Aurora Kinase A Is Overexpressed in Human Retinoblastoma and Correlates with Histopathologic High-Risk Factors: Implications for Targeted Therapy.

Retinoblastoma (RB) is an intraocular malignancy initiated by loss of RB1 function and/or dysregulation of MYCN oncogene. RB is primarily treated with chemotherapy; however, systemic toxicity and long-term adverse effects remain a significant challenge necessitating the identification of specific molecular targets. Aurora kinase A (AURKA), a critical cell cycle regulator, contributes to cancer pathogenesis, especially in RB1-deficient and MYCN-dysregulated tumors. Our immunohistochemistry study in patient specimens (n = 67) discovered that AURKA is overexpressed in RB, and elevated expression correlates with one or more histopathologic high-risk factors, such as tumor involvement of the optic nerve, choroid, sclera, and/or anterior segment. More specifically, AURKA is ubiquitously expressed in most advanced-stage RB tumors that show a suboptimal response to chemotherapy. shRNA-mediated depletion/pharmacologic inhibition studies in cell lines, patient-derived cells, in vivo xenografts, and enucleated patient specimens confirm that RB cells are highly sensitive to a lack of functional AURKA. In addition, we deciphered that AURKA and MYCN associate with each other to regulate their levels in RB cells. Overall, our results demonstrate a previously unknown up-regulation of AURKA in RB, facilitated by its crosstalk with MYCN, and elevated levels of this kinase may indicate unfavorable prognosis in tumors refractory to chemotherapy. This study provides a rationale and confirms that therapeutic targeting of elevated AURKA in RB could be a potential treatment approach.

Alterations of adipokines, pancreatic hormones and incretins in acute and convalescent COVID-19 children.

BACKGROUND: The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), accountable for Coronavirus disease 2019 (COVID-19), may cause hyperglycemia and additional systemic complexity in metabolic parameters. It is unsure even if the virus itself causes type 1 or type 2 diabetes mellitus (T1DM or T2DM). Furthermore, it is still unclear whether even recuperating COVID-19 individuals have an increased chance to develop new-onset diabetes. METHODS: We wanted to determine the impact of COVID-19 on the levels of adipokines, pancreatic hormones, incretins and cytokines in acute COVID-19, convalescent COVID-19 and control children through an observational study. We performed a multiplex immune assay analysis and compared the plasma levels of adipocytokines, pancreatic hormones, incretins and cytokines of children presenting with acute COVID-19 infection and convalescent COVID-19. RESULTS: Acute COVID-19 children had significantly elevated levels of adipsin, leptin, insulin, C-peptide, glucagon and ghrelin in comparison to convalescent COVID-19 and controls. Similarly, convalescent COVID-19 children had elevated levels of adipsin, leptin, insulin, C-peptide, glucagon, ghrelin and Glucagon-like peptide-1 (GLP-1) in comparison to control children. On the other hand, acute COVID-19 children had significantly decreased levels of adiponectin and Gastric Inhibitory Peptide (GIP) in comparison to convalescent COVID-19 and controls. Similarly, convalescent COVID-19 children had decreased levels of adiponectin and GIP in comparison to control children. Acute COVID-19 children had significantly elevated levels of cytokines, (Interferon (IFN)) IFNγ, Interleukins (IL)-2, TNFα, IL-1α, IL-1ß, IFNα, IFNß, IL-6, IL-12, IL-17A and Granulocyte-Colony Stimulating Factors (G-CSF) in comparison to convalescent COVID-19 and controls. Convalescent COVID-19 children had elevated levels of IFNγ, IL-2, TNFα, IL-1α, IL-1ß, IFNα, IFNß, IL-6, IL-12, IL-17A and G-CSF in comparison to control children. Additionally, Principal component Analysis (PCA) analysis distinguishes acute COVID-19 from convalescent COVID-19 and controls. The adipokines exhibited a significant correlation with the levels of pro-inflammatory cytokines. CONCLUSION: Children with acute COVID-19 show significant glycometabolic impairment and exaggerated cytokine responses, which is different from convalescent COVID-19 infection and controls.

Immune characterization of thyroid neoplasm's and its variants using immunohistochemical markers: CK-19, Galectin-3 and Hector Battifora mesothelial-1.

BACKGROUND: Nodular lesions of the thyroid are amongst the common palpable lesions that are encountered by the pathologists in the fine needle aspiration clinics and not only aspiration smears, but even biopsy sections pose significant challenges in their characterization and further classification. Neoplastic lesions of the thyroid have shown a steady rise worldwide and are diagnosed at age younger than most other cancers. Histopathology remains the gold standard in diagnosis and classification of thyroid neoplasms, with variable sensitivity and specificity of immunohistochemical markers, also attributed to variation in the inclusion criteria. We classified the thyroid neoplasms based on WHO Classification (2017) and aimed to study the diagnostic utility of immunohistochemical markers - CK-19, Galectin-3 and Hector Battifora mesothelial-1 performed on manual tissue microarray sections to differentiate various variants of papillary carcinoma from its mimickers, specifically follicular patterned papillary neoplasms from other follicular patterned lesions. METHOD: Prospective study of neoplastic lesions of thyroid from July 2018 to August 2020. Authors describe the clinico-radiological, cytological, histo-morphological and immunohistochemical features of neoplastic nodular lesions of the thyroid. RESULTS: Prospective analysis of nodular thyroid lesions yielded 76 cases, of which 38 were neoplastic. Cytology showed discordance in 10/24 cases, amongst the discordant cases, 70% were confirmed as papillary carcinoma. CK-19 showed high expression in all variants of papillary carcinomas (24/24), low expression in well differentiated tumor of uncertain malignant potential (WD-TUMP) and medullary carcinoma. It was negative in follicular and Hurthle cell neoplasms. Galectin-3 showed 100% specificity and HBME-1 showed 100% sensitivity in diagnosis of papillary carcinoma and its variants. Adenomatoid nodules did not express Gal-3 which helped in their differentiation from FVPTC. CONCLUSIONS: Gal-3 in combination either with CK-19 or HBME-1 improves the sensitivity and specificity of detection of papillary carcinoma, its variants and its differentiation from follicular patterned lesions to 100% with a significant p value.

Linezolid shows high safety and efficacy in the treatment of Pythium insidiosum keratitis in a rabbit model.

Efficacy and safety of three antibiotics (Linezolid-LZ, 0.2%; Azithromycin-AZ, 1%; Tigecycline-TG, 1%) were determined in the treatment of Pythium insidiosum keratitis in rabbits. Infection of right eye of 38 rabbits was induced by standard intracorneal injection of P. insidiosum zoospores (left eye, intracorneal saline). Corneal infection developed in all right eyes. One hourly eye drops of one of the three antibiotics was instilled in both eyes (3 groups of 12 rabbits each) except in controls. Half of the rabbits in each group received intracorneal injection of the respective antibiotic after 4 days of starting eye drops. Clinical scoring of eyes was done over next 3 weeks. The reduction in scores post-treatment was significant for each drug (LZ: p < 0.025, AZ: p < 0.025, TG: p < 0.01). Scores with LZ (median change of 3) was significantly (p = 0.013) higher than TG (median change of 2) and comparable (p = 0.06) to AZ (median change of 3). Reduction in clinical scores in eyes receiving intracorneal antibiotics was not significantly different from the eyes that did not receive intracorneal antibiotics (p = 0.73). While no adverse effect of LZ was seen in the control corneas, 66-100% of rabbits showed reaction to AZ and TG. Histopathology showed severe inflammation in all infected corneas and intraocular extension in some of the rabbits with poor response. The success rate was noted to be 16.7%, 25% and 50% in AZ, TG and LZ respectively (p = 0.45). LZ demonstrated superior efficacy and safety and can be considered for trial in human disease.

Primary De novo ductal adenocarcinoma of the lacrimal gland.

BACKGROUND: Primary ductal adenocarcinoma of the lacrimal gland is a rare and aggressive malignant epithelial lacrimal gland neoplasm, morphologically and phenotypically resembles salivary duct carcinoma, and both strongly resemble infiltrating ductal carcinoma of breast. METHOD: Retrospective Chart review of cases of malignant lacrimal gland tumors from 2013 July to 2020 July. Authors describe the clinico radiological, morphological and immunohistochemical features of primary ductal adenocarcinoma (PDA) of lacrimal gland. Extensive review of literature of PDA of lacrimal gland and salivary gland ductal carcinoma has been performed. RESULTS: Retrospective chart review of the last 7 years yielded 22 malignant lacrimal gland neoplasms of which 4 cases demonstrated features of primary ductal adenocarcinoma of lacrimal gland, 2/4 cases showed an evidence of a pre existing pleomorphic adenoma and 2 were found to be de novo ductal adenocarcinomas. PDA of lacrimal gland showed expression of CK7, CK19, AR, HER2, cyclin D1 and were negative for CK5/14, CK 20, ER, PR, PSA, TTF-1, S-100 and SMA. Expression of GCDFP-15 was noted in one case. The presence of multiple events of loco-regional recurrences and/or distant metastasis necessitated a multidisciplinary approach. CONCLUSIONS: Authors have expressed the need of clinical correlation; thorough tissue sampling and extensive immunohistochemical work up in identification of de novo PDA's and their molecular subtypes. A multi-institutional study might help in formulating the diagnostic criteria, identification of actionable targets, and thus study the role of targeted therapy in this rare and aggressive tumor which may result in better patient outcomes.

Acid and heat fastness in microsporidia: How acid fast are acid fast microsporidium?

Microsporidia are obligate spore-forming microorganisms with strong resemblance to fungi and can affect almost every organ system in immunocompetent or immunocompromised individuals. Mixed infections are also reported in immunocompromised hosts. Microsporidial spores show marked morphological variations and the small and slender forms can resemble bacilli. Modified Zeihl Neelsen (ZN) stain, cold method demonstrates them as bright red in color, leaving several spores blue or incompletely stained; thus, they are reported as weakly or variably acid fast. Variability in staining results with ZN stain and considering the fact that Mycobacterium tuberculosis, the commoner bug in developing countries is identified by its resistance to stronger acids on ZN staining, authors wished to demonstrate acid and heat fastness in microsporidium using corneal tissue specimens. Microsporidial spores stained bright red in color with conventional ZN stain, demonstrated strong acid fastness, and interestingly the staining results improved on heating. Thus, the authors conclude that they are strongly acid and heat fast and care must be warranted so that they are not misdiagnosed as Mycobacterium or other acid-fast organisms. Careful observation of morphology, battery of special stains, and molecular diagnostics should be advocated for diagnostic confirmation. To the best of the authors' knowledge, this is the first explicit report on acid and heat fastness on microsporidial spores.

Trichofolliculoma of the Eyelid Margin: A Case Report and Review of Literature.

Trichofolliculoma is a rare benign tumor of the skin, with distinct pilar differentiation and a predilection for the head and neck. To the best of the authors' knowledge, only 10 cases of eyelid trichofolliculoma has been described in the English literature. Moreover, these benign hair follicle lesions have been reported to clinically mimic eyelid malignancy. The authors report a case of a 58-year-old woman with a nodule on the eyelid margin, with typical clinical features and characteristic histopathological findings aiding the diagnosis of trichofolliculoma. Complete resection was performed to prevent recurrence. The authors also reviewed all the cases of eyelid trichofolliculoma reported in literature to highlight the demography, clinical features, and management of this rare eyelid tumor.

Retinal vasculitis associated with cutaneous leukocytoclastic vasculitis.

INTRODUCTION: To report a case of retinal vasculitis associated with cutaneous leukocytoclastic vasculitis. METHODS: Retrospective chart review. RESULTS: A 28-year-old man, who initially presented with occlusive retinal vasculitis and vitreous hemorrhage in right eye that resolved with sectoral photocoagulation. Laboratory investigations for tuberculosis, sarcoidosis, syphilis and sickle cell disease were negative. Past history included recent diagnosis of Enterobacter epididymo-orchitis and multiple red nodules on skin of forearm. Fourteen months later, he developed active retinal vasculitis in right eye and recurrent nodules on forearm. Skin biopsy revealed neutrophilic infiltrates in and around dermal vessels with destruction of vessel walls leading to scattered neutrophils, lymphocytes and histiocytes between collagen bundles, suggestive of leukocytoclastic vasculitis. Both skin and ocular lesions resolved with oral corticosteroid and methotrexate therapy and did not recur over a six-year period. CONCLUSION: We have reported the first case of clinically manifest retinal vasculitis, associated with a common form of cutaneous vasculitis.

Ocular surface squamous neoplasia in a setting of fungal keratitis: a rare co-occurrence.

PURPOSE: To describe a rare co-occurrence of ocular surface squamous neoplasia (OSSN) in a patient with microbial keratitis. METHODS: Case report. RESULTS: We describe a 68-years female who developed ocular surface squamous neoplasia (OSSN) in an eye with culture proven severe fungal keratitis of 5 months duration, which progressed to endophthalmitis. She was managed with extended enucleation for left eye. Histopathology examination was consistent with squamous cell carcinoma of ocular surface with no corneal stromal/scleral/anterior chamber involvement. She received adjuvant chemotherapy with topical Interferon alpha2b (3 cycles) for positive margins. Six months after treatment, she is completely tumor free. CONCLUSION: Co-occurrence of OSSN and chronic fungal keratitis is rare. We recommend that patients with chronic ocular infections should be examined and followed closely for abnormally thickened limbal areas.

Utility of intraocular endoscope for lacrimal canaliculi and sac examination.

PURPOSE: Intraocular endoscope was used as a dacryoendoscope, and its observations and performance in lacrimal drainage system (LDS) are reported. METHODS: The Endo Optiks (Little Silver, New Jersey, USA), an intraocular endoscope (modified with customized sheath), was used for LDS visualization in ten normal adults and five patients with lacrimal disorders. RESULTS: We were able to capture high-definition images of lacrimal canaliculi and sac in all normal adults. Smooth whitish canalicular mucosa with lumen could be appreciated in all normal individuals. Common canaliculus showed variable folds among individuals and reddish lacrimal sac mucosa could be appreciated with great details. In patients with canalicular obstruction, site of obstruction was presented as whitish gray area with no visible lumen, which could be opened up precisely with trephination. No false passage was formed in any of the cases. One of the cases had membranous canalicular obstruction, which was opened with probe itself. Nasolacrimal duct could not be examined due to the shorter length of the probe. CONCLUSION: Intraocular endoscope can be used as high-resolution dacryoendoscope for visualization of lacrimal canaliculi and sac.

Multifocal Ocular Surface Squamous Neoplasia.

A 64-year-old healthy female presented with a papillomatous limbal lesion involving 6 clock hours of superior limbus and diffuse involvement of upper tarsal conjunctiva of left eye of 6 months duration. Excision of superior limbal lesion on histopathology showed carcinoma in situ with focal breach in basement membrane and moderate degree of differentiation. The surgical base and margins were uninvolved. The tarsal lesion was initially treated with subconjunctival interferon alpha 2b (IFN alpha 2b) (3 cycles of IFN alpha 2b) with poor response. Subsequently treatment with topical mitomycin C 0.04% showed a dramatic response in the upper eyelid tarsal lesion. A small residual lesion needed excision. One year after treatment, she was completely tumor-free. In multifocal ocular surface squamous neoplasia, multimodal treatment with excision and topical mitomycin C may be effective in cases refractory to immunotherapy.

Unilateral Migratory Relapsing Orbital Myositis While on Immunosuppressant Therapy: An Uncommon Entity.

A young healthy female presented with acute onset left ocular pain, restricted ocular motility, and binocular diplopia. CT imaging showed left lateral rectus myositis that resolved with oral corticosteroids. Two sequential relapses occurred subsequently involving the superior rectus-levator complex followed by the medial rectus. Biopsy revealed orbital inflammatory disease with lymphocytic vasculitis. Detailed systemic work up was normal. The second relapse was seen while on long-term oral methotrexate although initial disease remission had been achieved with the same drug. A changeover to oral azathioprine was able to achieve disease remission after the second relapse. All relapses involved the same side and the contralateral orbit was not affected. This report presents the curious phenomenon of unilateral migratory relapsing orbital myositis of unknown cause that recurred even while on immunosuppressant therapy. It highlights the unpredictable nature of this uncommon entity and the challenges faced in managing such cases.

Orbital tuberculosis: Clinicopathological correlation and diagnosis using PCR in formalin-fixed tissues.

This article describes the clinicopathological correlation and challenges encountered in the diagnosis of orbital tuberculosis (TB). Retrospective, interventional case series. A chart review of six patients who underwent biopsy for an orbital mass between January 2012 and December 2013 was performed. Institutional review board approval was obtained for the study. Clinical, radiological, and laboratory findings were documented, and response to antitubercular therapy (ATT) was noted. Age at presentation ranged from 18 to 64 years and duration of complaints varied from 2 weeks to 2 months. Pain, redness, and swelling with an orbital mass on computerized tomography (CT) were the common features. None of the patients was clinically suspected to have orbital TB at presentation. History of prior contact with a patient of TB and history of prior TB were present in one case each. Chest radiography (CXR) showed pulmonary consolidation in one case. Tuberculin skin test (TST) readings ranged from nonreactive to 23 mm. The presence of sputum acid fast bacilli (AFB) was tested in three cases and was negative. Polymerase chain reaction (PCR) for MPB64 gene was positive in all six cases. All cases responded to ATT. Clinical presentation of orbital TB can be variable and can simulate conditions like inflammatory disease and malignancy. Biopsy with histopathology plays a key role in diagnosis. Supportive laboratory investigations are necessary to clinch the diagnosis in cases where histopathology is suggestive of TB. In this regard, PCR for Mycobacterium tuberculosis (MTB) on tissue biopsy specimens may be a sensitive diagnostic tool.

Descemet Stripping Automated Endothelial Keratoplasty for Endothelial Dysfunction in Xeroderma Pigmentosum: A Clinicopathological Correlation and Review of Literature.

Xeroderma pigmentosum (XP) mainly affects the ocular surface; however, endothelial damage may also occur. We would like to report changes in the endothelial-Descemet layer and review the literature on similar findings in patients with XP, including the role of Descemet stripping automated endothelial keratoplasty (DSAEK) in the management of a 21-year-old man who presented with nonresolving corneal edema in the right eye after excision biopsy for conjunctival intraepithelial neoplasia. His best-corrected visual acuity (BCVA) was 20/200 in the right eye and 20/20 in the left eye. On general examination, there was patchy hyperpigmentation of the exposed areas of skin suggestive of XP. On examination of the right eye, there was stromal edema involving the exposed half of cornea. The left eye appeared normal. Pachymetry readings were 860 and 600 µm in the right and left eye, respectively. Descemet stripping automated endothelial keratoplasty was performed for endothelial dysfunction and the stripped endothelium, and Descemet membrane (DM) was sent for histopathologic evaluation. Postoperatively, the donor lenticule was well apposed and the overlying stromal edema resolved. The patient achieved a BCVA of 20/30 in the right eye without progression of corneal scarring at 1-year follow-up. In the meanwhile, however, the left eye developed corneal edema. Histopathology revealed gross attenuation of endothelial cells with uniform thickness of the DM. Corneal endothelial dysfunction in XP is amenable to treatment with DSAEK.

Acantholytic Acanthoma of the Eyelid: Unusual Presentation.

Acantholytic acanthoma is a benign epidermal tumor with a truncal predisposition and is not previously reported as an eyelid mass. A 63-year-old man, presented with a history of nodular masses of both his eyelid margin and eyelid surface of 3 years duration. Excision biopsy of lesion of eyelid margin was consistent with dermal nevus. Lesions of the eyelid surface displayed prominent acanthosis, acantholysis, and spongiosis. Variable hyperkeratosis and papillomatosis was also noted. There was absence of cytological atypia or mitoses. The microscopic picture was consistent with acantholytic acanthoma. The presence of extensive acantholysis in the present case excluded incidental focal epidermolytic hyperkeratosis and focal acantholytic dyskeratosis. Acantholytic vesiculobullous disorders and numerous acanthotic disorders, which are more common in the eyelid, need exclusion. To the authors' best knowledge, as acantholytic acanthoma of the eyelid is not previously reported, they recommend that it should be included as differential diagnoses of benign epidermal lesions of eyelid.

Spindle cell lipoma of the orbit.

A 30-year-old otherwise healthy female patient presented to the oculoplastic service with complaints of gradually increasing proptosis and discomfort of the OD of about 4 months' duration. On imaging, an ill-defined mass was seen in the right orbit which, on biopsy, turned out to be a spindle cell lipoma. Lipomas, the commonest among the mesenchymal soft tissue tumors, are surprisingly of rare occurrence in the orbit, despite the presence of abundant fat in the intraorbital space. The authors describe the presentation, management, and outcome of a rare orbital pathology--an orbital spindle cell lipoma.