Clinical and Physiologic Predictors and Postoperative Outcomes of Near Dehiscence Syndrome.

OBJECTIVE: To identify predictors of near dehiscence (ND) or thin rather than dehiscent bone overlying the superior semicircular canal in patients with signs and symptoms suggestive of superior semicircular canal dehiscence syndrome (SCDS), as well as postoperative outcomes. STUDY DESIGN: Retrospective case-control study. SETTING: Tertiary referral center. PATIENTS: All 288 patients who underwent middle cranial fossa approach for repair of SCDS (1998-2018) were reviewed for cases of ND. Demographics, symptoms, and clinical signs including nystagmus, ocular vestibular-evoked myogenic potential (oVEMP) amplitude, cervical vestibular-evoked myogenic potential (cVEMP) thresholds, and low-frequency air-bone gap were compared before and after surgery. MAIN OUTCOME MEASURE: Presence of preoperative ND and postoperative symptoms and physiologic measures. RESULTS: Seventeen cases of ND (16 patients, 17 ears) and 34 cases (34 ears) of frank SCDS were identified. ND cases differed from frank dehiscence cases in that they were less likely to have nystagmus in response to ear canal pressure or loud sounds, OR = 0.05 (95% CI 0.01-0.25) and Valsalva, OR = 0.08 (0.01-0.67), smaller peak-to-peak oVEMP amplitudes, OR = 0.84 (0.75-0.95), and higher cVEMP thresholds, OR = 1.21 (1.07-1.37). Patients with ND had similar symptoms to those with frank SCDS before surgery, and after surgery had outcomes similar to patients with frank SCDS. CONCLUSIONS: In patients with symptoms consistent with SCDS, predictors of ND include absence of nystagmus in response to pressure/loud sounds, greater cVEMP thresholds, and smaller oVEMP amplitudes. We propose ND is on a spectrum of dehiscence that partially accounts for the diversity of clinical presentations of patients with SCDS.

A CS1-NKG2D Bispecific Antibody Collectively Activates Cytolytic Immune Cells against Multiple Myeloma.

Multiple myeloma (MM) is an incurable hematologic malignancy of plasma cells, with an estimated 30,000 new cases diagnosed each year in the United States, signifying the need for new therapeutic approaches. We hypothesized that targeting MM using a bispecific antibody (biAb) to simultaneously engage both innate and adaptive cytolytic immune cells could present potent antitumor activity. We engineered a biAb by fusing an anti-CS1 single-chain variable fragment (scFv) and an anti-NKG2D scFv (CS1-NKG2D biAb). Although NKG2D is a potent activation receptor ubiquitously expressed on mostly cytolytic immune cells including NK cells, CD8+ T cells, γδ T cells, and NKT cells, the CS1 tumor-associated antigen on MM represents a promising target. CS1-NKG2D biAb engaged human MM cell lines and NKG2D+ immune cells, forming immune synapses. In effector cells, CS1-NKG2D biAb triggered the phosphorylation of AKT, a downstream protein kinase of the activated NKG2D-DAP10 complex. The EC50 values of CS1-NKG2D biAb for CS1high and for CS1low MM cell lines with effector PBMCs were 10-12 and 10-9 mol/L, respectively. CS1-NKG2D biAb acted through multiple types of immune cells, and this induced cytotoxicity was both CS1- and NKG2D-specific. In vivo, survival was significantly prolonged using CS1-NKG2D biAb in a xenograft NOD-SCIDIL2γc-/- (NSG) mouse model engrafted with both human PBMCs and MM cell lines. Collectively, we demonstrated that the CS1-NKG2D biAb facilitated an enhanced immune synapse between CS1+ MM cells and NKG2D+ cytolytic innate and antigen-specific effector cells, which, in turn, activated these immune cells for improved clearance of MM. Cancer Immunol Res; 6(7); 776-87. ©2018 AACR.