Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR): 48-week results from a randomised, double-masked, non-inferiority, phase 3 trial.

BACKGROUND: Intravitreal aflibercept 8 mg could improve treatment outcomes and provide sustained disease control in patients with neovascular age-related macular degeneration (nAMD), with extended dosing compared with aflibercept 2 mg. METHODS: PULSAR is a phase 3, randomised, three-group, double-masked, non-inferiority, 96-week trial conducted across 223 sites worldwide. Adults with nAMD were randomised 1:1:1 to aflibercept 8 mg every 12 weeks (8q12), aflibercept 8 mg every 16 weeks (8q16), or aflibercept 2 mg every 8 weeks (2q8), following three initial monthly doses in all groups. From week 16, patients in the aflibercept 8 mg groups had their dosing interval shortened if pre-specified dose regimen modification criteria denoting disease activity were met. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48. All patients with at least one dose of study treatment were included in the efficacy and safety analyses. This trial is registered with ClinicalTrials.gov (NCT04423718) and is ongoing. FINDINGS: Of 1011 patients randomised to aflibercept 8q12 (n=336), 8q16 (n=338), or 2q8 (n=337) between Aug 11, 2020, and July 30, 2021, 1009 patients received study treatment (aflibercept 8q12 n=335; aflibercept 8q16 n=338; and aflibercept 2q8 n=336). Aflibercept 8q12 and 8q16 showed non-inferior BCVA gains versus aflibercept 2q8 (mean BCVA change from baseline +6·7 [SD 12·6] and +6·2 [11·7] vs +7·6 [12·2] letters). The least squares mean differences between aflibercept 8q12 versus 2q8 and 8q16 versus 2q8, respectively, were -0·97 (95% CI -2·87 to 0·92) and -1·14 (-2·97 to 0·69) letters (non-inferiority margin at 4 letters). The incidence of ocular adverse events in the study eye was similar across groups (aflibercept 8q12 n=129 [39%]; aflibercept 8q16 n=127 [38%]; and aflibercept 2q8 n=130 [39%]). INTERPRETATION: Aflibercept 8 mg showed efficacy and safety with extended dosing intervals, which has the potential to improve the management of patients with nAMD. FUNDING: Bayer AG and Regeneron Pharmaceuticals.

Intravitreal aflibercept 8 mg in diabetic macular oedema (PHOTON): 48-week results from a randomised, double-masked, non-inferiority, phase 2/3 trial.

BACKGROUND: A high-dose formulation of intravitreal aflibercept (8 mg) could improve treatment outcomes in diabetic macular oedema (DMO) by requiring fewer injections than the standard comparator, aflibercept 2 mg. We report efficacy and safety results of aflibercept 8 mg versus 2 mg in patients with DMO. METHODS: PHOTON was a randomised, double-masked, non-inferiority, phase 2/3 trial performed at 138 hospitals and specialty retina clinics in seven countries. Eligible patients were adults aged 18 years or older with type 1 or 2 diabetes and centre-involved DMO. Patients were randomly assigned (1:2:1) to intravitreal aflibercept 2 mg every 8 weeks (2q8), aflibercept 8 mg every 12 weeks (8q12), or aflibercept 8 mg every 16 weeks (8q16), following initial monthly dosing. From week 16, dosing intervals for the aflibercept 8 mg groups were shortened if patients met prespecified dose regimen modification criteria denoting disease activity. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48 (non-inferiority margin of 4 letters). Efficacy and safety analyses included all randomly assigned patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov (NCT04429503). FINDINGS: Between June 29, 2020, and June 28, 2021, 970 patients were screened for eligibility. After exclusions, 660 patients were enrolled and randomly assigned to receive aflibercept 8q12 (n=329), 8q16 (n=164), or 2q8 (n=167); two patients were randomly assigned in error and did not receive treatment. 658 (99·7%) patients were treated and included in the full analysis set and safety analysis set (8q12 n=328, 8q16 n=163, and 2q8 n=167). Mean patient age was 62·3 years (SD 10·4). 401 (61%) patients were male. 471 (72%) patients were White. Aflibercept 8q12 and 8q16 demonstrated non-inferior BCVA gains to aflibercept 2q8 (BCVA mean change from baseline 8·8 letters [SD 9·0] in the 8q12 group, 7·9 letters [8·4] in the 8q16 group, and 9·2 letters [9·0] in the 2q8 group). The difference in least squares means was -0·57 letters (95% CI -2·26 to 1·13, p value for non-inferiority <0·0001) between 8q12 and 2q8 and -1·44 letters (-3·27 to 0·39, p value for non-inferiority 0·0031) between aflibercept 8q16 and 2q8. Proportions of patients with ocular adverse events in the study eye were similar across groups (8q12 n=104 [32%], 8q16 n=48 [29%], and 2q8 n=46 [28%]). INTERPRETATION: Aflibercept 8 mg demonstrated efficacy and safety with extended dosing intervals and could decrease treatment burden in patients with DMO. FUNDING: Regeneron Pharmaceuticals and Bayer.

Simulation of long-term impact of intravitreal anti-VEGF therapy on patients with severe non-proliferative diabetic retinopathy.

OBJECTIVE: A simulation model was constructed to assess long-term outcomes of proactively treating severe non-proliferative diabetic retinopathy (NPDR) with anti-vascular endothelial growth factor (anti-VEGF) therapy versus delaying treatment until PDR develops. METHODS AND ANALYSIS: Simulated patients were generated using a retrospective real-world cohort of treatment-naive patients identified in an electronic medical records database (IBM Explorys) between 2011 and 2017. Impact of anti-VEGF treatment was derived from clinical trial data for intravitreal aflibercept (PANORAMA) and ranibizumab (RISE/RIDE), averaged by weighted US market share. Real-world risk of PDR progression was modelled using Cox multivariable regression. The Monte Carlo simulation model examined rates of progression to PDR and sustained blindness (visual acuity <20/200) for 2 million patients scaled to US NPDR disease prevalence. Simulated progression rates from severe NPDR to PDR over 5 years and blindness rates over 10 years were compared for delayed versus early-treatment patients. RESULTS: Real-world data from 77 454 patients with mild-to-severe NPDR simulated 2 million NPDR patients, of which 86 680 had severe NPDR. Early treatment of severe NPDR with anti-VEGF therapy led to a 51.7% relative risk reduction in PDR events over 5 years (15 704 early vs 32 488 delayed), with a 19.4% absolute risk reduction (18.1% vs 37.5%). Sustained blindness rates at 10 years were 4.4% for delayed and 1.9% for early treatment of severe NPDR. CONCLUSION: The model suggests treating severe NPDR early with anti-VEGF therapy, rather than delaying treatment until PDR develops, could significantly reduce PDR incidence over 5 years and sustained blindness over 10 years.

Comparison of surgical techniques for recurrent pterygium.

OBJECTIVE: Although conjunctival autograft (CAU) and amniotic membrane grafting (AMG) with mitomycin-C (MMC) are most effective for the treatment of primary pterygium, the optimal surgical treatment of recurrent pterygium is not well established. We thus aimed to examine recurrence rates after recurrent pterygium excision surgery performed with CAU or AMG with or without MMC. METHODS: We performed a retrospective review of adult patients who underwent recurrent pterygium excision surgery at Boston Medical Center between January 1999 and July 2019. Postoperative recurrence rates were compared between surgical treatment groups: CAU + MMC, CAU, AMG + MMC, and AMG. Postoperative and any intraoperative complications were recorded. RESULTS: We identified 41 eyes of 38 patients having undergone recurrent pterygium excision surgery that met our criteria. The observed postoperative recurrence rates were 0% (0 of 8 eyes) with CAU + MMC, 17.7% (3 of 17 eyes) with CAU, 45.5% (5 of 11 eyes) with AMG + MMC, and 80.0% (4 of 5 eyes) with AMG. The postoperative recurrence rate was significantly lower with CAU than with AMG, both with (p = 0.045) and without (p = 0.021) adjuvant MMC. There were no statistically significant differences in repeat recurrence rates with or without MMC with CAU (p = 0.52) or with AMG (p = 0.31). There was 1 reported case of possible complication from MMC resulting in complete amniotic membrane melt. CONCLUSIONS: Our study suggests that CAU results in less repeat recurrence than AMG in the treatment of recurrent pterygium. The use of intraoperative MMC may decrease the recurrence rate, but it is not statistically significant and may be associated with complications.

Technology-based Comprehensive Cardiac Rehabilitation Therapy (TaCT) for women with cardiovascular disease in a middle-income setting: A randomized controlled trial protocol.

Women are underrepresented in cardiac rehabilitation (CR) despite the benefits, and this is exacerbated in lower-resource settings where CR is insufficiently available. In this randomized controlled trial, the effectiveness of the Technology-based Comprehensive Cardiac Rehabilitation Therapy (TaCT) electronic cardiac rehabilitation (eCR) intervention on functional capacity, risk factors, quality of life, heart-health behaviors, symptoms, and morbidity will be tested among women with CVD in a middle-income country. Following a pilot study, a single-center, single-blinded, 2 parallel-arm (1:1 SNOSE) superiority trial comparing an eCR intervention (TaCT) to usual care, with assessments pre-intervention and at 3 and 6 months will be undertaken. One hundred adult women will be recruited. Permuted block (size 10) randomization will be applied. The 6-month intervention comprises an app, website, SMS texts with generic heart-health management advice, and bi-weekly 1:1 telephone calls with a nurse trainee. Individualized exercise prescriptions will be developed based on an Incremental Shuttle Walk Test (primary outcome) and dietary plans based on 24 h dietary recall. A yoga/relaxation video will be provided via WhatsApp, along with tobacco cessation support and a moderated group chat. At 3 months, intervention engagement and acceptability will be assessed. Analyses will be conducted based on intent-to-treat. If results of this novel trial of women-focused eCR in a middle-income country demonstrate clinically-significant increases in functional capacity, this could represent an important development for the field considering this would be an important outcome for women and would translate to lower mortality.

Clinical and radiographic features of hydrolyzed MIRAgel scleral buckles: A comparative analysis.

The MIRAgel (hydrogel) scleral buckle, introduced in the 1980s, was a novel material to repair retinal detachments. It was later discontinued due to the frequency of long-term complications related to buckle hydrolysis and expansion. These complications included pain, limited extraocular motility, and more serious complications such as infection or scleral perforation, which ultimately necessitated surgical extraction as late as 20-30 years after placement. Prompt and proper diagnosis and treatment is often delayed as these buckle-associated complications frequently mimic other orbital pathologies such as tumors or infections. The hydrolyzed MIRAgel buckle exhibits distinct radiographic features that are helpful in arriving at the correct diagnosis, particularly in cases of ambiguous clinical presentation or history. Here, we expand on the previously described radiographic features of hydrolyzed MIRAgel and compare them to features of common, mimicking orbital pathology.

Descemet Membrane Endothelial Keratoplasty After Failed Descemet Stripping Without Endothelial Keratoplasty.

PURPOSE: To describe the clinical course, surgical experience, and postoperative outcomes of 3 patients with Fuchs endothelial dystrophy who underwent Descemet membrane endothelial keratoplasty (DMEK) after failed Descemet stripping without endothelial keratoplasty. METHODS: Three patients who underwent DMEK for management of persistent corneal edema after deliberate Descemet stripping in the setting of Fuchs endothelial dystrophy were identified. Patients were examined at day 1, week 1, and months 1, 3, and 6 after DMEK. Visual acuity, central corneal thickness (CCT), and evaluation of central corneal endothelial cell counts were recorded. RESULTS: Two women and one man, aged 56, 72, and 68 years, were included. The time interval between primary Descemet stripping and DMEK ranged from 3.5 to 8 months. Preoperative visual acuities were 20/200, 20/300, and 20/80. Immediately before DMEK, no patients had countable central endothelial cells, and CCTs were 825, 1034, and 878 µm. After DMEK, all patients had improvement in visual acuity to 20/70, 20/20, and 20/20 with CCTs of 529, 504, and 528. The postoperative period in the first case was notable for the immediate development of a pigmented pupillary membrane with posterior synechiae, as well as cystoid macular edema, of uncertain chronicity, noted 1 month postoperatively. The second case also developed posterior synechiae. Two cases completed 6-month endothelial cell counts totaling 2200 and 3114 cells per square millimeter (endothelial cell loss of 13% and 5.3%). CONCLUSIONS: DMEK is a reliable procedure to facilitate corneal rehabilitation and visual recovery in the event of poor corneal clearance after Descemet stripping without endothelial keratoplasty.

Current trends in the management of thyroid eye disease.

PURPOSE OF REVIEW: The present review summarizes the body of literature concerning the medical and surgical treatment of thyroid eye disease (TED) from 1 January 2014 through 30 March 2015. RECENT FINDINGS: Corticosteroids continue to be the primary medical therapy for TED. Recent research has offered insight into potential differences between oral corticosteroid and intravenous corticosteroid treatment regimens in terms of efficacy and side-effect profiles. Steroid-sparing medications, for example, rituximab and others, are an area of active study. There has been renewed interest in the role of radiation therapy as a nonmedical treatment for TED with some promising data. The use of balanced orbital decompression techniques have become popular, although the data regarding postoperative diplopia are mixed, and 'fat decompression' offers an alternative or an augmentation to bony decompression. Stereotactic image guidance is a useful adjunct to orbital decompression surgery. SUMMARY: TED continues to be a difficult condition for the patient to cope with and for the clinician to treat, and recent research builds on the present foundation of knowledge and treatments, but unfortunately does not offer paradigm-shifting information at the present time.

Open repair versus fenestrated endovascular aneurysm repair of juxtarenal aneurysms.

BACKGROUND: Open repair is the gold standard management for juxtarenal aneurysms. Fenestrated endovascular aneurysm repair (FEVAR) is indicated for high-risk patients. The long-term outcomes of FEVAR are largely unknown, and there is no Level I comparative evidence. This systematic review and meta-analysis of case series compares elective juxtarenal aneurysm surgery by open repair and FEVAR. METHODS: A systematic literature search was conducted for all published studies on elective repair of juxtarenal aneurysms by FEVAR and open repair. The MEDLINE, EMBASE, and Cochrane databases were searched from 1947 to April 2013. The exclusion criteria were case series of <10 patients or ruptured aneurysms. The primary outcomes were perioperative mortality and postoperative renal insufficiency. The secondary outcomes were secondary reinterventions and long-term survival. RESULTS: We identified 35 case series with data on 2326 patients. Perioperative mortality was 4.1% in open repair and FEVAR case series (odds ratio for open repair with FEVAR, 1.059; 95% confidence interval, 0.642-1.747; P = .822). Postoperative renal insufficiency was not significantly different (odds ratio for open repair with FEVAR, 1.136; 95% confidence interval, 0.754-1.713; P = .542). FEVAR patients had higher rates of secondary reintervention, renal impairment during follow-up, and a lower long-term survival compared with open repair patients. CONCLUSIONS: FEVAR and open repair have similar short-term outcomes but have diverging long-term outcomes that may be secondary to the selection bias of FEVAR being offered to high-risk patients. FEVAR is a favorable option in high-risk patients, and open repair remains viable as the gold standard.

Participation in clinical research: perspectives of adult patients and parents of pediatric patients undergoing hematopoietic stem cell transplantation.

Despite major improvements over the past several decades, many patients undergoing hematopoietic stem cell transplantations (HSCT) continue to suffer from significant treatment-related morbidity and mortality. Clinical research studies (trials) have been integral to advancing the standard of care in HSCT. However, 1 of the biggest challenges with clinical trials is the low participation rate. Although barriers to participation in cancer clinical trials have been previously explored, studies specific to HSCT are lacking. The current study was undertaken to examine the knowledge, attitudes, and perceptions of HSCT patients regarding clinical trials. As members of focus groups, participants responded to open-ended questions that assessed factors influencing decision-making about HSCT clinical trials. Suggestions for improvements in the recruitment process were also solicited among participants. Seventeen adult HSCT patients and 6 parents of pediatric HSCT patients participated in the study. The median age was 56 years (range, 18 to 70) and 44 years (range, 28 to 54) for adult patients and parents, respectively. Participants universally indicated that too much information was provided within the informed consents and they were intimidated by the medical and legal language. Despite the large amount of information provided to them at the time of study enrollment, the participants had limited knowledge retention and recall of study details. Nevertheless, participants reported overall positive experiences with clinical trial participation and many would readily choose to participate again. A common concern among participants was the uncertainty of study outcome and general lack of feedback about results at the end of the study. Participants suggested that investigators provide more condensed and easier to understand informed consents and follow-up of study findings. These findings could be used to help guide the development of improved consent documents and enhanced participation in research studies, thereby affecting the future design of HSCT research protocols.

Magnetic systems for tarsorrhaphy.

PURPOSE: Paralytic lagophthalmos can cause exposure keratopathy. Current treatments have difficulties: extrusion, migration, allergic reaction, anatomical disruption, and technically difficult surgeries. The goal of this study was to design, create, and assess a new method for eyelid closure using magnets. METHODS: This experimental study is approved by institutional review board. Creation of eyelid model and magnet systems: A model of the eyelid and eyeball was constructed to determine the necessary magnetic strength. Neodymium magnets were cast in silicone mold carriers. Assessment of temporary magnet systems in humans: 1) a magnet was affixed to the upper and lower eyelids, and 2) a magnet was affixed to the upper eyelid and another to eyeglasses. Parameters evaluated were eyelid positions and success of eyelid closure in healthy adult volunteers. RESULTS: Magnetic force required to create the average eyelid opening force was calculated from the eyelid model to be equivalent to 4 magnets. The magnet system affixed to upper and lower eyelids resulted in complete eyelid closure in 5 of 5 normal controls, while the magnet system affixed to the upper eyelid and to spectacles resulted in complete eyelid closure in 10 of 13 normal controls. CONCLUSIONS: Magnetic systems for eyelid closure were designed that used either magnets affixed to both upper and lower eyelids or an upper eyelid magnetic component combined with a magnetic element in the lower rim of spectacles. Both were effective in eyelid closure in a model eye and normal controls. These systems may ultimately provide a simplified, safer, and less invasive method to treat paralytic lagophthalmos.

Breast cancer pseudometastasis in a sentinel lymph node with cytokeratin-positive debris.

We report extensive pseudometastasis detected by immunohistochemical (IHC) staining within a sentinel lymph node. An 83-year-old woman underwent simple mastectomy and sentinel lymph node biopsy (SLNB) for infiltrating ductal carcinoma. Intraoperative frozen section of the SLNB specimen appeared histologically negative for metastasis. IHC staining for cytokeratin in permanent sections, however, showed what was reported as micrometastasis in the subcapsular sinus. Since these cells did not resemble the primary tumor cells morphologically, and had actually been called histiocytes in the frozen section, further IHC staining was done. The subcapsular cells were negative for epithelial membrane antigen (EMA) staining, but they were positive for CD68, a macrophage marker. Thus the cytokeratin-positive cells were not metastatic breast tumor cells, but rather were histiocytes with phagocytized cytokeratin debris. This case report illustrates that IHC staining for cytokeratin in SLNB specimens for breast cancer must be supported by morphologic assessment and further appropriate staining before it can become the basis for treatment decisions.