utility of the Neuro MCBS in a neuro-oncology patient cohort enrolled in MTB@ZPM. METHODS MTB@ZPM (NCT03503149) is a longitudinal observational study that provides comprehensive molecular profiling, consensus-guided and ranked targeted therapy recommendations and collection of prospective clinical outcome data. The Neuro-MCBS (grade 1 + 2=clinical benefit, grade 3=minimal benefit, grade 0=no benefit) was applied and correlated with PFS, the PFS2/PFS1 ratio, performance status (KPS, ECOG), and imaging parameters. RESULTS From February 1st, 2022 until January 31st, 2023, 70 patients were enrolled. While only a minority of n=17/36 (47%) glioblastoma and n=2/8 (25%) IDH-mutant astrocytoma patients benefited from targeted therapies, n=7/8 (88%) meningioma, n=9/10 (90%) brain metastases, and n=5/8 (63%) other tumor patients achieved a Neuro-MCBS of 1 or 2, i.e. derived clinical benefit from the molecularly based therapy. CONCLUSIONS The Neuro-MCBS is a comprehensive and clinically relevant assessment tool that incorporates clinical, imaging, and survival outcome data to determine the degree of clinical benefit from targeted therapies in patients with primary and secondary CNS tumors. Its incorporation into clinical practice provides an objective outcome measure of clinical utility vs. futility of targeted therapies.
Large-scale lipidomics profiling reveals characteristic lipid signatures associated with an increased cardiovascular risk
2023-11-01

Abstract Background Patients with cardiovascular disease (CVD) are at high risk to develop adverse events.1 The distinct risk of developing recurring adverse cardiovascular events is not solely explained by traditional risk factors.2-4 Platelets are essentially involved in progression of CVD including coronary artery disease (CAD) and platelet hyperreactivity leads to development of adverse cardiovascular (CV) events.5-7 Alterations in the platelet lipidome are associated with disease severity in CAD and lead to platelet hyperresponsiveness and thus might alter the individual risk profile.8,9 Objective In this study we investigate the platelet lipidome of CAD patients by untargeted lipidomics and elucidate alterations in the lipid composition of patients with recurring adverse cardiovascular events. Methods We characterized the platelet lipidome in a large consecutive CAD cohort (n=1057) by an untargeted lipidomics approach using liquid chromatography coupled to mass spectrometry. Results The platelet lipidome in this study covered 767 lipids and characteristic changes occurred in patients with adverse cardiovascular events. The most prominent upregulated lipids in patients with cardiovascular events primarily belong to the class of phospholipids (lysophosphatidylethanolamines (LPE)) and fatty acyls (acylcarnitines (CAR) and unsaturated fatty acids (FA)). It was striking that patients with ischemic events exclusively showed upregulation of LPE whereas mainly CAR and FA were upregulated in patients with major bleeding events in contrast to patients without CV events (Figure 1 A, B). PCA revealed a major separation of patients with adverse CV events when compared to patients free from any events during follow-up indicating a substantial change in the platelet lipidome of patients with adverse CV events (Figure 1C). Further, upregulated platelet lipids are associated with an increased cardiovascular or bleeding risk and independently predict upcoming adverse events (Figure 2 A, B). Stratification of an increased CV risk in patients with CAD including platelet lipids outperformed conventional risk assessment utilizing conventional lipids measurements (e.g. plasma lipoproteins) (Figure 2 C). In addition, specific alterations of the platelet lipidome, including LPE and CAR are associated with modulation of in vitro platelet functions and thus, might contribute to the development of adverse CV events by promotion or inhibition of platelet functions (Figure 2D, E). Conclusions Our results reveal that the composition of the platelet lipidome is altered in CVD patients with an increased cardiovascular risk and distinct platelet lipids may indicate adverse events. Results of this study may contribute to improved risk discrimination and classification for cardiovascular events in patients with CVD. Further, altered lipid signatures might modulate platelet function and contribute to disease progression and development of adverse CV events in patients with CVD.Figure 1Figure 2
Mitochondrial succinate transport as a novel therapeutic target for cardiac ischemia/reperfusion injury
2023-11-01

Abstract Background The accumulation of the mitochondrial metabolite succinate during ischemia and its rapid oxidation by succinate dehydrogenase (SDH) upon reperfusion drives ischemia/reperfusion injury (IRI) in myocardial infarction. Succinate oxidation leads to the production of reactive oxygen species (ROS) by reverse electron transport (RET) at mitochondrial complex I, orchestrating a cascade of events leading to cardiomyocyte death. Modulating succinate metabolism, such as SDH inhibition, is a promising therapeutic strategy. During ischemia, the mitochondria produced succinate is transported into the cytosol, enabling the accumulation of a large succinate pool. On reperfusion, the succinate is transported back into mitochondria and oxidised by SDH, thus we hypothesised that targeting succinate mitochondrial transport could be a novel therapeutic target to prevent cardiac IRI. Purpose To assess the role of succinate mitochondrial transport as a novel therapeutic target to prevent cardiac IRI. Methods Isolated heart mitochondria were used to assess mitochondrial respiration by Oroboros, RET-ROS production by Amplex Red and butylmalonate delivery. Cultured H9C2 myoblasts and isolated primary adult cardiomyocytes from C57BL/6J mice were used to assess butylmalonate uptake and delivery from esters, as well as their impact on succinate accumulation and oxidation in vitro. LAD ligation and reperfusion in C57BL/6J mice was used as an in vivo MI model. Metabolite levels were measured by LC-MS/MS. Results Butylmalonate, an inhibitor of the mitochondrial dicarboxylate carrier (DIC), blocks succinate-dependent respiration and RET-ROS production in isolated mitochondria. However, butylmalonate entry into cells was inefficient and does not impact infarct size after IRI in vivo. We developed novel butylmalonate esters to improve butylmalonate delivery to cardiomyocytes in vivo. We found that diacetoxymethyl butylmalonate (DAB) effectively delivered butylmalonate and could prevent succinate accumulation and oxidation in vitro. DAB could also prevent succinate-mediated respiration and RET-ROS at lower concentrations than butylmalonate alone. Finally, DAB reduced acute infarct size in vivo when administered at reperfusion. Conclusions Blocking succinate transport back into mitochondria at reperfusion prevents the damage in IRI by preventing the oxidation of succinate by SDH and downstream RET-ROS production. Therefore, targeting the mitochondrial transport of succinate may be a promising novel strategy in preventing cardiac IRI.
Long-term effects of directional deep brain stimulation in Parkinson’s disease: a randomized clinical trial on motor and non-motor symptoms
2023-11-01

Abstract Background Deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson’s disease (PD) that is more precisely focused to the desired target structure may avoid nearby structures that are responsible for undesired side effects. Objective Comparing the long-term effects of STN-DBS with segmented or ring contacts on motor and non-motor symptoms in akinetic-rigid PD patients. Methods This study was a prospective randomized clinical trial. At 6-months postoperatively, the optimal omnidirectional (OS) and directional (DS) stimulation contacts were compared in MedOFF within a double-blind cross-over design, both acutely (within one day) and chronically, i.e., after 3-week stimulation blocks of each condition. The examination included motor and non-motor evaluations (e.g., cognition, mood and quality of life). Importantly, the stimulation intensity of the optimal DS was adjusted such that the total electrical energy delivered (TEED) was equivalent to the TEED of the optimal OS. Results There were no significant differences between OS and DS with regard to all outcome parameters, with 30% less stimulation intensity of the latter. Notably, OS scored (non-significantly) better than DS in all motor and non-motor measures apart from the cognitive evaluation, where OS led to a deterioration of executive functions. However, in 3 of 19 patients, the stimulation intensity of DS needed to be increased above the TEED-estimated values to reach the motor benefits of OS. Conclusions Reliable comparisons between OS and DS require long-term clinical evaluations. A potential differential influence on motor and non-motor symptoms needs to be investigated in future confirmatory studies. Registration: ClinicalTrials.gov: NCT03548506
EXTH-53. VEGFR2-SPECIFIC CAR-T CELLS SHOW IMPROVED TUMOR INFILTRATION IN SYNGENEIC MOUSE GLIOMA MODELS
2023-11-01

Abstract BACKGROUND Chimeric antigen receptor (CAR-)T cell therapy, a powerful immunotherapy against hematological malignancies, has so far limited efficiency in solid tumors. Also in glioblastoma, a major obstacle remains limited infiltration of CAR-T cells into the tumor. Vessel-targeting CAR-T cells have been shown to infiltrate solid tumors more efficiently. Vascular endothelial growth factor receptor 2 (VEGFR2) is expressed in the glioma vasculature and VEGFR2-specific CAR-T cells prolong the survival of xenograft glioma-bearing mice. In this study, we investigated the efficacy of murine VEGFR2-specific CAR-T cells against syngeneic experimental gliomas and assessed the CAR-T cell infiltration of this approach. METHODS VEGFR2-CAR-T cells were generated by retroviral transduction to express a second generation CAR construct. Their activity was assessed in co-culture assays in vitro against murine endothelial and glioma cells, respectively. Syngeneic orthotopic mouse glioma models were used to explore the infiltration of intravenously administered CAR-T cells by in vivo fluorescence molecular tomography (FMT), ex vivo flow cytometry as well as ex vivo 3D light-sheet fluorescence microscopy (LSFM). RESULTS VEGFR2-CAR-T cells showed anti-endothelial and anti-glioma activity in vitro. Intravenous treatment with fluorescently labeled CAR-T or mock-transduced T cells of tumor-bearing mice resulted in a higher FMT signal at the tumor site. This was confirmed by ex vivo flow cytometry, wherein CAR-T cells represented a larger fraction of all T cells within the tumor (26.5% CAR versus 5.4% Mock, p = 0.0013) resulting in a higher donor T cell to tumor cell ratio. Similarly, significantly more VEGFR2-CAR-T cells were detected at the tumor site compared to tumor-targeting (but not vessel-targeting) control CAR-T cells. Currently, VEGFR2-CAR-T cell infiltration patterns as well as vasculature density are further investigated and visualized by LSFM. CONCLUSION VEGFR2-CAR-T cells show improved glioma infiltration in syngeneic mouse models. Therefore, VEGFR2 might be a relevant target that could improve CAR-T cell infiltration in glioblastoma.
Better therapeutic efficiency of omnidirectional than directional subthalamic deep brain stimulation in Parkinson’s disease
2023-11-01

Abstract Background Deep brain stimulation (DBS) using segmented electrode contacts allows for directionally steered stimulation (DS), while the conventional ring mode provides omnidirectional stimulation (OS). However, with regard to achieving better effects with the same stimulation intensity or equivalent effects with lower intensity, the comparative therapeutic efficiency of these approaches remains unclear. Objective To compare the therapeutic efficiency of subthalamic DBS using segmented and ring contacts in Parkinson’s disease (PD) patients with akinetic-rigid symptoms. Methods A double-blind, randomized monopolar review was conducted with patients in the dopaminergic medication-off state at 10 weeks postoperatively on three upper ring contacts and three contacts of the upper segmented level. Impedance measurements were obtained, and the therapeutic threshold (current strength for complete biceps brachii muscle rigidity resolution) was estimated by increasing stimulation intensity in 0.2 mA increments. Results OS with ring contacts showed an improved therapeutic threshold compared to DS with segmented contacts. At 1.1 mA stimulation intensity, complete rigidity resolution was achieved in 90% of patients with the best ring contact, whereas only 40% achieved the same outcome with the best segmented contact. In addition, OS with ring contacts exhibited 50% lower impedance than DS with segmented contacts. Conclusions Incremental adjustments in current intensity during parameter titration generate valuable stimulus-response curves for assessing therapeutic efficiency. In clinical practice, the monopolar review should give priority to identifying the optimal ring level and therapeutic threshold. Segmented contacts should be carefully considered as a potential alternative when side effects limit the feasibility of other options.
PATH-52. MENINGIOMA MOLECULAR GROUPS PREDICT RESPONSE TO SURGERY AND RADIOTHERAPY
2023-11-01

Abstract INTRODUCTION Aside from surgery, radiotherapy (RT) remains the only accepted treatment for meningiomas. However, patient selection for adjuvant RT remains controversial. We aimed to evaluate whether novel molecular and methylation groups could more accurately predict outcomes following surgery and adjuvant RT compared to WHO grade using a large clinical-molecular dataset. Method: We utilized publicly available, clinically annotated molecular datasets of meningiomas and generated de novo DNA-methylation and RNA-sequencing data. Meningiomas were classified into different molecular and methylation groups based on the methodologies of their original publications (Nassiri et al. [2021], Bayley et al.[2022], Choudhury et al.[2022], Sahm et al.[2017]) and progression-free survival (PFS) following surgery with and without adjuvant RT were analyzed. RESULTS A total of 2029 meningiomas from 11 different institutions with adjuvant RT data were included. Adjuvant RT was associated with improved PFS in WHO grade 1 meningiomas following subtotal resection(STR) and WHO grade 2 meningiomas following gross total resection(GTR) or STR. Multivariable analysis using Cox proportional hazards regression models showed that having a meningioma belonging to a hypermetabolic (MG3)(HR 3.63, 95%CI 1.47-8.99), or proliferative (MG4)(HR 7.24, 95%CI 2.84-18.49) molecular group were associated with worse PFS following surgery and adjuvant RT when controlling for age, gender, WHO grade, and extent of resection. Meningiomas belonging to DKFZ MC-intermediate, MC-malignant and UCSF hypermitotic methylation groups were also associated with worse outcomes. These relationships held true even in subgroup analysis with only WHO grade 2 meningiomas and following propensity score matching for the same clinical covariates above. Nearly all molecular and methylation classifications predicted 5-year PFS including following surgery and adjuvant RT (area under the curve [AUC] 0.61-0.72) better than WHO grade (AUC 0.51). CONCLUSIONS Molecular classification improves clinical outcome prediction for meningiomas following surgery and adjuvant radiotherapy, supporting the rationale for molecularly informed treatment decisions and potential clinical trial stratification.
CTIM-30. A PHASE 1B, OPEN-LABEL, DOSE-ESCALATION TRIAL OF THE DELTA-LIKE LIGAND 3 (DLL3)/CD3 IGG-LIKE T CELL ENGAGER, BI 764532, IN PATIENTS WITH DLL3-POSITIVE GLIOMA
2023-11-01

Abstract BACKGROUND Patients with progressive diffuse gliomas have limited treatment options. DLL3, a Notch ligand, is expressed on most diffuse gliomas. BI 764532, a humanized IgG-like T cell engager, binds selectively to DLL3-positive cells and promotes T cell-mediated cytotoxicity. Preclinical data showed activity of BI 764532 against intracranial tumors. In an ongoing first-in-human trial in patients with DLL3-positive small-cell lung carcinoma and other neuroendocrine carcinomas (NECs) including extrapulmonary NECs and large-cell NECs of the lung (NCT04429087), BI 764532 exhibited promising efficacy and manageable tolerability. Here we describe a planned Phase Ib dose-escalation/expansion trial of BI 764532 monotherapy in patients with DLL3-positive refractory/relapsed diffuse glioma. METHODS The dose-escalation part will include ~12–20 patients (≥3 patients per dose level) from 12 sites across Europe/USA. Dose escalation will be guided by Bayesian logistic regression model with overdose control. BI 764532 will be administered intravenously. Treatment will continue until disease progression, undue toxicity, informed consent withdrawn, or other reasons requiring treatment discontinuation. Once a recommended dose for expansion is established, ~15 patients from Europe will be treated in a dose-expansion phase. Key inclusion criteria: ≥18 years old; histologically confirmed primary progressive diffuse glioma who have failed on standard-of-care therapies; DLL3-positivity by IHC on archived tumor tissue by central pathology review. Key exclusion criteria: extracranial metastatic or leptomeningeal disease; previous treatment with DLL3-targeting therapies; prior treatment with bevacizumab/other anti-VEGF/anti-angiogenic treatment ≤6 months prior to first administration of BI 764532; persistent toxicity from previous treatments that has not resolved to ≤CTCAE Grade 1; diagnosis of immunodeficiency, or intake of immunosuppressive therapy ≤7 days prior to first administration of BI 764532. Primary endpoints: dose-limiting toxicities (DLTs) during the maximum tolerated dose evaluation period (escalation phase); DLTs during the entire treatment period (expansion phase). Other objectives include pharmacokinetics, pharmacodynamics, preliminary efficacy and evaluation of DLL3 as a potential biomarker.
NCOG-32. THE SPECIFIC PSYCHOSOCIAL BURDEN OF CAREGIVERS OF ADULT NEURO-ONCOLOGICAL PATIENTS - A PROSPECTIVE STUDY
2023-11-01

Abstract OBJECTIVE The diagnosis of a brain tumor represents high burden for the patients’ caregivers (CG). Psychosocial screening tools adapted to the burden profile of CG are urgently required but do not exist. The aim was to develop a problem list for neuro-oncological CGs’ unmet needs for an application in combination to the Distress Thermometer scale. METHODS CG were prospectively assessed regarding changes in everyday life, relationship, social life, emotional, physical problems, and support needs, either via questionnaire (Center A) or by a qualitative interview (center B). A qualitative content analysis was performed by an inductive/deductive approach using MAXQDA® software. RESULTS A total of 50 caregivers were assessed (25 in center A via questionnaire, 25 in center B via interviews) during outpatient visits. Most frequently reported need was the need for psychological support (29/50, 58%). This was true after initial diagnosis (26/50, 52%) as well as in case of clinical deterioration of their loved-one (30/50, 60%). The results leaded to problem categories, congruent to the NCCN distress thermometer categories for cancer patients (practical, social, emotional, physical, and spiritual/existential problems). We detected new topics including “constraints/organization of (medical) appointments” (25/50, 50%) or “constant availability required for partner” (21/50, 42%). Also, 70% (35/50) put their own interests last or adapted their leisure activities. In the qualitative interviews (Center B), further items were identified, e.g., “dealing with psychological problems of the patient” (3/25, 12%), “different coping strategies among patient/caregiver” (4/25, 16%). We defined additional problem categories specifically adapted to CG of neurooncological patients, e.g., “problems due to neurocognitive/neuropsychological symptoms of the loved-one” and “problems with role as a caregiver”. CONCLUSION The interviews reflected the unmet needs of brain tumor caregivers. Our problem list developed for CG of neurooncological patients might allow for the targeted assessment and optimization of care.