Teprotumumab: a novel therapeutic monoclonal antibody for thyroid-associated ophthalmopathy.

INTRODUCTION: Thyroid-associated ophthalmopathy (TAO) is a disfiguring, potentially blinding, and sub-optimally managed autoimmune condition. Current therapy of active TAO consists most frequently of glucocorticoid steroids, orbital radiation, or B-cell depletion; all of which are associated with substantial side effects. Teprotumumab (Tepezza) is a human monoclonal antibody against the insulin-like growth factor type I receptor (IGF-IR), recently evaluated in two clinical trials for active moderate-to-severe TAO that was recently approved by the United States Food and Drug Administration (FDA) for use in TAO. AREAS COVERED: This article reviews phase II and III placebo-controlled, double-masked, prospective, multicenter studies assessing the efficacy and safety of teprotumumab for the treatment of active, moderate-to-severe TAO. EXPERT OPINION: Teprotumumab has demonstrated substantial and rapid improvement in Clinical Activity Score and proptosis reduction in TAO compared to placebo. Subjective diplopia and quality of life were also improved in both clinical trials. Teprotumumab exhibited a favorable safety profile, with transient hyperglycemia, muscle cramps, and auditory side effects being associated with the drug; these were usually transient. The trial findings indicate that teprotumumab is a promising, potential first-line therapy for treating TAO.

Supernumerary Lacrimal Caruncle: A Case Series.

A 12-year-old boy and 63-year-old woman were incidentally found to have a solitary, well-defined, raised, ovoid lesion involving the inferomedial palpebral conjunctiva. Both lesions were separate from the lacrimal caruncle with normal conjunctiva surrounding the lesions. Excisional biopsies were consistent with caruncular tissue. In the English literature, supernumerary lacrimal caruncle has only been previously described in adults despite the congenital nature of the lesion.

The Use of Umbilical Amnion for Conjunctival Socket, Fornix, and Eyelid Margin Reconstruction.

PURPOSE: To describe outcomes using umbilical amnion for conjunctival fornix, socket, and eyelid margin reconstruction. METHODS: A medical record review was performed to identify patients who had received umbilical amnion over a 2-year period in their department. Patient demographics, disease etiology, and data regarding surgical outcomes were collected. The primary outcome was the success rate of the surgical intervention. RESULTS: Twenty-one patients received umbilical amnion for anophthalmic socket contracture (n = 16), orbital implant exposure (n = 3), ocular surface burn (n = 1), and cicatricial entropion repair (n = 1). The primary outcome was met in 76% of patients overall. In anophthalmic socket contracture, the primary outcome was met in 86% and 0% of patients with acquired and congenital anophthalmia, respectively. The primary outcome was met in all cases of orbital implant exposure and cicatricial entropion. The primary outcome was not met in a Roper-Hall grade IV ocular surface burn. CONCLUSIONS: Umbilical amnion is an ideal substrate graft for reconstruction of the conjunctival fornix, socket, and eyelid margin. Umbilical amnion appears to be efficacious for the management of socket contracture in acquired anophthalmia, orbital implant exposure, and cicatricial entropion. Further experience is needed to determine the efficacy of umbilical amnion in ocular surface burns.

Characteristics of Industry Payments to Ophthalmologists in the Open Payments Database.

Importance: An increased awareness of the interactions between the medical industry and health care professionals may lead to lower health care costs and more effective health care practices. Objective: To assess the characteristics of industry payments made to ophthalmologists between 2013 and 2017. Design, Setting, and Participants: This analysis included data reported in the June 29, 2018, update of the Centers for Medicare & Medicaid Services Open Payments Database (OPD). The OPD contains public records of industry payments made to physicians and teaching hospitals from August 1, 2013, to December 31, 2017, as reported by the medical industry. All general or research payments distributed to US ophthalmologists and contained in the OPD were included in this study. Data are summarized by practitioner, manufacturer, payment category, and geographic location. Main Outcomes and Measures: Main outcomes were the distribution, quantity, and value of payments made to ophthalmologists practicing in the United States or US territories. The financial characteristics of payment category, manufacturer, product, and location were also assessed. Results: This analysis revealed that the OPD showed industry reporting a total of 20 943 ophthalmologists receiving 736 517 payments worth $543 679 603.53 (1.67% of all industry-reported funds in the OPD). The median payment value was $22.44. Most payments were for food and beverages (581 588 [78.96%]), whereas most funds were allocated toward research ($310 142 151.88 [57.05%]) and consulting fees ($73 565 327.71 [13.51%]). The median payout to each ophthalmologist was $637.75 (interquartile range, $167.33-$2065.54). California was the highest-grossing state, receiving $101 135 980.34 (18.60%) of all payments. Fifteen companies were responsible for 87.68% of all funds distributed ($476 719 470.11) and were mostly involved in the production of pharmaceutical agents (anti-vascular endothelial growth factor agents, glaucoma eyedrops, and ocular lubricants) and surgical devices (cataract and glaucoma). Conclusions and Relevance: Although there is no way to know the veracity of these reports, the findings suggest the financial ophthalmologist-industry relationship is substantial. These relationships may be adding to health care costs and affecting the quality of care, although those associations were not evaluated in this study.

Novel Use of Cryopreserved Ultra-thick Human Amniotic Membrane for Management of Anophthalmic Socket Contracture.

PURPOSE: To describe the use of cryopreserved ultra-thick human amniotic membrane for management of anophthalmic socket contracture. METHODS: A chart review was performed to identify patients undergoing fornix reconstruction with cryopreserved ultra-thick human amniotic membrane for management of anophthalmic socket contracture. Patient demographics, disease etiology, and data regarding postoperative prosthesis fit and complications were collected. RESULTS: The technique is described in 3 female patients with anophthalmic socket contracture who underwent fornix reconstruction using cryopreserved ultra-thick human amniotic membrane. All patients had excellent prosthesis fit at final follow up (range, 10-14 months). There were no clinically significant complications and no reoperations were performed. One pyogenic granuloma developed and was excised without affecting ocular prosthesis fit. CONCLUSIONS: Cryopreserved ultra-thick human amniotic membrane is easy to use, well tolerated, and produces good outcomes for management of anophthalmic socket contracture.

Orbital malignant meningioma: a unique presentation of a rare entity.

An elderly female with progressive proptosis was found to have an aggressive retrobulbar solid orbital mass. The mass was distinct from the optic nerve sheath and intracranial meninges, and produced concave erosion of the sphenoid wing. Operative findings demonstrated an orbital mass adherent to the dura of the superior orbital fissure. The mass did not demonstrate meningeal violation, infiltrate the superior orbital fissure, or display intracranial spread. The dura remained intact after gross total resection. Histopathology revealed a malignant meningioma with papillary and focal rhabdoid morphology and bony invasion (WHO grade III). The patient received 2500cGy of stereotactic radiotherapy in addition to gross total resection. Postoperatively, the signs and symptoms of orbital mass effect resolved (proptosis, relative afferent papillary defect, and periorbital edema) and the vision improved. There was no orbital recurrence or intracranial extension. The follow-up time was limited to eight months secondary to the patient succumbing to metastatic lung adenocarcinoma, which was demonstrated to be a separate process from the orbital meningioma. We propose the etiology of this tumor to be most consistent with an orbital malignant primary extradural meningioma - the first case reported in the literature.

Proteome-wide measurement of protein half-lives and translation rates in vasopressin-sensitive collecting duct cells.

Vasopressin regulates water excretion, in part, by controlling the abundances of the water channel aquaporin-2 (AQP2) protein and regulatory proteins in the renal collecting duct. To determine whether vasopressin-induced alterations in protein abundance result from modulation of protein production, protein degradation, or both, we used protein mass spectrometry with dynamic stable isotope labeling in cell culture to achieve a proteome-wide determination of protein half-lives and relative translation rates in mpkCCD cells. Measurements were made at steady state in the absence or presence of the vasopressin analog, desmopressin (dDAVP). Desmopressin altered the translation rate rather than the stability of most responding proteins, but it significantly increased both the translation rate and the half-life of AQP2. In addition, proteins associated with vasopressin action, including Mal2, Akap12, gelsolin, myosin light chain kinase, annexin-2, and Hsp70, manifested altered translation rates. Interestingly, desmopressin increased the translation of seven glutathione S-transferase proteins and enhanced protein S-glutathionylation, uncovering a previously unexplored vasopressin-induced post-translational modification. Additional bioinformatic analysis of the mpkCCD proteome indicated a correlation between protein function and protein half-life. In particular, processes that are rapidly regulated, such as transcription, endocytosis, cell cycle regulation, and ubiquitylation are associated with proteins with especially short half-lives. These data extend our understanding of the mechanisms underlying vasopressin signaling and provide a broad resource for additional investigation of collecting duct function (http://helixweb.nih.gov/ESBL/Database/ProteinHalfLives/index.html).

Quantitative protein and mRNA profiling shows selective post-transcriptional control of protein expression by vasopressin in kidney cells.

Previous studies in yeast have supported the view that post-transcriptional regulation of protein abundances may be more important than previously believed. Here we ask the question: "In a physiological regulatory process (the response of mammalian kidney cells to the hormone vasopressin), what fraction of the expressed proteome undergoes a change in abundance and what fraction of the regulated proteins have corresponding changes in mRNA levels?" In humans and other mammals, vasopressin fulfills a vital homeostatic role (viz. regulation of renal water excretion) by regulating the water channel aquaporin-2 in collecting duct cells. To address the question posed, we utilized large-scale quantitative protein mass spectrometry (LC-MS/MS) employing stable isotopic labeling in cultured mpkCCD cells ('SILAC') coupled with transcriptomic profiling using oligonucleotide expression arrays (Affymetrix). Preliminary studies analyzing two nominally identical control samples by SILAC LC-MS/MS yielded a relative S.D. of 13% (for ratios), establishing the precision of the SILAC approach in our hands. We quantified nearly 3000 proteins with nontargeted SILAC LC-MS/MS, comparing vasopressin- versus vehicle-treated samples. Of these proteins 786 of them were quantified in each of 3 experiments, allowing statistical analysis and 188 of these showed significant vasopressin-induced changes in abundance, including aquaporin-2 (20-fold increase). Among the proteins with statistically significant abundance changes, a large fraction (at least one-third) was found to lack changes in the corresponding mRNA species (despite sufficient statistical power), indicating that post-transcriptional regulation of protein abundance plays an important role in the vasopressin response. Bioinformatic analysis of the regulated proteins (versus all transcripts) shows enrichment of glutathione S-transferase isoforms as well as proteins involved in organization of the actin cytoskeleton. The latter suggests that long-term regulatory processes may contribute to actomyosin-dependent trafficking of the water channel aquaporin-2. The results provide impetus for increased focus on translational regulation and regulation of protein degradation in physiological control in mammalian epithelial cells.