Correction to: NSABP FB-7: a phase II randomized neoadjuvant trial with paclitaxel + trastuzumab and/or neratinib followed by chemotherapy and postoperative trastuzumab in HER2+ breast cancer.

After the publication of this work [1] the authors have reported that in Table 3 The letter "T" in columns 5 and 7 should not be there.

NSABP FB-7: a phase II randomized neoadjuvant trial with paclitaxel + trastuzumab and/or neratinib followed by chemotherapy and postoperative trastuzumab in HER2+ breast cancer.

PURPOSE: The primary aim of NSABP FB-7 was to determine the pathologic complete response (pCR) rate in locally advanced HER2-positive (HER2+) breast cancer patients treated with neoadjuvant trastuzumab or neratinib or the combination and weekly paclitaxel followed by standard doxorubicin plus cyclophosphamide. The secondary aims include biomarker analyses. EXPERIMENTAL DESIGN: pCR was tested for association with treatment, gene expression, and a single nucleotide polymorphism (SNP) in the Fc fragment of the IgG receptor IIIa-158V/F (FCGR3A). Pre-treatment biopsies and residual tumors were also compared to identify molecular changes. RESULTS: The numerical pCR rate in the trastuzumab plus neratinib arm (50% [95%CI 34-66%]) was greater than that for single-targeted therapies with trastuzumab (38% [95%CI 24-54]) or neratinib (33% [95%CI 20-50]) in the overall cohort but was not statistically significant. Hormone receptor-negative (HR-) tumors had a higher pCR rate than HR+ tumors in all three treatment arms, with the highest pCR rate in the combination arm. Diarrhea was the most frequent adverse event and occurred in virtually all patients who received neratinib-based therapy. Grade 3 diarrhea was reported in 31% of patients; there were no grade 4 events. Our 8-gene signature, previously validated for trastuzumab benefit in two different clinical trials in the adjuvant setting, was correlated with pCR across all arms of NSABP FB-7. Specifically, patients predicted to receive no trastuzumab benefit had a significantly lower pCR rate than did patients predicted to receive the most benefit (P = 0.03). FCGR genotyping showed that patients who were homozygous for the Fc low-binding phenylalanine (F) allele for FCGR3A-158V/F were less likely to achieve pCR. CONCLUSIONS: Combining trastuzumab plus neratinib with paclitaxel increased the absolute pCR rate in the overall cohort and in HR- patients. The 8-gene signature, which is validated for predicting trastuzumab benefit in the adjuvant setting, was associated with pCR in the neoadjuvant setting, but remains to be validated as a predictive marker in a larger neoadjuvant clinical trial. HR status, and the FCGR3A-158V/F genotype, also warrant further investigation to identify HER2+ patients who may benefit from additional anti-HER2 therapies beyond trastuzumab. All of these markers will require further validation in the neoadjuvant setting. TRIALS REGISTRATION: ClinicalTrials.gov, NCT01008150. Retrospectively registered on October 5, 2010.

First-Line Nivolumab Plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer (CheckMate 568): Outcomes by Programmed Death Ligand 1 and Tumor Mutational Burden as Biomarkers.

PURPOSE: CheckMate 568 is an open-label phase II trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment of advanced/metastatic non-small-cell lung cancer (NSCLC). We assessed the association of efficacy with programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB). PATIENTS AND METHODS: Two hundred eighty-eight patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was objective response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1 expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a secondary end point. RESULTS: Of treated patients with tumor available for testing, 252 patients (88%) of 288 were evaluable for PD-L1 expression and 98 patients (82%) of 120 for TMB. ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than 1% tumor PD-L1 expression, respectively. ORR increased with higher TMB, plateauing at 10 or more mutations/megabase (mut/Mb). Regardless of PD-L1 expression, ORRs were higher in patients with TMB of 10 or more mut/Mb (n = 48: PD-L1, ≥ 1%, 48%; PD-L1, < 1%, 47%) versus TMB of fewer than 10 mut/Mb (n = 50: PD-L1, ≥ 1%, 18%; PD-L1, < 1%, 5%), and progression-free survival was longer in patients with TMB of 10 or more mut/Mb versus TMB of fewer than 10 mut/Mb (median, 7.1 v 2.6 months). Grade 3 to 4 treatment-related adverse events occurred in 29% of patients. CONCLUSION: Nivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. TMB of 10 or more mut/Mb was associated with improved response and prolonged progression-free survival in both tumor PD-L1 expression 1% or greater and less than 1% subgroups and was thus identified as a potentially relevant cutoff in the assessment of TMB as a biomarker for first-line nivolumab plus ipilimumab.

Examining Wrong Eye Implant Adverse Events in the Veterans Health Administration With a Focus on Prevention: A Preliminary Report.

OBJECTIVE: The study goals were to examine wrong intraocular lens (IOL) implant adverse events in the Veterans Health Administration (VHA), identify root causes and contributing factors, and describe system changes that have been implemented to address this challenge. DESIGN: This study represents collaboration between the VHA's National Center for Patient Safety (NCPS) and the National Surgery Office (NSO). PARTICIPANTS: This report includes 45 wrong IOL implant surgery adverse events reported to established VHA NCPS and NSO databases between July 1, 2006, and June 31, 2014. There are approximately 50,000 eye implant procedures performed each year in the VHA. METHODS: Wrong IOL implant surgery adverse events are reported by VHA facilities to the NCPS and the NSO. Two authors (A.C. and J.N.) coded the reports for event type (wrong lens or expired lens) and identified the primary contributing factor (coefficient κ = 0.837). A descriptive analysis was conducted, which included the reported yearly event rate. MAIN OUTCOME MEASURE: The main outcome measure was the reported wrong IOL implant surgery adverse events. RESULTS: There were 45 reported wrong IOL implant surgery adverse events. Between 2011 and June 30, 2014, there was a significant downward trend (P = 0.02, R = 99.7%) at a pace of -0.08 (per 10,000 cases) every year. The most frequently coded primary contributing factor was incomplete preprocedure time-out (n = 12) followed by failure to perform double check of preprocedural calculations based upon original data and implant read-back at the time the surgical eye implant was performed (n = 10). CONCLUSIONS: Preventing wrong IOL implant adverse events requires diligence beyond performance of the preprocedural time-out. In 2013, the VHA has modified policy to ensure double check of preprocedural calculations and implant read-back with positive impact. Continued analysis of contributing human factors and improved surgical team communication are warranted.

History of the American Board of Ophthalmology Oral Examination.

The oral examination has been an integral part of certification by the American Board of Ophthalmology (ABO) since its founding in 1916. An overview is provided regarding the history, evolution, and application of new technology for the oral examination. This part of the certifying process allows the ABO to assess candidates for a variety of competencies, including communication skills and professionalism.

Factor V Leiden mutation and thromboembolism risk in women receiving adjuvant tamoxifen for breast cancer.

BACKGROUND: Tamoxifen use has been associated with increased risk of thromboembolic events (TEs) in women with breast cancer and women at high risk for the disease. Factor V Leiden (FVL) is the most common inherited clotting factor mutation and also confers increased thrombosis risk. We investigated whether FVL was associated with TE risk in women with early-stage breast cancer who took adjuvant tamoxifen. METHODS: A case-control study was conducted among 34 Cancer and Leukemia Group B (CALGB) institutions. We matched each of 124 women who had experienced a documented TE while taking adjuvant tamoxifen for breast cancer (but who were not necessarily on a CALGB treatment trial) to two control subjects (women who took adjuvant tamoxifen but did not experience TE) by age at diagnosis (+/-5 years). DNA from blood was analyzed for FVL mutations. Conditional logistic regression was used to estimate odds ratios (ORs) and to evaluate other potential factors associated with TE and tamoxifen use. All P values are based on two-sided tests. RESULTS: FVL mutations were identified in 23 (18.5%) case and 12 (4.8%) control subjects (OR = 4.66, 95% confidence interval = 2.14 to 10.14, P < .001). In the multivariable model, FVL mutation was associated with TE (OR = 4.73, 95% confidence interval = 2.10 to 10.68, P < .001). Other statistically significant factors associated with TE risk were personal history of TE and smoking. CONCLUSIONS: Among women taking adjuvant tamoxifen for early-stage breast cancer, those who had a TE were nearly five times more likely to carry a FVL mutation than those who did not have a TE. Postmenopausal women should be evaluated for the FVL mutation before prescription of adjuvant tamoxifen if a positive test would alter therapeutic decision making.

Eye and visual function in traumatic brain injury.

Combat blast is an important cause of traumatic brain injury (TBI) in the Department of Veterans Affairs polytrauma population, whereas common causes of TBI in the civilian sector include motor vehicle accidents and falls. Known visual consequences of civilian TBI include compromised visual acuity, visual fields, and oculomotor function. The visual consequences of TBI related to blast remain largely unknown. Blast injury may include open globe (eye) injury, which is usually detected and managed early in the rehabilitation journey. The incidence, locations, and types of ocular damage in eyes without open globe injury after exposure to powerful blast have not been systematically studied. Initial reports and preliminary data suggest that binocular function, visual fields, and other aspects of visual function may be impaired after blast-related TBI, despite relatively normal visual acuity. Damage to the ocular tissues may occur from blunt trauma without rupture or penetration (closed globe injury). Possible areas for research are development of common taxonomy and assessment tools across services, surgical management, and outcomes for blast-related eye injury; the incidence, locations, and natural history of closed globe injury; binocular and visual function impairment; quality of life in affected service members; pharmacological and visual therapies; and practice patterns for screening, management, and rehabilitation.

Human orbital sympathetic nerve pathways.

PURPOSE: To determine pathways of sympathetic nerves from the orbital apex to the eyelids in human cadaver tissue using immunohistochemistry. METHODS: Human cadaver orbit tissue was sectioned and immunolabeled with a monoclonal antityrosine hydroxylase antibody. RESULTS: In the orbital apex, the nasociliary, frontal, lacrimal, and maxillary branches of the trigeminal nerve demonstrated intense staining upon entering the orbit. Immunoreactive axons from the nasociliary and frontal nerves were observed to join the extraocular motor nerves in the posterior orbit. A plexus of immunolabeled nerves was observed to accompany the ophthalmic artery as it entered the orbital apex. The ophthalmic artery and its branches throughout the orbit demonstrated staining of nerve fibers in the peripheral muscularis. The nasociliary nerve contributed sympathetic branches to the ciliary ganglion. Nerves passing through the ciliary ganglion and a few ganglion cell bodies demonstrated mild to moderate tyrosine hydroxylase reactivity. Axons within the short and long ciliary nerves demonstrated strong tyrosine hydroxylase reactivity and were observed to enter the posterior sclera and the suprachoroidal space. The lacrimal gland demonstrated mild pericapillary staining and occasional stromal nerve fibers reactive to the antityrosine hydroxylase antibody. Müller muscle and the inferior tarsal muscle possessed a strong tyrosine hydroxylase-reactive nerve supply that appeared to originate from the anterior terminal branches of the nasociliary and lacrimal nerves. CONCLUSIONS: Sympathetic nerves enter the orbit via the first and second divisions of the trigeminal nerve and a plexus of nerves surrounding the ophthalmic artery. Extraocular motor nerves receive a sympathetic nerve supply from the sensory nerves in the posterior orbit. Some ciliary ganglion cell bodies demonstrated tyrosine hydroxylase-like reactivity, suggesting a sympathetic modulatory role for the ciliary ganglion. Sympathetics innervate ocular structures via the posterior ciliary nerves. Sympathetic axons travel anteriorly in the orbit via the nasociliary and lacrimal nerves to innervate the sympathetic eyelid muscles. Sympathetic nerves also travel with the frontal branch of the ophthalmic nerve to innervate the forehead skin. The ophthalmic artery and all of its branches contain a perivascular sympathetic nerve supply that may be involved in regulation of blood flow to ocular and orbital structures.

Framework for a national teleretinal imaging program to screen for diabetic retinopathy in Veterans Health Administration patients.

Digital retinal imaging with remote image interpretation (teleretinal imaging) is an emerging healthcare technology for screening patients for diabetic retinopathy (DR). The Veterans Health Administration (VHA) convened an expert panel in 2001 to determine and resolve the requisite clinical, quality and training, information technology, and healthcare infrastructure issues associated with deploying a teleretinal imaging system. The panel formulated consensus recommendations based on available literature and identified areas of uncertainty that merited further clarification or research. Subsequent VHA experience with teleretinal imaging and accumulated scientific evidence support nationwide regionalized deployment of teleretinal imaging to screen for DR. The goal is to screen approximately 75,000 patients in the first year of the program, which commenced in 2006. This program will increase patients' access to screening for DR, provide outcomes data, and offer a unique platform for systematically evaluating the role of this technology in the care of diabetic eye disease and routine eye-care practice.

Decreased carotenoid content in preaponeurotic orbital fat of patients with involutional ptosis.

PURPOSE: The underlying cause of involutional blepharoptosis is unknown. The carotenoid content of preaponeurotic and nasal orbital fat among patients with and without involutional ptosis was evaluated to investigate the hypothesis that development of ptosis may be related to low carotenoid content of preaponeurotic orbital fat. METHODS: Through a case-control design, the carotenoid content of preaponeurotic and nasal fat of 10 patients with ptosis and 11 patients without ptosis was measured by spectrophotometry analysis. Differences in carotenoid content between patients with and without ptosis were evaluated in unadjusted analyses and in multivariate models adjusted for age, sex, race, and presence of thyroid eye disease as potential confounders. RESULTS: The total carotenoid content of the preaponeurotic fat of patients with ptosis was 59% lower than patients without ptosis (2.98 versus 7.26 absorbance/mg, p = 0.005). When adjustments were made for age, sex, race, and presence of thyroid eye disease, this difference was attenuated, but there was still a trend toward lower preaponeurotic fat carotenoid content among patients with ptosis (p = 0.09). The carotenoid content of the nasal fat was not significantly different among patients with and without ptosis (2.69 versus 3.40 absorbance/mg, p = 0.33). A lower ratio of preaponeurotic to nasal carotenoid content was demonstrated among patients with ptosis compared with patients without ptosis (1.4 versus 2.1; p = 0.06 unadjusted, p = 0.10 adjusted). CONCLUSIONS: Patients with involutional ptosis show trends toward having lower carotenoid content in preaponeurotic fat. Further investigation of the potential role of orbital fat carotenoids in the development of involutional ptosis is warranted.

Eye disease in veterans with diabetes.

OBJECTIVE: To describe the screening, prevalence, and management of eye disease in veterans cared for by the Veterans Affairs (VA) System. RESEARCH DESIGN AND METHODS: Eye examinations, treatments, and diseases were identified in veterans with diabetes who received care in inpatient and outpatient VA settings during FY1998. Analysis was conducted to characterize the patient population and screened population and to compare them to the total VA patient population with diabetes. Logistic regression was performed to predict eye screening. RESULTS: Overall 48% of veterans with diabetes had an eye examination in FY1998. One-third of all veterans had an eye condition and 8.6% of veterans had ophthalmic manifestations of diabetes. In addition 11% reported glaucoma and 17.8% reported cataract surgery. Approximately 11,500 (2.7%) veterans were blind. CONCLUSIONS: Visual impairment is a common complication of diabetes. Half of this population of veterans had a visual examination recorded in VA. The VA is testing a more targeted screening and treatment approach for diabetic eye disease in order to prevent the serious eye complications.

Immunophenotype of conjunctival melanomas: comparisons with uveal and cutaneous melanomas.

OBJECTIVE: To characterize the immunophenotypic expression pattern of conjunctival melanomas, with the use of standard melanoma markers as well as microphthalmia transcription factor and p75 neurotrophin receptor. DESIGN: Eleven conjunctival melanomas, including 1 caruncular melanoma, were immunolabeled with a panel of antibodies that included S100, tyrosinase, melan-A, HMB-45 and HMB-50 combination, microphthalmia transcription factor, and p75 neurotrophin receptor. The results were tabulated on the basis of intensity and pervasiveness of labeling and compared with a previous study of uveal melanomas. RESULTS: Immunolabeling with S100 was at significantly higher levels in conjunctival melanomas than in uveal melanomas. Tyrosinase, HMB-45 and HMB-50 combination, melan-A, and microphthalmia transcription factor were expressed at high levels in conjunctival melanomas, whereas p75 neurotrophin receptor was not expressed. CONCLUSIONS: Melanomas of the conjunctiva, including the caruncle, expressed S100, tyrosinase, melan-A, HMB-45 and HMB-50 combination, and microphthalmia transcription factor at high levels, suggesting that these are good markers for this melanoma subtype. Expression of S100 was significantly higher in conjunctival melanomas than in uveal melanomas. The immunophenotypic pattern of conjunctival melanomas is most similar to the epithelioid subtype of cutaneous melanomas.

Histiocytoid variant of eccrine sweat gland carcinoma of the eyelid and orbit: report of five cases.

OBJECTIVE: To study the clinicopathologic features of the histiocytoid variant of adenocarcinoma of the eccrine sweat gland of the eye and orbit. DESIGN: Retrospective case series. PARTICIPANTS: Five patients undergoing orbital and eyelid biopsy as a diagnostic procedure. METHODS: The authors examined the clinical histories and pathologic findings of five patients with eccrine adenocarcinoma of the eyelid with orbital invasion. MAIN OUTCOME MEASURES: Clinical and histopathologic examinations, including routine histopathology, immunohistochemistry, and electron microscopy studies. RESULTS: The tumors presented as insidious, diffusely infiltrative, firm cutaneous masses in the periocular area that later infiltrated the orbit. Histopathologic examination revealed that the tumors infiltrated the dermis and were composed of cells with a histiocytic to signet ring appearance. Tumor cells exhibited intracellular mucin production. Immunohistochemical stains were positive in tumor cells for low and high molecular weight cytokeratins, carcinoembryonic antigen, and epithelial membrane antigen. Electron microscopic examination showed lumen formation and intracytoplasmic mucin in tumor cells. CONCLUSIONS: The histiocytoid variant of adenocarcinoma of the eccrine sweat gland of the eyelid may present as an insidious tumor and diffusely invade the orbit. These cases may be confused with metastatic adenocarcinoma.