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Abstract Background Endovascular therapy has become established as a first-line therapy in most arterial regions. However, open vascular surgery (endarterectomy) remains the treatment of choice for common femoral artery (CFA) lesions. The aim of this study is to investigate the acute and mid-term results of directional atherectomy plus drug-coated balloon (DCB) in comparison to endarterectomy in treatment of de novo arteriosclerotic CFA lesions. Methods This prospective, randomized, multicenter non-inferiority study will enroll 306 participants with symptomatic (Rutherford category 1 to 5) de novo stenosis of the CFA including the bifurcation. Patients eligible for both treatment groups could be included in this 1:1 randomized trial. Primary efficacy endpoint is patency of the target lesion at 12 months defined as restenosis

Abstract Aims The conditions of hypoxia are suggested to induce permanent atrial fibrillation (AF). The regulation of COX4I2 and COX4I1 depends on oxygen availability in tissues. A role of COX4I2 in the myocardium of AF patients is supposed for pathogenesis of AF and subsequent alterations in the electron transfer chain (ETC) under hypoxia. Methods and results In vitro, influence of hypoxia on HeLa 53 cells was studied and elevated parts of COX 4I2 were confirmed. Myocardial biopsies were taken ex vivo from the patients' Right Atria with SR (n = 31) and AF (n = 11), respectively. RT‐ PCR for mRNA expresson, mitochondrial respiration by polarography and the protein content of cytochrome c oxidase (CytOx) subunit 4I1 and CytOx subunit 4I2 by ELISA were studied. Clinical data were correlated to the findings of gene expressions in parallel. Patients with permanent AF had a change in isoform 4I2/4I1 expression along with a decrease of isoform COX 4I1 expression. The 4I2/4I1 ratio of mRNA expression was increased from 0.630 to 1.058 in comparison. However, the protein content of CytOx subunit 4 was much lower in the AF group, whereas the respiration/units enzyme activity in both groups remained the same. Conclusions This study describes a possible molecular correlate for the development of AF. Due to the known functional significance of COX 4I2, mitochondrial dysfunction can be assumed as a part of the pathogenesis of AF.

IntroductionMyalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) presents substantial challenges in patient care due to its intricate multisystem nature, comorbidities, and global prevalence. The heterogeneity among patient populations, coupled with the absence of FDA-approved diagnostics and therapeutics, further complicates research into disease etiology and patient managment. Integrating longitudinal multi-omics data with clinical, health,textual, pharmaceutical, and nutraceutical data offers a promising avenue to address these complexities, aiding in the identification of underlying causes and providing insights into effective therapeutics and diagnostic strategies.MethodsThis study focused on an exceptionally severe ME/CFS patient with hypermobility spectrum disorder (HSD) during a period of marginal symptom improvements. Longitudinal cytokine profiling was conducted alongside the collection of extensive multi-modal health data to explore the dynamic nature of symptoms, severity, triggers, and modifying factors. Additionally, an updated severity assessment platform and two applications, ME-CFSTrackerApp and LexiTime, were introduced to facilitate real-time symptom tracking and enhance patient-physician/researcher communication, and evaluate response to medical intervention.ResultsLongitudinal cytokine profiling revealed the significance of Th2-type cytokines and highlighted synergistic activities between mast cells and eosinophils, skewing Th1 toward Th2 immune responses in ME/CFS pathogenesis, particularly in cognitive impairment and sensorial intolerance. This suggests a potentially shared underlying mechanism with major ME/CFS comorbidities such as HSD, Mast cell activation syndrome, postural orthostatic tachycardia syndrome (POTS), and small fiber neuropathy. Additionally, the data identified potential roles of BCL6 and TP53 pathways in ME/CFS etiology and emphasized the importance of investigating adverse reactions to medication and supplements and drug interactions in ME/CFS severity and progression.DiscussionOur study advocates for the integration of longitudinal multi-omics with multi-modal health data and artificial intelligence (AI) techniques to better understand ME/CFS and its major comorbidities. These findings highlight the significance of dysregulated Th2-type cytokines in patient stratification and precision medicine strategies. Additionally, our results suggest exploring the use of low-dose drugs with partial agonist activity as a potential avenue for ME/CFS treatment. This comprehensive approach emphasizes the importance of adopting a patient-centered care approach to improve ME/CFS healthcare management, disease severity assessment, and personalized medicine. Overall, these findings contribute to our understanding of ME/CFS and offer avenues for future research and clinical practice.

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.

The pathogenesis of aortic aneurysm and dissection continues to be under discussion. Extracellular matrix (ECM) remodeling processes in the aortic wall are hypothesized to be involved in the development of the disorders. Therefore, in a histological study, we investigated the expression of metalloproteases 1 and 9 (MMP1 and MMP9) and their inhibitors (TIMP 1 and TIMP 2) in cardiac surgery patients. In parallel, we studied the aortic roots by echocardiography. Clinical reports of 111 patients (30 women and 81 men) who suffered from aortic aneurysms and aortic dissection were evaluated and studied by transesophageal echocardiography. Seven patients who had coronary heart disease served as “healthy controls”. All patients underwent the necessary surgical procedure according to the diagnosed aortic disease in the period from 2007 to 2015. A tissue sample of the aortic biopsies was collected from each patient during surgery. Immunohistochemical staining was performed for MMP1 and MMP9 and TIMP1 and TIMP2 as well. Vascularization was monitored by a CD 31 antibody. In direct comparison, the expressions are not homogeneous. We found the smallest changes in the intima area at all. TIMP 1 and TIMP 2 distribution increases from the lumen of the vessel outward in the wall layers of the aorta. In the case of arteriosclerotic changes, intima had a capillarization, but not in the media. An opposite pattern was found in the dissected aortas. There are differences in the vascularization between the aneurysm and dissection and the different layers, respectively. A different remodeling process of the ECM in comparison to the vascular layers must be hypothesized. Reading the patterns of staining and with regard to the known inhibitory effect of MMP9 on ECM remodeling, but especially TIMP 2 on neoangiogenesis, disturbed nutrition, and dysfunctional vasa vasorum remodeling must be assumed as causes of dissection.

Background: There is a paucity of evidence on people with thoracic aortic aneurysm and dissection. We aimed to determine the prevalence of genetic variants and their associations with phenotypes. Methods: In this cross-sectional single-centre cohort study of consecutive patients who underwent endovascular or open-surgical repair of thoracic aortic aneurysm and dissection, genetic analysis was performed using four-stage Next Generation Sequencing, and findings were confirmed with Sanger sequencing. We collected personal and family history on comorbidities, clinical examination, anthropometrics, skeletal deformities, joint function, and ophthalmological measures. Cardiovascular risk and phenotype scores were calculated. Results: Ninety-five patients were eligible (mean age 54 ± 9 years, 70% males, 56% aortic dissection). One-fifth had a family history of aortic disease. Furthermore, 95% and 54% had a phenotype score of ≤5 and ≤2, respectively. There were no significant differences in the distribution of phenotype characteristics according to age, sex, aortic pathology, or performed invasive procedures. Genetic variants of uncertain significance were detected in 40% of patients, with classic mutations comprising 18% of all variants. We observed no significant association with cardiovascular and phenotype scores but with higher joint function scores (p = 0.015). Conclusion: Genetic variants are highly present in clinically relevant aortic pathologies. Variants appear to play a larger role than previously described. The different variants do not correlate with specific phenotypes, age, pathology, sex, or family history.

Approximately 30% of patients with depressive episodes do not respond to conventional antidepressant medication or develop side effects. As a result, effective new treatments are urgently needed. Mood-enhancing effects of Whole body hyperthermia (WBH) have repeatedly been observed in various fields of medicine (e.g. rheumatology). A recent study by Janssen and colleagues (2016) with a randomized, double-blind and sham-controlled approach, was able to demonstrate a significant, rapid and partially lasting reduction of depressive symptoms in unmedicated patients with MDD following a WBH single session.Two randomized, double-blind, and (sham-) controlled clinical studies are currently conducted by our group in Essen (Germany). Overall, the studies focus on safety and tolerability data and the question whether WBH improves depressive symptoms in patients without any antidepressant treatment (HYPE I trial) or in patients with stable antidepressant treatment but non- or only partial response (HYPE II trial). In each subgroup, patients are randomized to either a verum group with two treatments with WBH in two weeks or a waiting group as controls. Beside response data, immune parameters in the serum of patients will be assessed.Preliminary results regarding safety and tolerability from the first 34 participants (N=16 treatment naive, N=18 non- or partly responder) showed, that WBH was well tolerated in most patients with or without antidepressant treatment. No serious side effects of WBH were observed that would have required further treatment. Overall, the risk for adverse effects during WBH was increased in case of somatic comorbidities.In summary, whole-body hyperthermia appears to be an interesting concept for a non-pharmacological treatment of perhaps subgroups like stress or immune induced depression.

We report a complex case of a 53-year-old male patient with recurrent ischemic ventricular septal defect that had been occluded by a surgical patch. Treatment was accomplished utilizing a 3-dimensional–printed model for preprocedural planning. In the future, printing of 3-dimensional models could offer new therapeutic strategies on an individual level. (Level of Difficulty: Intermediate.)

IntroductionComplete recovery after surgery depends on psychological factors such as preoperative information, expectations, and surgery-associated anxiety. Prior studies have shown that even a short preoperative psychological intervention aiming at optimized expectations (EXPECT) can improve postoperative outcomes in coronary artery bypass patients. However, this intervention may benefit only a small subgroup of heart surgery patients since implementing preoperative psychological interventions into the daily clinical routine is difficult due to the additional time and appointments. It is unclear whether the EXPECT intervention can be shortened and whether heart valve patients would also benefit from interventions that optimize patients’ expectations. The multicenter ValvEx trial aims (i) to adapt an effective preoperative psychological intervention (EXPECT) to make it brief enough to be easily integrated into the preoperative routine of heart valve patients and (ii) to examine if the adapted preoperative psychological intervention improves the subjectively perceived illness-related disability (PDI) up to 3 months after surgery.Materials and analysisIn two German university hospitals, N = 88 heart valve patients who undergo heart surgery are randomized into two groups [standard of care (SOC) vs. standard of care plus interventional expectation manipulation (SOC and EXPECT)] after baseline assessment. Patients in the EXPECT group additionally to standard of care participate in the preoperative psychological intervention (30–40 min), focusing on optimizing expectations and have two booster-telephone calls (4 and 8 weeks after the surgery, approx. 15 min). Both groups have assessments again on the evening before the surgery, 4 to 6 days, and 3 months after the surgery.DiscussionThe trial demonstrates excellent feasibility in the clinical routine and a high interest by the patients.Ethics and disseminationThe Ethics Committees of the Department of Medicine of the Philipps University of Marburg and the Department of Medicine of the University of Giessen approved the study protocol. Study results will be published in peer-reviewed journals and presented at congresses.Clinical trial registrationClinicalTrials.gov, identifier NCT04502121.

Background Cardiac non-Hodgkin's lymphoma is rare and has a poor prognosis. Here we report a rare case mimicking pulmonary embolism. Case Description A 38-year-old woman suffered from severe dyspnea after cesarean section. With the clinical picture of fulminant central pulmonary embolism, lysis therapy was initiated. Further deterioration necessitated extracorporeal membrane oxygenation (ECMO) support and cardiosurgical intervention. Intraoperatively, a massive intravascular tumor obstructed the pulmonary bifurcation and was found to be B-cell lymphoma. Aggressive excision and pulmonary tree reconstruction improved the critical condition and initiated convalescence. Conclusion High suspicion in central pulmonary embolism and early cardiosurgical therapy after ineffective lysis are essential.

Abstract Aims Worldwide applications of extracorporeal circulation for mechanical support in cardiac and circulatory failure, which are referred to as extracorporeal life support (ECLS) or veno‐arterial extracorporeal membrane oxygenation (va‐ECMO), have dramatically increased over the past decade. In spite of the expanding use and the immense medical as well as socio‐economic impact of this therapeutic approach, there has been a lack of interdisciplinary recommendations considering the best available evidence for ECLS treatment. Methods and Results In a multiprofessional, interdisciplinary scientific effort of all scientific societies involved in the treatment of patients with acute cardiac and circulatory failure, the first evidence‐ and expert consensus‐based guideline (level S3) on ECLS/ECMO therapy was developed in a structured approach under regulations of the AWMF (Association of the Scientific Medical Societies in Germany) and under use of GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria. This article presents all recommendations created by the expert panel, addressing a multitude of aspects for ECLS initiation, continuation, weaning and aftercare as well as structural and personnel requirements. Conclusions This first evidence‐ and expert consensus‐based guideline (level S3) on ECLS/ECMO therapy should be used to apply the best available care nationwide. Beyond clinical practice advice, remaining important research aspects for future scientific efforts are formulated.

Background/Objective: To investigate the prevalence and effects of genetic variants (GVs) in survivors of thoracic aortic dissection/aneurysm repair. Methods: Patients aged 18–80 years who survived follow-up after cardiosurgical or endovascular repair of thoracic aortic aneurysm or dissection at a single tertiary center between 2008 and 2019 and underwent genetic testing were enrolled. The exclusion criteria were age >60 years, no offspring, and inflammatory- or trauma-related pathogenesis. Follow-up entailed computed tomography-angiography at 3 and 9 months and annually thereafter. All patients underwent genetic analyses of nine genes using next-generation sequencing. In cases of specific suspicion, the analysis was expanded to include 32 genes. Results: The study included 95 patients. The follow-up period was 3 ± 2.5 years. GVs were detected in 40% of patients. Correlation analysis according to primary diagnosis showed no significant correlation in disease persistence, progression, or in reintervention rates in aneurysm patients and a correlation of disease persistence with genetic variants according to variant class in dissection patients (p = 0.037). Correlation analysis according to follow-up CD finding revealed that patients with detected dissection, irrespective of original pathology, showed a strong correlation with genetic variants regarding disease progression and reintervention rates (p = 0.012 and p = 0.047, respectively). Conclusions: The prevalence of VUS is high in patients with aortic pathology. In patients with dissected aorta in the follow-up, irrespective of original pathology, genetic variants correlate with higher reintervention rates, warranting extended-spectrum genetic testing. The role of VUS may be greater than is currently known. [ABSTRACT FROM AUTHOR]

We evaluated the feasibility of hybrid percutaneous coronary intervention (PCI) and minimally invasive mitral valve surgery (MIMVS) in patients with concomitant coronary and mitral disease. Of 534 patients who underwent MIMVS at our institution between 2012 and 2018, those with combined mitral and single vessel coronary pathologies who underwent MIMVS and PCI were included. Patients were excluded if they had endocarditis or required emergency procedures. Preprocedural, procedural, and postprocedural data were retrospectively analyzed. In total, 10 patients (median age, 75 years; 7 males) with a median ejection fraction (EF) of 60% were included. Nine patients underwent PCI before and one after MIMVS. The success rate was 100% in both procedures. There were no postoperative myocardial infarctions or strokes. Two patients developed delirium and one required re-thoracotomy for bleeding. The median stay in intensive care and the hospital was 3 and 8 days, respectively. The 30-day survival rate was 100%. A hybrid PCI and MIMVS approach is feasible in patients with mitral valve and single vessel coronary disease. In combined pathologies, the revascularization strategy should be evaluated independent from the mitral valve pathology in the presence of MIMVS expertise. Extension of this recommendation to multivessel disease should be evaluated in future studies.

Heat transfer enhancement techniques are accompanied by pressure drop amplification, detrimentally affecting their performance; entropy generation analysis is an effective approach to assess heat transfer enhancement along with resulting pressure drop. Current study investigates and compares the performance of micro-fin (as a passive enhancement technique) and smooth tubes during flow condensation (for R134a refrigerant) through conducting entropy generation analysis. First, the impact of geometrical and operating variables on pressure losses and heat transfer contributions to entropy generation and total generated entropy inside both types of tubes is examined. Then, the conditions at which the application of micro-fin tubes in lieu of smooth ones is justifiable and of superior performance are identified utilizing entropy generation number. The simulation results indicate that entropy generation enhances in the micro-fin tubes as tube diameter, mass velocity, vapor quality, and wall heat flux rise, and saturation temperature declines. The same is observed in the smooth tube except for the mass velocity; an increase in this parameter leads to a decreasing-increasing trend in entropy generation. Moreover, the entropy generation number results indicate that applying micro-fin tubes rather than smooth ones is justifiable, i.e., has better performance, at lower mass velocities and vapor qualities, but higher saturation temperatures and wall heat fluxes.

Abstract Background The timing for heart surgery following cerebral embolization after cardiac valve vegetation is vital to postoperative recovery being uneventful, additionally Covid-19 may negatively affect the outcome. Minimally invasive methods and upgraded surgical instruments maximize the benefits of surgery also in complex cardiac revision cases with substantial perioperative risk. Case presentation A 68 y.o. patient, 10 years after previous sternotomy for OPCAB was referred to cardiac surgery on the 10th postoperative day after neurosurgical intervention for intracerebral bleeding with suspected mitral valve endocarditis. Mitral valve vegetation, tricuspid valve insufficiency and coronary stenosis were diagnosed and treated by minimally invasive revision cardiac surgery on the 14th postoperative day after neurosurgery. Conclusion The present clinical case demonstrates for the first time that the minimally invasive approach via right anterior mini-thoracotomy can be safely used for concomitant complex mitral valve reconstruction, tricuspid valve repair and aorto-coronary bypass surgery, even as a revision procedure in the presence of florid endocarditis after recent neurosurgical intervention. The Covid-19 pandemic and prophylactic patient isolation slow down the efficacy of pulmonary weaning and mobilisation and prolong the need for ICU treatment, without adversely affecting long-term outcome.

Sonic Hedgehog medulloblastoma (Shh-MB) comprises four subtypes each with distinct clinical traits. Here the authors characterize the genome, transcriptome, and methylome of Shh-MB subtypes, revealing a complex fusion landscape and the molecular convergence of MYCN and cAMP signaling pathways.

Aims: The conditions of hypoxia are suggested to induce permanent atrial fibrillation (AF). The regulation of COX4I2 and COX4I1 depends on oxygen availability in tissues. A role of COX4I2 in the myocardium of AF patients is supposed for pathogenesis of AF and subsequent alterations in the electron transfer chain (ETC) under hypoxia. Methods and results: In vitro, influence of hypoxia on HeLa 53 cells was studied and elevated parts of COX 4I2 were confirmed. Myocardial biopsies were taken ex vivo from the patients' Right Atria with SR (n = 31) and AF (n = 11), respectively. RT‐ PCR for mRNA expresson, mitochondrial respiration by polarography and the protein content of cytochrome c oxidase (CytOx) subunit 4I1 and CytOx subunit 4I2 by ELISA were studied. Clinical data were correlated to the findings of gene expressions in parallel. Patients with permanent AF had a change in isoform 4I2/4I1 expression along with a decrease of isoform COX 4I1 expression. The 4I2/4I1 ratio of mRNA expression was increased from 0.630 to 1.058 in comparison. However, the protein content of CytOx subunit 4 was much lower in the AF group, whereas the respiration/units enzyme activity in both groups remained the same. Conclusions: This study describes a possible molecular correlate for the development of AF. Due to the known functional significance of COX 4I2, mitochondrial dysfunction can be assumed as a part of the pathogenesis of AF. [ABSTRACT FROM AUTHOR]

The meteorological conditions markedly affect the energy efficiencies and cost/power rate of the wind turbines. The dusty environment is common in arid windy areas and airborne particles generally degrade wind turbine performance. The National Renewable Energy Laboratory (NREL) Phase VI wind turbine has been designed to be insusceptible to surface roughness, a consequence of facing dusty winds. This study numerically investigates the wake flow topology and analyses the performance of this turbine for either clean or dusty air. First, the numerical approach is validated against the available experimental data for clean air. Following this, the model is developed into a Lagrangian-Eulerian multiphase approach to comprehensively analyze the effects of the dusty air. The dependence of aerodynamic performance on the wind speed (U∞ = 5–25 m/s), particle diameter (dp = 0.025–0.9 mm), and angle of attack (AoA = 0°–44°) is investigated. The turbine performance deteriorates acutely for dp ≥ 0.1 mm and post-stall state. As such, the generated power is reduced by 4.3% and 13.3% on average for the air with the dp = 0.05 and 0.9 mm, respectively. The particles change the flow field profoundly, declining the pressure difference between the suction/pressure sides of the blade-airfoil, advancing the boundary layer separation, and strengthening the recirculation zones. The above changes account for a lower lift coefficient and a higher drag coefficient. [ABSTRACT FROM AUTHOR]

Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) presents substantial challenges in patient care due to its intricate multisystem nature, comorbidities, and global prevalence. The heterogeneity among patient populations, coupled with the absence of FDA-approved diagnostics and therapeutics, further complicates research into disease etiology and patient managment. Integrating longitudinal multi-omics data with clinical, health, textual, pharmaceutical, and nutraceutical data offers a promising avenue to address these complexities, aiding in the identification of underlying causes and providing insights into effective therapeutics and diagnostic strategies. Methods: This study focused on an exceptionally severe ME/CFS patient with hypermobility spectrum disorder (HSD) during a period of marginal symptom improvements. Longitudinal cytokine profiling was conducted alongside the collection of extensive multi-modal health data to explore the dynamic nature of symptoms, severity, triggers, and modifying factors. Additionally, an updated severity assessment platform and two applications, ME-CFSTrackerApp and LexiTime, were introduced to facilitate real-time symptom tracking and enhance patient-physician/researcher communication, and evaluate response to medical intervention. Results: Longitudinal cytokine profiling revealed the significance of Th2-type cytokines and highlighted synergistic activities between mast cells and eosinophils, skewing Th1 toward Th2 immune responses in ME/CFS pathogenesis, particularly in cognitive impairment and sensorial intolerance. This suggests a potentially shared underlying mechanism with major ME/CFS comorbidities such as HSD, Mast cell activation syndrome, postural orthostatic tachycardia syndrome (POTS), and small fiber neuropathy. Additionally, the data identified potential roles of BCL6 and TP53 pathways in ME/CFS etiology and emphasized the importance of investigating adverse reactions to medication and supplements and drug interactions in ME/CFS severity and progression. Discussion: Our study advocates for the integration of longitudinal multi-omics with multi-modal health data and artificial intelligence (AI) techniques to better understand ME/CFS and its major comorbidities. These findings highlight the significance of dysregulated Th2-type cytokines in patient stratification and precision medicine strategies. Additionally, our results suggest exploring the use of low-dose drugs with partial agonist activity as a potential avenue for ME/CFS treatment. This comprehensive approach emphasizes the importance of adopting a patient-centered care approach to improve ME/CFS healthcare management, disease severity assessment, and personalized medicine. Overall, these findings contribute to our understanding of ME/CFS and offer avenues for future research and clinical practice. [ABSTRACT FROM AUTHOR]

Background Cardiac myxoma is the most common primary cardiac tumor. Although benign, it can cause life-threatening complications due to embolization. Case Presentation We describe an ST-elevation myocardial infarction (STEMI) involving a giant right atrial myxoma and persisting foramen ovale (PFO) in a 64-year-old male patient and report on emergency percutaneous interventional therapy and subsequent cardiac surgery to remove the right atrial myxoma. Conclusion A right atrial myxoma, combined with a PFO, can cause a STEMI. Therefore, every acute coronary syndrome patient should undergo ultrafast exploratory emergency echocardiography to protect the physician from unpleasant surprises.

Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood-brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor [alpha]2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor [alpha]2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans. Intraventricularly delivered monovalent and trivalent CAR T cells exhibit greater therapeutic efficacy as compared with intravenously delivered CAR T cells in medulloblastoma xenograft mouse models and show potency in ependymoma xenograft mouse models., Author(s): Laura K. Donovan [sup.1] [sup.2] , Alberto Delaidelli [sup.3] , Sujith K. Joseph [sup.4] [sup.5] , Kevin Bielamowicz [sup.4] [sup.5] , Kristen Fousek [sup.4] [sup.5] , Borja L. Holgado [...]