Publications by authors named "Charles G Eberhart"

319 Publications

Complement component 3 from astrocytes mediates retinal ganglion cell loss during neuroinflammation.

Acta Neuropathol 2021 Sep 6. Epub 2021 Sep 6.

Division of Neuroimmunology and Neurological Infections, Johns Hopkins Hospital, Pathology Building 509, 600 N. Wolfe St., Baltimore, Md, 21287, USA.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) characterized by varying degrees of secondary neurodegeneration. Retinal ganglion cells (RGC) are lost in MS in association with optic neuritis but the mechanisms of neuronal injury remain unclear. Complement component C3 has been implicated in retinal and cerebral synaptic pathology that may precede neurodegeneration. Herein, we examined post-mortem MS retinas, and then used a mouse model, experimental autoimmune encephalomyelitis (EAE), to examine the role of C3 in the pathogenesis of RGC loss associated with optic neuritis. First, we show extensive C3 expression in astrocytes (C3/GFAP cells) and significant RGC loss (RBPMS cells) in post-mortem retinas from people with MS compared to retinas from non-MS individuals. A patient with progressive MS with a remote history of optic neuritis showed marked reactive astrogliosis with C3 expression in the inner retina extending into deeper layers in the affected eye more than the unaffected eye. To study whether C3 mediates retinal degeneration, we utilized global C3 EAE mice and found that they had less RGC loss and partially preserved neurites in the retina compared with C3 EAE mice. C3 EAE mice had fewer axonal swellings in the optic nerve, reflecting reduced axonal injury, but had no changes in demyelination or T cell infiltration into the CNS. Using a C3-tdTomato reporter mouse line, we show definitive evidence of C3 expression in astrocytes in the retina and optic nerves of EAE mice. Conditional deletion of C3 in astrocytes showed RGC protection replicating the effects seen in the global knockouts. These data implicate astrocyte C3 expression as a critical mediator of retinal neuronal pathology in EAE and MS, and are consistent with recent studies showing C3 gene variants are associated with faster rates of retinal neurodegeneration in human disease.
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http://dx.doi.org/10.1007/s00401-021-02366-4DOI Listing
September 2021

NGS Analysis Confirms Common and Mutations, and Suggests Amplification in Ocular Adnexal Sebaceous Carcinomas.

Int J Mol Sci 2021 Aug 6;22(16). Epub 2021 Aug 6.

Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Ocular adnexal (OA) sebaceous carcinomas generally demonstrate more aggressive clinical and histopathological phenotypes than extraocular cases, but the molecular drivers implicated in their oncogenesis remain poorly defined. A retrospective review of surgical and ocular pathology archives identified eleven primary resection specimens of OA sebaceous carcinomas with adequate tissue for molecular analysis; two extraocular cases were also examined. Next-generation sequencing was used to evaluate mutations and copy number changes in a large panel of cancer-associated genes. Fluorescence in situ hybridization (FISH) confirmed copy number gain in select cases, and immunohistochemistry to evaluate MYC protein expression. The commonest mutations occurred in (10/13) and (7/13). Additional mutations in clinically actionable genes, or mutations with a frequency of at least 25%, included the (3/12), (4/12), (3/12), (4/12), (6/12), (4/12), (3/12), and (3/12) loci. Low level copy number gain suggestive of amplification of the locus was seen in two cases, and confirmed using FISH. MYC protein expression, as assessed by immunohistochemistry, was present in almost all sebaceous carcinoma cases. Our findings support the concept that alterations in and are the commonest alterations in sebaceous carcinoma, and suggest that may contribute to the oncogenesis of these tumors.
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http://dx.doi.org/10.3390/ijms22168454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395148PMC
August 2021

Subgroup and subtype-specific outcomes in adult medulloblastoma.

Acta Neuropathol 2021 Aug 18. Epub 2021 Aug 18.

Department of Neurosurgery, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital and Medical School, Hwasun-gun, Chonnam, South Korea.

Medulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomics International Consortium. We identified 30 WNT, 112 SHH, 6 Group 3, and 41 Group 4 tumours. Patients with SHH tumours were significantly older at diagnosis compared to other subgroups (p < 0.0001). Five-year progression-free survival (PFS) for WNT, SHH, Group 3, and Group 4 tumours was 64.4 (48.0-86.5), 61.9% (51.6-74.2), 80.0% (95% CI 51.6-100.0), and 44.9% (95% CI 28.6-70.7), respectively (p = 0.06). None of the clinical variables (age, sex, metastatic status, extent of resection, chemotherapy, radiotherapy) were associated with subgroup-specific PFS. Survival among patients with SHH tumours was significantly worse for cases with chromosome 3p loss (HR 2.9, 95% CI 1.1-7.6; p = 0.02), chromosome 10q loss (HR 4.6, 95% CI 2.3-9.4; p < 0.0001), chromosome 17p loss (HR 2.3, 95% CI 1.1-4.8; p = 0.02), and PTCH1 mutations (HR 2.6, 95% CI 1.1-6.2; p = 0.04). The prognostic significance of 3p loss and 10q loss persisted in multivariable regression models. For Group 4 tumours, chromosome 8 loss was strongly associated with improved survival, which was validated in a non-overlapping cohort (combined cohort HR 0.2, 95% CI 0.1-0.7; p = 0.007). Unlike in pediatric medulloblastoma, whole chromosome 11 loss in Group 4 and chromosome 14q loss in SHH was not associated with improved survival, where MYCN, GLI2 and MYC amplification were rare. In sum, we report unique subgroup-specific cytogenetic features of adult medulloblastoma, which are distinct from those in younger patients, and correlate with survival disparities. Our findings suggest that clinical trials that incorporate new strategies tailored to high-risk adult medulloblastoma patients are urgently needed.
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http://dx.doi.org/10.1007/s00401-021-02358-4DOI Listing
August 2021

Long non-coding RNAs in brain tumors.

NAR Cancer 2021 Mar 15;3(1):zcaa041. Epub 2021 Jan 15.

Department of Oncology, Johns Hopkins University School of Medicine, 1650 Orleans St., Baltimore, MD 21231, USA.

Long non-coding RNAs (lncRNAs) have been found to be central players in the epigenetic, transcriptional and post-transcriptional regulation of gene expression. There is an accumulation of evidence on newly discovered lncRNAs, their molecular interactions and their roles in the development and progression of human brain tumors. LncRNAs can have either tumor suppressive or oncogenic functions in different brain cancers, making them attractive therapeutic targets and biomarkers for personalized therapy and precision diagnostics. Here, we summarize the current state of knowledge of the lncRNAs that have been implicated in brain cancer pathogenesis, particularly in gliomas and medulloblastomas. We discuss their epigenetic regulation as well as the prospects of using lncRNAs as diagnostic biomarkers and therapeutic targets in patients with brain tumors.
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http://dx.doi.org/10.1093/narcan/zcaa041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210177PMC
March 2021

Unbiased Proteomic and Phosphoproteomic Analysis Identifies Response Signatures and Novel Susceptibilities After Combined MEK and mTOR Inhibition in BRAF Mutant Glioma.

Mol Cell Proteomics 2021 Jul 21;20:100123. Epub 2021 Jul 21.

Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Electronic address:

The mitogen-activated protein kinase pathway is one of the most frequently altered pathways in cancer. It is involved in the control of cell proliferation, invasion, and metabolism, and can cause resistance to therapy. A number of aggressive malignancies, including melanoma, colon cancer, and glioma, are driven by a constitutively activating missense mutation (V600E) in the v-Raf murine sarcoma viral oncogene homolog B (BRAF) component of the pathway. Mitogen-activated protein kinase kinase (MEK) inhibition is initially effective in targeting these cancers, but reflexive activation of mammalian target of rapamycin (mTOR) signaling contributes to frequent therapy resistance. We have previously demonstrated that combination treatment with the MEK inhibitor trametinib and the dual mammalian target of rapamycin complex 1/2 inhibitor TAK228 improves survival and decreases vascularization in a BRAF mutant glioma model. To elucidate the mechanism of action of this combination therapy and understand the ensuing tumor response, we performed comprehensive unbiased proteomic and phosphoproteomic characterization of BRAF mutant glioma xenografts after short-course treatment with trametinib and TAK228. We identified 13,313 proteins and 30,928 localized phosphosites, of which 12,526 proteins and 17,444 phosphosites were quantified across all samples (data available via ProteomeXchange; identifier PXD022329). We identified distinct response signatures for each monotherapy and combination therapy and validated that combination treatment inhibited activation of the mitogen-activated protein kinase and mTOR pathways. Combination therapy also increased apoptotic signaling, suppressed angiogenesis signaling, and broadly suppressed the activity of the cyclin-dependent kinases. In response to combination therapy, both epidermal growth factor receptor and class 1 histone deacetylase proteins were activated. This study reports a detailed (phospho)proteomic analysis of the response of BRAF mutant glioma to combined MEK and mTOR pathway inhibition and identifies new targets for the development of rational combination therapies for BRAF-driven tumors.
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http://dx.doi.org/10.1016/j.mcpro.2021.100123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363840PMC
July 2021

Clinicopathologic analysis of conjunctivochalasis and paste-pinch-cut conjunctivoplasty for management.

Can J Ophthalmol 2021 Jun 27. Epub 2021 Jun 27.

Ocular Surface Diseases and Dry Eye Clinic, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Md.. Electronic address:

Objective: To correlate the histopathologic results of conjunctival specimens with clinical findings in patients with conjunctivochalasis and report the results of the paste-pinch-cut technique for management.

Design: Retrospective chart review.

Methods: SETTING: Single tertiary ophthalmological centre (Ocular Surface Diseases and Dry Eye Clinic, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Md.).

Methods: Twenty-five patients (32 eyes) with clinically significant conjunctivochalasis. All patients were referred for clinically significant dry eye without previous diagnosis of chalasis. Sixteen patients had an underlying inflammatory systemic condition. Intervention or Observation Procedure(s): Patients underwent surgery with paste-pinch-cut technique. Subjective dry eye symptoms and ocular surface staining scores (corneal and conjunctival staining using fluorescein and lissamine green respectively) were assessed at every visit.

Main Outcome Measures: Change in patient symptoms and ocular surface staining scores and histopathologic findings in conjunctival specimens.

Results: After surgery, significant improvement was achieved in dry-eye symptoms as well as both corneal and conjunctival staining scores in 29 eyes on reduced topical therapy. Only 3 eyes had persisting conjunctival lissamine staining. Light microscopic examination disclosed mild to moderate lymphoplasmocytic inflammation of the conjunctivae with areas of epithelial goblet cell loss, squamous metaplasia, stromal edema, and fibrosis.

Conclusion: Conjunctivochalasis appears to be associated with significant inflammation in the setting of dry eye and underlying inflammatory systemic conditions. Although topical anti-inflammatory treatment could be attempted in the initial management, surgical excision should be considered in the absence of clinical response.
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http://dx.doi.org/10.1016/j.jcjo.2021.06.001DOI Listing
June 2021

Reimagining Pilocytic Astrocytomas in the Context of Pediatric Low-Grade Gliomas.

Neuro Oncol 2021 Jun 16. Epub 2021 Jun 16.

Department of Neurology, Washington University School of Medicine, St. Louis MO, USA.

Pediatric low-grade gliomas (pLGGs) are the most common brain tumor in children, and are associated with life-long clinical morbidity. Relative to their high-grade adult counterparts or other malignant childhood brain tumors, there is a paucity of authenticated preclinical models for these pediatric low-grade gliomas and an incomplete understanding of their molecular and cellular pathogenesis. While large scale genomic profiling efforts have identified the majority of pathogenic driver mutations, which converge on the MAPK/ERK signaling pathway, it is now appreciated that these events may not be sufficient by themselves for gliomagenesis and clinical progression. In light of the recent World Health Organization reclassification of pLGGs, and pilocytic astrocytoma (PA) in particular, we review our current understanding of these pediatric brain tumors, provide a conceptual framework for future mechanistic studies, and outline the challenges and pressing needs for the pLGG clinical and research communities.
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http://dx.doi.org/10.1093/neuonc/noab138DOI Listing
June 2021

Mutant IDH1 promotes phagocytic function of microglia/macrophages in gliomas by downregulating ICAM1.

Cancer Lett 2021 Oct 5;517:35-45. Epub 2021 Jun 5.

Hugo W. Moser Research Institute at Kennedy Krieger, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Tumor-associated microglia/macrophages (TAMs) are the main innate immune effector cells in malignant gliomas and have both pro- and anti-tumor functions. The plasticity of TAMs is partially dictated by oncogenic mutations in tumor cells. Heterozygous IDH1 mutation is a cancer driver gene prevalent in grade II/III gliomas, and IDH1 mutant gliomas have relatively favorable clinical outcomes. It is largely unknown how IDH mutation alters TAM phenotypes to influence glioma growth. Here we established clinically relevant isogenic glioma models carrying monoallelic IDH1 R132H mutation (IDH1) and found that IDH1 significantly downregulated immune response-related pathways in glioma cells, indicating an immunomodulation role of mutant IDH1. Co-culturing IDH1 glioma cells with human macrophages promoted anti-tumor phenotypes of macrophages and increased macrophage migration and phagocytic capacity. In orthotopic xenografts, IDH1 decreased tumor growth and prolonged animal survival, accompanied by increased TAM recruitment and upregulated phagocytosis markers, suggesting the induction of anti-tumor TAM functions. Using human cytokine arrays that query 36 proteins, we identified significant downregulation of ICAM-1/CD54 in IDH1 gliomas, which was further confirmed by ELISA and immunoblotting analyses. ICAM1 gain-of-function studies revealed that ICAM1 downregulation in IDH1 cells played a mechanistic role to mediate the immunomodulation function of IDH1. ICAM-1 silencing in IDH1 wild-type glioma cells decreased tumor growth and increased the anti-tumor function of TAMs. Together, our studies support a new TAM-mediated phagocytic function within IDH1 mutant gliomas, and improved understanding of this process may uncover novel approaches to targeting IDH1 wild type gliomas.
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http://dx.doi.org/10.1016/j.canlet.2021.05.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324572PMC
October 2021

Expression of the SARS-CoV-2 Receptor ACE2 in Human Retina and Diabetes-Implications for Retinopathy.

Invest Ophthalmol Vis Sci 2021 06;62(7)

Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States.

Purpose: To investigate the expression of angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2 in human retina.

Methods: Human post-mortem eyes from 13 non-diabetic control cases and 11 diabetic retinopathy cases were analyzed for the expression of ACE2. To compare the vascular ACE2 expression between different organs that involve in diabetes, the expression of ACE2 was investigated in renal specimens from nondiabetic and diabetic nephropathy patients. Expression of TMPRSS2, a cell-surface protease that facilitates SARS-CoV-2 entry, was also investigated in human nondiabetic retinas. Primary human retinal endothelial cells (HRECs) and primary human retinal pericytes (HRPCs) were further used to confirm the vascular ACE2 expression in human retina.

Results: We found that ACE2 was expressed in multiple nonvascular neuroretinal cells, including the retinal ganglion cell layer, inner plexiform layer, inner nuclear layer, and photoreceptor outer segments in both nondiabetic and diabetic retinopathy specimens. Strikingly, we observed significantly more ACE2 positive vessels in the diabetic retinopathy specimens. By contrast, in another end-stage organ affected by diabetes, the kidney, ACE2 in nondiabetic and diabetic nephropathy showed apical expression of ACE2 tubular epithelial cells, but no endothelial expression in glomerular or peritubular capillaries. Western blot analysis of protein lysates from HRECs and HRPCs confirmed expression of ACE2. TMPRSS2 expression was present in multiple retinal neuronal cells, vascular and perivascular cells, and Müller glia.

Conclusions: Together, these results indicate that retina expresses ACE2 and TMPRSS2. Moreover, there are increased vascular ACE2 expression in diabetic retinopathy retinas.
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http://dx.doi.org/10.1167/iovs.62.7.6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185397PMC
June 2021

DEK-AFF2 Carcinoma of the Sinonasal Region and Skull Base: Detailed Clinicopathologic Characterization of a Distinctive Entity.

Am J Surg Pathol 2021 May 27. Epub 2021 May 27.

Departments of Pathology Oncology Ophthalmology Otolaryngology-Head and Neck Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital, Erlangen, Germany Department of Laboratory Medicine and Pathobiology, University of Toronto Department of Pathology & Laboratory Medicine, Mount Sinai Hospital Department of Pathology, Sunnybrook Health Sciences Centre Department of Pathology, University Health Network, Toronto, ON Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX Department of Pathology, Kaiser Permanente Walnut Creek Medical Center, Walnut Creek, CA Department of Head and Neck Pathology, Guy's and St Thomas' NHS Foundation Trust, London, UK.

A novel DEK-AFF2 fusion was recently reported in 4 nonkeratinizing squamous cell carcinomas of the sinonasal region and skull base, including 1 with exceptional response to immunotherapy, but it is not yet clear if this rearrangement defines a unique clinicopathologic category or represents a rare event. This study aims to characterize a larger cohort of carcinomas with DEK-AFF2 fusions to assess whether they truly constitute a distinctive entity. Among 27 sinonasal and skull base nonkeratinizing squamous cell carcinoma that were negative for human papillomavirus and Epstein-Barr virus, RNA sequencing identified DEK-AFF2 fusions in 13 cases (48%). Nine were centered in the nasal cavity, 2 in the middle ear/temporal bone, 1 in the nasopharynx, and 1 in the orbit. These tumors displayed recurrent histologic features including (1) complex endophytic and exophytic, frequently papilloma-like growth, (2) transitional epithelium with eosinophilic to amphophilic cytoplasm, (3) absent or minimal keratinization with occasional compact keratin pearls, (4) monotonous nuclei, and (5) prominent tumor-infiltrating neutrophils or stromal lymphocytes. This appearance not only overlaps with high-grade basaloid sinonasal carcinomas but also with benign papillomas and tumors reported as low-grade papillary Schneiderian carcinoma. However, DEK-AFF2 carcinomas showed frequent local recurrence, cervical lymph node metastases, and distant metastasis with 2 deaths from disease, confirming they are aggressive malignancies despite relatively bland histology. Overall, the distinctive molecular, histologic, and clinical features of DEK-AFF2 carcinomas suggest they represent a unique entity in the sinonasal region. This tumor merits increased pathologic recognition to better understand its prognostic and therapeutic implications.
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http://dx.doi.org/10.1097/PAS.0000000000001741DOI Listing
May 2021

Transcriptomic and Immunohistochemical Analysis of Progressive Keratoconus Reveal Altered WNT10A in Epithelium and Bowman's Layer.

Invest Ophthalmol Vis Sci 2021 05;62(6):16

The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States.

Purpose: To identify global gene expression changes in the corneal epithelium of keratoconus (KC) patients compared to non-KC myopic controls.

Methods: RNA-sequencing was performed on corneal epithelium samples of five progressive KC and five myopic control patients. Selected results were validated using TaqMan quantitative PCR (qPCR) on 31 additional independent samples, and protein level validation was conducted using western blot analysis on a subset. Immunohistochemistry was performed on tissue microarrays containing cores from over 100 KC and control cases. WNT10A transcript levels in corneal epithelium were correlated with tomographic indicators of KC disease severity in 15 eyes. Additionally, WNT10A was overexpressed in vitro in immortalized corneal epithelial cells.

Results: WNT10A was found to be underexpressed in KC epithelium at the transcript (ratio KC/control = 0.59, P = 0.02 per RNA-sequencing study; ratio = 0.66, P = 0.03 per qPCR) and protein (ratio = 0.07, P = 0.06) levels. Immunohistochemical analysis also indicated WNT10A protein was decreased in Bowman's layer of KC patients. In contrast, WNT10A transcript level positively correlated with increased keratometry (Kmax ρ = 0.57, P = 0.02). Finally, WNT10A positively regulated COL1A1 expression in corneal epithelial cells.

Conclusions: A specific Wnt ligand, WNT10A, is reduced at the mRNA and protein level in KC epithelium and Bowman's layer. This ligand positively regulates collagen type I expression in corneal epithelial cells. The results suggest that WNT10A expression in the corneal epithelium may play a role in progressive KC.
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http://dx.doi.org/10.1167/iovs.62.6.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132000PMC
May 2021

IDH-mutant brainstem gliomas in adolescent and young adult patients: Report of three cases and review of the literature.

Brain Pathol 2021 Jul 7;31(4):e12959. Epub 2021 May 7.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA.

Isocitrate dehydrogenase (IDH) mutations are rare in pediatric and adolescent gliomas. We recently identified three adolescent/young adult (AYA) patients with IDH-mutant low grade gliomas of the brainstem with several key clinicopathologic and molecular features in common. We discuss these three cases and review the current literature.
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http://dx.doi.org/10.1111/bpa.12959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412065PMC
July 2021

BCOR Internal Tandem Duplication Expression in Neural Stem Cells Promotes Growth, Invasion, and Expression of PRC2 Targets.

Int J Mol Sci 2021 Apr 10;22(8). Epub 2021 Apr 10.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Central nervous system tumor with BCL6-corepressor internal tandem duplication (CNS-BCOR ITD) is a malignant entity characterized by recurrent alterations in exon 15 encoding the essential binding domain for the polycomb repressive complex (PRC). In contrast to deletion or truncating mutations seen in other tumors, BCOR expression is upregulated in CNS-BCOR ITD, and a distinct oncogenic mechanism has been suggested. However, the effects of this change on the biology of neuroepithelial cells is poorly understood. In this study, we introduced either wildtype BCOR or BCOR-ITD into human and murine neural stem cells and analyzed them with quantitative RT-PCR and RNA-sequencing, as well as growth, clonogenicity, and invasion assays. In human cells, BCOR-ITD promoted derepression of PRC2-target genes compared to wildtype BCOR. A similar effect was found in clinical specimens from previous studies. However, no growth advantage was seen in the human neural stem cells expressing BCOR-ITD, and long-term models could not be established. In the murine cells, both wildtype BCOR and BCOR-ITD overexpression affected cellular differentiation and histone methylation, but only BCOR-ITD increased cellular growth, invasion, and migration. BCOR-ITD overexpression drives transcriptional changes, possibly due to altered PRC function, and contributes to the oncogenic transformation of neural precursors.
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http://dx.doi.org/10.3390/ijms22083913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070097PMC
April 2021

EGFR Activates a TAZ-Driven Oncogenic Program in Glioblastoma.

Cancer Res 2021 Jul 28;81(13):3580-3592. Epub 2021 Apr 28.

Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland.

Hyperactivated EGFR signaling is a driver of various human cancers, including glioblastoma (GBM). Effective EGFR-targeted therapies rely on knowledge of key signaling hubs that transfer and amplify EGFR signaling. Here we focus on the transcription factor TAZ, a potential signaling hub in the EGFR signaling network. TAZ expression was positively associated with EGFR expression in clinical GBM specimens. In patient-derived GBM neurospheres, EGF induced TAZ through EGFR-ERK and EGFR-STAT3 signaling, and the constitutively active EGFRvIII mutation caused EGF-independent hyperactivation of TAZ. Genome-wide analysis showed that the EGFR-TAZ axis activates multiple oncogenic signaling mechanisms, including an EGFR-TAZ-RTK positive feedback loop, as well as upregulating HIF1α and other oncogenic genes. TAZ hyperactivation in GBM stem-like cells induced exogenous mitogen-independent growth and promoted GBM invasion, radioresistance, and tumorigenicity. Screening a panel of brain-penetrating EGFR inhibitors identified osimertinib as the most potent inhibitor of the EGFR-TAZ signaling axis. Systemic osimertinib treatment inhibited the EGFR-TAZ axis and growth of GBM stem-like cell xenografts. Overall these results show that the therapeutic efficacy of osimertinib relies on effective TAZ inhibition, thus identifying TAZ as a potential biomarker of osimertinib sensitivity. SIGNIFICANCE: This study establishes a genome-wide map of EGFR-TAZ signaling in glioblastoma and finds osimertinib effectively inhibits this signaling, justifying its future clinical evaluation to treat glioblastoma and other cancers with EGFR/TAZ hyperactivation. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/13/3580/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277712PMC
July 2021

Orbital inflammation in the setting of a nylon foil implant.

Orbit 2021 Apr 27:1-4. Epub 2021 Apr 27.

Department of Ophthalmology, Johns Hopkins Wilmer Eye Institute, Baltimore, Maryland, USA.

A 61-year-old man underwent left medial wall and floor fracture repair with a Suprafoil® implant. He had postoperative orbital congestion and lower eyelid swelling that persisted for over seven weeks. Examination demonstrated hyperglobus with supraduction, infraduction, and adduction deficits. Imaging revealed a 3.7 × 3.6 × 2.6 cm isodensity along the implant, thought to be hematoma. The patient elected to pursue exploration and possible drainage. Intraoperatively, there was no hematoma; rather, we found a fibroinflammatory rind along the periorbita surrounding the implant. This was biopsied, and the implant was removed, as the fractures had sufficiently healed. Pathology showed dense fibroconnective tissue with associated inflammation. The patient completed a steroid taper with improvement in all symptoms and resolution of diplopia. To our knowledge, this is the first reported case of such a prominent orbital inflammatory reaction to nylon foil, a departure from the delayed hematic cysts typically associated with these implants.
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http://dx.doi.org/10.1080/01676830.2021.1918725DOI Listing
April 2021

The long noncoding RNA lnc-HLX-2-7 is oncogenic in Group 3 medulloblastomas.

Neuro Oncol 2021 04;23(4):572-585

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland.

Background: Medulloblastoma (MB) is an aggressive brain tumor that predominantly affects children. Recent high-throughput sequencing studies suggest that the noncoding RNA genome, in particular long noncoding RNAs (lncRNAs), contributes to MB subgrouping. Here we report the identification of a novel lncRNA, lnc-HLX-2-7, as a potential molecular marker and therapeutic target in Group 3 MBs.

Methods: Publicly available RNA sequencing (RNA-seq) data from 175 MB patients were interrogated to identify lncRNAs that differentiate between MB subgroups. After characterizing a subset of differentially expressed lncRNAs in vitro and in vivo, lnc-HLX-2-7 was deleted by CRISPR/Cas9 in the MB cell line. Intracranial injected tumors were further characterized by bulk and single-cell RNA-seq.

Results: Lnc-HLX-2-7 is highly upregulated in Group 3 MB cell lines, patient-derived xenografts, and primary MBs compared with other MB subgroups as assessed by quantitative real-time, RNA-seq, and RNA fluorescence in situ hybridization. Depletion of lnc-HLX-2-7 significantly reduced cell proliferation and 3D colony formation and induced apoptosis. Lnc-HLX-2-7-deleted cells injected into mouse cerebellums produced smaller tumors than those derived from parental cells. Pathway analysis revealed that lnc-HLX-2-7 modulated oxidative phosphorylation, mitochondrial dysfunction, and sirtuin signaling pathways. The MYC oncogene regulated lnc-HLX-2-7, and the small-molecule bromodomain and extraterminal domain family‒bromodomain 4 inhibitor Jun Qi 1 (JQ1) reduced lnc-HLX-2-7 expression.

Conclusions: Lnc-HLX-2-7 is oncogenic in MB and represents a promising novel molecular marker and a potential therapeutic target in Group 3 MBs.
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http://dx.doi.org/10.1093/neuonc/noaa235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041340PMC
April 2021

High-risk human papillomavirus and ZEB1 in ocular adnexal sebaceous carcinoma.

J Cutan Pathol 2021 Aug 6;48(8):1027-1033. Epub 2021 Apr 6.

Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background: Ocular adnexal (OA) sebaceous carcinoma is an aggressive malignancy. Oncologic drivers of ocular sebaceous carcinoma are incompletely understood.

Methods: A retrospective search of our pathology archives for OA sebaceous carcinoma identified 18 primary resection specimens. Immunohistochemistry for p16 and ZEB1 and RNA in situ hybridization for high-risk human papillomavirus (HPV) subtypes were performed.

Results: High-risk HPV was demonstrated in 2/11 (18%) cases. p16 overexpression was observed in 10/11 (91%). No association between gender, age at presentation, tumor location, intraepithelial spread, tumor size, and T stage was observed between HPV-driven and nonviral cases. High expression of ZEB1 was observed in the intraepithelial component of 4/14 (28%) cases and in the subepithelial component of 1/13 (7%) cases. ZEB1 overexpression was not associated with HPV status, T stage, or tumor size.

Conclusion: As previously described by others, our findings suggest that a subset of OA sebaceous carcinomas may arise via an HPV-dependent pathway. However, unlike high-risk HPV-driven carcinomas of the oropharynx, we did not identify an association between HPV-status and prognostic features. Furthermore, p16 expression was not a useful surrogate marker for HPV-driven disease. ZEB1 overexpression is not associated with HPV in our cohort of ocular sebaceous carcinoma.
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http://dx.doi.org/10.1111/cup.13987DOI Listing
August 2021

The transcriptional landscape of Shh medulloblastoma.

Nat Commun 2021 03 19;12(1):1749. Epub 2021 Mar 19.

Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.
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http://dx.doi.org/10.1038/s41467-021-21883-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979819PMC
March 2021

Frondoside A Inhibits an MYC-Driven Medulloblastoma Model Derived from Human-Induced Pluripotent Stem Cells.

Mol Cancer Ther 2021 06 15;20(6):1199-1209. Epub 2021 Mar 15.

Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. MYC-driven MBs, commonly found in the group 3 MB, are aggressive and metastatic with the worst prognosis. Modeling MYC-driven MB is the foundation of therapeutic development. Here, we applied a synthetic mRNA-driven strategy to generate neuronal precursors from human-induced pluripotent stem cells (iPSCs). These neuronal precursors were transformed by the oncogene combined with loss of function to establish an MYC-driven MB model recapitulating the histologic and transcriptomic hallmarks of group 3 MB. We further show that the marine compound Frondoside A (FA) effectively inhibits this MYC-driven MB model without affecting isogenic neuronal precursors with undetectable MYC expression. Consistent results from a panel of MB models support that MYC levels are positively correlated with FA's antitumor potency. Next, we show that FA suppresses MYC expression and its downstream gene targets in MB cells, suggesting a potential mechanism underlying FA's inhibitory effects on MYC-driven cancers. In orthotopic xenografts of MYC-driven MB, intratumoral FA administration potently induces cytotoxicity in tumor xenografts, significantly extends the survival of tumor-bearing animals, and enhances the recruitment of microglia/macrophages and cytotoxic T lymphocytes to tumors. Moreover, we show that MYC levels also predict FA potency in glioblastoma and non-small cell lung cancer cells. Taken together, this study provides an efficient human iPSC-based strategy for personalizable cancer modeling, widely applicable to mechanistic studies (e.g., genetic predisposition to cancer) and drug discovery. Our preclinical results justify the clinical translation of FA in treating MYC-driven MB and other human cancers.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172454PMC
June 2021

Novel Glutamine Antagonist JHU395 Suppresses MYC-Driven Medulloblastoma Growth and Induces Apoptosis.

J Neuropathol Exp Neurol 2021 Mar;80(4):336-344

From the Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.

Medulloblastoma is the most common malignant pediatric brain tumor. Amplification of c-MYC is a hallmark of a subset of poor-prognosis medulloblastoma. MYC upregulates glutamine metabolism across many types of cancer. We modified the naturally occurring glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) by adding 2 promoeities to increase its lipophilicity and brain penetration creating the prodrug isopropyl 6-diazo-5-oxo-2-(((phenyl (pivaloyloxy) methoxy) - carbonyl) amino) hexanoate, termed JHU395. This prodrug was shown to have a 10-fold improved CSF-to-plasma ratio and brain-to-plasma ratio relative to DON. We hypothesized that JHU395 would have superior cell penetration compared with DON and would effectively and more potently kill MYC-expressing medulloblastoma. JHU395 treatment caused decreased growth and increased apoptosis in multiple human high-MYC medulloblastoma cell lines at lower concentrations than DON. Parenteral administration of JHU395 in Nu/Nu mice led to the accumulation of micromolar concentrations of DON in brain. Treatment of mice bearing orthotopic xenografts of human MYC-amplified medulloblastoma with JHU395 increased median survival from 26 to 45 days compared with vehicle control mice (p < 0.001 by log-rank test). These data provide preclinical justification for the ongoing development and testing of brain-targeted DON prodrugs for use in medulloblastoma.
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http://dx.doi.org/10.1093/jnen/nlab018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985826PMC
March 2021

TORC1/2 kinase inhibition depletes glutathione and synergizes with carboplatin to suppress the growth of MYC-driven medulloblastoma.

Cancer Lett 2021 04 8;504:137-145. Epub 2021 Feb 8.

Division of Pediatric Oncology, Department of Oncology, USA; Division of Neuropathology, Department of Pathology, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, USA. Electronic address:

Medulloblastoma is the most common malignant pediatric brain tumor. Tumors having high levels of c-MYC have the worst clinical prognosis, with only a minority of patients surviving. To address this unmet clinical need, we generated a human neural stem cell model of medulloblastoma that recapitulated the most aggressive subtype phenotypically and by mRNA expression profiling. An in silico analysis of these cells identified mTOR inhibitors as potential therapeutic agents. We hypothesized that the orally bioavailable TORC1/2 kinase inhibitor TAK228 would have activity against MYC-driven medulloblastoma. TAK228 inhibited mTORC1/2, decreased cell growth and caused apoptosis in high-MYC medulloblastoma cell lines. Comprehensive metabolic profiling of medulloblastoma orthotopic xenografts showed upregulation of glutathione compared to matched normal brain. TAK228 suppressed glutathione production. Because glutathione is required to detoxify platinum-containing chemotherapy, we hypothesized that TAK228 would cooperate with carboplatin in medulloblastoma. TAK228 synergized with carboplatin to inhibit cell growth and induce apoptosis and extended survival in orthotopic xenografts of high-MYC medulloblastoma. Brain-penetrant TORC1/2 inhibitors and carboplatin may be an effective combination therapy for high-risk medulloblastoma.
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http://dx.doi.org/10.1016/j.canlet.2021.02.001DOI Listing
April 2021

Temperature and species-dependent regulation of browning in retrobulbar fat.

Sci Rep 2021 Feb 4;11(1):3094. Epub 2021 Feb 4.

Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Retrobulbar fat deposits surround the posterior retina and optic nerve head, but their function and origin are obscure. We report that mouse retrobulbar fat is a neural crest-derived tissue histologically and transcriptionally resembles interscapular brown fat. In contrast, human retrobulbar fat closely resembles white adipose tissue. Retrobulbar fat is also brown in other rodents, which are typically housed at temperatures below thermoneutrality, but is white in larger animals. We show that retrobulbar fat in mice housed at thermoneutral temperature show reduced expression of the brown fat marker Ucp1, and histological properties intermediate between white and brown fat. We conclude that retrobulbar fat can potentially serve as a site of active thermogenesis, that this capability is both temperature and species-dependent, and that this may facilitate regulation of intraocular temperature.
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http://dx.doi.org/10.1038/s41598-021-82672-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862600PMC
February 2021

Peripheral retinal arteriolar leakage in giant cell arteritis: a case report.

J Ophthalmic Inflamm Infect 2021 Jan 29;11(1). Epub 2021 Jan 29.

Division of Neuro-Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 N Wolfe Street, Baltimore, MD, 21287, USA.

A 76-year old African American female with a history of arteritic ischemic optic neuropathy (AION) secondary to biopsy-proven giant cell arteritis (GCA) presented with unilateral vision loss in her contralateral eye despite high-dose oral steroid treatment. Dilated fundus examination revealed three cotton wool spots. Fluorescein angiography showed slowed arteriolar filling with late staining of small peripheral arteries, consistent with small vessel arteritis. Laboratory tests for alternative vasculitides were negative. Review of her temporal artery biopsy specimen confirmed lymphoplasmacytic inflammation around small adventitial vessels with no destructive granulomatous or leukocytoclastic small vessel vasculitis, consistent with GCA. Our unique case demonstrates peripheral small vessel retinal arteriolar leakage in GCA, which is a rare finding. This association is of interest because GCA is commonly associated with medium to large vessel pathology without small vessel involvement.
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http://dx.doi.org/10.1186/s12348-021-00235-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843844PMC
January 2021

Conditional reprogramming culture conditions facilitate growth of lower-grade glioma models.

Neuro Oncol 2021 05;23(5):770-782

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background: The conditional reprogramming cell culture method was developed to facilitate growth of senescence-prone normal and neoplastic epithelial cells, and involves co-culture with irradiated fibroblasts and the addition of a small molecule Rho kinase (ROCK) inhibitor. The aim of this study was to determine whether this approach would facilitate the culture of compact low-grade gliomas.

Methods: We attempted to culture 4 pilocytic astrocytomas, 2 gangliogliomas, 2 myxopapillary ependymomas, 2 anaplastic gliomas, 2 difficult-to-classify low-grade neuroepithelial tumors, a desmoplastic infantile ganglioglioma, and an anaplastic pleomorphic xanthoastrocytoma using a modified conditional reprogramming cell culture approach.

Results: Conditional reprogramming resulted in robust increases in growth for a majority of these tumors, with fibroblast conditioned media and ROCK inhibition both required. Switching cultures to standard serum containing media, or serum-free neurosphere conditions, with or without ROCK inhibition, resulted in decreased proliferation and induction of senescence markers. Rho kinase inhibition and conditioned media both promoted Akt and Erk1/2 activation. Several cultures, including one derived from a NF1-associated pilocytic astrocytoma (JHH-NF1-PA1) and one from a BRAF p.V600E mutant anaplastic pleomorphic xanthoastrocytoma (JHH-PXA1), exhibited growth sufficient for preclinical testing in vitro. In addition, JHH-NF1-PA1 cells survived and migrated in larval zebrafish orthotopic xenografts, while JHH-PXA1 formed orthotopic xenografts in mice histopathologically similar to the tumor from which it was derived.

Conclusions: These studies highlight the potential for the conditional reprogramming cell culture method to promote the growth of glial and glioneuronal tumors in vitro, in some cases enabling the establishment of long-term culture and in vivo models.
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http://dx.doi.org/10.1093/neuonc/noaa263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099469PMC
May 2021

GLI3 Is Associated With Neuronal Differentiation in SHH-Activated and WNT-Activated Medulloblastoma.

J Neuropathol Exp Neurol 2021 01;80(2):129-136

Department of Pathology, Brain Research Institute, Niigata University.

Glioma-associated oncogene homolog 3 (GLI3), whose main function is to inhibit GLI1, has been associated with neuronal differentiation in medulloblastoma. However, it is not clear what molecular subtype(s) show increased GLI3 expression. GLI3 levels were assessed by immunohistochemistry in 2 independent cohorts, including a total of 88 cases, and found to be high in both WNT- and SHH-activated medulloblastoma. Analysis of bulk mRNA expression data and single cell RNA sequencing studies confirmed that GLI1 and GLI3 are highly expressed in SHH-activated medulloblastoma, whereas GLI3 but not GLI1 is highly expressed in WNT-activated medulloblastoma. Immunohistochemical analysis has shown that GLI3 is expressed inside the neuronal differentiated nodules of SHH-activated medulloblastoma, whereas GLI1/2 are expressed in desmoplastic areas. In contrast, GLI3 is diffusely expressed in WNT-activated medulloblastoma, whereas GLI1 is suppressed. Our data suggest that GLI3 may be a master regulator of neuronal differentiation and morphology in these subgroups.
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http://dx.doi.org/10.1093/jnen/nlaa141DOI Listing
January 2021

Shear-Thinning Viscous Materials for Subconjunctival Injection of Microparticles.

AAPS PharmSciTech 2020 Nov 25;22(1). Epub 2020 Nov 25.

Center for Nanomedicine, The Johns Hopkins University School of Medicine, 400 North Broadway, Baltimore, Maryland, 21231, USA.

While drug-loaded microparticles (MPs) can serve as drug reservoirs for sustained drug release and therapeutic effects, needle clogging by MPs poses a challenge for ocular drug delivery via injection. Two polymers commonly used in ophthalmic procedures-hyaluronic acid (HA) and methylcellulose (MC)-have been tested for their applicability for ocular injections. HA and MC were physically blended with sunitinib malate (SUN)-loaded PLGA MPs for subconjunctival (SCT) injection into rat eyes. The HA and MC viscous solutions facilitated injection through fine-gauged needles due to their shear-thinning properties as shown by rheological characterizations. The diffusion barrier presented by HA and MC reduced burst drug release and extended overall release from MPs. The significant level of MP retention in the conjunctiva tissue post-operation confirmed the minimal leakage of MPs following injection. The safety of HA and MC for ocular applications was demonstrated histologically.
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http://dx.doi.org/10.1208/s12249-020-01877-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086054PMC
November 2020

Validation of the Newly Proposed World Health Organization Classification System for Conjunctival Melanocytic Intraepithelial Lesions: A Comparison with the C-MIN and PAM Classification Schemes.

Am J Ophthalmol 2021 03 30;223:60-74. Epub 2020 Oct 30.

Department of Pathology, Wills Eye Hospital, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA; Department of Ophthalmology, Wills Eye Hospital, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

Purpose: We sought to compare the sensitivity, specificity, accuracy, and interobserver agreement of the two most commonly used classification systems for conjunctival melanocytic intraepithelial lesions with the new World Health Organization (WHO) classification.

Design: Retrospective case series and evaluation of classification systems.

Methods: We reviewed the pathology and medical records of all patients who underwent a primary biopsy procedure for conjunctival primary acquired melanosis (PAM) at Wills Eye Hospital between 1974 and 2002 who had ≥36 months of follow-up. Data collected included age, sex, clinical findings, recurrence, and progression to melanoma. Twelve ophthalmic pathologists analyzed scanned hematoxylin and eosin-stained virtual microscopic slides using 3 classification systems: PAM, conjunctival melanocytic intraepithelial neoplasia, and the WHO 4th edition classification of conjunctival melanocytic intraepithelial lesions. Observer agreement, sensitivity, specificity, and diagnostic accuracy of each classification system were assessed.

Results: There were 64 patients who underwent 83 primary excisions with cryotherapy for conjunctival PAM who had adequate tissue for histopathologic evaluation. The interobserver agreement in distinction between the low- and high-grade lesions was 76% for PAM, 67% for conjunctival melanocytic intraepithelial neoplasia, and 81% for WHO classification system. Low-grade lesions provided the greatest interpretative challenge with all 3 classification systems. The 3 classification systems had comparable accuracy of 81%-83% in their ability to identify lesions with potential for recurrence.

Conclusions: This study highlights the comparable strengths and limitations of the 3 classification systems for conjunctival melanocytic intraepithelial lesions and suggests that the simplified WHO classification scheme is appropriate for evaluation of these lesions.
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http://dx.doi.org/10.1016/j.ajo.2020.10.020DOI Listing
March 2021

Chocolate Cysts Associated With Porous Polyethylene Orbital Implants.

Ophthalmic Plast Reconstr Surg 2021 Mar-Apr 01;37(2):e75-e80

Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, U.S.A.

Late-onset orbital hemorrhage is a rare complication of alloplastic implant use in orbital wall reconstruction following trauma. The authors report 3 patients with chocolate cysts presenting 3 to 9 years after orbital fracture repair with porous polyethylene implants. All patients were managed by implant removal and evacuation of cyst contents. Complete excision of the cyst was performed in 1 patient, while partial excision of the capsule was performed in 2 patients. Improvement of symptoms associated with the mass effects of the cyst was noted after surgical intervention. The authors also report the first case of orbital volume expansion from a chocolate cyst associated with a nonbarriered porous polyethylene implant. Delayed hemorrhage with capsule formation, although extremely rare, is a possible complication following orbital fracture repair with porous polyethylene implants.
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http://dx.doi.org/10.1097/IOP.0000000000001797DOI Listing
April 2021

Tarsal Epithelial Cysts: Prevalence, Case Series, and Synthesis of Existing Literature.

Ophthalmic Plast Reconstr Surg 2021 May-Jun 01;37(3):255-261

Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.

Purpose: Tarsal epithelial cysts (TECs) are squamous epithelial-lined lesions of the eyelid that are often mistaken for chalazia or epidermal inclusion cysts. They remain poorly described in the literature. This study is designed to characterize the prevalence and clinical features of TEC.

Methods: We conducted a single-center retrospective review of adult patients with a diagnosis of eyelid neoplasm, eyelid cyst, hordeolum, stye, or chalazion between January 1, 2011 and July 1, 2017. Among this cohort, we identified patients with a histopathologic diagnosis of TEC. We also conducted a PubMed literature review and synthesis of existing clinical data of patients reported to have TEC, noting common clinical and histopathological features.

Results: Of 7,516 patients, we identified 6 patients with a histopathological diagnosis of TEC, amounting to a prevalence of 0.08% amongst patients with eyelid lesions. Average age was 49.7 years (range 18-76 years), with a 1:1 male to female ratio. The most common presenting symptom was a painless eyelid mass, and the majority (66.6%) had a preoperative diagnosis of chalazion. All but 1 patient had surgical excision from the posterior approach and there was 1 recurrence in the follow-up period. On review of the literature, we identified 68 prior cases of TEC from 18 clinical studies, with clinical features mirroring our case series.

Conclusions: TEC has stereotypical clinical and histologic features that distinguish it from other tarsal lesions. Our review identified TEC as a relatively rare cause of eyelid lesions.
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http://dx.doi.org/10.1097/IOP.0000000000001795DOI Listing
May 2021
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