Pan-cancer Genomic Analysis of AXL Mutations Reveals a Novel, Recurrent, Functionally Activating AXL W451C Alteration Specific to Myxofibrosarcoma.

Myxofibrosarcoma (MFS) is a common soft tissue sarcoma of the elderly that typically shows low tumor mutational burden, with mutations in TP53 and in genes associated with cell cycle checkpoints ( RB1 , CDKN2A ). Unfortunately, no alterations or markers specific to MFS have been identified and, as a consequence, there are no effective targeted therapies. The receptor tyrosine kinase AXL, which drives cellular proliferation, is targetable by new antibody-based therapeutics. Expression of AXL messenger RNA is elevated in a variety of sarcoma types, with the highest levels reported in MFS, but the pathogenic significance of this finding remains unknown. To assess a role for AXL abnormalities in MFS, we undertook a search for AXL genomic alterations in a comprehensive genomic profiling database of 463,546 unique tumors (including 19,879 sarcomas, of which 315 were MFS) interrogated by targeted next-generation DNA and/or RNA sequencing. Notably, the only genomic alterations recurrent in a specific sarcoma subtype were AXL W451C (n = 8) and AXL W450C (n = 2) mutations. The tumors involved predominantly older adults (age: 44 to 81 [median: 72] y) and histologically showed epithelioid and spindle-shaped cells in a variably myxoid stroma, with 6 cases diagnosed as MFS, 3 as undifferentiated pleomorphic sarcoma (UPS), and 1 as low-grade sarcoma. The AXL W451C mutation was not identified in any non-sarcoma malignancy. A review of publicly available data sets revealed a single AXL W451C-mutant case of UPS that clustered with MFS/UPS by methylation profiling. Functional studies revealed a novel activation mechanism: the W451C mutation causes abnormal unregulated dimerization of the AXL receptor tyrosine kinase through disulfide bond formation between pairs of mutant proteins expressing ectopic cysteine residues. This dimerization triggers AXL autophosphorylation and activation of downstream ERK signaling. We further report sarcomas of diverse histologic subtypes with AXL gene amplifications, with the highest frequency of amplification identified in MFS cases without the W451C mutation. In summary, the activating AXL W451C mutation appears highly specific to MFS, with a novel mechanism to drive unregulated signaling. Moreover, AXL gene amplifications and messenger RNA overexpression are far more frequent in MFS than in other sarcoma subtypes. We conclude that these aberrations in AXL are distinct features of MFS and may aid diagnosis, as well as the selection of available targeted therapies.

Pre-resection Embolization of a Focal Lumbar Chordoma.

Chordoma is a slow-growing local invasive tumor with high mortality and recurrence rates after surgical resection. It can affect the clivus and sacrum and rarely involve the lumbar vertebra. There is limited literature research describing lumbar embolization before surgical resection in lumbar chordoma. Thus, this case report describes an atypical patient with chronic lower back pain who presented to the hospital for worsening pain. Radiological images show an aggressive focal lesion at the second lumbar spine extending into the posterior element. The patient underwent lumbar artery embolization before surgical resection. The final pathology diagnosis confirmed a conventional chordoma. Therefore, patients with radiological imaging features of conventional chordoma may benefit from embolization prior to surgical resection to decrease intraoperative bleeding.

Cardiac CT and Transesophageal Echocardiogram Evaluation of a Sinus Venosus-Type Atrial Septal Defect With Partial Anomalous Pulmonary Venous Return and a Persistent Left Superior Vena Cava.

The sinus venosus (SV) plays a significant role in the embryological heart as the initial structure where the cardinal, umbilical, and vitelline veins drain before remodeling into the caval veins. As the human heart develops, the SV incorporates into the posterior wall of the right atrium. Sinus venosus atrial septal defects (SVASDs) result from a defect in the wall present among the right pulmonary veins, the superior vena cava (SVC), and the right atrium. Persistent left superior vena cava (PLSVC) occurs when the Marshall ligament does not regress, and in most cases, the PLSVC enters the coronary sinus before draining into the right atrium. Pulmonary hypertension from chronic left to right shunting makes recognizing this condition clinically significant. In this case report, both cardiac CT and transesophageal echocardiogram were used to further evaluate an SVASD with partial anomalous pulmonary venous return (PAPVR) of the right superior pulmonary vein, in addition to a PLSVC. The incidence of the co-occurrence of SVASD and PLSVC, as well as the association between the two, were discussed in this case report. Future research should focus on the potential genetic causes of this co-occurrence. It should also focus on patient treatment and outcomes at different stages of presentation to optimize patient management and improve mortality.

Distribution of Mediastinal Lesions Across Multi-Institutional, International, Radiology Databases.

INTRODUCTION: Mediastinal lesions are uncommon; studies on their distribution are, in general, small and from a single institution. Furthermore, these studies are usually based on pathology or surgical databases and, therefore, miss many lesions that did not undergo biopsy or resection. Our aim was to identify the distribution of lesions in the mediastinum in a large international, multi-institutional cohort. METHODS: At each participating institution, a standardized retrospective radiology database search was performed for interpretations of computed tomography, positron emission tomography-computed tomography, and magnetic resonance imaging scans including any of the following terms: "mediastinal nodule," "mediastinal lesion," "mediastinal mass," or "mediastinal abnormality" (2011-2014). Standardized data were collected. Statistical analysis was performed. RESULTS: Among 3308 cases, thymomas (27.8%), benign mediastinal cysts (20.0%), and lymphomas (16.1%) were most common. The distribution of lesions varied among mediastinal compartments; thymomas (38.3%), benign cysts (16.8%), and neurogenic tumors (53.9%) were the most common lesions in the prevascular, visceral, and paravertebral mediastinum, respectively (p < 0.001). Mediastinal compartment was associated with age; patients with paravertebral lesions were the youngest (p < 0.0001). Mediastinal lesions differed by continent or country, with benign cysts being the most common mediastinal lesions in the People's Republic of China, thymomas in Europe, and lymphomas in North America and Israel (p < 0.001). Benign cysts, thymic carcinomas, and metastases were more often seen in larger hospitals, whereas lymphomas and thymic hyperplasia occurred more often in smaller hospitals (p < 0.01). CONCLUSIONS: Our study confirmed that the spectrum and frequency of mediastinal lesions depend on mediastinal compartment and age. This information provides helpful demographic data and is important when considering the differential diagnosis of a mediastinal lesion.