Cardiomagnetic source imaging

Magnetocardiographic (MCG) source imaging has received increasing interest in recent years. With a high enough localization accuracy of the current sources in the heart, valuable information can be provided, e.g., for the pre-ablative evaluation of arrhythmia patients. Furthermore, preliminary studies indicate that ischemic areas, i.e. areas which are suffering from lack of oxygen, and infarcted regions could be localized from multichannel MCG recordings. In this thesis, the accuracy of cardiomagnetic source imaging results, obtained by using different current source models, was investigated. In addition, the effect of the torso model on the localization accuracy was examined. In some studies, also body surface potential mapping (BSPM) data were used for comparison purposes. A high impact was given to clinical validation, i.e. how the calculation methods would work in patients. The equivalent current dipole (ECD) source model was found to produce accurate (within 3-11 mm) localizations of focal current sources in a thorax phantom and in 15 patients with a non-magnetic stimulation catheter in the heart. The accuracy was found to depend on the signal-to-noise ratio and on the goodness of fit of the localizations. The corresponding accuracy determined from simultaneous multichannel BSPM recordings in 10 patients was 25 mm. In order to localize wider source regions in the heart, distributed source models were also investigated in the thesis. Current density estimates (CDEs) were calculated in the catheter patients and in 13 patients with coronary artery disease (CAD). Promising results were obtained by using second-order Tikhonov regularization in the calculations. CDEs were found to localize both myocardial ischemia in single-vessel CAD patients, as well as more complex chronic ischemia in three-vessel CAD patients. In addition to the ECD and CDE source models, the uniform double layer (UDL) model was used in the source imaging studies. With the UDL model, the whole depolarization of the ventricles can be represented with a single inverse solution. In the validation of the activation time maps calculated from MCG and BSPM recordings, invasively measured epicardial electrograms were used to construct the reference epicardial activation times. The overall patterns of activation in the reference data were reproduced relatively well in the calculated activation time maps. The high quality of the inverse solutions obtained in this thesis prompts the use of cardiomagnetic source imaging in several clinical applications, such as in electrophysiological studies and in the estimation of myocardial viability.reviewe

Amplification of the PLAG-family genes—PLAGL1 and PLAGL2—is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification

Abstract Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0–14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type ( n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2 , and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/β-Catenin pathway, and the potential drug targets RET and CYP2W1 , which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1 -amplified tumors, 25% for PLAGL2 -amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers ( PLAGL2 ) or adolescents ( PLAGL1 ) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined

Correction to: Amplification of the PLAG-family genes—PLAGL1 and PLAGL2—is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification (Acta Neuropathologica, (2023), 145, 1, (49-69), 10.1007/s00401-022-02516-2)

In the original publication, incorrect version of Fig. 6 was published and the correct version (Fig. 6) is given below. The original article has been corrected

Amplification of the PLAG-family genes—PLAGL1 and PLAGL2—is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification

Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0–14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/β-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined