Periocular Microcystic Adnexal Carcinoma: A Case Report and a Major Review.

PURPOSE: To describe a patient with periocular microcystic adnexal carcinoma (MAC) and to review the clinical presentation, systemic work-up, histopathologic features, and outcome of all previously reported periocular MAC. METHODS: A major literature review. PubMed/MEDLINE and Google Scholar databases were searched for all well-documented cases of periocular MAC. RESULTS: The final analysis yielded 93 patients with MAC, 48 (52%) females, 39 (42%) males, and 6 with sex not specified (6%) with an average age of 56 years (range 3 days-95 years). Most tumors were localized to the eyebrow (26/93, 28%) and lower eyelid (20/93, 22%). Of patients with known information, MAC most commonly presented as a nodule (37/68, 54%) or plaque (20/68, 29%) with poorly-defined margins (20/51, 39%) and distortion of eyelid margin (13/51, 25%). Orbital involvement at any point of the disease course was seen in 20 of 93 (22%) patients. An accurate histopathologic diagnosis on initial biopsy was made in 25 of 70 (36%) cases. Initial management included surgical excision (47/93, 51%), Mohs micrographic surgery (17/93, 18%), and excision with frozen section control of margins (8/93, 9%). Aggressive or recurrent MAC was managed with multimodal therapies, including adjuvant radiation (10/34, 29%). The average follow-up after the last treatment was 3 years (median 2, range 0.2-20 years). In total, 33 of 86 (38%) tumors recurred, and 6 of 87 (7%) metastasized. Disease-related mortality occurred in 3 of 79 (4%) of patients. CONCLUSIONS: Periocular MAC is frequently misdiagnosed on initial biopsy and has a tendency for recurrence and locally aggressive behavior, highlighting the importance of accurate timely diagnosis, and appropriate management.

Assessing the Carcinogenicity of Vadadustat, an Oral Hypoxia-Inducible Factor Prolyl-4-Hydroxylase Inhibitor, in Rodents.

Vadadustat is an investigational oral hypoxia-inducible factor (HIF) prolyl-4-hydroxylase inhibitor to treat anemia due to chronic kidney disease (CKD). Some studies suggest that HIF activation promotes tumorigenesis by activating angiogenesis downstream of vascular endothelial growth factor, while other studies suggest that elevated HIF activity may produce an antitumor phenotype. To evaluate the potential carcinogenicity of vadadustat in mice and rats, we dosed CByB6F1/Tg.rasH2 hemizygous (transgenic) mice orally by gavage with 5 to 50 mg/kg/d of vadadustat for 6 months and dosed Sprague-Dawley rats orally by gavage with 2 to 20 mg/kg/d for approximately 85 weeks. Doses were selected based on the maximally tolerated dose established for each species in previous studies. The tumors that were identified in the studies were not considered to be treatment-related for statistical reasons or within the historical control range. There was no carcinogenic effect attributed to vadadustat in mice or rats.

Postoperative diplopia after medial-inferior orbital wall decompression in patients with thyroid eye disease.

KEY POINTS: 10% of patients undergoing MAI decompression for TED developed new-onset diplopia MAI decompression remains an excellent option for orbital decompression for TED.

Preclinical Characterization of Vadadustat (AKB-6548), an Oral Small Molecule Hypoxia-Inducible Factor Prolyl-4-Hydroxylase Inhibitor, for the Potential Treatment of Renal Anemia.

Pharmacological inhibition of prolyl-4-hydroxylase domain (PHD) enzymes stabilizes hypoxia-inducible factors (HIFs), transcription factors that activate target genes that, among others, increase erythropoietin (EPO) synthesis, resulting in the production of new red blood cells (RBCs). Herein, we summarize the preclinical characteristics of the small molecule HIF prolyl-4-hydroxylase inhibitor vadadustat (AKB-6548), which is in development for the treatment of anemia in patients with chronic kidney disease (CKD). Vadadustat inhibits the enzyme activity of all three human PHD isozymes, PHD1, PHD2, and PHD3, with similar low nanomolar inhibitory constant values. PHD enzyme inhibition by vadadustat is competitive with endogenous cofactor 2-oxoglutarate and is insensitive to free iron concentration. In the human hepatocellular carcinoma cell line (Hep 3B) and human umbilical vein endothelial cells, PHD inhibition by vadadustat leads to the time- and concentration-dependent stabilization of HIF-1α and HIF-2α In Hep 3B cells, this in turn results in the synthesis and secretion of EPO; vascular endothelial growth factor is not measured at detectable levels. A single oral dose of vadadustat in rats potently increases circulating levels of EPO, and daily oral dosing for 14 days increases RBC indices in healthy rats and in the 5/6 nephrectomy model of CKD. In mice and dogs, once-daily repeat oral dosing increases hemoglobin and hematocrit. Vadadustat has a relatively short half-life in all nonclinical species evaluated and does not accumulate when administered as a single bolus dose (oral or intravenous) or upon repeat oral dosing. The pharmacological profile of vadadustat supports continued development for treatment of renal anemia. SIGNIFICANCE STATEMENT: Vadadustat (AKB-6548) is an orally bioavailable small molecule prolyl-4-hydroxylase inhibitor in development for anemia of chronic kidney disease. It is an equipotent inhibitor of the three human prolyl-4-hydroxylase domain isoforms, which activates erythropoiesis through stabilization of hypoxia-inducible factor (HIF)-1α and HIF-2α, increasing production of erythropoietin, without detectable stimulation of vascular endothelial growth factor.

Cyclin D1 Expression and Molecular Genetic Findings in Periocular Histiocytoses and Neoplasms of Macrophage-Dendritic Cell Lineage.

PURPOSE: Frequent activating mutations in the mitogen-activated protein kinase (MAPK) pathway genes have been identified in histiocytoses. MAPK signaling consistently upregulates cyclin D1. The goal of this study was to determine whether cyclin D1 expression by immunohistochemistry is a useful diagnostic marker for periocular histiocytoses and to further characterize their genetic basis. DESIGN: Retrospective observational case series. METHODS: Pathology records were searched for all patients with histiocytoses diagnosed between 1995 and 2020. Eleven histiocyte-rich inflammatory lesions and 10 xanthelasma served as controls. Cyclin D1 immunohistochemistry was performed on all tissues. A subset of histiocytoses was evaluated by next-generation sequencing (NGS) and droplet digital PCR (ddPCR). RESULTS: There were 36 patients, 15 males (42%) and 21 females (58%), with histiocytoses: 9 juvenile xanthogranuloma (25%), 8 adult-onset asthma and periocular xanthogranuloma (22%), 7 Langerhans cell histiocytosis (19%), 5 Rosai-Dorfman disease (14%), 5 xanthogranuloma-not otherwise specified (14%), 1 Erdheim-Chester disease (3%), and 1 histiocytic sarcoma (3%). Moderate to strong nuclear cyclin D1 expression was present in ≥50% of lesional cells in histiocytoses (23/36, 64%), significantly more when compared to histiocyte-rich inflammatory lesions (0/11, 0%, P<.001) and xanthelasma (0/10, 0%, P<.001). Cyclin D1 was expressed in <10% of lesional cells in all 11 histiocyte-rich inflammatory lesions (P<.001) and all 10 xanthelasma lesions (P<.001). MAPK pathway gene mutations were detected in 12 of 14 (86%) histiocytoses successfully assayed by NGS and/or ddPCR. CONCLUSIONS: Our study confirms that the cyclin D1 immunohistochemical stain is a useful diagnostic marker for periocular histiocytoses, correlating with underlying mutations in MAPK pathway genes.

Lacrimal drainage apparatus melanoma remotely following treatment and resolution of conjunctival melanoma.

Lacrimal drainage apparatus melanoma is a rare entity that may arise primarily or, more commonly, as secondary involvement from melanoma originating elsewhere. Conjunctival melanoma may involve the lacrimal drainage apparatus (LDA) via spread along the canalicular epithelium, separate in situ processes, or direct invasion. Only seven cases exist in the literature where conjunctival melanoma remotely recurred in the LDA. We report three additional patients, two with invasive conjunctival melanoma and one with primary acquired melanosis (PAM) with severe atypia/melanoma in situ, who developed LDA melanoma at 5, 8, and 16 years after initial treatment of conjunctival melanoma. This report confirms the ability of conjunctival melanoma to give rise to spatially and temporally remote LDA melanoma despite adequate local treatment, and reviews the proposed mechanisms and associated characteristics of LDA recurrence in conjunctival melanoma.

Management of Orbital Masses: Outcomes of Endoscopic and Combined Approaches With No Orbital Reconstruction.

INTRODUCTION: The endoscopic endonasal approach to management of orbital pathology has expanded. Due to the rarity of these conditions, most reports in the literature consist of small case reports. We report a series from a single institution with a focus on outcomes. METHODS: A retrospective chart review was carried out between 2010 and 2018. RESULTS: Twenty-four patients were identified (average age 58 years, 15 males, 9 females). Average follow-up was 14.9 months. Most common etiologies included cavernous hemangioma (7), metastases (6), idiopathic orbital inflammatory syndrome (6), orbital hematoma/clot (2), and schwannoma (1). Most common presenting symptoms were decreased visual acuity (8), proptosis (8), diplopia (7), and incidental findings (2). All patients underwent endoscopic medial wall orbital decompressions. Sixteen involved a combined open approach by an ophthalmologist. Pathology was either biopsied (15), resected (6), or could not be identified (3). No intraoperative complications were noted. No patients underwent orbital reconstruction of the medial wall. Six patients developed postoperative sinusitis successfully managed with antibiotics. One patient developed epistaxis managed conservatively. In 5 patients, Sino-Nasal Outcome Test-22 scores increased immediately postop and then decreased, whereas scores only decreased in 6 patients. Six patients noted reduced proptosis. There were no new cases of diplopia or worsening visual acuity. CONCLUSIONS: A combined endoscopic endonasal and external approach can be useful for managing orbital lesions. Patients tolerated the procedure well with improvement in ocular symptoms and minimal sinonasal complications. Reconstruction of the medial wall may not be warranted to prevent postoperative diplopia.

Combined Endoscopic and External Resection of an Inverted Papilloma of the Lacrimal Sac: A Case Report and Review of the Literature.

BACKGROUND: Inverted papillomas (IPs) are benign, locally aggressive neoplasms with a high recurrence rate that most commonly arise from the lateral nasal wall. Rarely, IP can originate from the lacrimal sac and/or nasolacrimal duct (NLD) system. A 58-year-old man presented with chronic epiphora and an enlarging mass inferior to his left medial canthal tendon (MCT) for 2 years. OBJECTIVE: The patients' clinical presentation and surgical management are described. A literature review on IP of the lacrimal sac and NLD system was conducted. METHODS: Case report. RESULTS: We present a case of an IP that arose primarily from the lacrimal sac and grew below the MCT rather than extending above it. This is one of few published case reports detailing the use of a combined endoscopic and external approach for the resection of an IP of the lacrimal sac. CONCLUSION: Combined endoscopic and external resection is a viable approach for complete removal of extensive IP of the lacrimal sac and NLD system. IP arising from the lacrimal sac may grow below the MCT or extend above it as previously reported.

Beyond Traditional Structure-Based Drug Design: The Role of Iron Complexation, Strain, and Water in the Binding of Inhibitors for Hypoxia-Inducible Factor Prolyl Hydroxylase 2.

A combination of structure-based drug design and medicinal chemistry efforts led us from benzimidazole-2-carboxamide with modestly active hypoxia-inducible factor prolyl hydroxylase 2 inhibition to certain benzimidazole-2-pyrazole carboxylic acids that were more potent as well as orally efficacious stimulators of erythropoietin secretion in our in vivo mouse model. To better understand the structure-activity relationship, it was necessary to account for (i) the complexation of the ligand with the active site Fe2+, (ii) the strain incurred by the ligand upon binding, and (iii) certain key water interactions identified by a crystal structure analysis. With this more complete computational model, we arrived at an overarching paradigm that accounted for the potency differences between benzimidazole-2-carboxamide and benzimidazole-2-pyrazole carboxylic acid enzyme inhibitors. Moreover, the computational paradigm allowed us to anticipate that the bioisostere replacement strategy (amide → pyrazole), which had shown success in the benzimidazole series, was not generally applicable to other series. This illustrates that to fully reconcile the important ligand-active site interactions for certain targets, one often needs to move beyond traditional structure-based drug design (such as crystallographic analysis, docking, etc.) and appeal to a higher level of computational theory.

Endoscopic Management of Lacrimal System Dysgenesis and Dacryocystoceles in Fraser Syndrome: A Case Report and Literature Review.

BACKGROUND: Fraser syndrome is an autosomal recessive disorder characterized primarily by syndactyly, cryptophthalmos, urinary tract anomalies, ambiguous genitalia, and laryngeal anomalies. A 28-year-old man with Fraser syndrome presented with cryptophthalmos, microphthalmia, lacrimal system dysgenesis, and chronic sinusitis. OBJECTIVE: The patients' clinical condition and surgical treatment are described. A literature review was conducted, and articles relevant to the case are presented. METHODS: Case report. RESULTS: To our knowledge, this is the first published case report of endonasal management of dacryocystoceles in a Fraser syndrome patient. The patient was treated via endoscopic endonasal marsupialization and drainage. CONCLUSION: Fraser syndrome patients may initially present to many different specialties as the spectrum of clinical manifestations is broad. Physicians treating these patients should take a collaborative approach to surgical and medical management.

Concerns about Quadrupole ICP-MS Lead Isotopic Data and Interpretations in the Environment and Health Fields.

There has been a massive increase in recent years of the use of lead (Pb) isotopes in attempts to better understand sources and pathways of Pb in the environment and in man or experimental animals. Unfortunately, there have been many cases where the quality of the isotopic data, especially that obtained by quadrupole inductively coupled plasma mass spectrometry (Q-ICP-MS), are questionable, resulting in questionable identification of potential sources, which, in turn, impacts study interpretation and conclusions. We present several cases where the isotopic data have compromised interpretation because of the use of only the major isotopes 208Pb/206Pb and 207Pb/206Pb, or their graphing in other combinations. We also present some examples comparing high precision data from thermal ionization (TIMS) or multi-collector plasma mass spectrometry (MC-ICP-MS) to illustrate the deficiency in the Q-ICP-MS data. In addition, we present cases where Pb isotopic ratios measured on Q-ICP-MS are virtually impossible for terrestrial samples. We also evaluate the Pb isotopic data for rat studies, which had concluded that Pb isotopic fractionation occurs between different organs and suggest that this notion of biological fractionation of Pb as an explanation for isotopic differences is not valid. Overall, the brief review of these case studies shows that Q-ICP-MS as commonly practiced is not a suitable technique for precise and accurate Pb isotopic analysis in the environment and health fields.

Orbital T-cell lymphoma versus lupus panniculitits: a T-cell-mediated spectrum of orbital lymphoproliferative disease.

This is a case description of a single male patient found to have T-cell-mediated inflammation and lymphoproliferation of the orbit. Chronic T-cell-mediated inflammatory disease can pose a diagnostic challenge particularly in its differentiation from a neoplastic process. The histopathology in this case demonstrated features of both lupus erythematosus panniculitis and features of orbital T-cell lymphoma. While both are rare, lupus erythematosus panniculitis of the orbit is even more exceptional; this patient's indolent, chronic relapsing course distinguished itself from the typical aggression of orbital T-cell lymphoma. We believe this rare case may actually represent an example of a newly described disease spectrum that incorporates lupus erythematosus panniculitis as well as subcutaneous panniculitis-like T-cell lymphoma.

Basaloid adenocarcinoma of the lacrimal sac: A rare entity and approach to management.

Presented is a rare case of basaloid adenocarcinoma of the lacrimal sac. Low grade features of this malignancy permitted a conservative surgical approach to maximize functional and cosmetic outcomes. This is retrospective case description of a single 77-year-old-female patient who underwent a dacryocystorhinostomy with silicone tubes at an outside hospital for epiphora, but was referred to the Wills Eye Hospital Oculoplastics Department for a lacrimal sac biopsy showing low-grade carcinoma with basaloid features. She was treated with complete excision of the mass, common canaliculus and distal canaliculi, and the nasolacrimal duct. The associated maxillary, lacrimal, and ethmoidal bones were similarly excised. Frozen sections were sent of the surrounding periosteum, orbital fat, nasal and sinus mucosa, and soft tissues, and all were negative. Reconstruction of the lacrimal system was performed with silicone tube intubation and the defect was closed with large glabellar and mid-facial flaps. One year post-operatively she maintained a normal ocular examination, and her eyelids and silicone tubes were well positioned. Systemic evaluation remained unrevealing. Basaloid adenocarcinoma of the lacrimal sac is relatively rare, and we highlight the role of a more conservative surgical intervention given the high rates of survival and low incidence of progression to metastatic disease when treating this rare malignancy.

A case of concurrent silent sinus syndrome, thyroid eye disease, idiopathic orbital inflammatory syndrome, and dacryoadenitis.

This is a retrospective case description of a single female patient found to have concomitant bilateral silent sinus syndrome, bilateral thyroid eye disease, unilateral dacryoadenitis, and idiopathic orbital inflammation that presented as progressive unilateral right-sided proptosis. The spectrum of inflammatory orbital diseases can make discerning between different entities challenging, but more unique in this case was the simultaneous presentation with bilateral silent sinus syndrome, a rare entity in its own right. Identifying each of these concurrent disease processes is important to establishing a multidisciplinary treatment approach to address all the patient's orbital and peri-orbital pathology. We hope to highlight the clinical and radiographic findings unique to each of these entities and share our approach to treatment in this complex case.

Paranasal sinus lymphoma: Retrospective review with focus on clinical features, histopathology, prognosis, and relationship to systemic lymphoma.

BACKGROUND: Paranasal sinus lymphoma is a rare clinical entity. METHODS: We conducted a retrospective case series of 68 patients with biopsy-confirmed paranasal sinus lymphoma with attention on systemic disease association. RESULTS: Of 63 patients with paranasal sinus lymphoma, 35 (56%) had systemic involvement. Four patient groups were identified: (1) primary paranasal sinus lymphoma (44%); (2) systemic disease occurring concurrently with paranasal sinus lymphoma (25%); (3) paranasal sinus lymphoma with relapse of preexisting systemic lymphoma (22%); and (4) progression to systemic disease after primary paranasal sinus lymphoma (8%). Most of the patients with systemic disease were diagnosed at 50 + years and had positive smoking histories. There was a trend toward disease activity in the neighboring ocular location. For patients with preexisting systemic lymphoma, the mean time to paranasal sinus lymphoma was 65 months. When systemic lymphoma developed after localized paranasal sinus lymphoma, mean time to progression was 23 months. Diffuse large B cell lymphoma was the most common paranasal sinus lymphoma. CONCLUSION: There is a risk of systemic involvement during the disease course of paranasal sinus lymphoma. Biopsy is the preferred first management step and should precede debulking or mass resection in nonemergent cases. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1065-1070, 2017.

Giant Ocular Horn Occurring in a 10-Year-Old Female.

Cutaneous horns uncommonly involve the periocular region. Involvement of the ocular surface is particularly rare. The authors present a patient who underwent a perinatal buccal mucosal graft for corneal perforation due to congenital corneal ectasia, most likely resulting from Peters anomaly. She developed a giant ocular horn 10 years later.

Solitary Extramedullary Plasmacytoma of the Orbital Apex and Dura Masquerading as Idiopathic Inflammation.

This is a retrospective case description of a single female patient found to have a primary solitary extramedullary plasmacytoma of the orbital apex and temporal/parietal dura. These monoclonal plasma cell neoplasms account for fewer than 5% of plasma cell neoplasms. Although most commonly found in the head and neck, orbital and dural solitary extramedullary plasmacytomas are extremely uncommon. The authors present a case of an extramedullary plasmacytoma involving both of these structures in a middle-age otherwise healthy female to highlight this rare entity and elucidate current treatment modalities and future considerations.

A rare case of orbital hodgkin lymphoma demonstrating therapeutic response to a novel systemic medication.

Orbital Hodgkin lymphoma is infrequent, representing less than 1% of adult orbital malignancies. It is typically seen in the setting of terminally advanced systemic disease. This case highlights orbital, head, and neck disease in a systemically stable individual treated with the novel anti-CD30 monoclonal antibody brentuximab vedotin.

Goat horn-induced intracranial emphysema and orbital injury.

This is a case description of a male patient found to have orbital and intracranial emphysema, specifically with air in his cavernous sinuses bilaterally following penetrating trauma to the medial orbit from a goat's horn. There were no orbital or skull base fractures. Although the presence of traumatic intracranial emphysema is not uncommon, it is typically the result of direct communication of the cranial vault with the paranasal sinuses in the setting of associated fracture or, alternatively, from direct penetration and inoculation. We present a rare case of orbital emphysema with traumatic intracranial emphysema without these previously described associations and postulate a mech``anism behind its development.

Glutamatergic stimulation induces GluN2B translation by the nitric oxide-Heme-Regulated eIF2α kinase in cortical neurons.

The activation of N-Methyl D-Aspartate Receptor (NMDAR) by glutamate is crucial in the nervous system function, particularly in memory and learning. NMDAR is composed by two GluN1 and two GluN2 subunits. GluN2B has been reported to participate in the prevalent NMDAR subtype at synapses, the GluN1/2A/2B. Here we studied the regulation of GluN2B expression in cortical neurons finding that glutamate up-regulates GluN2B translation through the action of nitric oxide (NO), which induces the phosphorylation of the eukaryotic translation initiation factor 2 α (eIF2α). It is a process mediated by the NO-heme-regulated eIF2α kinase (HRI), as the effect was avoided when a specific HRI inhibitor or a HRI small interfering RNA (siHRI) were used. We found that the expressed GluN2B co-localizes with PSD-95 at the postsynaptic ending, which strengthen the physiological relevance of the proposed mechanism. Moreover the receptors bearing GluN2B subunits upon NO stimulation are functional as high Ca2+ entry was measured and increases the co-localization between GluN2B and GluN1 subunits. In addition, the injection of the specific HRI inhibitor in mice produces a decrease in memory retrieval as tested by the Novel Object Recognition performance. Summarizing our data suggests that glutamatergic stimulation induces HRI activation by NO to trigger GluN2B expression and this process would be relevant to maintain postsynaptic activity in cortical neurons.