Vivian T. Yin

Antibiotic Resistance of Ocular Surface Flora With Repeated Use of a Topical Antibiotic After Intravitreal Injection

IMPORTANCE Treatment with intravitreal (IVT) injections has increased during the last several years as evidence has accumulated demonstrating the efficacy of anti-vascular endothelial growth factor agents in the treatment of neovascular age-related macular degeneration (AMD) and various retinal vascular diseases. Although IVT injections are generally safe, infectious endophthalmitis is a rare but devastating complication, and the risk of morbidity and vision loss from endophthalmitis is high. OBJECTIVE To examine the change in antibiotic resistance of ocular surface flora with repeated prophylactic use of antibiotics after IVT injection for AMD. DESIGN AND SETTING Prospective, nonrandomized cohort study in 2 tertiary academic hospitals. PARTICIPANTS Patients 65 years and older with newly diagnosed AMD were recruited by 7 retinal specialists from July 1, 2010, through December 31, 2011. INTERVENTION The study group received topical moxifloxacin hydrochloride for 3 days after each monthly IVT injection. MAIN OUTCOME MEASURE Resistance to moxifloxacin and ceftazidime in cultured isolates at baseline and monthly for 3 months by change in minimal inhibitory concentration (MIC) of culture isolates was studied. RESULTS The study group consisted of 84 patients, and the control group had 94 patients. In the study group, the baseline adjusted MIC increased (from 1.04 to 1.25 μg/mL; P = .01) as did the MIC for 50% of isolates (MIC50) (from 0.64 to 1.00 μg/mL) and the MIC for 90% of isolates (MIC90) (from 0.94 to 4.00 μg/mL). In both groups, the culture-positive rate did not change significantly when adjusted for baseline. No significant change was found in the MIC level, culture-positive rate, MIC50 level, and MIC90 level in the control group. Subgroup analysis found diabetes mellitus to be noncontributory to both the MIC and culture-positive rate. No endophthalmitis or adverse events were reported. CONCLUSIONS AND RELEVANCE Repeated use of topical moxifloxacin after IVT injection significantly increases antibiotic resistance of ocular surface flora. We recommend that routine use of prophylactic antibiotics after IVT injection be discouraged. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01181713.

Targeted therapy for orbital and periocular basal cell carcinoma and squamous cell carcinoma.

Purpose: To review the literature on targeted therapy for orbital and periocular basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (SCC) and provide examples of patients recently treated with such therapy. Methods: The authors reviewed the literature on clinical results of targeted therapy and the molecular basis for targeted therapy in orbital and periocular BCC and cutaneous SCC. The authors also present representative cases from their practice. Results: Mutation in the patched 1 gene (PTCH1) has been implicated in BCC, and overexpression of epidermal growth factor receptor (EGFR) has been shown in SCC. Vismodegib, an inhibitor of smoothened, which is activated upon binding of hedgehog to Ptc, has been shown to significantly decrease BCC tumor size or even produce complete resolution, especially in cases of basal cell nevus syndrome. Similarly, EGFR inhibitors have been shown to significantly decrease SCC tumor size in cases of locally advanced and metastatic disease. The authors describe successful outcomes after vismodegib treatment in a patient with basal cell nevus syndrome with numerous bulky lesions of the eyelid and periocular region and erlotinib (EGFR inhibitor) treatment in a patient with SCC who was deemed not to be a good surgical candidate because of advanced SCC of the orbit with metastasis to the regional lymph nodes, advanced age, and multiple medical comorbidities. Conclusions: Targeted therapy using hedgehog pathway and EGFR inhibitors shows significant promise in treatment of orbital and periocular BCC and cutaneous SCC, respectively. Such targeted therapy may be appropriate for patients who are not good candidates for surgery.

Eyelid and ocular surface carcinoma: Diagnosis and management

Eyelid cancers account for 5% to 10% of all cutaneous malignancies. The incidence of eyelid cancer is approximately 15 cases per 100,000 individuals per year. Basal cell carcinoma is by far the most common cutaneous malignancy in the periocular area; other cutaneous malignancies that occur in this area include, in decreasing order of frequency, squamous cell carcinoma, sebaceous carcinoma, melanoma, and Merkel cell carcinoma. The most common treatment for eyelid carcinomas is surgical resection with frozen section examination for margin control, but exenteration may be needed when there is orbital invasion. Adjuvant radiotherapy may be needed in patients at high risk for local recurrence; sentinel lymph node biopsy may be considered in patients at high risk for lymph node metastasis. Primary or residual in situ disease of the conjunctiva can be treated with topical chemotherapy, such as mitomycin C, 5-fluorouracil, or interferon alpha-2 b. For patients with metastatic or locally advanced basal cell or squamous cell carcinoma not amenable to surgical excision or radiotherapy, targeted therapy against the hedgehog pathway (for basal cell carcinoma) or epidermal growth factor receptor (for squamous cell carcinoma) has been shown to be effective in preventing disease progression. Patients with eyelid and ocular surface malignancies need to be monitored with careful clinical examination for at least 5years after surgical treatment, and additional investigations may be warranted in some cases.

Ocular adnexal lymphoma: validation of American Joint Committee on Cancer seventh edition staging guidelines

Background/aims To validate the prognostic significance of the American Joint Committee on Cancer (AJCC) seventh edition staging criteria for ocular adnexal lymphoma (OAL) of all histologic subtypes. Methods Retrospective review of clinical records for all consecutive patients with OAL treated from November 1998 to December 2012. Results 130 patients were evaluated, 82 with primary and 34 with secondary OAL. Fourteen patients were excluded due to incomplete records. 71 women (61.2%) and 45 men (38.8%) had a median age of 61.5 years. Patients were followed for a median of 32.5 months. Treatment varied, in part, related to lymphoma histologic subtype. Overall, there were 17 recurrences (8 local and 9 distant) in patients with primary OAL. For primary OAL, the 5-year disease-free survival (DFS) and overall survival (OS) rates were 55.9% and 85.8%, respectively. For primary OAL, while there was a trend towards decreased 5-year DFS for more aggressive subtypes, this was not statistically significant. More advanced Ann Arbor stage was associated with decreased 5-year DFS; however, this trend was not statistically significant. However, increased AJCC seventh edition T category was associated with decreased 5-year DFS (T1=67.8%, T2=59.2%, T3=28.6%, T4=33.3%; p=0.025). Conclusion AJCC seventh edition T category was predictive of DFS in patients with OAL.

Hedgehog Pathway Inhibition for Locally Advanced Periocular Basal Cell Carcinoma and Basal Cell Nevus Syndrome.

PURPOSE To review our experience treating patients with the Hedgehog pathway inhibitor, vismodegib, in patients with orbital or periocular locally advanced or metastatic basal cell carcinoma (BCC) or basal cell nevus syndrome. DESIGN Retrospective interventional case series. METHODS We reviewed all patients with locally advanced or metastatic orbital or periocular BCC or basal cell nevus syndrome treated with the Hedgehog pathway inhibitor, vismodegib, at a comprehensive cancer center from 2009 through 2015. Reviewed data included age; sex; American Joint Commission on Cancer tumor, node, metastasis staging system designation; type and grade of drug-related side effects; response to treatment; duration of follow-up, and status at last follow-up. RESULTS The study included 10 white men and 2 white women; the median age was 64.5 years. Ten patients had locally advanced BCC; 2 had basal cell nevus syndrome. Among the patients with locally advanced BCC, 5 had T3bN0M0 disease at presentation; 1 each had T3aN0M0, T3bN1M0, T2N1M1, T4N1M1, and T4N2cM1 disease. Overall, 3 patients had a complete response, 6 had a partial response, and 3 had stable disease at last follow-up. Two patients developed progressive disease after a complete response for 38 months and stable disease for 16 months, respectively. All patients developed grade I drug-related adverse effects, most commonly muscle spasms (12 patients), weight loss (10), dysgeusia (9), alopecia (9), decreased appetite (5), and fatigue (4). Five patients developed grade II adverse effects. At last follow-up, none of the 5 patients presenting with T3bN0M0, nor the patient with T3bN1M0 disease, had required orbital exenteration. CONCLUSION Hedgehog pathway inhibition produces a significant clinical response in most patients with locally advanced or metastatic orbital or periocular BCC or basal cell nevus syndrome and can obviate orbital exenteration in some patients. Drug-related adverse effects are manageable in most patients.

Impact of AJCC ‘T’ designation on risk of regional lymph node metastasis in patients with squamous carcinoma of the eyelid

Background/aims Squamous cell carcinoma (SCC) of eyelid is the second most common cancer of the eyelid with the potential for nodal metastasis. The purpose of this report is to determine whether primary tumour size and ‘T’ designation in the American Joint Committee on Cancer (AJCC) staging system, 7th edition, correlate with the risk of regional nodal metastasis in patients with eyelid SCC. Methods Sixty-five consecutive patients with eyelid SCC treated by one ophthalmologist from March 1999 through July 2011 were included in this retrospective cohort study. Disease was staged using the AJCC 7th edition criteria based on clinical, pathological and radiographical data. Main outcome measures included regional lymph node metastasis at presentation, local recurrence, distant metastasis and survival at last follow-up. Results 40 men and 25 women had a median age of 67.0 years (range 41–89). TNM designations at presentation per the AJCC 7th edition were as follows: T1N0M0, 6 patients; T2aN0M0, 11 patients; T2bN0M0, 17 patients; T2bN1M0, 2 patients; T3aN0M0, 22 patients; T3bN0M0, 2 patients; T3bN1M0, 1 patient; T4N0M0, 3 patients; and T4N1M0, 1 patient. Median follow-up was 27 months (range 1–150). Four patients had nodal metastasis at presentation. Two of these four patients had T2bN1M0 disease, one had T3bN1M0 disease and one had T4N1M0 disease. Two patients, with T3aN0M0 and T4N0M0 tumours, respectively, at presentation, developed lymph node metastasis at 2 weeks and 8.4 months, respectively, after tumour excision. The four patients who had lymph node metastases at presentation and the two who developed lymph node metastases during follow-up had tumours ≥18 mm in greatest dimension or T2b or higher at presentation. Seven local recurrences were observed during follow-up. Two-year and 3-year recurrence-free survival rates were 93% (95% CI 80% to 98%) and 82% (95% CI 63% to 92%), respectively. No distant metastasis or tumour-related death was observed during follow-up. The 2-year and 3-year disease-free survival rates were 90% (95% CI 77% to 96%) and 79% (95% CI 61% to 89%), respectively. Conclusions Regional nodal metastases were observed among patients who presented with tumours >T2b. Tumour size and the AJCC TNM designations correlate with metastasis and should be reported more often for eyelid SCCs to allow comparisons across centres.

Eye-sparing multidisciplinary approach for the management of lacrimal gland carcinoma.

We analyzed local control and early ocular toxicity after eye‐sparing management of lacrimal gland carcinoma.

Distinct Pathways in the Pathogenesis of Sebaceous Carcinomas Implicated by Differentially Expressed MicroRNAs

IMPORTANCE The molecular-genetic alterations contributing to the pathogenesis of sebaceous carcinoma and sebaceous adenoma remain poorly understood. Given that sebaceous carcinoma is associated with substantial morbidity and mortality, there is a critical need to delineate the pathways driving sebaceous carcinoma and candidate molecules for targeted therapy. OBJECTIVE To describe differentially expressed microRNAs (miRNAs) in a series of periocular sebaceous carcinomas compared with sebaceous adenomas in order to identify pathways driving the pathogenesis of sebaceous carcinoma. DESIGN, SETTING, AND PARTICIPANTS Thirty sebaceous carcinomas and 23 sebaceous adenomas (including 11 that were confirmed to be related to Muir-Torre syndrome and 6 that were confirmed to be sporadic) were obtained from archives (from 48 patients) of 2 institutions (University of Texas MD Anderson Cancer Center, Houston, and Siriraj Hospital, Mahidol University, Bangkok, Thailand) and profiled. MAIN OUTCOMES AND MEASURES Expression of miRNAs was determined using total RNA from formalin-fixed, paraffin-embedded tissue and real-time reverse transcription-polymerase chain reaction performed in a microfluidics card containing 378 unique miRNAs. Fold change was determined using the ΔΔCt method (reference probe, RNU48). Median centering was used to normalize the data. Two-sample t tests were used to identify differentially expressed miRNAs. The false discovery rate was assessed by β-uniform mixture analysis of P values from the t statistics. Significance was defined by this estimated false discovery rate. RESULTS Serial testing and validation confirmed overexpression of 2 miRNAs previously reported to be oncogenic, miR-486-5p (4.4-fold; P = 2.4 × 10-8) and miR-184 (3.5-fold; P = 1.7 × 10-6), in sebaceous carcinoma compared with sebaceous adenoma and downregulation of 2 miRNAs previously reported to have tumor-suppressive properties, miR-211 (-5.8-fold; P = 2.3 × 10-9) and miR-518d (-4.5-fold; 6.7 × 10-5), in sebaceous carcinoma compared with sebaceous adenoma. CONCLUSIONS AND RELEVANCE Sebaceous carcinoma exhibits an miRNA expression profile distinct from that of sebaceous adenoma, implicating dysregulation of NF-κB and PTEN (targets of miR-486-5p) and TGF-β signaling (target of miR-211) in the pathogenesis of sebaceous carcinoma. The identification of miRNAs whose expression is altered in sebaceous carcinoma compared with sebaceous adenoma provides a novel entry point for a more comprehensive understanding of the molecular-genetic alterations pivotal to the development of sebaceous carcinoma.

Number of excisions required to obtain clear surgical margins and prognostic value of AJCC T category for patients with eyelid melanoma.

Aims To determine the number of excisions needed to achieve clear margins and the prognostic value of the 7th edition of American Joint Committee on Cancer (AJCC) classification for eyelid melanoma. Methods Retrospective chart review of consecutive patients treated for eyelid melanoma from January 2006 through May 2013 by the senior author at a tertiary care cancer centre. Results Of the 64 patients (25 men and 39 women), clear surgical margins were achieved with a single excision in 38 patients (62%), 2 excisions in 21 patients (34%), and 3 excisions in 2 patients (3%). Need for repeat excision was not correlated with the size of the surgical margin (p=0.14) or AJCC TNM classification (p=0.15). Nodal disease at presentation was significantly associated with T category greater than T2b (p=0.0026) and shorter time to disease progression (p=0.007). Patients followed for a minimum of 1 year with T category greater than T2b had a significantly higher risk of nodal or distant metastasis (p=0.0061). Conclusions More than a third of patients with eyelid melanoma required more than 1 excision to achieve clear margins, supporting delayed reconstruction for eyelid melanoma. Nodal metastasis at presentation was significantly correlated with AJCC T category and time to progression.

Regional Nodal Recurrence of Sebaceous Carcinoma of the Caruncle 11 Years After Primary Tumor Resection

action against CPXV, facilitating viral persistence and the graft failure. It is unclear whether the underlying diabetic condition had any effect on disease progression. No specific antiviral therapy exists for CPXV infection, but the application of cidofovir probably inhibited viral replication. Nevertheless, therapeutic options are limited, underscoring the potential risk of CPXV infection to humans.