Narsoplimab, a Mannan-Binding Lectin-Associated Serine Protease-2 Inhibitor, for the Treatment of Adult Hematopoietic Stem-Cell Transplantation-Associated Thrombotic Microangiopathy.

PURPOSE: Hematopoietic stem-cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) is a serious complication with significant mortality and no approved therapy. HSCT-TMA results from endothelial injury, which activates the lectin pathway of complement. Narsoplimab (OMS721), an inhibitor of mannan-binding lectin-associated serine protease-2 (MASP-2), was evaluated for safety and efficacy in adults with HSCT-TMA. METHODS: In this single-arm open-label pivotal trial (NCT02222545), patients received intravenous narsoplimab once weekly for 4-8 weeks. The primary end point (response rate) required clinical improvement in two categories: (1) laboratory TMA markers (both platelet count and lactate dehydrogenase) and (2) organ function or freedom from transfusion. Patients receiving at least one dose (full analysis set [FAS]; N = 28) were analyzed. RESULTS: The response rate was 61% in the FAS population. Similar responses were observed across all patient subgroups defined by baseline features, HSCT characteristics, and HSCT complications. Improvement in organ function occurred in 74% of patients in the FAS population. One-hundred-day survival after HSCT-TMA diagnosis was 68% and 94% in FAS population and responders, respectively, whereas median overall survival was 274 days in the FAS population. Narsoplimab was well tolerated, and adverse events were typical of this population, with no apparent safety signal of concern. CONCLUSION: In this study, narsoplimab treatment was safe, significantly improved laboratory TMA markers, and resulted in clinical response and favorable overall survival.

The development of a reference database with the Topcon 3D OCT-1 Maestro.

IMPORTANCE: The paper presents the range for measurements taken with a new spectral domain optical coherence tomography (OCT) device to establish a reference database for discrimination purposes. OBJECTIVE: To report the range of thickness values for the new Topcon Maestro 3D OCT device with 2 scan size settings: the 12×9 mm wide field and 6×6 mm scans. DESIGN: Prospective, multicenter cohort study conducted at 7 clinical sites across the USA. SETTING: Primary eyecare clinics within academic, hospital, and private practice locations. PARTICIPANTS: Healthy volunteers; all enrolled participants underwent a complete ophthalmological examination to confirm healthy ocular status prior to being enrolled in the study. MAIN OUTCOME MEASURE: Average and 1st, 5th, 95th, and 99th percentile ranges for OCT parameters Early Treatment Diabetic Retinopathy Study macula full retinal thickness, ganglion cell + inner plexiform layer thickness (GCL + IPL), ganglion cell complex (GCC) thickness, circumpapillary retinal nerve fiber layer (cpRNFL) thickness. RESULTS: Three hundred and ninety-nine eyes of 399 subjects were included in the analysis. Mean (SD) age was 46.3 (16.3) years (range 18-88 years). Forty-three percent of the subjects were male. Mean (SD) measurements (in µm) for the 12×9 mm wide scan were as follows: foveal thickness=237.079 (20.899), GCL + IPL=71.363 (5.924), GCC=105.949 (8.533), cpRNFL=104.720 (11.829); measurements for the 6×6 mm scans were as follows: foveal thickness=234.000 (20.657), GCL + IPL=71.726 (5.880), GCC=106.698 (9.094), cpRNFL=104.036 (11.341). CONCLUSION: The overall normal thickness values reported with Topcon 3D OCT-1 Maestro were like those studies with OCT from different manufactures. The reference limits at the 1st, 5th, 95th, and 99th percentile points establish the thresholds for the quantitative comparison of the cpRNFL and the macula in the human retina to a database of known healthy subjects.

Intracameral phenylephrine and ketorolac during cataract surgery to maintain intraoperative mydriasis and reduce postoperative ocular pain: Integrated results from 2 pivotal phase 3 studies.

PURPOSE: To evaluate the efficacy and safety of phenylephrine 1.0%-ketorolac 0.3% (Omidria) for maintenance of mydriasis during, and reduction of ocular pain after, cataract surgery. SETTING: Twenty centers in the United States and the Netherlands. DESIGN: Prospective randomized clinical trials. METHODS: Patients having cataract surgery or refractive lens exchange were enrolled in 2 clinical trials. Phenylephrine 1.0%-ketorolac 0.3% or placebo was added to irrigation solution and administered intracamerally during the procedure. Integrated analyses of primary and secondary endpoints were conducted. RESULTS: The clinical trials comprised 808 patients (403 treatment and 405 placebo). Phenylephrine 1.0%-ketorolac 0.3% was superior to placebo for the maintenance of mydriasis during, and reduction of ocular pain following, cataract surgery. The mean area under the curve (AUC) change from baseline in pupil diameter was 0.08 mm for treatment compared with -0.50 mm for placebo (P < .0001). The mean AUC of ocular pain visual analog scale scores within 12 hours postoperatively was 4.16 mm for the treatment group and 9.06 mm for the placebo group (P < .001). Results of all secondary efficacy analyses demonstrated a significant treatment effect associated with phenylephrine 1.0%-ketorolac 0.3%. Treatment-emergent adverse events were as expected for a population having cataract surgery; no clinically significant differences in safety measures were observed between treatment groups. CONCLUSION: In this integrated analysis, phenylephrine 1.0%-ketorolac 0.3% administered intracamerally with irrigation solution during cataract surgery was safe and effective for maintaining mydriasis during the procedure and reducing postoperative ocular pain. FINANCIAL DISCLOSURE: Dr. Schaaf is an employee and holds an equity interest in Omeros Corporation. Drs. Hovanesian, Sheppard, Trattler, Gayton, and Ng are consultants to Omeros Corporation. No other author has a financial or proprietary interest in any material or method mentioned.

Dacetuzumab plus rituximab, ifosfamide, carboplatin and etoposide as salvage therapy for patients with diffuse large B-cell lymphoma relapsing after rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone: a randomized, double-blind, placebo-controlled phase 2b trial.

Single-agent dacetuzumab has demonstrated antitumor activity in relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Preclinical data demonstrated improved dacetuzumab antitumor activity in combination with rituximab, ± chemotherapy. We designed a phase 2b, double-blind, placebo-controlled trial to compare rituximab, ifosfamide, carboplatin and etoposide (R-ICE) + dacetuzumab with R-ICE + placebo in patients with DLBCL who relapsed after rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (ClinicalTrials.gov #NCT00529503). The primary endpoint was complete response (CR); additional endpoints included failure-free survival and overall survival (OS). Overall, 151 patients were randomized (75 dacetuzumab, 76 placebo). No notable differences between arms in demographics or subsequent treatment parameters were observed. Cytopenias, cough and infection were more frequent with dacetuzumab. Futility analysis failed to demonstrate higher CR rates with dacetuzumab (36% dacetuzumab, 42% placebo); consequently, enrollment was stopped. Unplanned post hoc analysis showed that patients who underwent subsequent autologous stem cell transplant experienced improvement in OS (hazard ratio = 0.195, p = 0.004), which may be explained by potential immunomodulatory effects of dacetuzumab on antigen-presenting cells.

Fluoroscopic evaluation of oropharyngeal dysphagia: anatomic, technical, and common etiologic factors.

OBJECTIVE: The purposes of this article are to review the anatomy of the upper gastrointestinal tract; review techniques and contrast agents used in the fluoroscopic examination of the oropharynx and hypopharynx; provide a pictorial review of some important causes of oropharyngeal dysphagia; and link these causes to key findings in the clinical history to assist in establishing a clinical diagnosis. CONCLUSION: Many important causes and presentations of oropharyngeal dysphagia are sometimes overlooked during conventional upper gastrointestinal studies. Videofluoroscopic evaluation for assessment of both structural abnormalities and motility disorders of the oropharynx by use of various compositions of barium contrast medium is the standard of practice. Using best-practices radiographic techniques and having knowledge of swallowing mechanisms and various diseases are important for assessment of dysphagia. Dynamic fluoroscopic imaging remains an essential tool for assessing functional disorders of swallowing. Detailed videofluoroscopic assessment can guide treatment decisions with the goal of decreasing the secondary complications of dysphagia.

AMPLATZER Vascular Plug 4 for proximal splenic artery embolization in blunt trauma.

A consecutive case series was conducted evaluating proximal splenic artery embolization (SAE) with the AMPLATZER Vascular Plug 4 (AVP4) (St. Jude Medical, Inc, St. Paul, Minnesota) in eight patients with high-grade splenic trauma. Three proximal and five combined proximal and distal subselective coiling procedures were successfully performed. Mean time from device deployment to splenic artery occlusion was 4.5 minutes (range, 2.1-10.0 min; standard deviation, 2.8 min). There were no immediate complications. One patient developed a perisplenic abscess requiring percutaneous drainage and antibiotics. Results of this initial study show the suitability of the AVP4, with its ease of deployment without a guiding sheath and accurate placement, as a viable adjunct to nonoperative management of blunt splenic injury.

Heart rate variability predicts anti-tumor necrosis factor therapy response for inflammatory arthritis.

To consider autonomic status as a predictor of anti-tumor necrosis factor (TNF) treatment response for inflammatory arthritis, we conducted an exploratory, double-blind, 52-week study with 33 patients with rheumatoid (25) or psoriatic (8) arthritis using heart rate variability (HRV). All were assessed for parasympathetic, sympathetic, total power and tension index measures of autonomic reactivity at initiation of anti-TNF therapy with etanercept (15) or adalimumab (18). Clinical response was assessed at 6, 12, 26 and 52 weeks by internationally accepted outcome criteria (ACR20/50/70 and DAS28 response). Predictive value was demonstrated for all HRV assessments (p-value range 0.001-0.032), except sympathetic (p-value range 0.06-0.22), for ACR20, ACR50 and ACR70 at 52 weeks and at as early as 6 weeks for some measures. Only parasympathetic and tension index predicted DAS28 outcome (p-value range 0.009-0.024). Poor anti-TNF response was associated with low parasympathetic, low total power, high sympathetic and high tension index measures, a profile also predominant in the prior anti-TNF failure subset (12). In conclusion, this unique, exploratory study suggests that HRV may be a novel, useful predictor of response to anti-TNF therapy in patients with inflammatory arthritis, and emphasizes the importance of autonomic influence of autoimmune disease expression.