Systemic Mastocytosis Presenting as Pathologic Intertrochanteric Femur Fracture.

Systemic mastocytosis (SM) is pathologically characterized by the proliferation of mast cells with infiltrates in various organs, almost always including bone marrow, leading to defects in bone remodeling. Osteoporosis and subsequent fragility fractures are the most common and clinically relevant presentation, although pathologic fracture through the focal lytic lesions can also be observed. Here, we report the case of a 54-year-old woman, with a recent history of unexplained severe allergic reactions, presenting with intertrochanteric fracture of the left femur which on careful history, physical and radiological evaluation was determined to be pathological. The patient was found to have lytic lesions on the CT scan at the fracture site and the pelvis, bilateral femurs, ribs, and sternum, raising suspicion for malignancy. The malignancy workup failed to reveal a primary neoplasm, and the patient was indicated for intramedullary fixation of the left femur along with intraoperative biopsy. Pathologic evaluation of the femoral biopsy was positive for aggregates of mast cells with CD117 (c-KIT, D816V). This finding prompted a bone marrow biopsy, which ultimately led to the diagnosis of aggressive SM. Femoral intramedullary fixation was done with a trochanteric femoral nail, and the patient was postoperatively started on calcium, vitamin D, and physical therapy. Systemic disease was managed by the hematology-oncology team, and the patient was given an epinephrine autoinjector (EpiPen) and managed with midostaurin (Rydapt, Novartis Pharmaceuticals). Treating surgeons should be aware that a pathological long bone fracture can be the initial presentation of SM. Furthermore, surgeons should consider following patients with SM for longer than usual considering a higher risk of complications, such as implant loosening, nonunion, and refracture due to poor and progressively worsening quality of the bone. Our patient was followed with routine visits for 30 months and showed no clinical or radiographical signs of any complications.

Inflammatory Myofibroblastic Tumor 12 Years After Treatment for Synovial Sarcoma: A Case Report.

Inflammatory myofibroblastic tumors (IMTs) are mesenchymal neoplasms most seen in the abdominopelvic region, lung, and retroperitoneum; and less commonly seen in virtually any other site. We report a case of two lower limb masses consistent with diagnosis of IMTs. This is a 39-year-old woman with a history of right lower extremity popliteal fossa synovial sarcoma diagnosed 12 years prior and treated with chemotherapy, surgery, and radiation. She presented with two new - one anterior and one posterior - right thigh masses. Biopsies of the lesions demonstrated low-grade inflammatory spindle cell lesions at both sites. Wide resection was performed for both masses and further characterization of the surgical specimens was most consistent with IMT. At follow-up, the patient is well with no signs of recurrence 19 and 7 months postoperative to the resection of the anterior and posterior thigh masses, respectively. This case represents the first reported IMTs occurring as late as 12 years after primary cancer treatment, and the first occurring after synovial sarcoma.

Anti-Phospho-Tau Gene Therapy for Chronic Traumatic Encephalopathy.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder caused by repetitive trauma to the central nervous system (CNS) suffered by soldiers, contact sport athletes, and civilians following accident-related trauma. CTE is a CNS tauopathy, with trauma-induced inflammation leading to accumulation of hyperphosphorylated forms of the microtubule-binding protein Tau (pTau), resulting in neurofibrillary tangles and progressive loss of neurons. At present, there are no therapies to treat CTE. We hypothesized that direct CNS administration of an adeno-associated virus (AAV) vector coding for an anti-pTau antibody would generate sufficient levels of anti-pTau in the CNS to suppress pTau accumulation thus interrupting the pathogenic process. Using a serotype AAVrh.10 gene transfer vector coding for a monoclonal antibody directed against pTau, we demonstrate the feasibility of this strategy in a murine CTE model in which pTau accumulation was elicited by repeated traumatic brain injury (TBI) using a closed cortical impact procedure over 5 days. Direct delivery of AAVrh.10 expression vectors coding for either of the two different anti-pTau antibodies to the hippocampus of these TBI mice significantly reduced pTau levels across the CNS. Using doses that can be safely scaled to humans, the data demonstrate that CNS administration of AAVrh.10anti-pTau is effective, providing a new strategy to interrupt the CTE consequences of TBI.

AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive degenerative neurological disorder affecting nearly one in nine elderly people in the United States. Population studies have shown that an inheritance of the apolipoprotein E (APOE) variant APOE4 allele increases the risk of developing AD, whereas APOE2 homozygotes are protected from late-onset AD. It was hypothesized that expression of the "protective" APOE2 variant by genetic modification of the central nervous system (CNS) of APOE4 homozygotes could reverse or prevent progressive neurologic damage. To assess the CNS distribution and safety of APOE2 gene therapy for AD in a large-animal model, intraparenchymal, intracisternal, and intraventricular routes of delivery to the CNS of nonhuman primates of AAVrh.10hAPOE2-HA, an AAVrh.10 serotype coding for an HA-tagged human APOE2 cDNA sequence, were evaluated. To evaluate the route of delivery that achieves the widest extent of APOE2 expression in the CNS, the expression of APOE2 in the CNS was evaluated 2 months following vector administration for APOE2 DNA, mRNA, and protein. Finally, using conventional toxicology assays, the safety of the best route of delivery was assessed. The data demonstrated that while all three routes are capable of mediating ApoE2 expression in AD relevant regions, intracisternal delivery of AAVrh.10hAPOE2-HA safely mediated wide distribution of ApoE2 with the least invasive surgical intervention, thus providing the optimal strategy to deliver vector-mediated human APOE2 to the CNS.