Conservative Management of Penile and Urethral Lichen Sclerosus: A Systematic Review.

PURPOSE: We evaluate the efficacy and safety profiles of currently available conservative management options for penile and urethral lichen sclerosus. MATERIALS AND METHODS: A systematic review of existing literature on lichen sclerosus was conducted utilizing the PubMed, Embase, and Web of Science databases. References were assessed for relevance to nonsurgical management of male genital lichen sclerosus by title and abstract by 3 independent reviewers, then reviewed in full and in duplicate by 5 independent reviewers. RESULTS: Seventeen studies describing conservative management of histologically confirmed penile and urethral lichen sclerosus in male patients were included in the final review. We present available evidence supporting the use of 4 major treatment modalities represented in the existing literature: topical corticosteroids, tacrolimus, platelet-rich plasma, and CO2 laser. We also briefly discuss the limited studies on the use of oral acitretin and polydeoxyribonucleotide injections. Outcomes assessed include symptoms, clinical appearance, quality of life, sexual satisfaction, adverse effects, and long-term efficacy of treatment. CONCLUSIONS: Topical corticosteroids remain the mainstay of conservative management of penile and urethral lichen sclerosus, with current literature supporting the use of other therapies such as tacrolimus and platelet-rich plasma as alternatives or adjuvant treatments when escalation of treatment is necessary. Future research should further explore the efficacy and safety of newer therapies through additional controlled clinical trials in the targeted population.

Neoantigen-targeted CD8+ T cell responses with PD-1 blockade therapy.

Neoantigens are peptides derived from non-synonymous mutations presented by human leukocyte antigens (HLAs), which are recognized by antitumour T cells1-14. The large HLA allele diversity and limiting clinical samples have restricted the study of the landscape of neoantigen-targeted T cell responses in patients over their treatment course. Here we applied recently developed technologies15-17 to capture neoantigen-specific T cells from blood and tumours from patients with metastatic melanoma with or without response to anti-programmed death receptor 1 (PD-1) immunotherapy. We generated personalized libraries of neoantigen-HLA capture reagents to single-cell isolate the T cells and clone their T cell receptors (neoTCRs). Multiple T cells with different neoTCR sequences (T cell clonotypes) recognized a limited number of mutations in samples from seven patients with long-lasting clinical responses. These neoTCR clonotypes were recurrently detected over time in the blood and tumour. Samples from four patients with no response to anti-PD-1 also demonstrated neoantigen-specific T cell responses in the blood and tumour to a restricted number of mutations with lower TCR polyclonality and were not recurrently detected in sequential samples. Reconstitution of the neoTCRs in donor T cells using non-viral CRISPR-Cas9 gene editing demonstrated specific recognition and cytotoxicity to patient-matched melanoma cell lines. Thus, effective anti-PD-1 immunotherapy is associated with the presence of polyclonal CD8+ T cells in the tumour and blood specific for a limited number of immunodominant mutations, which are recurrently recognized over time.

Attitudes and Awareness of Cornea Specialists and Oculoplastic Surgeons toward Methicillin-Resistant Staphylococcus aureus Decolonization.

Background: Methicillin-resistant Staphylococcus aureus (MRSA) decolonization is widely utilized in many medical subspecialities to reduce surgical site infections, but routine ophthalmic implementation has been limited. The aim of this study was to investigate the attitudes and actual practice of corneal specialists and oculoplastic surgeons toward MRSA decolonization as a preventive measure in ophthalmic surgery. Materials and Methods: A web-based survey was sent to cornea specialists and oculoplastic surgeons to assess their knowledge, beliefs, and practices regarding MRSA prophylaxis and the use of MRSA decolonization to prevent post-operative infections. Results: A total of 180 surgeons participated in this study: 71% of respondents agreed that MRSA colonization plays a role in post-operative infection of the eye and adnexal structures; 65% stated that MRSA decolonization could help prevent MRSA infection. Although 41% of respondents would change their management in response to a positive pre-operative MRSA screening result, only 18% performed pre-operative screening. Seventeen percent of respondents indicated that they offer pre-operative decolonization for MRSA-positive patients; the most frequently applied technique was the use of nasal antibiotic agents such as mupirocin, followed by antiseptic baths. Peri-operative MRSA prophylaxis was used by 18% of respondents; pre-operative MRSA decolonization was used in conjunction by 8.5 % of respondents. Conclusions: Although MRSA decolonization has been validated in fields outside of ophthalmology, there has not been widespread adoption of this practice among oculoplastic surgeons and cornea specialists. Prospective MRSA decolonization ophthalmic studies are necessary if evidence-based management guidelines are to be developed.

MRSA Decolonization and the Eye: A Potential New Tool for Ophthalmologists.

PURPOSE: Methicillin-resistant Staphylococcus aureus (MRSA) is an opportunistic pathogen that can cause vision-threatening infections of the ocular surface, orbit, and periorbital structures. MRSA decolonization is a widespread technique employed outside of ophthalmology to reduce MRSA transmission and infection rates. Herein we explore whether decolonization protocols have a place in ophthalmology for combatting ocular MRSA infections. METHODS: We conducted a focused review of the MRSA decolonization literature using PubMed and Cochrane databases to identify key studies in ophthalmology and the broader medical literature. RESULTS: We summarize the relevance of the recent literature from an ophthalmic perspective, focusing on the clinical evidence supporting pre-operative MRSA decolonization. We also discuss current real-world decolonization practices, existing challenges, and propose recommendations for future opportunities to address these issues. CONCLUSION: Incorporating pre-operative MRSA decolonization approaches discussed herein may offer a new frontier for enhancing the ophthalmic care of patients colonized with MRSA.

Corneal perforation in ocular graft-versus-host disease.

PURPOSE: Corneal perforation is a rare, vision-threatening complication of ocular graft-versus-host disease (GVHD) and is not well understood. Our objective was to examine the clinical disease course and histopathologic correlation in patients who progressed to this outcome. METHODS: This study is a retrospective case series from four academic centers in the United States. All patients received a hematopoietic stem cell transplant (HSCT) prior to developing ocular GVHD. Variables of interest included patient demographics, time interval between HSCT and ocular events, visual acuity throughout clinical course, corticosteroid and infection prophylaxis regimens at time of corneal perforation, medical/surgical interventions, and histopathology. RESULTS: Fourteen eyes from 14 patients were analyzed. Most patients were male (86%) and Caucasian (86%), and average age at time of hematopoietic stem cell transplant was 47 years. The mean interval between hematopoietic stem cell transplant and diagnosis of ocular graft-versus-host disease was 9.5 months, and between hematopoietic stem cell transplant and corneal perforation was 37 months. Initial best-corrected visual acuity was 20/40 or better in 9 eyes, and all eyes had moderate or poor visual outcomes despite aggressive management, including corneal gluing in all patients followed by keratoplasty in 8 patients. The mean follow-up after perforation was 34 months (range 2-140 months). Oral prednisone was used prior to perforation in 11 patients (79%). On histopathology, representative specimens in the acute phase demonstrated ulcerative keratitis with perforation but minimal inflammatory cells and no microorganisms, consistent with sterile corneal "melt" in the setting of immunosuppression; and in the healed phase, filling in of the perforation site with fibrous scar. CONCLUSIONS: In these patients, an extended time interval was identified between the diagnosis of ocular graft-versus-host disease and corneal perforation. This represents a critical window to potentially prevent this devastating outcome. Further study is required to identify those patients at greatest risk as well as to optimize prevention strategies.

Case Report: Significant Complications of Cosmetic Iris Implantation.

SIGNIFICANCE: The complications of cosmetic iris implantation may result in irreversible vision loss. Patients who obtain these implants against general medical consensus may present to providers when sequelae develop. In symptomatic patients, providers must recognize the imminent risk to vision and mitigate further ocular damage. PURPOSE: This is an observational clinical case report of a patient with significant, progressive, vision-threatening ocular pathology from prior cosmetic iris implantation, despite medical and surgical efforts to preserve vision. CASE REPORT: A 35-year-old HIV-positive man with a history of cosmetic iris implants in India 16 months prior was referred to our center. He had a history of 4 months of steroid-refractory uveitis and secondary glaucoma, with IOP measurements of more than 50 mmHg in the outpatient setting. Slit-lamp examination revealed ciliary flush, pannus formation, corneal edema, and keratic precipitates. Optical coherence tomography suggested possible retinal nerve fiber layer loss in the left eye. He was diagnosed with uveitis and glaucoma, and after a short course of IOP-lowering medication, the implants were removed sequentially. Post-operatively, his course was complicated by IOP elevation, cataract development, and corneal decompensation. This led to bilateral Ahmed tube placement, Descemet's stripping endothelial keratoplasty of the right eye, and pending cataract surgery because of now-dense bilateral cataracts. CONCLUSIONS: This case emphasizes the vision-threatening dangers of cosmetic iris implantation. It also demonstrates that sequelae may persist and develop despite implant removal and anticipatory management. Providers managing similar patients should carefully monitor for disease progression and maintain a low threshold for referral and/or decisive surgical intervention.

Aftermarket effects of cenegermin for neurotrophic keratopathy in pediatric patients.

PURPOSE: Neurotrophic keratopathy (NK) is a rare condition characterized by poor corneal sensation and healing. Cenegermin (topical recombinant nerve growth factor) has gained traction as a medical therapy for NK in recent years, and is FDA-approved for patients over two years old. However, no major trials have demonstrated the drug's efficacy in children. This study reviews the outcomes of cenegermin therapy in a pediatric patient population. METHODS: Retrospective case series of patients from three tertiary referral institutions who 1) initiated an 8-week course of cenegermin therapy, and 2) were 18 years or less at time of treatment initiation. RESULTS: Eight pediatric patients, with a total of nine affected eyes, underwent cenegermin therapy. All eight patients had previously trialed other NK-specific treatments, none of which had been entirely successful. Five patients (63%) completed the full eight-week therapy course. Five patients (63%) experienced clinical improvement not attributed to another treatment, through improved corneal ulcer stage (n = 5) and best-corrected visual acuity (n = 2). Clinical improvements persisted through a mean recurrence-free period of 10 months. Adverse effects reported during therapy included ocular pain, difficulty sleeping, and continued corneal thinning. CONCLUSION: The results provide modest support for the use of cenegermin in pediatric patients with neurotrophic keratopathy. The primary benefit was an improvement in corneal epithelial stability. Clinicians should be aware that pre-existing corneal scarring in NK may significantly limit the ability of cenegermin alone to improve visual acuity, and should closely monitor the corneal epithelial status during therapy in pediatric patients.

Gastrointestinal toxicities of immune checkpoint inhibitors: a multicenter retrospective analysis.

BACKGROUND: Immune checkpoint inhibitors are monoclonal antibodies that augment immune cell function and are used to treat malignancy. However, they may cause proinflammatory adverse events. This study investigated gastrointestinal (GI) adverse events associated with specific immune checkpoint inhibitors. METHODS: Charts of patients aged >18 years with a solid tumor who underwent treatment with immune checkpoint inhibitors between 1st April 2011 and 1st August 2019 were reviewed for GI toxicities. Clinical data, including interventions, treatment duration and outcomes, were recorded. RESULTS: One hundred patients were included in the study, of whom 22 experienced a GI adverse event directly attributable to immune checkpoint inhibitors. Transaminitis (9/22; 40.9%) and colitis (8/22; 36.3%) were most prevalent. The majority of events occurred within 4 cycles of treatment onset and were most prevalent with the nivolumab + ipilimumab combination (7/12; 58.3%). In 91% of cases (20/22), patients showed improvement or resolution of the event. Among the colitis cases, there was a significant difference (P=0.004) in recovery time between those who received infliximab and those who did not. Despite symptom resolution, only 7/22 were left on the same or part of the same treatment regimen. CONCLUSIONS: Most patients experienced their GI adverse events within 4 cycles of starting treatment, the most common being transaminitis and colitis. Nivolumab + ipilimumab dual therapy was most strongly associated with colitis. Most adverse events self-resolved, with infliximab being particularly helpful in improving colitis symptoms. However, most patients were unable to tolerate the same immunotherapy regimen and ultimately expired.

Surgical management of large bilateral epibulbar dermoids with autologous oral mucous membrane transplantation.

PURPOSE: To report the surgical management of extensive epibulbar dermoids with autologous oral mucous membrane transplantation. OBSERVATIONS: While rare, extensive dermoids that encroach upon the visual axis carry a poor prognosis. We report the case of a 7-week old premature male infant who presented with large bilateral epibulbar dermoids obscuring the visual axis. He was treated first with sequential bilateral optical iridectomies under the clearest corneal areas, followed several months later by sequential dermoid excision and amniotic membrane transplantation in each eye. He subsequently underwent autologous "simple" oral mucosal epithelial transplantation (SOMET) as well as strabismus surgery. Conclusions and Importance: Here we present the first case, to the best of our knowledge, of the use of SOMET in managing post-operative pseudopterygium following dermoid excision. To our knowledge it is the also the first application of this technique in a young pediatric patient. A good clinical outcome may be achieved with SOMET, which may offer a minimally invasive alternative to other traditional modalities.

Timely diagnosis and staging of non-alcoholic fatty liver disease using transient elastography and clinical parameters.

BACKGROUND AND AIM: There is no standardized guideline to screen, image, or refer patients with non-alcoholic fatty liver disease (NAFLD) to a specialist. In this study, we used transient elastography (TE) to examine the fibrosis stages at which patients are first diagnosed with NAFLD. Subsequently, we analyzed metabolic markers to establish cut-offs beyond which noninvasive imaging should be considered to confirm NAFLD/non-alcoholic steatohepatitis fibrosis in patients. METHODS: Charts spanning July 2015-April 2018 for 116 NAFLD patients who had TE performed were reviewed. Univariate and multivariate analysis of metabolic markers was conducted. RESULTS: At the first hepatology visit, TE showed 73% F0-F2 and 27% F3-F4. Univariate analysis showed that high-density lipoproteins (HDL), hemoglobin A1c (A1c), aspartate transaminase (AST), and alanine transaminase (ALT) were significantly different between the F0-F2 and F3-F4 groups. Multivariate analysis showed that AST (P = 0.01) and A1c (P = 0.05) were significantly different. Optimal cut-offs for these markers to detect liver fibrosis on TE were AST >43 U/L and A1c >6.6%. The logistic regression function combining these two variables to reflect the probability (P) of the patient having advanced fibrosis (F3-F4) on TE yielded the formula: P = e R /(1 + e R ), where R = -8.56 + 0.052 * AST + 0.89 * A1c. CONCLUSIONS: Our study suggested that >25% of patients presenting to a specialist for NAFLD may have advanced fibrosis (F3-F4). Diabetes (A1c >6.6%) and AST >43 U/L were the most predictive in identifying NAFLD patients with advanced fibrosis on imaging. We proposed a formula that may be used to prioritize NAFLD patients at higher risk of having advanced fibrosis for specialist referral and imaging follow-up.

Atypical Reactivation of Varicella Zoster Virus Associated with Pancreatitis in a Heart Transplant Patient.

BACKGROUND Acute pancreatitis is rare following solid organ transplantation but is associated with high mortality. It has been most commonly reported following renal transplant but can occur with other solid organ transplantations. CASE REPORT A 46-year-old male who had an orthotopic heart transplant 6 months ago presented with a 3-week history of abdominal pain. The patient described it as intermittent, sharp, and stabbing, originating in the periumbilical area and radiating to the back. His lipase was elevated at 232 U/L. Given that the patient's symptoms and lipase were elevated to greater than three times the upper limit of normal, he patient was diagnosed with acute pancreatitis. The patient also mentioned a diffuse itchy rash that started a few days prior to admission. Dermatology was consulted, and given the man's clinical presentation, there was concern for atypical reactivation of varicella zoster virus (VZV). VZV polymerase chain reaction of the vesicles returned positive. The patient was started on acyclovir and his symptoms improved. CONCLUSIONS This is the first reported case of VZV-associated pancreatitis in a heart transplant patient. Our patient presented with acute pancreatitis and was treated supportively. However, he did not receive antiviral treatment until his rash was discovered. Timely treatment of VZV resulted in resolution of both the rash and pancreatitis. Timely diagnosis of pancreatitis and VZV is important to prevent development of multiorgan failure and death.

Pediatric ocular surface disease associated with suspected abuse.

PURPOSE: To describe one of the largest case series of children whose ocular surface disease was strongly suspicious for nonaccidental injury (NAI). METHODS: This multicenter retrospective case series includes 4 patients whose presentations were concerning for anterior segment NAI. The history, examination, treatment, and outcomes of these patients is presented, along with a brief review of case reports in the literature. RESULTS: A broad spectrum of anterior segment findings was noted in our case series and in cases previously reported in the literature. NAI appears to be associated with bilateral and recurrent disease as well as improvement during hospitalization that is better than initially expected. CONCLUSIONS: Ocular surface NAI is a diagnosis of exclusion and necessitates a thorough history and examination. Clinician concern for ocular NAI should prompt examination or referral for signs of other bodily injuries, especially in young children. Siblings of patients who have received the diagnosis of NAI may also be at risk.

SJS/TEN 2019: From science to translation.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are potentially life-threatening, immune-mediated adverse reactions characterized by widespread erythema, epidermal necrosis, and detachment of skin and mucosa. Efforts to grow and develop functional international collaborations and a multidisciplinary interactive network focusing on SJS/TEN as an uncommon but high burden disease will be necessary to improve efforts in prevention, early diagnosis and improved acute and long-term management. SJS/TEN 2019: From Science to Translation was a 1.5-day scientific program held April 26-27, 2019, in Vancouver, Canada. The meeting successfully engaged clinicians, researchers, and patients and conducted many productive discussions on research and patient care needs.

Correction: GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder.

PURPOSE: Determination of genotypic/phenotypic features of GATAD2B-associated neurodevelopmental disorder (GAND). METHODS: Fifty GAND subjects were evaluated to determine consistent genotypic/phenotypic features. Immunoprecipitation assays utilizing in vitro transcription-translation products were used to evaluate GATAD2B missense variants' ability to interact with binding partners within the nucleosome remodeling and deacetylase (NuRD) complex. RESULTS: Subjects had clinical findings that included macrocephaly, hypotonia, intellectual disability, neonatal feeding issues, polyhydramnios, apraxia of speech, epilepsy, and bicuspid aortic valves. Forty-one novelGATAD2B variants were identified with multiple variant types (nonsense, truncating frameshift, splice-site variants, deletions, and missense). Seven subjects were identified with missense variants that localized within two conserved region domains (CR1 or CR2) of the GATAD2B protein. Immunoprecipitation assays revealed several of these missense variants disrupted GATAD2B interactions with its NuRD complex binding partners. CONCLUSIONS: A consistent GAND phenotype was caused by a range of genetic variants in GATAD2B that include loss-of-function and missense subtypes. Missense variants were present in conserved region domains that disrupted assembly of NuRD complex proteins. GAND's clinical phenotype had substantial clinical overlap with other disorders associated with the NuRD complex that involve CHD3 and CHD4, with clinical features of hypotonia, intellectual disability, cardiac defects, childhood apraxia of speech, and macrocephaly.