Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Aims Brain-derived Neurotrophic Factor (BDNF) is markedly decreased in heart failure patients. Both BDNF and its receptor, Tropomyosin Related Kinase Receptor (TrkB), are expressed in cardiomyocytes, however the role of myocardial BDNF signaling in cardiac pathophysiology is poorly understood. Here we investigated the role of BDNF/TrkB signaling in cardiac stress response to exercise and pathological stress. Methods and Results We found that myocardial BDNF expression was increased in mice with swimming exercise, but decreased in a mouse heart failure model and human failing hearts. Cardiac-specific TrkB knockout (cTrkB KO) mice displayed a blunted adaptive cardiac response to exercise, with attenuated upregulation of transcription factor networks controlling mitochondrial biogenesis/metabolism, including Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α). In response to pathological stress (transaortic constriction, TAC), cTrkB KO mice showed an exacerbated heart failure progression. The downregulation of PGC-1α in cTrkB KO mice exposed to exercise or TAC resulted in decreased cardiac energetics. We further unraveled that BDNF induces PGC-1α upregulation and bioenergetics through a novel signaling pathway, the pleiotropic transcription factor Yin Yang 1 (YY1). Conclusion Taken together, our findings suggest that myocardial BDNF plays a critical role in regulating cellular energetics in the cardiac stress response.

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INTRODUCTION To evaluate outcomes of patients with primary chordomas treated with spine stereotactic radiosurgery (SRS) alone or in combination with surgery, drawing from a single-institution database to elucidate treatment options associated with durable radiographic control of these conventionally radioresistant tumors. Chordomas result in significant morbidity, with a high rate of local recurrence and potential for metastases. SRS as a primary treatment could save patients from extensive surgery. Spine SRS outcomes support exploration of its role in the durable control of these conventionally radioresistant tumors. METHODS Clinical records were reviewed for outcomes of patients with primary chordoma of the mobile spine and sacrum who underwent single-fraction SRS between 2006 and 2017. Radiographic local recurrence-free survival (LRFS), overall survival (OS), symptom response, and toxicity were assessed in relation to extent of surgery. RESULTS In total, 35 patients with de novo chordoma of the mobile spine (49%) and sacrum (51%) received SRS with a median post-SRS follow-up of 38.8 mo (range: 2.0-122.9). The median PTV dose was 24Gy (range: 18–24Gy). Overall, 12 patients (33%) underwent definitive SRS and 23 patients (66%) underwent surgery followed by adjuvant SRS. Surgical strategies included separation surgery prior to SRS, curettage/intralesional resection, and en bloc resection in 7, 6, and 10 patients, respectively. The 3- and 5-yr LRFS rates were 86.2% and 80.5% respectively. Among 32 patients receiving 24 Gy (91%), the 3- and 5-yr LRFS were 96.3% and 89.9%. The 3- and 5-yr OS rates were 90.0% and 84.3%. The symptom response rate to treatment was 88% for pain and radiculopathy. Extent or type of surgery was not associated with LRFS, OS, or symptom response rates (P > .05), but en bloc resection was associated with higher CTCAE v. 5.0 surgical toxicity compared to epidural decompression and curettage/intralesional resection (P = .03). The long-term = grade 2 SRS toxicity rate was 31%, including 17% grade 3 tissue necrosis, recurrent laryngeal nerve palsy, fracture, and secondary malignancy. CONCLUSION High-dose spine SRS offers the chance of durable radiographic control and effective symptom relief with acceptable toxicity for primary chordomas as either definitive or adjuvant therapy.

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