Epidemiology, Pathophysiology, and Treatment Strategies of Concussions: A Comprehensive Review.

A concussion is a particular manifestation of a traumatic brain injury, which is the leading cause of mortality and disabilities across the globe. The global prevalence of traumatic brain injury is estimated to be 939 instances per 100,000 individuals, with approximately 5.48 million people per year experiencing severe traumatic brain injury. Epidemiology varies amongst different countries by socioeconomic status with diverse clinical manifestations. Additionally, classifying concussions is an ambiguous process as clinical diagnoses are the only current classification method, and morbidity rates differ by demographic location as well as populations examined. In this article, we critically reviewed the pathophysiology of concussions, classification methods, treatment options available including both pharmacologic and nonpharmacologic intervention methods, etiologies as well as global etiologic differences associated with them, and clinical manifestations along with their associated morbidities. Furthermore, analysis of the current research regarding the incidence of concussion based traumatic brain injuries and future directions are discussed. Investigation on the efficacy of new therapeutic-related interventions such as exosome therapy and electromagnetic field stimulation are warranted to properly manage and treat concussion-induced traumatic brain injury.

A Case of a Rare Parathyroid Hormone (PTH)-Producing Neuroendocrine Tumor.

BACKGROUND Neuroendocrine neoplasms are commonly seen in association with hormone production, and clinical signs that arise from these hormonal effects often manifest as the first presentation of malignancy. The excess production of parathyroid hormone (PTH) in particular, however, is primarily sporadic (80-85%) in clinical settings. In the context of malignancy, hyperparathyroidism manifestations arise most frequently from non-neuroendocrine pulmonary tumors through a ligand mimicker, parathyroid hormone-related peptide (PHrP). Excess PTH or PTHrP production has been very rarely described in association with gastrointestinal tumors and almost never described as a primary paraneoplastic syndrome from a neuroendocrine tumor (NET) alone. CASE REPORT We present a patient with a prior surgically resected carcinoid tumor who later presented with an elevated parathyroid hormone level, hypercalcemia, and clinical manifestations of primary hyperparathyroidism. She was found to have a low-grade, recurrent neuroendocrine tumor on resection of a parathyroid mass suspected to be a productive adenoma. Despite no longer having parathyroid glands given the extent of resection, her PTH level remained elevated and was rising. Further investigation via repeat sestamibi nuclear scan excluded the possibility of exogenous parathyroid tissue, and subsequent dotatate positron emission tomography/computed tomography (PET/CT) revealed the source of the PTH production: multiple sites of metastatic neuroendocrine tumors producing native PTH. CONCLUSIONS This case highlights the rare possibility of NETs to secrete PTH and the importance of considering early staging with dotatate PET/CT to evaluate the extent of disease. Additionally, our case reveals the importance of considering NET as an alternative etiology for refractory hypercalcemia.

The Irreversible FLT3 Inhibitor FF-10101 Is Active Against a Diversity of FLT3 Inhibitor Resistance Mechanisms.

Small-molecule FLT3 inhibitors have recently improved clinical outcomes for patients with FLT3-mutant acute myeloid leukemia (AML) after many years of development, but resistance remains an important clinical problem. FF-10101 is the first irreversible, covalent inhibitor of FLT3 which has previously shown activity against FLT3 tyrosine kinase inhibitor resistance-causing FLT3 F691L and D835 mutations. We report that FF-10101 is also active against an expanded panel of clinically identified FLT3 mutations associated with resistance to other FLT3 inhibitors. We also demonstrate that FF-10101 can potentially address resistance mechanisms associated with growth factors present in the bone marrow microenvironment but is vulnerable to mutation at C695, the amino acid required for covalent FLT3 binding. These data suggest that FF-10101 possesses a favorable resistance profile that may contribute to improved single-agent efficacy when used in patients with FLT3-mutant AML.