A Review of Current Uses of Amniotic Membrane Transplantation in Ophthalmic Plastic and Reconstructive Surgery.

PURPOSE: To review and summarize the existing literature on the clinical applications of amniotic membrane transplantation (AMT) in ophthalmic plastic and reconstructive surgery. METHODS: A literature review was conducted on the PubMed database using the following search terms: "amniotic membrane" and "eyelid" or "orbit" or "fornix" or "socket" or "lacrimal". RESULTS: In total 516 articles resulted from the search, of which 62 were included. Numerous cases and case series have been published on the use of amniotic membrane transplantation for ocular surface reconstruction, eyelid and forniceal reconstruction, and cicatricial eyelid abnormalities. Surgical methods of securing the graft vary. Few comparative studies exist; some show a similar or improved result when compared to oral mucous membrane grafting for certain indications. CONCLUSIONS: Amniotic membrane transplantation can be a useful tool for the oculoplastic surgeon when faced with a case requiring reconstruction of the posterior lamellae, particularly in patients without other graft donor sites available, and uses of AMT continue to expand. Additional studies directly comparing AMT to other reconstructive techniques would be helpful in choosing between the available surgical techniques and standardizing best practices.

Human Papillomavirus and Rising Oropharyngeal Cancer Incidence in the United States.

PURPOSE: Recent increases in incidence and survival of oropharyngeal cancers in the United States have been attributed to human papillomavirus (HPV) infection, but empirical evidence is lacking. PATIENTS AND METHODS: HPV status was determined for all 271 oropharyngeal cancers (1984-2004) collected by the three population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) Residual Tissue Repositories Program by using polymerase chain reaction and genotyping (Inno-LiPA), HPV16 viral load, and HPV16 mRNA expression. Trends in HPV prevalence across four calendar periods were estimated by using logistic regression. Observed HPV prevalence was reweighted to all oropharyngeal cancers within the cancer registries to account for nonrandom selection and to calculate incidence trends. Survival of HPV-positive and HPV-negative patients was compared by using Kaplan-Meier and multivariable Cox regression analyses. RESULTS: HPV prevalence in oropharyngeal cancers significantly increased over calendar time regardless of HPV detection assay (P trend < .05). For example, HPV prevalence by Inno-LiPA increased from 16.3% during 1984 to 1989 to 71.7% during 2000 to 2004. Median survival was significantly longer for HPV-positive than for HPV-negative patients (131 v 20 months; log-rank P < .001; adjusted hazard ratio, 0.31; 95% CI, 0.21 to 0.46). Survival significantly increased across calendar periods for HPV-positive (P = .003) but not for HPV-negative patients (P = .18). Population-level incidence of HPV-positive oropharyngeal cancers increased by 225% (95% CI, 208% to 242%) from 1988 to 2004 (from 0.8 per 100,000 to 2.6 per 100,000), and incidence for HPV-negative cancers declined by 50% (95% CI, 47% to 53%; from 2.0 per 100,000 to 1.0 per 100,000). If recent incidence trends continue, the annual number of HPV-positive oropharyngeal cancers is expected to surpass the annual number of cervical cancers by the year 2020. CONCLUSION: Increases in the population-level incidence and survival of oropharyngeal cancers in the United States since 1984 are caused by HPV infection.

Intraocular Spread of Ocular Surface Squamous Neoplasia Presenting as a Postoperative Anterior Chamber Opacity after Excisional Biopsy.

We describe a rare case of ocular surface squamous neoplasia (OSSN) with intraocular spread after excisional biopsy which presented as a postoperative anterior chamber (A/C) opacity, initially thought to be a hypopyon. A 60-year-old female with history of a right (OD) conjunctival mass involving the cornea, surgically excised and diagnosed as OSSN, presented 2 months postoperatively with an A/C opacity concerning for infection. The patient was prescribed prednisolone acetate and ofloxacin drops postoperatively; topical chemotherapy was not given. When the opacity did not respond to 3 weeks of topical treatment, they were referred to an ocular oncologist for management. Intraoperative records from biopsy were unavailable; use of cryotherapy is unknown. On presentation, the patient had reduced vision OD. On slit-lamp exam, a white plaque in the A/C was seen, obscuring the iris. Given concern for postoperative intraocular cancer spread and extent of disease, enucleation with extended conjunctival excision was done. Gross pathology revealed an A/C mass with a diffuse hazy membrane. Histopathology diagnosed moderately differentiated OSSN with extensive intraocular invasion; a full-thickness limbal defect was visualized. Disease was confined to the globe, without residual conjunctival malignancy. This case emphasizes the importance of taking surgical precaution when excising conjunctival lesions, especially large lesions which obscure ocular anatomy, to maintain scleral integrity and Bowman's layer with limbal lesions. Intraoperative cryotherapy and postoperative chemotherapy should also be employed. If a patient with history of ocular surface malignancy displays symptoms concerning postoperative infection, this case highlights the importance of considering invasive disease.

Multiple Cases of Facial Disfigurement From Filler Use and One Injector.

PURPOSE: To present a case of facial disfigurement from an injectable permanent filler and describe the consequences to patients exposed to the same injector (common source outbreak). METHODS: Case report and discussion of a common source outbreak after a group of persons developed complications years after permanent filler given by one injector. RESULTS: A 39-year-old transgender model underwent polymethylmethacrylate (Artefill) facial filler injections to the lips, cheeks, and chin in 2018. A year later, the patient presented to the emergency room with severe facial swelling and difficulty breathing. Treatments have included 4 surgeries to remove filler and scar tissue and chronic low-dose oral steroid therapy. Upon questioning the patient, 6 additional people suffered from similar facial swelling years after injection by the same injector. The injector cannot be located. CONCLUSIONS: Care must be taken in giving all facial fillers, particularly permanent ones. When one source patient is identified, questioning the patient's knowledge of others affected is critical to help manage an epidemic problem and to report a rogue injector. Physicians have a duty to investigate and report such cases.

Histopathology of Intraocular Medulloepithelioma following Iodine-125 Plaque Brachytherapy.

We report the case of a 15-year-old female with a medulloepithelioma who underwent enucleation following plaque brachytherapy. To our knowledge, this is the first report of the histopathological findings of medulloepithelioma following brachytherapy. Histopathology revealed radiation-related changes such as hyalinized vessels, photoreceptor atrophy, degenerative changes of the retina, and preretinal fibrous tissue. Additionally, the retinal nerve fiber layer showed signs of cystoid edema. Subretinal fluid, not commonly associated with medulloepithelioma, was also noted on histology; interestingly, it was seen adjacent to the tumor on B scan prior to brachytherapy. After enucleation, hyaline cartilage was also present on histology, although neuroepithelium was absent. Although we do not have pathological confirmation that neuroepithelium was present prior to brachytherapy, it is possible that brachytherapy preferentially affected neuroepithelium, leading to decrease in tumor size.

GPR158 in the Visual System: Homeostatic Role in Regulation of Intraocular Pressure.

Purpose: GPR158 is a newly characterized family C G-protein-coupled receptor, previously identified in functional screens linked with biological stress, including one for susceptibility to ocular hypertension/glaucoma induced by glucocorticoid stress hormones. In this study, we investigated GPR158 function in the visual system. Methods: Gene expression and protein immunolocalization analyses were performed in mouse and human brain and eye to identify tissues where GPR158 might function. Gene expression was perturbed in mice, and in cultures of human trabecular meshwork cells of the aqueous outflow pathway, to investigate function and mechanism. Results:GPR158 is highly expressed in the brain, and in this study, we show prominent expression specifically in the visual center of the cerebral cortex. Expression was also observed in the eye, including photoreceptors, ganglion cells, and trabecular meshwork. Protein was also localized to the outer plexiform layer of the neural retina. Gpr158 deficiency in knockout (KO) mice conferred short-term protection against the intraocular pressure increase that occurred with aging, but this was reversed over time. Most strikingly, the pressure lowering effect of the acute stress hormone, epinephrine, was negated in KO mice. In contrast, no disruption of the electroretinogram was observed. Gene overexpression in cell cultures enhanced cAMP production in response to epinephrine, suggesting a mechanism for intraocular pressure regulation. Overexpression also increased survival of cells subjected to oxidative stress linked to ocular hypertension, associated with TP53 pathway activation. Conclusions: These findings implicate GPR158 as a homeostatic regulator of intraocular pressure and suggest GPR158 could be a pharmacological target for managing ocular hypertension.

Extending far and wide: the role of biopsy and staging in the management of ocular surface squamous neoplasia.

IMPORTANCE: Although the most recent American Joint Committee on cancer staging guidelines for ocular surface squamous neoplasia place a heightened emphasis on biopsy and histopathologic analysis, the interpretation and clinical relevance of these staging criteria are not always clear. We address limitations of using histopathologic analysis to predict clinical outcomes and suggest less-invasive assessments. BACKGROUND: To investigate the impact of histopathologic depth of invasion on outcomes for tumours with the common presentation of multiple structure involvement. DESIGN: Retrospective chart review at tertiary institution. SAMPLES: Of 41 eyes with ocular surface squamous neoplasia between 2012 and 2017, 27 tumours involving multiple ocular structures clinically were included. METHODS: Biopsied tumours were determined to be invasive beyond the basement membrane or non-invasive; non-biopsied tumours were clinically identified with unknown depth of invasion. Outcomes were compared using Fisher's exact or Student's t tests. MAIN OUTCOME MEASURES: Proportion of tumours cured, recurred and/or persisting. RESULTS: Twelve tumours (44%) received primary excisional biopsy, 10 (37%) received chemotherapy without biopsy and 5 (19%) received chemotherapy and biopsy. Clinical diagnosis was correct in all biopsied cases. While there were no significant differences in outcomes between invasive vs non-invasive tumours or treatments, there was a trend toward larger basal diameter in recurrent tumours regardless of treatment. CONCLUSIONS AND RELEVANCE: When ocular surface squamous neoplasia tumours with similar clinical involvement were compared, histopathologic depth of invasion was not predictive of clinical outcomes. Future staging criteria may consider the potential of largest basal dimension for more accurate prognostication.

Late Apical Recurrence of Choroidal Melanoma 10 Years after Successful Treatment with Brachytherapy.

PURPOSE: To describe late apical relapse of a choroidal melanoma at the site of fine needle aspiration biopsy 10 years following successful treatment with 125I brachytherapy. METHODS: Retrospective case report of a 78-year-old male presenting 10 years following successful 125I brachytherapy for a choroidal melanoma with a medium-sized nodular amelanotic tumor recurrence at the site of the prior tumor biopsy. RESULTS: Fundus photography and B-scan ultrasound documented the findings at presentation at our institution. The patient was followed closely for 8 weeks while information was retrieved from the treating institution. During this short period, there was significant apical tumor growth. Additionally, there was a clear clinical change compared to the last documented photos from 5 years prior at the treating institution. Enucleation was recommended. Pathological analysis confirmed the diagnosis of recurrent choroidal melanoma at the apex of the treated lesion, at the site of prior biopsy. Systemic surveillance was negative for metastatic disease. CONCLUSION: Current literature suggests the majority of choroidal melanoma recurrences occur within 5 years following treatment. However, this case of recurrence 10 years after brachytherapy emphasizes the importance of life-long ophthalmic care for these patients. Additionally, this case demonstrates the possibility of a rare recurrence at a prior biopsy site.

Quadruple Neoplasms following Radiation Therapy for Congenital Bilateral Retinoblastoma.

PURPOSE: The aim of this study was to describe a 34-year-old male with hereditary bilateral retinoblastoma treated with radiotherapy as a child who developed 4 distinct tumors within the radiation field. METHODS: A 34-year-old male with bilateral retinoblastoma status postradiation therapy and recurrence requiring enucleation presented with left-eye visual acuity changes. Magnetic resonance imaging demonstrated a left orbital mass and a right parasellar complex lobulated mass (right sphenoid and right cavernous sinus). Two weeks later, the patient underwent excision of the orbital mass and biopsy of an upper-lid nodule. This was followed by craniotomy for removal of the complex mass. RESULTS: Histology revealed 4 distinct tumors, including an undifferentiated pleomorphic sarcoma (left orbit), a radiation-induced meningioma (right sphenoid), a schwannoma (right cavernous sinus), and a basal-cell carcinoma (left lid). CONCLUSION: Although occurrence of a second neoplasm is a well-known outcome following radiation treatment in patients with hereditary retinoblastoma, the diagnosis of 4 additional neoplasms is rare. Pleomorphic sarcoma, radiation-induced meningioma, and schwannoma are uncommon tumors and not well represented in the literature describing irradiated retinoblastoma patients. Secondary malignancies are a leading cause of early death in retinoblastoma survivors, and long-term follow-up is crucial for patient care.

Human papillomavirus and rising oropharyngeal cancer incidence in the United States.

PURPOSE: Recent increases in incidence and survival of oropharyngeal cancers in the United States have been attributed to human papillomavirus (HPV) infection, but empirical evidence is lacking. PATIENTS AND METHODS: HPV status was determined for all 271 oropharyngeal cancers (1984-2004) collected by the three population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) Residual Tissue Repositories Program by using polymerase chain reaction and genotyping (Inno-LiPA), HPV16 viral load, and HPV16 mRNA expression. Trends in HPV prevalence across four calendar periods were estimated by using logistic regression. Observed HPV prevalence was reweighted to all oropharyngeal cancers within the cancer registries to account for nonrandom selection and to calculate incidence trends. Survival of HPV-positive and HPV-negative patients was compared by using Kaplan-Meier and multivariable Cox regression analyses. RESULTS: HPV prevalence in oropharyngeal cancers significantly increased over calendar time regardless of HPV detection assay (P trend < .05). For example, HPV prevalence by Inno-LiPA increased from 16.3% during 1984 to 1989 to 71.7% during 2000 to 2004. Median survival was significantly longer for HPV-positive than for HPV-negative patients (131 v 20 months; log-rank P < .001; adjusted hazard ratio, 0.31; 95% CI, 0.21 to 0.46). Survival significantly increased across calendar periods for HPV-positive (P = .003) but not for HPV-negative patients (P = .18). Population-level incidence of HPV-positive oropharyngeal cancers increased by 225% (95% CI, 208% to 242%) from 1988 to 2004 (from 0.8 per 100,000 to 2.6 per 100,000), and incidence for HPV-negative cancers declined by 50% (95% CI, 47% to 53%; from 2.0 per 100,000 to 1.0 per 100,000). If recent incidence trends continue, the annual number of HPV-positive oropharyngeal cancers is expected to surpass the annual number of cervical cancers by the year 2020. CONCLUSION: Increases in the population-level incidence and survival of oropharyngeal cancers in the United States since 1984 are caused by HPV infection.

Associations between selected biomarkers and prognosis in a population-based pancreatic cancer tissue microarray.

Pancreatic cancer is the fourth leading cause of cancer death in the United States. Prognostic biomarkers are lacking, and treatment has limited effect on survival. Tissues from Surveillance, Epidemiology, and End Results registries (Iowa, Hawaii, and Los Angeles) were used to build a tissue microarray of 161 pancreatic tumors (113 resections and 48 biopsies). Proportional hazard models adjusted for age, race, sex, stage, time-period of diagnosis, and treatment. Associations were examined between markers (MUC1, MUC2, MUC5AC, synaptophysin, chromogranin, neuron specific enolase, epidermal growth factor receptor, HER2, CD5, CD138, CK5/6, CK19, CK20, and p53) and survival time from diagnosis. After adjusting for covariates, borderline statistically significant associations were seen between expression of each of the three mucins (MUC1, MUC2, and MUC5AC) and shorter survival time. The associations strengthened for 154 (96%) adenocarcinomas, particularly the 120 (75%) well-differentiated to moderately differentiated ductal adenocarcinomas, a tumor type that occurred more often in the cohort among White cases than cases of other racial origin (P<0.01). For differentiated ductal adenocarcinomas, associations with shorter survival time were seen for expression of all three mucins combined versus other mucin expression patterns (adjusted hazard ratio, 1.8; 95% confidence interval, 1.2-2.6) and for MUC2(+) versus MUC2(-) expression (adjusted hazard ratio, 1.6; 95% confidence interval, 1.1-2.4). Mucin gene expression, particularly MUC2 expression, may have prognostic value for differentiated adenocarcinomas. Tumor histologies differed in this and Japanese cohorts. The tissue microarray is available to evaluate other biomarkers. Tissue-based surveillance can be used to monitor tumor histology in populations and facilitate applied research.