Long-term outcomes of margin-controlled excision for eyelid melanoma.

OBJECTIVES: To provide evidence for long-term outcomes for margin-controlled excision of eyelid melanoma. METHODS: Retrospective single-centre observational case series of patients treated for eyelid melanoma between 2007 and 2016, with a minimum of 5-year follow-up. Tumour excision involved rush-paraffin en face horizontal sections and delayed repair (Slow Mohs; SM). RESULTS: Twenty-two cases were seen with a survival of 91% (two deaths from nodular and lentigo maligna melanoma) and seven with melanoma in situ (MIS). Invasive melanoma includes eight lentigo maligna melanoma, four nodular, two amelanotic and one desmoplastic. Mean Breslow thickness was 6 mm for invasive (range 0.5-26). Mean excision margin for MIS was 3 mm (range 2-5 mm) and for invasive was 5 mm (range 2-10). Further excisions were performed in nine (41%); two went on to recur. Local recurrence was 36%; six invasive (27%) at a mean of 24 months (range 1.5-5 years) and two for MIS at a mean of 15 months (range 1-1.5 years). Imaging occurred for suspected advanced disease. Sentinel node biopsy was not performed. Advanced melanoma therapy was performed in two cases. No vitamin D testing occurred. CONCLUSIONS: Survival rates are in line with 90% overall survival in the UK. Prescriptive excision margins are not applicable in the periocular region and margin-controlled excision with a delayed repair is recommended, but patients need to know further excision may be needed to obtain clearance. Evidence recommending vitamin D therapy needs to be put into clinical practice. In addition, upstaging of MIS occurred advocating excision rather than observation of MIS. More studies are needed to determine the best management of eyelid melanoma.

Differential expression of phosphorylated MEK and ERK correlates with aggressive BCC subtypes.

Basal cell carcinoma (BCC) is associated with aberrant Hedgehog (HH) signalling through mutational inactivation of PTCH1; however, there is conflicting data regarding MEK/ERK signalling in BCC and the signalling pathway interactions in these carcinomas. To address this, expression of active phospho (p) MEK and ERK was examined in a panel of 15 non-aggressive and 14 aggressive BCCs. Although not uniformly expressed, both phospho-proteins were detected in the nuclei and/or cytoplasm of normal and tumour-associated epidermal cells however, whereas phospho-MEK (pMEK) was present in all non-aggressive BCCs (14/14), phospho-ERK (pERK) was rarely expressed (2/14). In contrast pERK expression was more prevalent in aggressive tumours (11/14). Interestingly, pMEK was only localized to the tumour mass whereas pERK was expressed in tumours and stroma of aggressive BCCs. Similarly, pERK (but not pMEK) was absent in mouse BCC-like tumours derived from X-ray irradiated Ptch1+/- mice with stromal pERK observed in myofibroblasts of the aggressive variant as well as in the tumour mass. RNA sequencing analysis of tumour epithelium and stroma of aggressive and non-aggressive BCC revealed the upregulation of epidermal growth factor receptor- and ERK-related pathways. Angiogenesis and immune response pathways were also upregulated in the stroma compared with the tumour. PTCH1 suppressed NEB1 immortalized keratinocytes (shPTCH1) display upregulated pERK that can be independent of MEK expression. Furthermore, epidermal growth factor pathway inhibitors affect the HH pathway by suppressing GLI1. These studies reveal differential expression of pERK between human BCC subtypes that maybe active by a pathway independent of MEK.

The Genetic and Clinical Features of FOXL2-Related Blepharophimosis, Ptosis and Epicanthus Inversus Syndrome.

Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a craniofacial disorder caused by heterozygous variants of the forkhead box L2 (FOXL2) gene. It shows autosomal dominant inheritance but can also occur sporadically. Depending on the mutation, two phenotypic subtypes have been described, both involving the same craniofacial features: type I, which is associated with premature ovarian failure (POF), and type II, which has no systemic features. The genotype-phenotype correlation is not fully understood, but it has been hypothesised that type I BPES involves more severe loss of function variants spanning the whole gene. Type II BPES has been linked to frameshift mutations that result in elongation of the protein rather than complete loss of function. A mutational hotspot has been identified within the poly-alanine domain, although the exact function of this region is still unknown. However, the BPES subtype cannot be determined genetically, necessitating informed genetic counselling and careful discussion of family planning advice in view of the associated POF particularly as the patient may still be a child. Following puberty, female patients should be referred for ovarian reserve and response assessment. Oculofacial features can be managed with surgical intervention and regular monitoring to prevent amblyopia.

Diplopia Following the Insertion of a Canalicular Bypass Tube: Etiology, Risk Factors, Management, and Outcomes.

PURPOSE: To report the etiology, management, and possible risk factors for diplopia after canalicular bypass surgery. METHODS: A multicenter retrospective, noncomparative case series of patients who developed diplopia following canalicular bypass surgery were assessed. RESULTS: Twenty-four cases of diplopia were identified across 12 institutions. Tubes were inserted as a primary procedure with external dacryocystorhinostomy (DCR) (1; 4%) or without DCR (10; 42%) or as a secondary procedure after external (8; 33%) or endonasal (5; 21%) DCR. Factors predisposing to local damage were noted in 17 (71%): these factors included preexisting autoimmune/inflammatory condition (7 cases), medial canthal tumor resection (5 cases), preoperative radiotherapy (2 cases), 2 drug treatments (topical and systemic), and 1 local surgery. Horizontal diplopia was due to restriction of abduction and first noted at a median of 3.5 months (mean: 17.8 months, range: 1 day to 112 months) and persisted in 23 (96%) cases with a mean restriction of -2, affecting primary gaze in 4 patients and activities of daily living in 13 (42%). Seventeen patients received various treatments: 10 were operated on resulting in cure in 1 and improvement in 9. A stable degree of diplopia persisted in all but one patient. CONCLUSIONS: Restriction of abduction causing horizontal diplopia is a rare complication with canalicular bypass surgery and a notably high proportion occurred after tube placement without DCR; carunculectomy was not ubiquitous. Although in some the diplopia may be improved with intervention, the chance of cure is low. This complication should probably be included during informed consent for canalicular bypass tubes.

Switchover study of onabotulinumtoxinA to incobotulinumtoxinA for facial dystonia.

IMPORTANCE: When making a cost-saving it is important to ensure there is no loss of efficacy. BACKGROUND: Clinical effectiveness and efficiency of incobotulinumtoxinA compared to onabotulinumtoxinA in facial dystonia is unclear. Our aim is to evaluate switching from onabotulinumtoxinA to incobotulinumtoxinA in the treatment of essential blepharospasm (EB), hemifacial spasm (HFS) and aberrant facial nerve regeneration (AFR). DESIGN: A retrospective study of a prospective, single-masked switchover audit from onabotulinumtoxinA to incobotulinumtoxinA. PARTICIPANTS: Twenty essential EB, 12 HFS and six AFR patients. METHODS: A switchover from stable onabotulinumtoxinA to incobotulinumtoxinA using a 1:1 unit ratio and contemporaneous efficacy measures. Two nurse injectors performed the injections over a period of 6 years. Each masked patient received three onabotulinumtoxinA and three incobotulinumtoxinA over a minimum of 2 years. MAIN OUTCOME METHODS: At each visit, a blepharospasm disability score (BDS), Jankovic score (JS), subjective improvement (SI), duration of maximum effect (DME) and complications were recorded. A cost comparison per unit dose was made. RESULTS: Twenty EB, 12 HFS and six AFR received 114 onabotulinumtoxinA and 114 incobotulinumtoxinA treatments. Both brands had similar efficacy, but SI (P < .01) and DME (P < .05) were higher in the HFS group with incobotulinumtoxinA. Complications included bruising (two onabotulinumtoxinA, one incobotulinumtoxinA) and ptosis (three onabotulinumtoxinA, zero incobotulinumtoxinA). OnabotulinumtoxinA was 33% pricier. CONCLUSION AND RELEVANCE: Switching from onabotulinumtoxinA to incobotulinumtoxinA did not result in an inferior outcome for the treatment of facial dystonia and led to a cost-saving for the department.

Reporting outcomes of hyaluronic gel filler as a treatment for epiblepharon.

PURPOSE: Epiblepharon occurs when an extra skin fold overlaps on the eyelid margin with the isolated form mainly seen in children of east Asian origin. If symptomatic and the use of conservative measures such as lubricants have failed, surgery is usually indicated. This traditionally involves everting sutures or combined skin excision, such as a modified Hotz procedure. However, a temporizing non-surgical alternative to a skin removal procedure, especially if the natural history is for improvement as the child grows older, would be ideal. METHODS: This is a retrospective single-centre case review of epiblepharon cases treated with hyaluronic acid (HA; Restylane, Galderma UK) treated in the past 5 years by a single surgeon (RM). Institutional review board approval was obtained. Success is defined as improvement or stabilization of the class and/or keratopathy score of the epiblepharon. RESULTS: Five patients were identified with epiblepharon between 2012 and 2017 who had hyaluronic acid filler to 8 eyelids. Six eyelids had improvement, 1 remained stable and 1 was worse equating to an 87% success rate; however, 2 opted for reversal using hyaluronidase due to aesthetic reasons. Two went on to have further surgery as they partially responded to filler treatment. CONCLUSION: This study provides further proof of concept that HA is a simple non-surgical and reversible option that may avoid the need for surgery for epiblepharon in selected cases. It may even be considered in older children or adolescents with the caveat that fullness may require hyaluronidase to dissolve.

Dry eye after Lester Jones tube insertion for epiphora.

Purpose: To report the occurrence of dry eye after Lester Jones tube (LJT) insertion. Methods: Retrospective case series from a single unit. The dacrocystorhinostomy (DCR) was carried out using both endoscopic and external approachs; however, insertion of LJT used the same method as either a primary or secondary procedure. Dry eye as an outcome measure was only confirmed after three separate visits using the presence of both patient symptoms and dry eye signs with none preceding tube insertion. Results: Fifty-four patients underwent consecutive LJT insertion over a 5-year period. Mean age was 52.6 (range 25-73 years). The majority were female 39 (72%). Revision surgery was required in 15 (27%) with 3 or more occurring in 6 (11%). In total, 9 patients developed dry eyes (17%). Mean age was 60 (range 47-73) years, 5 females and 4 males. Four of the dry eye individuals had undergone primary LJT insertion and the remaining five received their first LJT 6-24 (mean 15) months post-DCR. Two dry eye patients had previously undergone LASIK and radiotherapy. Conclusion: A risk of dry eye following LJT placement is higher than the literature suggests. This should be considered and counseled, especially in those who have underlying pre-disposing factors. Ease of removal may be a desirable attribute in such cases.

Long-term outcome of flexible onabotulinum toxin A treatment in facial dystonia.

PURPOSE: The purpose of this study was to assess the long-term outcome of onabotulinum used to treat facial dystonia and compare a flexible and fixed treatment regimen. METHODS: This was a retrospective comparative study looking at benign essential blepharospasm (BEB), hemifacial spasm (HFS) and aberrant facial nerve regeneration synkinesis (AFR) treatment with onabotulinum toxin A (Botox®) over a minimum of 10 years. Fifty-one patients were recruited into the study, with each dystonia subgroup having 17 patients. Blepharospasm disability score (BDS), subjective improvement score (SIS), duration of maximal effect (DME) and complications were recorded at each visit. RESULTS: The mean age was 63 years and gender predominately female. Thirty-seven patients underwent flexible treatment intervals compared to 14 fixed treatment intervals, averaging 3.4 and 4 per annum, respectively. Mean BDS significantly improved from 6 to 3 at last review across all 3 groups, with the highest effect on BEB. BDS improvement was greater in flexible intervals. SIS remained similar for all three conditions during follow-up, but in those undergoing flexible intervals, SIS increased by a small margin compared to fixed interval. Mean DME was 10.5 weeks across all dystonias, but increased progressively only in the flexible interval group. Complications included ptosis (30%), dry eye (14%) and lagophthalmos (8%). CONCLUSION: Flexible onabotulinum provided better long-term relief on BDS for facial dystonia than a fixed regimen. Flexible interval treatment may also provide better patient satisfaction and longer DME compared to fixed treatment. Both have similar complication rates. With flexible treatment however, fewer injections were required over 10 years, leading to cost saving.

MicroRNA and transcriptome analysis in periocular Sebaceous Gland Carcinoma.

Sebaceous gland carcinoma (SGC) is a rare, but life-threatening condition with a predilection for the periocular region. Eyelid SGC can be broadly categorised into two subtypes, namely either nodular or pagetoid with the latter being more aggressive and requiring radical excision to save life. We have identified key altered microRNAs (miRNA) involved in SGC shared by both subtypes, hsa-miR-34a-5p and hsa-miR-16-5p. However, their gene targets BCL2 and MYC were differentially expressed with both overexpressed in pagetoid but unchanged in nodular suggesting different modes of action of these two miRNAs on BCL/MYC expression. Hsa-miR-150p is nodular-specifically overexpressed, and its target ZEB1 was significantly downregulated in nodular SGC suggesting a tumour suppressor role. Invasive pagetoid subtype demonstrated specific overexpression of hsa-miR-205 and downregulation of hsa-miR-199a. Correspondingly, miRNA gene targets, EZH2 (by hsa-miR-205) and CD44 (by hsa-miR-199a), were both overexpressed in pagetoid SGC. CD44 has been identified as a potential cancer stem cell marker in head and neck squamous cell carcinoma and its overexpression in pagetoid cells represents a novel treatment target. Aberrant miRNAs and their gene targets have been identified in both SGC subtypes, paving the way for better molecular understanding of these tumours and identifying new treatment targets.

Analysis of hedgehog signaling in periocular sebaceous carcinoma.

PURPOSE: Sebaceous carcinoma (SC) is a clinical masquerader of benign conditions resulting in significant eye morbidity, sometimes leading to extensive surgical treatment including exenteration, and even mortality. Little is known about the genetic or molecular basis of SC. This study identifies the involvement of Hedgehog (Hh) signaling in periocular SC. METHODS: Fifteen patients with periocular SC patients were compared to 15 patients with eyelid nodular basal cell carcinoma (nBCC; a known Hh tumor), alongside four normal individuals as a control for physiological Hh expression. Expression of Patched 1 (PTCH1), Smoothened (SMO), and glioma-associated zinc transcription factors (Gli1 and Gli2) were assessed in histological sections using immunohistochemistry and immunofluorescence (IF) techniques. Antibody specificity was verified using Western-blot analysis of a Gli1 over-expressed cancer cell line, LNCaP-Gli1. Semi-quantification compared tumors and control tissue using IF analysis by ImageJ software. RESULTS: Expression of the Hh pathway was observed in SC for all four major components of the pathway. PTCH1, SMO, and Gli2 were more significantly upregulated in SC (P < 0.01) compared to nBCC. Stromal expression of PTCH1 and Gli2 was observed in SC (P < 0.01). In contrast, stromal expression of these proteins in nBCC was similar or down-regulated compared to physiological Hh controls. CONCLUSIONS: The Hh signaling pathway is significantly more upregulated in periocular SC compared to nBCC, a known aberrant Hh pathway tumor. Furthermore, the stroma of the SC demonstrated Hh upregulation, in particular Gli2, compared to nBCC. Targeting of this pathway may be a potential treatment strategy for SC.