Recurrent scarring papulovesicular lesions on sun-exposed skin in a 22-year-old man.

KEY TEACHING POINTS.

Glyoxylate reductase isoform 1 is localized in the cytosol and not peroxisomes in plant cells.

Glyoxylate reductase (GLYR) is a key enzyme in plant metabolism which catalyzes the detoxification of both photorespiratory glyoxylate and succinic semialdehdye, an intermediate of the γ-aminobutyrate (GABA) pathway. Two isoforms of GLYR exist in plants, GLYR1 and GLYR2, and while GLYR2 is known to be localized in plastids, GLYR1 has been reported to be localized in either peroxisomes or the cytosol. Here, we reappraised the intracellular localization of GLYR1 in Arabidopsis thaliana L. Heynh (ecotype Lansberg erecta) using both transiently-transformed suspension cells and stably-transformed plants, in combination with fluorescence microscopy. The results indicate that GLYR1 is localized exclusively to the cytosol regardless of the species, tissue and/or cell type, or exposure of plants to environmental stresses that would increase flux through the GABA pathway. Moreover, the C-terminal tripeptide sequence of GLYR1, -SRE, despite its resemblance to a type 1 peroxisomal targeting signal, is not sufficient for targeting to peroxisomes. Collectively, these results define the cytosol as the intracellular location of GLYR1 and provide not only important insight to the metabolic roles of GLYR1 and the compartmentation of the GABA and photorespiratory pathways in plant cells, but also serve as a useful reference for future studies of proteins proposed to be localized to peroxisomes and/or the cytosol.

Anti-PD-L1 and anti-CD73 combination therapy promotes T cell response to EGFR-mutated NSCLC.

Treatment with anti-PD-1 and anti-PD-L1 therapies has shown durable clinical benefit in non-small cell lung cancer (NSCLC). However, patients with NSCLC with epidermal growth factor receptor (EGFR) mutations do not respond as well to treatment as patients without an EGFR mutation. We show that EGFR-mutated NSCLC expressed higher levels of CD73 compared with EGFR WT tumors and that CD73 expression was regulated by EGFR signaling. EGFR-mutated cell lines were significantly more resistant to T cell killing compared with WT cell lines through suppression of T cell proliferation and function. In a xenograft mouse model of EGFR-mutated NSCLC, neither anti-PD-L1 nor anti-CD73 antibody alone inhibited tumor growth compared with the isotype control. In contrast, the combination of both antibodies significantly inhibited tumor growth, increased the number of tumor-infiltrating CD8+ T cells, and enhanced IFN-γ and TNF-α production of these T cells. Consistently, there were increases in gene expression that corresponded to inflammation and T cell function in tumors treated with the combination of anti-PD-L1 and anti-CD73. Together, these results further support the combination of anti-CD73 and anti-PD-L1 therapies in treating EGFR-mutated NSCLC, while suggesting that increased T cell activity may play a role in response to therapy.

A Case Series of Two Patients Presenting With Pericardial Effusion as First Manifestation of Non-Small Cell Lung Cancer With BRAF Mutation and Expression Of PD-L1.

Lung cancer is the number one cause of cancer-related deaths in the United States. Involvement of pericardium occurs once cancer has progressed to stage IV which can cause massive effusion in the pericardial sac. This can lead to cardiac tamponade which can be fatal very quickly if untreated. The following is a two patient case series in which both patients presented with large pericardial effusion. The first patient sought medical attention due to new onset palpitations and was found to have hemorrhagic pericardial effusion and pulmonary embolism (PE). The second patient presented with shortness of breath. Investigations revealed that she had pericardial and pleural effusions along with multiple metastases throughout the body. Both patients ended up with a diagnosis of non-small cell lung cancer (NSCLC) with BRAF mutation. One patient had V600E mutation; other patient had a variant p.D594N mutation. Both patients also had expression of PD-L1.

Cellular Infiltrate in Rheumatoid Arthritis-associated Paracentral Corneal Ulceration.

PURPOSE: To investigate an immunopathogenesis of central and paracentral corneal ulceration associated with rheumatoid arthritis. METHODS: Sparse infiltrating cells in the ulcer area were identified by immunohistochemistry applied to archived formalin fixed, paraffin embedded tissues that had been recovered from patients undergoing penetrating keratoplasty necessitated by rheumatoid-associated central or paracentral corneal ulceration. RESULTS: Clinically, the ulcers presented as non-infiltrated lesions with a modicum of other ocular inflammation. Sparse T-lymphocytes were consistently identified in the subepithelial areas adjacent to the ulcer, with some neutrophils and macrophages in the stroma. B-lymphocytes were not detected. MHC Class II antigens reactivity was noted on some infiltrating cells and on corneal endothelium of two specimens. CONCLUSIONS: Immunohistochemistry of archival tissue facilitated detection and identification of sparse infiltrate in this infrequent corneal melting. Selective, consistent finding of T-lymphocyte infiltration in the ulcer area supports an immunopathogenesis of this clinical entity.

Anterior uveitis and iris nodules that are associated with Langerhans cell histiocytosis.

PURPOSE: To describe a case of Langerhans cell histiocytosis (LCH) that involved the anterior uveal tract. DESIGN: Interventional case report. METHODS: A retrospective review was conducted on a patient with iris nodules and anterior uveitis in the setting of LCH. Visual acuity and clinical findings that were noted on slit lamp biomicroscopy were extracted. RESULTS: An 18-year-old male patient with unilateral anterior segment inflammation and iris nodules experienced visual improvement from 20/200 to 20/25 after treatment with a 5-day course of topical corticosteroids. Regression of the iris nodules and anterior segment inflammation was also noted. Bone marrow aspirate confirmed recurrent, active LCH. CONCLUSION: The clinician should include LCH in the differential diagnosis when faced with anterior segment inflammation in conjunction with iris nodules. Additionally, LCH can be treated successfully with topical corticosteroid therapy.

The Diagnostic and Therapeutic Challenges of Posttraumatic Iris Implantation Cysts: Illustrative Case Presentations and a Review of the Literature.

Posttraumatic iris implantation cysts are rare ocular findings that are often associated with poor visual outcomes. Iris implantation cysts can present clinicians with diagnostic and therapeutic challenges given their variable presentations and frequently destructive nature. In this paper, we provide descriptions of two unusual cases of posttraumatic iris implantation cysts. The first case is of a recurrent keratin-filled iris implantation cyst that developed after open globe injury and intraocular implantation of cilia and was treated with cyst debulking procedures, injections of 5-Fluorouracil, and iridocyclectomy. The second case is of recurrent posttraumatic serous iris implantation cysts that were treated with laser, cyst aspiration, and injections of 5-Fluorouracil. We use these cases as a platform to discuss the different manifestations of implantation cysts, the roles of anterior segment optical coherence tomography, ultrasound biomicroscopy, and histopathology in facilitating timely and accurate diagnosis and review the range of available therapeutic modalities. We discuss conservative treatment approaches, including the novel use of 5-Fluorouracil therapy as an adjunct therapy, as well as more aggressive surgical excision requiring ocular reconstruction. Through a discussion of these cases and review of the literature, we provide recommendations to assist clinicians in managing this uncommon but vision-threatening condition and minimizing complications.

Evidence of apoptotic cell death in keratoconus.

PURPOSE: To determine the potential role of apoptosis in the noninflammatory degeneration characteristic of keratoconus. METHODS: Four normal corneas and 16 keratoconus corneas were obtained as archival specimens. Tissues were examined histopathologically for TUNEL immunoreactivity to detect the presence of DNA fragmentation. Tissues were also subjected to single-stranded DNA (ssDNA) analysis, a more apoptosis-specific stain. RESULTS: Normal corneas exhibited fewer than five TUNEL-positive epithelial cells per section, these being very lightly stained. All 16 keratoconus corneas demonstrated extensive, intense TUNEL staining in at least one layer. Fifteen of 16 exhibited staining in the epithelial layer, 11 of 16 in the stromal layer, and 13 of 16 in the endothelial layer, whereas 10 of 16 keratoconus cases demonstrated TUNEL immunoreactivity in all three layers. The ssDNA stain was also positive and evident in all three layers of the cornea, although to a lesser degree than the TUNEL assay. CONCLUSIONS: The noninflammatory nature of keratoconus, coupled with the TUNEL in situ results, suggests apoptosis as a mode of cell death in this degenerative disease.

Ocular rosacea can mimic trachoma: a case of cicatrizing conjunctivitis.

PURPOSE: To report the case of a patient with upper eyelid chronic cicatrizing conjunctivitis and entropion, presumably secondary to ocular rosacea. METHODS: Case report and review of medical literature. RESULTS: The patient has a history of chronic cicatrizing conjunctivitis since 1999. Despite an extensive workup for other possible causes, the patient's known history of acne rosacea is the most substantive explanation for her ocular disease. CONCLUSION: The presence of chronic cicatrizing conjunctivitis affecting mainly the upper eyelids, previously thought to be unique to trachoma, can be associated with ocular rosacea.

Recurrence of granular corneal dystrophy type I deposits within host stroma after non-descemet baring anterior lamellar keratoplasty.

PURPOSE: The aim of this study was to describe a case of recurrent granular deposits after non-Descemet baring anterior lamellar keratoplasty (nDALK). METHODS: A 28-year-old male with granular corneal dystrophy type I, found to have deposits throughout the anterior and midstroma, underwent nDALK. Three years later, he had a recurrence of the deposits. Slit-lamp photographs and optical coherence tomography were used to document the level of recurrence. Full-thickness penetrating keratoplasty was performed, and the residual host stroma was sent for pathology. RESULTS: Slit-lamp photographs and anterior segment optical coherence tomography confirmed that the recurrent hyaline deposits were confined to the residual host stroma just anterior to Descemet membrane. The anterior lamellar graft and epithelium remained clear. Pathology showed positive staining with Masson trichrome in the host stroma just anterior to Descemet membrane. CONCLUSIONS: Previous studies suggest that the recurrence of granular deposits after keratoplasty is usually anterior and may even be epithelial in origin. This case report documents the recurrence of granular dystrophy entirely within the residual host stroma after nDALK. These findings suggest that residual keratocytes may still be a source of recurrence.

Post-DSAEK optical changes: a comprehensive prospective analysis on the role of ocular wavefront aberrations, haze, and corneal thickness.

PURPOSE: The aim was to assess the visual impact of ocular wavefront aberrations, corneal thickness, and corneal light scatter prospectively after performing a Descemet stripping automated endothelial keratoplasty (DSAEK) in humans. METHODS: Data were obtained prospectively from 20 eyes preoperatively and at 1, 3, 6, and 12 months post-DSAEK. At each visit, the best spectacle-corrected visual acuity and visual acuity with glare (brightness acuity testing) were recorded, and ocular wavefront measurements and corneal optical coherence tomography (OCT) were performed. The magnitude and the sign of individual Zernike terms [higher-order aberrations (HOAs)] were determined. Epithelial, host stromal, donor stromal, and total corneal thicknesses were quantified. The brightness and intensity profiles of OCT images were generated to quantify light scatter in the whole cornea, subepithelial region, anterior and posterior host stroma, interface, and donor stroma. RESULTS: The mean best spectacle-corrected visual acuity and glare disability at low light levels improved from 1 to 12 months post-DSAEK. All corneal thicknesses and ocular lower-order aberrations and HOAs were found to be stable from 1 to 12 months, whereas total corneal, host stromal, and interface brightness intensities decreased significantly over the same period. A repeated measures analysis of variance performed across the follow-up period revealed that the change in scatter, but not the change in the HOAs, could account for the variability occurring in the acuity from 1 to 12 months post-DSAEK. CONCLUSIONS: Although ocular HOAs and scatter are both elevated over normal values post-DSAEK, our results demonstrate that the improvements in visual performance occurring over the first year post-DSAEK are associated with decreasing light scatter. In contrast, there were no significant changes in the ocular HOAs during this time. Because corneal light scatter decreased between 1 and 12 months despite there being stable corneal thicknesses over the same period, we conclude that factors that induced light scatter, other than tissue thickness or swelling (corneal edema), significantly impacted the visual improvements that occurred over time post-DSAEK. A better understanding of the cellular and extracellular matrix changes of the subepithelial region and interface, incurred by the surgical creation of a lamellar host-graft interface, and the subsequent healing of these tissues, is warranted.

Visual performance with wave aberration correction after penetrating, deep anterior lamellar, or endothelial keratoplasty.

PURPOSE: To investigate the contribution ocular aberrations have on visual performance by quantifying improvements in best-corrected visual acuity (VA) and contrast sensitivity (CS) obtained with higher-order aberration (HOA) correction after penetrating (PK), deep anterior lamellar (DALK), or Descemet's stripping automated endothelial keratoplasty (DSAEK). METHODS: Sixteen eyes were evaluated from 14 subjects who underwent PK (n = 5), DALK (n = 6), or DSAEK (n = 5) greater than 1 year prior to study enrollment. Ocular aberrations were measured and an adaptive optics system was used to correct ocular lower-order aberration (LOA) and HOA. VA and CS were measured for each subject with LOA or full-aberration correction. CS was measured at each of three spatial frequencies: 4, 8, and 12 cycles/deg. RESULTS: All keratoplasty groups had more aberration than that of a normal myopic population and experienced significant VA gains with full-aberration correction (P < 0.0013). PK subjects had better VA than that of DSAEK subjects with LOA correction (logMAR VA 0.03 ± 0.05 vs. 0.25 ± 0.05; P = 0.0870). After HOA correction this trend persisted (P = 0.1734). DSAEK subjects also experienced less VA benefit from full-aberration correction than that of PK and DALK subjects. All keratoplasty groups demonstrated similar CS benefits from full-aberration correction despite differing higher-order root-mean-square magnitudes. CONCLUSIONS: PK eyes had better logMAR VA than that of DSAEK eyes with LOA correction, whereas DALK eyes performed intermediate between the two. When full correction was applied, the same trend persisted. The findings suggest that factors other than aberration contribute to decrements in VA with DSAEK compared with PK.

The risk of posterior subcapsular cataracts in granulocyte donors.

BACKGROUND: Therapeutic use of adrenal corticosteroids is a risk factor for the development of posterior subcapsular cataract (PSC). Because corticosteroids are given to donors of apheresis granulocytes (PMNs) to improve yield, this study was performed to determine the prevalence of PSCs in PMN donors relative to a matched control group of apheresis platelet (PLT) donors. STUDY DESIGN AND METHODS: This study was a cross-sectional study stratified by age, sex, and lifetime apheresis experience at three sites. Individuals who had made at least five PMN donations preceded by corticosteroids were eligible. The presence of PSC was ascertained by grading digital retroillumination images of both lenses. A random subset of participants underwent clinical eye examinations by ophthalmologists masked as to study group. A logistic regression model was used to compute odds ratios (ORs). RESULTS: Granulocyte donors had given a mean of 13 donations (range, 5-39 donations) over a mean period of 8.5 years (range, 0.3-25.2 years). The mean corticosteroid exposure, in cortisol equivalents, was 2840 mg (range, 1067-9040 mg). Six of 89 PMN donors had photographic evidence of PSCs versus 4 of 89 controls. This difference was not significant (OR, 1.54; 95% confidence interval [CI], 0.46-5.08). Five of 33 PMN donors and 3 of 30 PLT donors had evidence of PSC by clinical examination. This difference was also not significant (OR, 1.61; 95% CI, 0.35-7.39). CONCLUSION: This study does not support the hypothesis that corticosteroid stimulation of PMN donors is associated with an increased risk of developing a PSC.