How we treat Merkel cell carcinoma: within and beyond current guidelines.

Merkel cell carcinoma (MCC) is an aggressive skin cancer associated with a high risk of local recurrence and distant metastasis. Optimal care of this potentially life-threatening cancer is critical but challenging because: physicians are often unfamiliar with its management due to rarity, and MCC management remains controversial, in part because it is rapidly evolving across multiple specialties. While guidelines offer a broad overview of management, they are often not sufficient when making decisions for individual patients. Herein, we present a literature review as well as practical approaches adopted at our institutions for staging, surveillance and therapy of MCC. Each of these areas are discussed in light of how they can be appropriately customized for prevalent but challenging situations. We also provide representative examples of MCC patient scenarios and how they were managed by a multidisciplinary team to identify suitable evidence-based, individualized treatment plans.

Lay abstract Merkel cell carcinoma (MCC) is a skin cancer with a high risk of recurrence and distant spread. Optimal care of this cancer is important. However, management is challenging because it is rare and its treatment is continuously evolving across multiple specialties. While treatment guidelines offer a broad overview of management, they are often not detailed enough to provide appropriate patient-specific assistance. Herein, we present a review of recent studies and our suggestions relevant to MCC staging, surveillance and treatment options. Each of these areas are discussed in light of how they can be appropriately customized for challenging situations often encountered by practitioners. We also provide representative examples of MCC patient scenarios and how they were managed by a multidisciplinary team to identify evidence-based, individualized treatment plans.

Self-Inflicted Laser-Induced Retinopathy.

This photo essay details a patient with self-inflicted laser-induced retinal injury progressing to full-thickness macular holes in both eyes. A 40-year-old patient presented after a self-inflicted injury by a handheld class 3 blue laser (450 nm) he purchased on the internet. The patient reported shining the laser through a window, which reflected the beam back into his eyes. Visual acuity was measured at 20/400 in both eyes. The initial fundus photographs revealed vitreous and preretinal hemorrhages in the right eye, and multiple yellow-white fresh laser burns in the macula of the left eye. Optical coherence tomography (OCT) showed preretinal hemorrhage in the right eye and retinal disruption with preretinal hyper-reflective lesion in the left eye. After one month, his vision deteriorated to finger counting in each eye. He developed a full-thickness macular hole and hyperfluorescent curvilinear streaks in the superior maculae in both eyes. OCT images showed retinal pigment epithelium clumping and outer retinal atrophy in curvilinear streak areas in both eyes, which point to self-inflicted injury. This case illustrates laser-pointer-induced retinopathy and reinforces the necessity of public education on the dangers of utilizing handheld lasers without eye protection.

Multivariate Models to Diagnose Early Referral-Warranted Retinopathy of Prematurity With Handheld Optical Coherence Tomography.

Purpose: The purpose of this study was to create multivariate models predicting early referral-warranted retinopathy of prematurity (ROP) using non-contact handheld spectral-domain optical coherence tomography (OCT) and demographic data. Methods: Between July 2015 and February 2018, infants ≤1500 grams birth weight or ≤30 weeks gestational age from 2 academic neonatal intensive care units were eligible for this study. Infants were excluded if they were too unstable to participate in ophthalmologic examination (2), had inadequate image quality (20), or received prior ROP treatment (2). Multivariate models were created using demographic variables and imaging findings to identify early referral-warranted ROP (referral-warranted ROP and/or pre-plus disease) by routine indirect ophthalmoscopy. Results: A total of 167 imaging sessions of 71 infants (45% male infants, gestational age 28.2+/-2.8 weeks, and birth weight 995.6+/-292.0 grams) were included. Twelve of 71 infants (17%) developed early referral-warranted ROP. The area under the receiver operating characteristic curve (AUC) was 0.94 for the generalized linear mixed model (sensitivity = 95.5% and specificity = 80.7%) and 0.83 for the machine learning model (sensitivity = 91.7% and specificity = 77.8%). The strongest variables in both models were birth weight, image-based Vitreous Opacity Ratio (an estimate of opacity density), vessel elevation, and hyporeflective vessels. A model using only birth weight and gestational age yielded an AUC of 0.68 (sensitivity = 77.3% and specificity = 63.4%), and a model using only imaging biomarkers yielded 0.88 (sensitivity = 81.8% and specificity = 84.8%). Conclusions: A generalized linear mixed model containing handheld OCT biomarkers can identify early referral-warranted ROP. Machine learning produced a less optimal model. Translational Relevance: With further validation, this work may lead to a better-tolerated ROP screening tool.

Vitreous opacities in infants born full-term and preterm by handheld swept-source optical coherence tomography.

PURPOSE: To compare vitreous opacity density in infants born at term and in infants born prematurely using an investigational handheld swept-source optical coherence tomography (SS-OCT). METHODS: Infants born at term underwent imaging once between 12 and 48 hours after birth; infants born prematurely were imaged at each routine retinopathy of prematurity (ROP) examination. Three masked, trained graders analyzed images. Semiautomated methods were used to quantify vitreous opacity density, which was correlated with ROP severity based on indirect ophthalmoscopy, other SS-OCT findings, and medical comorbidities. RESULTS: Between April 2018 and June 2019, 251 SS-OCT imaging sessions were performed on 78 infants (49% female; 36% preterm, with mean birth weight of 1018 ± 338 g and gestational age of 28.6 ± 3.2 weeks). All SS-OCT sessions produced images of adequate quality. Punctate vitreous opacities were present in 25 of 28 term infants (89%) and 41 of 50 premature infants (82%). Dice coefficient and F1 scores for intergrader agreement were 0.99 ± 0.03 and 0.77 ± 0.31, respectively. Vitreous opacity density was 0.118 ± 0.187 in prematurely born infants and 0.031 ± 0.118 in infants born at term (P = 0.009). In the former, vitreous opacity density was associated with ROP zone (P = 0.044) and stage (P = 0.031), intraventricular hemorrhage (P = 0.028), subchorionic hemorrhage (P = 0.026), and African American race (P = 0.023). In the latter, vitreous opacity density was associated with maternal diabetes (P = 0.049). CONCLUSIONS: Our investigational handheld SS-OCT achieved high-quality vitreoretinal images. In our study cohort, punctate vitreous opacities were a frequent finding in infants born at term and those born prematurely, with increased density in those born prematurely, particularly those with severe ROP.

Recurrence and Mortality Risk of Merkel Cell Carcinoma by Cancer Stage and Time From Diagnosis.

IMPORTANCE: Merkel cell carcinoma (MCC) often behaves aggressively; however, disease-recurrence data are not captured in national databases, and it is unclear what proportion of patients with MCC experience a recurrence (estimates vary from 27%-77%). Stage-specific recurrence data that includes time from diagnosis would provide more precise prognostic information and contribute to risk-appropriate clinical surveillance. OBJECTIVE: To estimate risk of stage-specific MCC recurrence and mortality over time since diagnosis. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study included 618 patients with MCC who were prospectively enrolled in a Seattle-based data repository between 2003 and 2019. Of these patients, 223 experienced a recurrence of MCC. Data analysis was performed July 2019 to November 2021. MAIN OUTCOMES AND MEASURES: Stage-specific recurrence and survival, as well as cumulative incidence and Kaplan-Meier analyses. RESULTS: Among the 618 patients included in the analysis (median [range] age, 69 [11-98] years; 227 [37%] female), the 5-year recurrence rate for MCC was 40%. Risk of recurrence in the first year was high (11% for patients with pathologic stage I, 33% for pathologic stage IIA/IIB, 30% for pathologic stage IIIA, 45% for pathologic stage IIIB, and 58% for pathologic stage IV), with 95% of recurrences occurring within the first 3 years. Median follow-up among living patients was 4.3 years. Beyond stage, 4 factors were associated with increased recurrence risk in univariable analyses: immunosuppression (hazard ratio [HR], 2.4; 95% CI, 1.7-3.3; P < .001), male sex (HR, 1.9; 95% CI, 1.4-2.5; P < .001), known primary lesion among patients with clinically detectable nodal disease (HR, 2.3; 95% CI, 1.4-4.0; P = .001), and older age (HR, 1.1; 95% CI, 1.0-1.3; P = .06 for each 10-year increase). Among 187 deaths in the cohort, 121 (65%) were due to MCC. The MCC-specific survival rate was strongly stage dependent (95% at 5 years for patients with pathologic stage I vs 41% for pathologic stage IV). Among patients presenting with stage I to II MCC, a local recurrence (17 arising within/adjacent to the primary tumor scar) did not appreciably diminish survival compared with patients who had no recurrence (85% vs 88% MCC-specific survival at 5 years). CONCLUSIONS AND RELEVANCE: In this cohort study, the MCC recurrence rate (approximately 40%) was notably different than that reported for invasive melanoma (approximately 19%), squamous cell carcinoma (approximately 5%-9%), or basal cell carcinoma (approximately 1%-2%) following definitive therapy. Because more than 90% of MCC recurrences arise within 3 years, it is appropriate to adjust surveillance intensity accordingly. Stage- and time-specific recurrence data can assist in appropriately focusing surveillance resources on patients and time intervals in which recurrence risk is highest.

Dome-shaped macula in premature infants visualized by handheld spectral-domain optical coherence tomography.

PURPOSE: To describe dome-shaped macula and associated clinical findings in premature infants. METHODS: This prospective, observational cohort study included a consecutive sample of premature infants screened for retinopathy of prematurity (ROP) with 9-month follow-up. Handheld spectral domain optical coherence tomography (SD-OCT) was performed at the time of ROP screening. Images were assessed for dome-shaped macula, cystoid macular edema, epiretinal membrane, vitreous bands, and punctate hyperreflective vitreous opacities. Dome height measurements were performed in a subset of images. Teller visual acuity and cycloplegic refraction were performed at an adjusted age of 8-10 months. RESULTS: Of 37 infants (74 eyes; 49% male; mean gestational age 27.8 ± 3.2 weeks; mean birth weight 949 ± 284 g), 24/37 (65%) demonstrated dome-shaped macula in at least one eye (13 both eyes, 5 right eye only, and 6 left eye only). Of the 74 eyes, 26 (35%) could be reliably measured, with a mean dome height of 139.0 ± 72.3 µm (range, 54-369 µm). Presence of dome-shaped macula was associated with a diagnosis of ROP (P = 0.02; OR, 3.03; 95% CI, 1.18-7.82) and pre-plus or plus disease (P = 0.02; OR, 4.20; 95% CI, 1.05-16.78). Infants with dome-shaped macula had lower birth weight compared with those without (877 vs 1081 g; P = 0.04). No associations with other demographics, OCT findings, and 9-month refractive outcomes were found. CONCLUSIONS: Dome-shaped macula was frequently identified by handheld SD-OCT in premature infants, especially those with lower birth weight and severe ROP. The long-term clinical significance of this finding is unknown.

Handheld swept-source optical coherence tomography with angiography in awake premature neonates.

BACKGROUND: Retinopathy of prematurity (ROP) can lead to retinal detachment and severe vision loss and is a common cause of childhood blindness. Optical coherence tomography angiography (OCTA) is a non-invasive imaging modality that can be used to detect potential abnormalities in the microvasculature in this population. The objective of this study is to assess the feasibility of a newly developed handheld swept source OCT (SS-OCT) device to successfully acquire structural vitreoretinal and retinal microvascular images in awake premature infants. METHODS: OCT and OCTA images were acquired at the time of routine ROP examinations from awake, unsedated preterm infants in the Neonatal Intensive Care Unit using a clinical research prototype handheld probe integrated with an SS-OCT system working at 1,060 nm wavelength and an imaging speed of 200,000 A-scans per second (200 kHz), enabling volume OCT and OCTA scans. Each volume was acquired with approximately 36˚ field of view (~6.3×6.3 mm in infants) in 4.8 s. Quality of acquired OCT and OCTA volume images, microvascular information, and vitreoretinal features were determined by 3-masked grader consensus. RESULTS: Twelve infants (5 females, mean gestational age 28.3 weeks, median birth weight 901 g, stages 0 to 3 ROP) underwent a total of 73 individual eye imaging sessions. High-quality OCT images of the fovea and the optic nerve were present in 69/73 (94.5%) and 56/73 (76.7%) scans, respectively. Vitreous bands were observed in 10/73 (13.7%); punctate hyperreflective vitreous opacities in 47/73 (64.4%); epiretinal membrane (ERM) in 6/73 (8.2%); and cystoid macular edema (CME) in 12/73 (16.4%) scans. Mild vessel elevation was noted in 3/73 (4.1%) images, and severe vessel elevation in 4/73 (5.5%) scans. OCTA images obtained in 8 awake infants revealed good quality images of the foveal microvasculature in 11/19 (58%) eye imaging sessions for 6/8 (75%) infants; and peripapillary microvasculature in 14/19 (74%) eye imaging sessions for 5/8 (63%) infants. CONCLUSIONS: The SS-OCTA handheld device can capture important vitreoretinal characteristics such as peripapillary and foveal microvasculature, as well as hyperreflective punctate vitreous opacities and tractional vitreous bands, which may predict ROP severity. These images were captured in awake, premature infants without the use of direct ocular contact, an eyelid speculum, or sedation.