A 75-year-old female patient presented with persistent cough and exertional dyspnea. Initial CT imaging revealed extensive mediastinal lymphadenopathy associated with a suspicious right-sided thyroid nodule and bilateral cervical lymph nodes.Fine-needle aspiration confirmed follicular thyroid carcinoma with cervical lymphogenous metastases. Molecular analysis detected no actionable mutations. FDG-PET-CT demonstrated multiple mediastinal and bihilar lymph node metastases and a small osseous metastasis in the left iliac bone.Advanced follicular thyroid carcinoma with extensive mediastinal lymphatic metastases and no curative treatment option.Following multidisciplinary tumor board discussion, palliative therapy with the tyrosine kinase inhibitor (TKI) lenvatinib was initiated. After eight months of treatment, a marked reduction in mediastinal tumor mass enabled total thyroidectomy with lymphadenectomy. Subsequently, adjuvant radioiodine therapy (5.5 GBq I-131) was performed. Histology revealed an anaplastic thyroid carcinoma with partial squamous differentiation. Six months postoperatively, due to metastatic progression, systemic combination therapy with lenvatinib and pembrolizumab was started. The patient remains in stable general condition under this regimen.In selected cases, initially palliative TKI therapy can lead to a neoadjuvant effect and enable a curative approach. Continuous multidisciplinary management and close follow-up are essential for successful outcomes.

Two groups of investigators investigated the heart pacemaker and its morphological basis in the early twentieth century. The first group was formed by Henrich Ewald Hering (physiologist), Sunao Tawara and Ludwig Aschoff (morphologists). The second group was composed of James Mackenzie (general practitioner and clinical investigator), Arthur Keith and Martin Flack (morphologists). These groups were formed almost at the same time in 1903. Their work resulted in the discovery of the atrioventricular node and Purkinje network (Sunao Tawara, in 1906), heart pacemaker (H E Hering, in 1907) and sinoatrial node (Keith and Flack, in 1907). Here, it is shown how the interconnections of the concurrent works of these groups resulted in the discovery not only of the function, but also of the structure of the sinoatrial node.

The mammalian cardiac conduction system (CCS) is a multifaceted continuum of electrically distinct, interconnected constructs within the myocardial mass. The key components are the sinus node (SAN), the atrioventricular node (AVN), the His bundle (HB), and the Purkinje fiber network (PF), the latter serendipitously discovered by Jan Evangelista Purkinje in 1839 in the sheep ventricle. In 1893, Wilhelm His, Jr. described a ventricular muscular tract conveying SAN-generated action potentials from the AVN (discovered by Sunao Tawara and Karl Albert Aschoff in 1906) to the PF. In 1906, Keith and Flack completed these explorations by localizing the SAN, the primum movens of CCS, which functions as a biologic oscillator emitting cadenced impulses that travel via the Bachmann bundle to the atrial myocytes and, via internodal pathways, to the AVN. Here these impulses are briefly delayed, enabling atrial systole before continuing via the AVN and the high-speed His-Purkinje conduction axis to signal ventricular contraction. The CCS canonical discoverers (Keith and Flack, Aschoff and Tawara, His, and Purkinje), historical controversies, fundamental notions of anatomy, physiology, and pathology, and therapeutic interventions pertaining to the CCS are the main themes of this review. Any scientist mentioned or unmentioned in this report who contributed directly or indirectly, with correct or inaccurate hypotheses, to the characterization of the CCS deserves our deepest gratitude for the long and painstaking hours spent microscopically scrutinizing heart specimens from multiple mammalian species, including humans.NEW & NOTEWORTHY This report presents the first comprehensive summary of the factors enabling the discovery of the cardiac conduction system (CCS). Biographical highlights and achievements of the CCS canonical discoverers, hypotheses concerning mechanisms underlying sinus node (SAN) automaticity, use of eponyms to denominate a discovery, famous controversies, possible reproachable behavior (e.g., intellectual support for eugenics in post-World War I Germany) by two of the discoverers, and examples of historical mentor-pupil relationships are discussed.

More than a century has passed since Tawara demonstrated the presence of the insulated pathways that extend from the "knoten" at the base of the atrial septum to their ramifications at the ventricular apexes. Having initially doubted the existence of the atrioventricular bundle until reading the monograph produced by Tawara, Keith, together with Flack, soon revealed the presence of the sinus node. Shortly thereafter, Thorel suggested that a special system might be found within the atrial walls, connecting the newly discovered atrial nodes. This prompted the convening of a special session of the German Pathological Society in 1910. The consensus was that no tracts existed within the atrial walls, with Aschoff and Mönckeberg establishing criteria to be met by those proposing recognition of "specialized" atrial conducting pathways. None of those who subsequently proposed the presence of such pathways have discussed their findings on the basis of the criteria established at the meeting of 1910. It remains the case, nonetheless, that drawings continue to be offered by cardiological experts showing narrow pathways within the atrial walls that parallel the arrangement used to show the ventricular conduction pathways. A similar drawing adorns the front cover of Heart Rhythm Journal. We are unaware of any evidence supporting the presence of pathways as illustrated existing within the overall walls of the atrial chambers. In this review, we summarize the evidence that shows, instead, that it is the aggregation of the working atrial cardiomyocytes within the atrial walls that underscores preferential anisotropic interatrial conduction.

Cardiac arrhythmias, notably Wolff-Parkinson-White syndrome, are known to represent a major issue in patients with Ebstein's malformation of the tricuspid valve. Abnormal conducting circuits, however, can also be produced by pathways extending either from the atrioventricular node or the ventricular components of the atrioventricular conduction axis, direct to the crest of the muscular ventricular septum. We hoped to provide further information on the potential presence of such pathways by investigations of six autopsied examples of Ebstein's malformation. All were studied by histological sectioning on the full extent of the atrioventricular conduction axis, with limited sectioning of the right atrioventricular junction supporting the inferior and antero-superior leaflets of the deformed tricuspid valve. We used the criteria established by Aschoff (Verhandlungen der Deutschen Gesellschaft für Pathologie, 14, 1910, 3) and Mönckeberg (Verhandlungen der Deutschen Gesellschaft für Pathologie, 14, 1910, 64) over a century ago to define abnormal connections across the atrioventricular junctions, as these definitions retain their validity for the identification of gross myocardial connections across the insulating tissues of the atrioventricular junctions. In one specimen, we found two discrete accessory myocardial connections across the parietal right atrioventricular junction. In all of the hearts, we found so-called nodoventricular connections, and in one heart we also observed a well-formed connection originating from the penetrating atrioventricular bundle. In addition to accessory myocardial connections across the parietal right atrioventricular junction, therefore, our histological findings demonstrate a potential role for direct connections between the atrioventricular conduction axis and the ventricular myocardium in the setting of Ebstein's malformation.

Sunao Tawara, who was born in 1873 and died in 1952, is considered the father of modern cardiac electrophysiology. He published his monumental monograph describing the atrioventricular conduction axis in 1906. He achieved this task in the face of multiple tribulations as a doctoral student working in a cultural environment that was not his own. Although his letters underscoring the publication of the monograph have been published, little emphasis has been placed on the potential problems he encountered in bringing his task to fruition. For example, it was not until the final 6 months of his studies that he resolved the issue of the connection between the atrioventricular bundle and the so called "Purkinje cardiomyocytes". His exchanges with his mentor, Ludwig Aschoff, emphasized that the difficulties he encountered in making the connection caused him quite some turmoil. We believe that this issue, and others that he identified in his correspondence, are worthy of further attention.

Already in 1664, the Danish anatomist and naturalist Niels Stensen proved that the heart is a muscle. But for a long time it remained unclear what triggered the heart contractions.The Dutch physiologist Willem Einthoven registered the electrical processes in the contraction of the heart muscle and thus provided the first electrophysiological basis of cardiac muscle activity. Since 1903, Sunao Tawara was assistant to Ludwig Aschoff in Marburg. Both left Marburg in 1906: Tawara went back to Japan and Aschoff to Freiburg. In 1905, Tawara discovered the connections of the His' bundle to the AV node and the Purkinje fibers. At that time, there was no thought of a functional interpretation. Tawara discovered a kind of "knot" that linked to the adjacent myocardial cells, as well as the "Tawara thighs", which frayed and went into structures known as Purkinje fibers. Tawara detected the tree-like structure he had discovered as a muscle-fiber system that controlled the arousal of the heart's musculature. Thus the old dispute between myogenic and neurogenic arousal of the heart was decided in favor of the myogenic excitation conduction. The atrioventricular node described by Tawara was given the eponym "Aschoff-Tawara node". Tawara's groundbreaking work on the conduction system was the basis for the discovery of the sinus node and the interpretation of the heart's electrophysiology.

The chronological succession of discoveries on the location and structure of the atrio-ventricular conducting system are described. The starting point of this system is located in the sinus atrial node, identified by the English scientists A. Keith and M. W. Flack in 1907. The atrioventricular conducting system was pointed out by the Swiss physician Wilhelm His Jr. in 1893. The atrioventricular node (AV) was first identified by the Japanese pathologist Sumao Tawara and his German professor Ludwig Aschoff in 1906. Likewise the structure and routes of the three internodal bundles are described. These bundles include: Bachmann's bundle (1916) connecting the right with the left atrium and the AV node; the middle Wenckebach's bundle (1910) and the posterior or Thörel's bundle (1910), extending from the region of the sinus atrial node towards the posterior margin of the AV node. Lastly, the ventricular left and right conduction systems are detailed. These include the main trunk and their peripheral subdivisions with respective networks. Regarding the controversial existence of the left middle subdivision, it can exist in animal and human hearts. Nevertheless, an intermediate left septal network of specialized fibers seems to act as a functional equivalent of this subdivision.

Rectal cancer is one of the most common causes of death from cancer. Accurate staging is necessary for optimal treatment. The tumor node metastasis (TNM) system is used to describe numerically the anatomical extent of cancer. Various diagnostic methods provide accurate staging. Endorectal ultrasound (EUS) and magnetic resonance tomography (MR) are most adequate for determining tumor stage. Moreover, MR is highly accurate in predicting the circumferential resection margin. Accurate node staging remains however difficult with both EUS and MR. Modern multidetector row CT is predestined for detecting distant metastases as it is a widespread, fast, and reproducible method.

Conduction across the atrioventricular junctions had long been controversial, with arguments raging as to whether such conduction was myogenic or neurogenic. The landmark study of Tawara in 1906 established the existence of an axis of histologically specialized myocardial cells contained within fibrous sheaths as being responsible for rapid conduction from the atrial to the ventricular myocardium. Keith and Flack then demonstrated that the atrial impulse was generated in the sinus node, with subsequent slowing within the atrioventricular node of Tawara. The detailed reviews of Aschoff and Monckeberg then emphasized the morphological features that permit unequivocal recognition of the nodes, along with rapidly conducting tracts. It is now pertinent that we remember these original criteria for anatomical recognition as we discuss the steps involved in the development of these conducting structures from their embryologic primordiums. In this review, we restate the criteria of Aschoff and Monckeberg, then discuss their relevance to the developmental issues, emphasizing that all myocardial cells have the potential to conduct. The important issues, therefore, are the changes that occur as the heart itself changes from a solitary muscular tube, already possessing the capacity t generate an electrocardiogram, to the four-chambered structure we recognize in postnatal life.