Michele M. Bloomer

Gene Expression Profiling of Transporters in the Solute Carrier and ATP-Binding Cassette Superfamilies in Human Eye Substructures

The barrier epithelia of the cornea and retina control drug and nutrient access to various compartments of the human eye. While ocular transporters are likely to play a critical role in homeostasis and drug delivery, little is known about their expression, localization and function. In this study, the mRNA expression levels of 445 transporters, metabolic enzymes, transcription factors and nuclear receptors were profiled in five regions of the human eye: cornea, iris, ciliary body, choroid and retina. Through RNA expression profiling and immunohistochemistry, several transporters were identified as putative targets for drug transport in ocular tissues. Our analysis identified SLC22A7 (OAT2), a carrier for the antiviral drug acyclovir, in the corneal epithelium, in addition to ABCG2 (BCRP), an important xenobiotic efflux pump, in retinal nerve fibers and the retinal pigment epithelium. Collectively, our results provide an understanding of the transporters that serve to maintain ocular homeostasis and which may be potential targets for drug delivery to deep compartments of the eye.

Clinicopathological characteristics of adamantinomatous and papillary craniopharyngiomas: University of California, San Francisco experience 1985-2005.

BACKGROUND:Craniopharyngiomas are rare epithelial tumors that are presumed to arise from the remnants of Rathkes pouch. OBJECTIVE:This study was designed to evaluate the outcome characteristics of craniopharyngiomas treated in a single institution and to determine whether the adamantinomatous craniopharyngioma should be considered more aggressive than a World Health Organization (WHO) grade I neoplasm. METHODS:We identified all patients with craniopharyngioma given their diagnoses at University of California, San Francisco in a 20-year period and performed a retrospective analysis of clinicopathological and outcome characteristics. Statistical analyses were performed to determine factors that affect survival characteristics. RESULTS:Eighty patients were included in the study based on the selection criteria. Sixty-nine tumors were adamantinomatous, 9 were papillary, and 2 were unclassified. All pediatric tumors were adamantinomatous. Visual field examination in 60 patients revealed a defect in 39 and only 14 showed bitemporal field defects. Hormonal tests with abnormal results were more common in younger patients. During a median follow-up of 82 months, 38 tumors recurred. Four of 9 gross total resections and 34 of 59 subtotal resections recurred. Median time to recurrence was 16.3 months for gross total and 11.7 for subtotal resections. Progression-free survival did not differ between males and females or children and adults. There was a negative correlation between age and overall survival. CONCLUSION:Adamantinomatous craniopharyngioma is a locally aggressive neoplasm with a significant rate of recurrence. This is not in keeping with the current designation of a WHO grade I neoplasm. Subtotal resection is associated with less mortality/morbidity but a higher recurrence rate. Given the high numbers of “silent” defects, formal visual field testing should be performed in all patients with craniopharyngiomas.

Management of nontraumatic corneal perforation with tectonic drape patch and cyanoacrylate glue

Purpose: To report a case of nontraumatic corneal perforation managed with a tectonic drape patch. Methods: Interventional case report. Results: A 60-year-old patient with a corneal scar in his left eye likely secondary to herpes simplex virus interstitial keratitis underwent laser peripheral iridotomy for narrow angles. He developed progressive thinning of the cornea overlying the scar that led to a descemetocele and then ultimately a 1.2- × 1.7-mm perforation. Intraoperatively, several attempts were made to seal the perforation with cyanoacrylate glue, but the wound continued to leak. Sterile plastic drape that was on the surgical field was fashioned into a 2-mm-diameter patch, and the peripheral edge of the tectonic drape patch was glued over the perforation, successfully sealing the cornea. One week later, the drape patch was intact without leak, and a penetrating keratoplasty was carried out without complication. Conclusions: Tectonic drape patch technique for nontraumatic corneal perforations in which there is tissue loss is a viable temporizing option when cyanoacrylate glue alone fails and when there is no corneal tissue or amniotic membrane available to close the wound.

Pilocytic astrocytomas of the optic nerve and their relation to pilocytic astrocytomas elsewhere in the central nervous system

Pilocytic astrocytoma is a low-grade glioma that affects mostly children and young adults and can occur anywhere in the central nervous system. Pilocytic astrocytoma of the optic nerve is an equally indolent subtype that is occasionally associated with neurofibromatosis type 1. In earlier studies, this subtype was considered within the larger category of ‘optic pathway glioma,’ which included infiltrating astrocytomas and other hypothalamic tumors. However, there have been suggestions that gliomas in the optic nerve, and especially pilocytic astrocytoma of the optic nerve, are biologically different from tumors within the hypothalamus and other parts of the optic tract. Furthermore, the recent discovery of BRAF duplication and fusion with the KIAA1549 gene is reported to be more typical for posterior fossa tumors, and the rate of this aberration is not well known in pilocytic astrocytoma of the optic nerve. To determine the distinction of pilocytic astrocytoma of the optic nerve from pilocytic astrocytoma of the posterior fossa and to investigate the prevalence of BRAF aberrations, we reviewed the clinicopathological and molecular features of all such patients in our institution. Our study demonstrates that BRAF duplication is more frequent in posterior fossa tumors compared with pilocytic astrocytoma of the optic nerve (P=0.011). However, the rates of phospho-MAPK1 and CDKN2A expression were high in both pilocytic astrocytoma of the optic nerve and posterior fossa pilocytic astrocytoma, suggesting that the MAPK pathway is active in these tumors. Our study supports the notion that BRAF duplication is more typical of posterior fossa pilocytic astrocytoma and that molecular alterations other than KIAA1549 fusion may underlie MAPK pathway activation in pilocytic astrocytoma of the optic nerve.

Human immunodeficiency virus-associated blepharoptosis.

Purpose: To better characterize an unusual blepharoptosis observed in HIV-positive patients and to evaluate histopathology. Methods: This retrospective case series evaluated patients with HIV/AIDS and blepharoptosis with reduced levator excursion. Exclusion criteria included patients with identifiable causes of ptosis (e.g., aponeurotic dehiscences, prior eyelid trauma or surgery), known myopathic/neuropathic systemic disorders, congenital ptosis, cranial neuropathies, and systemic infiltrative processes. Results: All 10 patients had bilateral symptomatic blepharoptosis. All patients (100%) were men with a mean age at presentation of 54 years (range, 42–77 years). Mean duration of HIV infection among 7 of 10 patients was 19 years (range, 13–24 years). Mean (±SD) MRD1 was 0.7 (±0.8) OD and 0.6 (±0.8) OS. Mean (±SD) levator excursion was 12 (±2.3) OD and 13 (±1.8) OS (normal levator excursion >15 mm). No patient was taking zidovudine (AZT) at the time of presentation. Nine patients (90%) underwent large bilateral levator resections for correction of blepharoptosis. Histopathologic specimens revealed abnormal levator muscle fibers with various degrees of atrophy, fibrosis, and regeneration without inflammation. Conclusions: The HIV-associated blepharoptosis observed among patients in this study is most consistent with a myopathy. Levator muscle histopathologic findings are virtually identical to muscle biopsies in individuals with HIV-associated myopathy, described before the advent of AZT or highly active antiretroviral therapy (HAART). Surgical management with levator resection provides optimal correction of HIV-associated blepharoptosis.

Secondary localized sectoral keratoconjunctival amyloidosis from ocular trauma.

Purpose: To report a case of unilateral localized sectoral conjunctival amyloidosis associated with corneal amyloidosis. Methods: Case report. Results: A 27-year-old woman with a history of ocular trauma presented with a limbus-based pink-yellow colored superonasal conjunctival lesion with adjacent superonasal sectoral corneal lattice-like changes. The lesion was monitored for 3 years with minimal enlargement, but conjunctival chalasis developed, which was bothersome to the patient. A conjunctival excisional biopsy confirmed the diagnosis of amyloidosis. Conclusions: To our knowledge, this is the first report of unilateral combined corneal and conjunctival amyloid deposition. Even more unusual was the sectoral distribution of the amyloid. This likely represents a local production and deposition of amyloid.

Analysis of Clinical Misdiagnoses in Children Treated With Enucleation

OBJECTIVE To evaluate discordant clinical and pathological diagnoses leading to pediatric enucleations over time. METHODS All pathology reports of pediatric enucleation specimens (subjects aged 0 to 18 years) from 1960 to 2008 were reviewed. Specimens with discordant clinical and pathologic diagnoses were further analyzed. Formalin-fixed, paraffin-embedded sections of enucleated eyes of any misdiagnosed cases were reevaluated. RESULTS Of 729 pediatric patients (746 eyes) who had enucleation from 1960 to 2008, 29 patients (4.0%) and 30 eyes (4.0%) had discordant clinical and pathological diagnoses. The misdiagnosis enucleation rate decreased with each respective decade studied, with the highest rate of 6.5% (18 of 276 eyes) in the 1960s and no misdiagnoses from 1990 to 2008. Of the 369 eyes enucleated for the clinical indication of malignancy, 22 eyes (6.0%) were misdiagnosed in that no evidence of malignancy was found on histopathological examination. Of the 377 eyes enucleated for benign clinical indications, 7 cases (1.9%) were found to be malignant by histopathology. CONCLUSIONS Misdiagnoses leading to pediatric enucleation have decreased during the past 5 decades, likely owing to improved diagnostic techniques. Benign and malignant intraocular conditions can simulate each other, especially retinoblastoma, Coats disease, nematode and bacterial endophthalmitis, panuveitis, and persistent hyperplastic primary vitreous.

Management of Primary Acquired Melanosis, Nevus, and Conjunctival Melanoma.

BACKGROUND The management of conjunctival melanoma is difficult because of the rarity of the disease, confusing terminology, high rates of local tumor recurrence, controversies regarding treatment, a poor evidence base, unreliable prognostication, and significant mortality rates. METHODS The medical literature was reviewed, focusing on treatment and management options for conjunctival melanoma. Recent trends and developments were summarized with respect to terminology, local treatment, histology, genetic analysis, prognostication, and systemic treatment, highlighting the scope for research and possible improvements in patient care. RESULTS Histopathological diagnostic terminology for primary acquired melanosis is being superseded by more explicit terminology, thus differentiating hypermelanosis from conjunctival melanocytic intraepithelial neoplasia. Topical chemotherapy and increased use of adjunctive radiotherapy have helped improve rates of local tumor control. Use of exenteration has become rare. Regional and systemic metastases are common in patients with nonbulbar conjunctival melanoma, although long-term survivors with metastases are growing in number. Prognostication is mainly based on tumor size and location, but histological and genetic data into multivariate analyses will soon be incorporated. The role of sentinel lymph-node biopsy continues to be controversial. Chemotherapy for metastatic disease is being superseded by targeted therapy based on genetic abnormalities such as BRAF mutations. CONCLUSIONS The management of conjunctival melanoma requires expert care from an experienced, multidisciplinary team. The goal of therapy is to provide good local tumor control with minimal morbidity, high-quality pathology, and adequate psychological support. Maximizing patient enrollment in multicenter clinical trials is likely to strengthen evidence-based decision-making.

Loss of contrast enhancement of the inferior rectus muscle on magnetic resonance imaging in acute fulminant invasive fungal sinusitis

Importance: This report describes a new magnetic resonance finding in acute fulminant invasive fungal sinusitis that may aid in the diagnosis of orbital involvement. Observations: The charts of two patients who presented with diabetic ketoacidosis and suspected acute fulminant invasive fungal sinusitis were retrospectively examined. Medical and surgical records, imaging studies, and histopathology specimens were reviewed. The two patients, a 58-year old female and 54-year-old male each had a contrast-enhanced magnetic resonance of the paranasal sinuses and orbits. Acute fulminant invasive fungal sinusitis with suspected orbital involvement was associated with focal loss of contrast enhancement of the inferior rectus muscle and adjacent orbital tissues. Fungal involvement of the inferior rectus muscle was confirmed on pathologic evaluation in both patients after exenteration. Conclusions and relevance: The finding of loss of contrast enhancement of an extraocular muscle on magnetic resonance may increase diagnostic confidence of orbital involvement in the setting of acute fulminant invasive fungal sinusitis and help guide surgical planning.

Thygeson superficial punctate keratitis and scarring.

Purpose: Thygeson superficial punctate keratitis (TSPK), a chronic, inflammatory disease, has traditionally been taught to resolve spontaneously and without scarring. We present 4 cases with TSPK who developed sight-altering scarring after a prolonged disease course. Methods: Retrospective chart review of cases seen at the Proctor Medical Group. Results: Patients age ranged from 31 to 68 years. All patients were male and had been symptomatic from 2 to 53 years. Follow-up period ranged from 1 month to 35 years. All 3 patients developed significant corneal scarring. Case 1 had bilateral corneal thickening and a Salzmann nodule with vascularization. Case 2 had bilateral stromal opacification. Case 3 developed corneal scarring to the point of needing an anterior lamellar corneal transplant. Pathological evaluation of this tissue showed disruption of the Bowman layer with band keratopathy, thickening of the basement membrane, and subepithelial fibrosis. The diagnosis of TSPK in these cases was never in doubt, 2 of the cases having been diagnosed by Dr Thygeson. Conclusions: Prolonged corneal inflammation associated with TSPK can cause visually significant scarring of the anterior corneal stroma. In those patients with chronic disease, the use of a topical corticosteroid may be needed not just for comfort but to reduce the risk of corneal scarring.