Publications by authors named "Rebecca C Stacy"

30 Publications

  • Page 1 of 1

The Discovery of ( S)-1-(6-(3-((4-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-2,3-dihydro-1 H-inden-4-yl)pyridin-2-yl)-5-methyl-1 H-pyrazole-4-carboxylic Acid, a Soluble Guanylate Cyclase Activator Specifically Designed for Topical Ocular Delivery as a Therapy for Glaucoma.

J Med Chem 2018 03 2;61(6):2552-2570. Epub 2018 Mar 2.

Global Discovery Chemistry , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States.

Soluble guanylate cyclase (sGC), the endogenous receptor for nitric oxide (NO), has been implicated in several diseases associated with oxidative stress. In a pathological oxidative environment, the heme group of sGC can be oxidized becoming unresponsive to NO leading to a loss in the ability to catalyze the production of cGMP. Recently a dysfunctional sGC/NO/cGMP pathway has been implicated in contributing to elevated intraocular pressure associated with glaucoma. Herein we describe the discovery of molecules specifically designed for topical ocular administration, which can activate oxidized sGC restoring the ability to catalyze the production of cGMP. These efforts culminated in the identification of compound (+)-23, which robustly lowers intraocular pressure in a cynomolgus model of elevated intraocular pressure over 24 h after a single topical ocular drop and has been selected for clinical evaluation.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00007DOI Listing
March 2018

Diagnostic genetic testing for patients with bilateral optic neuropathy and comparison of clinical features according to mutation status.

Mol Vis 2017 10;23:548-560. Epub 2017 Aug 10.

Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary Boston, MA.

Purpose: Inherited optic neuropathy is genetically heterogeneous, and genetic testing has an important role in risk assessment and counseling. The purpose of this study is to determine the prevalence and spectrum of mutations in a group of patients referred for genetic testing to a tertiary center in the United States. In addition, we compared the clinical features of patients with and without mutations in , the gene most commonly involved in dominantly inherited optic atrophy.

Methods: Clinical data and genetic testing results were reviewed for 74 unrelated, consecutive patients referred with a history of insidious, relatively symmetric, bilateral visual loss secondary to an optic neuropathy. Patients were evaluated for disease-causing variants in , , , and the entire mitochondrial genome with DNA sequencing and copy number variation (CNV) testing.

Results: Pathogenic DNA variants were found in 25 cases, with the majority (24 patients) located in . Demographics, clinical history, and clinical features for the group of patients with mutations in were compared to those without disease-causing variants. Compared to the patients without mutations, cases with mutations in were more likely to have a family history of optic nerve disease (p = 0.027); however, 30.4% of patients without a family history of disease also had mutations in . mutation carriers had less severe mean deviation and pattern standard deviation on automated visual field testing than patients with optic atrophy without mutations in (p<0.005). Other demographic and ocular features were not statistically significantly different between the two groups, including the fraction of patients with central scotomas (42.9% of mutation positive and 66.0% of mutation negative).

Conclusions: Genetic testing identified disease-causing mutations in 34% of referred cases, with the majority of these in Patients with mutations in were more likely to have a family history of disease; however, 30.4% of patients without a family history were also found to have an mutation. This observation, as well as similar frequencies of central scotomas in the groups with and without mutations in , underscores the need for genetic testing to establish an genetic diagnosis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5561143PMC
April 2018

Temporal artery biopsy in giant cell arteritis.

JAMA Ophthalmol 2015 Oct;133(10):1220

Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston4Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston5Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.

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http://dx.doi.org/10.1001/jamaophthalmol.2015.2552DOI Listing
October 2015

Correlation of clinical profile and specific histopathological features of temporal artery biopsies.

J Neuroophthalmol 2015 Jun;35(2):127-33

Department of Ophthalmology (RCS, ALG, JFR), Harvard Medical School, Boston, Massachusetts; Division of Neuro-Ophthalmology (RCS, JFR), Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; and Division of Ocular Pathology (RCS), Massachusetts Eye and Ear Infirmary, Boston, Massachusetts.

Background: This study sought to correlate the clinical features of patients with giant cell arteritis (GCA) who present with ophthalmic symptoms and signs, with 2 specific histopathological findings-the presence of giant cells and arterial wall neoangiogenesis. The goal was to assess if these pathological features might be useful in guiding the approach to patient management.

Methods: Medical charts were retrospectively reviewed from 58 patients who underwent a temporal artery biopsy at a single institution. Detailed information was collected about the clinical presentation and course, with an emphasis on visual function. Histopathological and immunohistochemical techniques were used to examine temporal artery biopsies for evidence of inflammation. Correlations were made between the clinical data and the presence of giant cells and neoangiogenesis.

Results: Twenty-one (34%) biopsies were positive for inflammation consistent with GCA. Although the percentage of positive biopsies with giant cells was high, neither the presence of giant cells nor neoangiogenesis was predictive of a patient's presenting visual symptoms, severity and bilaterality of vision loss, other ophthalmic manifestations of GCA, presence of headache or jaw claudication, or erythrocyte sedimentation rate. Giant cells were more common in patients with recent weight loss. Immunohistochemistry confirmed diagnoses but did not alter the clinical course or treatment plan.

Conclusions: There was no correlation between the clinical, specifically visual, features of GCA and the presence or absence of giant cells or neoangiogenesis in temporal artery biopsy specimens. Although the presence of neoangiogenesis may be important in the pathogenesis of GCA, our study showed no correlation between this finding and the clinical course.
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http://dx.doi.org/10.1097/WNO.0000000000000213DOI Listing
June 2015

Isolated optic nerve, chiasm, and tract involvement in Bing-Neel Syndrome.

J Neuroophthalmol 2014 Dec;34(4):340-5

Harvard University (MSH); University of Saskatchewan (EJA); Massachusetts Eye and Ear Infirmary (DMC, RCS); and Massachusetts General Hospital (FH), Boston, Massachusetts.

Central nervous system infiltration of Waldenström's macroglobulinemia is referred to as Bing-Neel Syndrome. We describe 2 patients whose clinical presentation was due to isolated involvement of the anterior visual pathways. The mechanism of visual failure in Bing-Neel Syndrome may involve both infiltrative and autoimmune processes.
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http://dx.doi.org/10.1097/WNO.0000000000000138DOI Listing
December 2014

Tick Infestation of the Eyelid With Histopathologic Characterization.

Ophthalmic Plast Reconstr Surg 2016 May-Jun;32(3):e55-8

*Department of Ophthalmology, David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary; †Department of Ophthalmology, Harvard Medical School; and ‡ Department of Ophthalmology, Ophthalmic Plastic Surgery, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, U.S.A.

Ocular tick infestation is a rare occurrence. The authors report a case that is unique for being the first published example from New England, for its chronic presentation, and for the inclusion of histopathologic analysis in its diagnostic workup. A 75-year-old man was evaluated for a persistent eyelid growth secondary to an incompletely removed tick that had attached 6 months earlier. The lesion was completely excised, and a partially destroyed arthropod was observed embedded within the tissue. Light microscopy demonstrated a mixed granulomatous reaction. Given the disruption of the tick's anatomy, speciation could not be performed. The patient had an uneventful recovery. A corresponding review of tick bites to the eye is provided.
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http://dx.doi.org/10.1097/IOP.0000000000000231DOI Listing
February 2017

Aggressive skull base metastasis from uveal melanoma: a clinicopathologic study.

Eur J Ophthalmol 2014 Sep-Oct;24(5):811-3. Epub 2014 May 12.

Retina Service, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts - USA.

Purpose: We present the clinical, pathologic, and genetic findings of the first reported case of choroidal melanoma that developed a late recurrence and aggressive metastasis to the skull base without evidence of hepatic involvement.

Methods: Retrospective chart review and clinicopathologic correlation of ocular and brain tissue, including sequencing of BAP1 for mutations.

Results: A 55-year-old woman was diagnosed with choroidal melanoma and treated with proton radiotherapy. Six years later, she developed a rapidly growing local recurrence involving the ciliary body and iris. Upon enucleation, histopathology revealed an iris and ciliary body epithelioid melanoma that was contiguous with the previously treated, regressed spindle cell choroidal melanoma. Imaging was initially negative for brain involvement. Two months later, she developed cranial neuropathies and was found to have a large skull base lesion that required surgical debulking for pain palliation. Histopathology confirmed the lesion to be metastatic melanoma. Both ocular and brain tumor specimens were wild-type for BAP1. Throughout her course, she developed no hepatic metastases.

Conclusions: Uveal melanoma may metastasize to the skull base. The present case was characterized by delayed onset and unusual aggressiveness of the metastatic disease, and lack of BAP1 mutation. The unusual course highlights a unique phenotype that may reflect an alternate molecular mechanism for metastatic disease.
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http://dx.doi.org/10.5301/ejo.5000468DOI Listing
November 2014

Posterior Necrotizing Scleritis Presenting as Sectoral Chorioretinitis.

Ocul Immunol Inflamm 2015 21;23(5):412-5. Epub 2014 Mar 21.

a Department of Ophthalmology , Massachusetts Eye and Ear Infirmary , Boston , Massachusetts , USA and.

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http://dx.doi.org/10.3109/09273948.2014.896467DOI Listing
September 2016

Absence of chromosomal abnormalities in herniated orbital fat.

Histopathology 2014 Aug 17;65(2):273-7. Epub 2014 Apr 17.

Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Aims: Lipomatous tumours of the orbit are rare, and can sometimes be difficult to characterize. Herniated orbital fat is thought to be a reactive process, but its presentation can mimic a lipomatous tumour such as an atypical lipomatous tumour or spindle cell/pleomorphic lipoma. Genetic studies to determine if it is indeed a reactive process rather than an adipocytic neoplasm have not been performed.

Methods And Results: Four samples of herniated orbital fat were reviewed clinically, histopathologically and immunohistochemically. Array comparative genomic hybridization (aCGH) was used to search for genome-wide copy number alterations within the tumours. Histological evaluation revealed that all four tumours contained collections of adipocytes surrounded by fibrous septae. Lochkern cells and floret-like multinucleated giant cells were present, consistent with herniated orbital fat. CD34 was positive in all tumours. Staining for MDM2 and CDK4 was negative. ACGH analysis demonstrated no copy number alterations.

Conclusions: Herniated orbital fat may share some histopathological features with lipoma and atypical lipomatous tumour, but the absence of copy number gains or losses is consistent with the impression that herniated orbital fat is a reactive process. Genetic analysis may be another method to help differentiate herniated orbital fat from a lipomatous orbital tumour when the diagnosis is in question.
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http://dx.doi.org/10.1111/his.12404DOI Listing
August 2014

Very low risk of light-induced retinal damage during Boston keratoprosthesis surgery: a rabbit study.

Cornea 2014 Feb;33(2):184-90

*Cornea Service, Massachusetts Eye and Ear Infirmary, Boston, MA; †Department of Ophthalmology, Harvard Medical School, Boston, MA; ‡Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, Boston, MA; and §Schepens Eye Research Institute, Boston, MA.

Purpose: The aim of this study was to assess the possibility of light damage to the retina by a surgical microscope during implantation of a Boston Keratoprosthesis (B-KPro) in rabbits.

Methods: The retinal irradiance from a Zeiss OPMI Lumera S7 operating microscope was measured at the working distance (16.5 cm). Light transmittance through an isolated B-KPro was measured. A B-KPro was implanted into 1 eye of 12 rabbits with the optic covered during the procedure. The operated eyes were then continuously exposed to a fixed light intensity under the microscope for 1 hour. Fluorescein angiography was carried out on days 2 and 9 postsurgery, after which the animals were euthanized. Further, we compared the potential of these retinal exposures to well-accepted light safety guidelines applicable to humans.

Results: Light transmittance of B-KPro revealed a blockage of short wavelengths (<390 nm) and of long wavelengths (1660-1750 nm) of light. In addition, the surgical microscope filtered a part of the blue, ultraviolet, and infrared wavelengths. Neither fluorescein angiography nor a histological examination showed any morphological retinal changes in our rabbits. Moreover, the retinal exposures were well below the safety limits.

Conclusions: Modern surgical microscopes have filters incorporated in them that block the most damaging wavelengths of light. The B-KPro is made of 100% poly(methyl methacrylate), which makes it in itself a blocker of short wavelengths of light. No damage could be demonstrated in the animal study, and the retinal exposures were well below the safety limits. Together, these results suggest that light exposures during B-KPro surgery present a low risk of photochemical damage to the retina.
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http://dx.doi.org/10.1097/ICO.0000000000000029DOI Listing
February 2014

Hyperplastic corneal pannus: an immunohistochemical analysis and review.

Surv Ophthalmol 2014 Jul-Aug;59(4):448-53. Epub 2013 Oct 20.

Cornea and External Disease Service, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.

An exuberant corneal pannus usually develops in adults with a history of surgery or trauma in the anterior central stroma and appears as a glistening, vascularized, moderately elevated, well circumscribed white nodule. We describe a 78-year-old woman with such a pannus, which in the past has typically been referred to as keloidal or hypertrophic. The involved eye had only light perception, and she underwent a penetrating keratoplasty that improved her vision to 20/100. Histopathologic and immunohistochemical evaluations of a the specimen disclosed a reactive spindle cell stromal proliferation of myofibroblasts that were smooth muscle actin positive with a low Ki67 proliferation index. Desmin, caldesmon, and calponin were negative, in keeping with the incomplete myofilamentary differentiation of a myofibroblast. There was a generous admixture of CD68/163-positive histiocytes and dispersed C3/5-positive T-lymphocytes. An absence of CD138- and IgG4-positive plasma cells ruled out an IgG4-related disease. For a lesion to be keloidal, the collagen must have a thick hyaline character, sharp edges, and a sparsity of intervening cells and vessels. A hypertrophic pannus would be composed of large swollen cells not necessarily increased in number. We therefore recommend adoption of the term hyperplastic for lesions like that described here because of the obvious increase in cellularity from proliferating myofibroblasts and the lack of true keloidal collagen.
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http://dx.doi.org/10.1016/j.survophthal.2013.10.005DOI Listing
December 2014

Deprivation amblyopia and congenital hereditary cataract.

Semin Ophthalmol 2013 Sep-Nov;28(5-6):321-6

Mass Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston , Massachusetts , USA and.

Amblyopia is a neurodevelopmental disorder of vision associated with decreased visual acuity, poor or absent stereopsis, and suppression of information from one eye.(1,2) Amblyopia may be caused by strabismus (strabismic amblyopia), refractive error (anisometropic amblyopia), or deprivation from obstructed vision (deprivation amblyopia). 1 In the developed world, amblyopia is the most common cause of childhood visual impairment, 3 which reduces quality of life 4 and also almost doubles the lifetime risk of legal blindness.(5, 6) Successful treatment of amblyopia greatly depends on early detection and treatment of predisposing disorders such as congenital cataract, which is the most common cause of deprivational amblyopia. Understanding the genetic causes of congenital cataract leads to more effective screening tests, early detection and treatment of infants and children who are at high risk for hereditary congenital cataract.
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http://dx.doi.org/10.3109/08820538.2013.825289DOI Listing
April 2014

Paraneoplastic dermatomyositis related to a chondrosarcoma involving the cavernous sinus.

J Neuroophthalmol 2013 Dec;33(4):363-6

Department of Ophthalmology (MMP, RCS), Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts.

Approximately one third of all cases of dermatomyositis may be associated with malignancy. We describe a patient with unexplained rash, joint pain, and muscle weakness, who subsequently developed a cavernous sinus syndrome due to a central nervous system chondrosarcoma. Discovery of this tumor and further dermatologic evaluation, including skin biopsy, resulted in diagnosis of paraneoplastic dermatomyositis due to cavernous sinus chondrosarcoma.
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http://dx.doi.org/10.1097/WNO.0b013e3182a30480DOI Listing
December 2013

Dacryops in the setting of a Boston type II keratoprosthesis.

Ophthalmic Plast Reconstr Surg 2014 May-Jun;30(3):e73-5

*Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, México; and †Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, U.S.A.

Dacryops of the lacrimal tissue can develop under diverse circumstances. Recent evidence suggests that scarring or obstruction of the lacrimal ducts may lead to their dilatation and formation of a cystic structure. Patients who undergo repeated orbital surgery may therefore be at greater risk of dacryops formation. In this report, a patient who underwent multiple corneal and glaucoma procedures including Boston type II keratoprosthesis, after acid burns to both eyes, is described. Over time, a fluid-filled collection developed in the lower orbit. On surgical exploration and incision, fluid was drained from a cystic lesion which abutted the lacrimal gland and spanned the upper and lower orbits. The lesion was removed and was proven by histopathology and immunohistochemistry to be dacryops. This is the first known case of dacryops associated with Boston type II keratoprosthesis.
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http://dx.doi.org/10.1097/IOP.0b013e31829d0270DOI Listing
October 2014

Collagenous fibroma (desmoplastic fibroblastoma) of the orbital rim.

Ophthalmic Plast Reconstr Surg 2013 Jul-Aug;29(4):e101-4

David G. Cogan Ophthalmic Pathology Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts 02114, USA.

A 40-year-old woman with left periorbital swelling for 1 month presented without diplopia or change in vision. Imaging studies revealed a 1-cm mass at the frontozygomatic junction at the orbital rim with slight bony erosion and spiculation. The lesion was applied to the periosteum and was excised along with a portion of the bony orbital rim. Histopathology revealed elongated and stellate fibroblasts within a dense collagenous matrix. Vimentin and Masson trichrome staining was consistent with a collagenous fibroma, a rare tumor that has, only once before, been reported in the orbit in the lacrimal fossa region. The current collagenous fibroma arose from the periosteum to grow exophytically, causing minimal bone changes. A literature review shows that this condition predominantly affects middle-aged and older adults rather than children.
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http://dx.doi.org/10.1097/IOP.0b013e31827deffeDOI Listing
January 2014

Diffuse large B-cell lymphoma of the orbit: clinicopathologic, immunohistochemical, and prognostic features of 20 cases.

Am J Ophthalmol 2012 Jul 13;154(1):87-98.e1. Epub 2012 Apr 13.

David G. Cogan Ophthalmic Pathology Laboratory, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.

Purpose: To evaluate a series of orbital diffuse large B-cell lymphomas (DLBCL) for prognostic features and therapeutic outcomes.

Design: Retrospective multicenter case study of clinical and immunohistochemical features of 20 patients.

Methods: Clinical, histopathologic, and immunohistochemical features were correlated with outcomes. Immunohistochemistry for biomarkers including Bcl-6, CD5, CD10, CD20, FOXP1, GCET1, and MUM1 was performed to differentiate between 2 major genetic subtypes of DLBCL: activated B-cell-like (ABC) and germinal center B-cell-like (GCB).

Results: Sixteen patients presented with unilateral and 4 with bilateral tumors. Three had bony erosion of the orbit on imaging studies. Of 14 patients with detailed follow-ups, 3 had a prior or concurrent lymphomatous disease; 8 had stage I disease (limited to the orbit) at presentation; and 3 were newly diagnosed with systemic (stage IV) DLBCL. Localized disease was treated with combined systemic chemotherapy, including rituximab and radiation with no deaths to date; there was 1 death related to systemic DLBCL. Clinical staging was the best predictive method and no immunohistochemical feature or subcategory (ABC vs GCB) correlated with outcome.

Conclusions: Primary orbital DLBCL has a more favorable prognosis than systemic DLBCL and may arise from a preexistent hematolymphomatous neoplasm (4 out of 20 cases). In our series, orbital DLBCL had a 57% likelihood of being restricted to the ocular adnexa. Clinical staging was more helpful in predicting outcome than any single immunohistopathologic feature or combination of biomarkers. Orbital radiation of 30 gray in conjunction with systemic chemotherapy with rituximab can achieve disease-specific survival approaching 100% in purely localized cases.
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http://dx.doi.org/10.1016/j.ajo.2012.01.021DOI Listing
July 2012

Subtleties in the histopathology of giant cell arteritis.

Semin Ophthalmol 2011 Jul-Sep;26(4-5):342-8

Temporal Artery Biopsy Histopathology, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.

A temporal artery biopsy is typically obtained in cases of suspected giant cell arteritis (GCA). The differentiation between a "positive" versus a "negative" biopsy is sometimes not simple. Degrees of inflammation can vary from obvious, florid accumulations of giant cells to subtle pockets of non-granulomatous inflammation. Areas of normal pathology, or "skip lesions," may be interspersed within inflamed sections of the artery, resulting in a false negative diagnosis. Other features of the biopsy, such as the state of the internal elastic lamina and inflammation of the adjacent, smaller vessels, must also be evaluated and considered as possible signs of disease. Finally, some biopsies have an intermediate histopathologic appearance with mild inflammation and scarring, which may indicate prior treatment with corticosteroids, or "healed" arteritis. Careful examination and clinical correlation is therefore essential to evaluate for these subtleties, which can affect the final diagnosis.
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http://dx.doi.org/10.3109/08820538.2011.588656DOI Listing
December 2011

Characterization of retrokeratoprosthetic membranes in the Boston type 1 keratoprosthesis.

Arch Ophthalmol 2011 Mar;129(3):310-6

David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, and Harvard Medical School, Boston, MA 02114, USA.

Objective: To evaluate retroprosthetic membranes that can occur in 25% to 65% of patients with the Boston type 1 keratoprosthesis (KPro).

Methods: Two patients with Peter anomaly and 2 with neurotrophic scarred corneas underwent revisions of their type 1 KPros because of visually compromising retroprosthetic membranes. The excised membranes were studied by light microscopy with hematoxylin-eosin, periodic acid-Schiff, and toluidine blue stains. Immunohistochemical and transmission electron microscopic examination were also used.

Results: Light microscopic examination revealed that the retro-KPro fibrous membranes originated from the host's corneal stroma. These mildly to moderately vascularized membranes grew through gaps in the Descemet membrane to reach behind the KPro back plate and adhere to the anterior iris surface, which had undergone partial lysis. In 2 cases, the fibrous membranes merged at the pupil with matrical portions of metaplastic lens epithelium, forming a bilayered structure that crossed the optical axis. Retro-KPro membranes stained positively for α-smooth muscle actin but negatively for pancytokeratin. Electron microscopy confirmed the presence of actin filaments within myofibroblasts and small surviving clusters of metaplastic lens epithelial cells.

Conclusions: Stromal downgrowth, rather than epithelial downgrowth, was the major element of the retro-KPro membranes in this series. Metaplastic lens epithelium also contributed to opacification of the visual axis. Florid membranous inflammation was not a prominent finding and thus probably not a requisite stimulus for membrane development. Further advances in prosthetic design and newer antifibroproliferative agents may reduce membrane formation.
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http://dx.doi.org/10.1001/archophthalmol.2011.26DOI Listing
March 2011

Pythium insidiosum keratitis in Israel.

Eye Contact Lens 2011 Mar;37(2):96-8

Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.

Purpose: To report with morphologic and phylogenetic speciation the first case from Israel of Pythium insidiosum keratitis associated with contact-lens wear.

Methods: Case report and literature review.

Results: A 21-year-old man with a history of contact-lens use and water exposure was hospitalized in Israel for a corneal ulcer. The ulcer progressed despite intensive antibiotics. He flew home to the United States for further care. Examination revealed a corneal ulcer with hypopyon. The infection progressed despite intensive medical therapy, and a therapeutic penetrating keratoplasty was performed. Histology and cornea cultures from the host cornea revealed sparsely septate, branching hyphae, consistent with P. insidiosum. DNA sequencing of the Pythium isolate supported the clinical history that the infection was acquired outside of the United States. Despite intensive medical therapy and a second corneal transplant, the ulcer progressed, ultimately requiring enucleation.

Conclusion: This is the first reported case of culture-proven, contact lens-related Pythium keratitis originating from Israel. Pythium is a fungus-like, aquatic oomycete found in tropical climates. Human pythiosis is uncommon but associated with high morbidity. Case reports describe surgical cure of Pythium keratitis, but this case recurred despite two penetrating keratoplasties and maximal antifungal therapy. In cases of presumed fungal keratitis that do not respond to antifungals, the fungus should be sent for speciation because early surgical intervention is the only means to save the eye in ocular pythiosis.
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http://dx.doi.org/10.1097/ICL.0b013e3182043114DOI Listing
March 2011

Clinical characterization and immunopathologic features of sclerosing dacryoadenitis and riedel thyroiditis.

Arch Ophthalmol 2010 Dec;128(12):1626-8

David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, Boston, 02114, USA.

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http://dx.doi.org/10.1001/archophthalmol.2010.299DOI Listing
December 2010

Blue nevus of the tarsus as the predominant component of a combined nevus of the eyelid.

Ophthalmic Plast Reconstr Surg 2011 Jul-Aug;27(4):e94-6

David G Cogan Laboratory of Ophthalmic Pathology, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts 02114, USA.

A 40-year-old man presented with a pigmented lesion of the palpebral conjunctiva and margin of the right lower eyelid. Because of suspicion of melanoma, the lesion was resected. Microscopic examination revealed 2 distinct components: a dominant blue nevus in the tarsus consisting of bland pigmented spindle and epithelioid cells that dissected among the orbicularis muscle fibers and meibomian glands, and a small subepithelial nevomelanocytic component with no overlying junctional activity. The diagnosis of a combined nevus was supported by minimal Ki-67 nuclear immunoreactivity. While the current lesion was proved to be an atypical nevus, all palpebral pigmented lesions should be routinely excised because many are melanomas.
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http://dx.doi.org/10.1097/IOP.0b013e3181f0b6d5DOI Listing
September 2011

Pigmented apocrine hidrocystoma of the caruncle.

Cornea 2010 Nov;29(11):1320-2

David G. Cogan Laboratory of Eye Pathology, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.

Purpose: To describe the clinical and immunopathologic features of the first convincing apocrine hidrocystoma of the caruncle that happened to be pigmented.

Methods: Case report with clinical evaluation, ultrasound biomicroscopy, and paraffin-embedded tissue stained with hematoxylin and eosin, periodic acid-Schiff, and immunohistochemical markers.

Results: Ultrasound biomicroscopy identified a cyst occurring in a 56-year-old white woman. Histopathologically, it was lined by an inner eosinophilic columnar epithelium that was gross cystic disease fluid protein-15-positive and evinced apical decapitation secretion and periodic acid-Schiff-positive, diastase-resistant cytoplasmic granules. Fontana- and MART-1-positive melanin granules were demonstrated. There was an outer layer of smooth muscle actin-positive myoepithelial cells. An adjacent apocrine gland was discovered with identical staining characteristics but without melanin granules.

Conclusions: Classical apocrine gland cysts can exceptionally develop in the caruncle. The light dispersion of cytoplasmic melanin found in the lining cells may have contributed to the cyst's clinical pigmentation, which is otherwise generally regarded as the result of the Tyndall effect, wherein blue wavelengths of light reflect from a colloidal solution of lipofuscin and cell debris.
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http://dx.doi.org/10.1097/ICO.0b013e3181d4fd71DOI Listing
November 2010

Unifocal and multifocal reactive lymphoid hyperplasia vs follicular lymphoma of the ocular adnexa.

Am J Ophthalmol 2010 Sep;150(3):412-426.e1

David G. Cogan Laboratory of Ophthalmic Pathology, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary and Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA.

Purpose: To characterize the differentiating histopathologic and immunophenotypic features of reactive lymphoid hyperplasia (RLH) and follicular lymphoma of the ocular adnexa.

Design: Retrospective case study with clinical follow-up and review of the literature.

Methods: Clinical records of 9 cases of RLH and 6 cases of follicular lymphoma from 2 institutions were reviewed. Light microscopic evaluation and immunohistochemical stains including CD20, CD3, CD5, CD21, CD23, BCL-2, BCL-6, CD10, kappa, lambda, and Ki67 were used to distinguish the 2 categories.

Results: RLH preferentially involved the conjunctiva, whereas follicular lymphoma had a propensity to involve the lacrimal gland. Microscopic analysis with immunohistochemical staining distinguished RLH from follicular lymphoma. BCL-2 was positive in follicular centers of follicular lymphoma but not in RLH. CD10 identified follicular center cells and Ki67 quantified cells in S-phase. CD21 and CD23 detected dendritic cell scaffoldings of indistinct germinal centers. None of the patients with RLH developed lymphoma during their clinical courses (up to 18 years). However, 3 patients with orbital, but not conjunctival, RLH developed immunohistochemically proven multifocal nonophthalmic supradiaphragmatic adnexal RLH (sites included lung, parotid, axillary nodes, and uvea). All 6 patients with follicular lymphoma had disseminated disease.

Conclusions: A correct diagnosis of RLH vs follicular lymphoma can be reliably established employing immunohistochemical methods. A heretofore undescribed "multifocal RLH" syndrome must be distinguished from follicular lymphoma. Conjunctival RLH can usually be managed surgically without radiotherapy, but "multifocal RLH" required systemic treatment in 2 of 3 patients. Follicular lymphoma requires systemic chemotherapy if discovered beyond stage 1E.
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http://dx.doi.org/10.1016/j.ajo.2010.04.007DOI Listing
September 2010

Recurrent conjunctival dermoid cyst with reactive lymphoid hyperplasia.

Ophthalmic Plast Reconstr Surg 2011 Mar-Apr;27(2):e28-30

Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02116, USA.

Conjunctival dermoid cysts are a rare subtype of dermoid cyst usually presenting in adulthood. The authors report a case of a recurrent conjunctival dermoid cyst with reactive lymphoid hyperplasia that was immunohistochemically demonstrated to be polyclonal. Follicular centers that were present within the cyst wall were negative for Bcl-2 and positive for the immunohistochemical markers CD20, Bcl-6, CD10, and Ki67, which helped to differentiate the lesion from a follicular lymphoma. The lesion did not recur after 14 months of follow-up.
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http://dx.doi.org/10.1097/IOP.0b013e3181c6873aDOI Listing
May 2011

Orbital involvement in Bing-Neel syndrome.

J Neuroophthalmol 2010 Sep;30(3):255-9

Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA.

Bing-Neel syndrome (BNS) is defined as intracranial involvement of Waldenström macroglobulinemia (WM). Few cases of orbital involvement have been reported. A 51-year-old man with a history of WM developed bilateral orbitopathy and optic neuropathy. Orbital biopsy, cerebrospinal fluid studies, and neuroimaging confirmed the diagnosis of BNS involving the orbital soft tissues, optic nerves, meninges, and cauda equina. The neuro-ophthalmic manifestations resolved after parenteral and intrathecal chemotherapy in addition to autologous stem cell transplantation. The rare neuro-ophthalmic manifestations of BNS may require a multifaceted approach to therapy.
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http://dx.doi.org/10.1097/WNO.0b013e3181dee96cDOI Listing
September 2010

Monocular nasal hemianopia from atypical sphenoid wing meningioma.

J Neuroophthalmol 2010 Jun;30(2):160-3

Department of Neuro-Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA.

Neurogenic monocular nasal field defects respecting the vertical midline are quite uncommon. We report a case of a unilateral nasal hemianopia that was caused by compression of the left optic nerve by a sphenoid wing meningioma. Histological examination revealed that the pathology of the meningioma was consistent with that of an atypical meningioma, which carries a guarded prognosis with increased chance of recurrence. The tumor was debulked surgically, and the patient's visual field defect improved.
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http://dx.doi.org/10.1097/WNO.0b013e3181de8b56DOI Listing
June 2010

Pathophysiology of postoperative diplopia after cataract surgery.

Int Ophthalmol Clin 2010 ;50(1):37-42

Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.

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http://dx.doi.org/10.1097/IIO.0b013e3181c570a9DOI Listing
March 2010

Conjunctival melanoma arising from primary acquired melanosis in a patient with neurofibromatosis type I.

Cornea 2010 Feb;29(2):232-4

Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard School of Medicine, Boston, MA 02114, USA.

Purpose: To describe a case of conjunctival malignant melanoma (MM) arising from primary acquired melanosis in a patient with neurofibromatosis type 1 (NF-1).

Methods: Case report and literature review.

Results: A 66-year-old woman with a history of NF-1 presented with extensive pigmentation of the left bulbar conjunctiva. Conjunctival biopsies demonstrated MM arising from primary acquired melanosis with atypia. Two excision and cryotherapy procedures did not completely eradicate the conjunctival pigment, which was then treated with topical mitomycin C. Subsequent biopsies and clinical examinations have revealed no remaining tumor.

Conclusion: Conjunctival MM is uncommon in patients with NF-1 and can be successfully treated with excision, cryotherapy, and topical mitomycin C.
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http://dx.doi.org/10.1097/ICO.0b013e3181ae27ddDOI Listing
February 2010

Disruption and recovery of patterned retinal activity in the absence of acetylcholine.

J Neurosci 2005 Oct;25(41):9347-57

Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Many developing neural circuits generate synchronized bursting activity among neighboring neurons, a pattern thought to be important for sculpting precise neural connectivity. Network output remains relatively constant as the cellular and synaptic components of these immature circuits change during development, suggesting the presence of homeostatic mechanisms. In the retina, spontaneous waves of activity are present even before chemical synapse formation, needing gap junctions to propagate. However, as synaptogenesis proceeds, retinal waves become dependent on cholinergic neurotransmission, no longer requiring gap junctions. Later still in development, waves are driven by glutamatergic rather than cholinergic synapses. Here, we asked how retinal activity evolves in the absence of cholinergic transmission by using a conditional mutant in which the gene encoding choline acetyltransferase (ChAT), the sole synthetic enzyme for acetylcholine (ACh), was deleted from large retinal regions. ChAT-negative regions lacked retinal waves for the first few days after birth, but by postnatal day 5 (P5), ACh-independent waves propagated across these regions. Pharmacological analysis of the waves in ChAT knock-out regions revealed a requirement for gap junctions but not glutamate, suggesting that patterned activity may have emerged via restoration of previous gap-junctional networks. Similarly, in P5 wild-type retinas, spontaneous activity recovered after a few hours in nicotinic receptor antagonists, often as local patches of coactive cells but not waves. The rapid recovery of rhythmic spontaneous activity in the presence of cholinergic antagonists and the eventual emergence of waves in ChAT knock-out regions suggest that homeostatic mechanisms regulate retinal output during development.
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http://dx.doi.org/10.1523/JNEUROSCI.1800-05.2005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6725714PMC
October 2005