Persistent subfoveal fluid following MH surgery is a common finding that appears to delay visual recovery but not effect final visual outcome. The incidence of persistent subfoveal fluid appears to be related to intraoperative alterations after ILM peeling in the outer retinal architecture (e.g., increased EZ-RPE height and SRHR width). This finding suggests a novel mechanism for facilitating MH closure through ILM peeling (e.g., altering photoreceptor/RPE adherence and increasing retinal mobility that allows for complete hole closure).

Purpose This “3+3” phase I study evaluated the safety, biologic, and clinical activity of lenvatinib, an oral multikinase inhibitor, in patients with solid tumors. Experimental Design Ascending doses of lenvatinib were administered po bid in 28-day cycles. Safety and response were assessed for all patients. Angiogenic and apoptotic factors were tested as possible biomarkers in an expanded melanoma cohort. Results Seventy-seven patients were treated in 3 cohorts: 18 with intermittent bid dosing (7 days on, 7 days off) of 0.1–3.2 mg; 33 with bid dosing of 3.2–12 mg; and 26 with bid dosing of 10 mg (expanded melanoma cohort). Maximum tolerated dose was established at 10 mg po bid. Prominent drug-related toxicities included hypertension (43%), fatigue (42%), proteinuria (39%), and nausea (25%); dose-limiting toxicities included hypertension, fatigue, and proteinuria. Twelve patients (15.6%) achieved partial response (PR, n=9) or unconfirmed PR (uPR, n=3), and 19 (24.7%) achieved stable disease (SD) ≥23 weeks. Total PR/uPR/SD≥23 weeks was 40.3% (n=31). Responses (PR/uPR) by disease were: melanoma, 5/29 patients (includes 1 patient with NRAS mutation); thyroid, 3/6; pancreatic, 1/2; lung, 1/1; renal, 1/1; endometrial, 1/4; and ovarian, 1/5. AUC0-24 and Cmax increased dose-proportionally. In multivariate Cox proportional hazard model analyses, increased baseline systolic blood pressure and decreased angiopoietin-1 ratio (2 hours:baseline) were associated with longer progression-free survival (PFS) in the expanded melanoma cohort (P=0.041 and P=0.03, respectively). Conclusions The toxicity profile, pharmacokinetics, and antitumor activity of lenvatinib are encouraging. Decreases in the angiopoietin-1 ratio correlated with longer PFS in melanoma patients.

BackgroundE7046 is a highly selective, small-molecule antagonist of the E-type prostanoid receptor 4 (EP4) for prostaglandin E2, an immunosuppressive mediator of the tumor immune microenvironment. This first-in-human phase 1 study assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, maximum tolerated dose (MTD) and recommended phase 2 dose of E7046.MethodsThis first-in-human study enrolled 30 patients with advanced tumors of cancer types associated with high levels of myeloid infiltrates. E7046 was administered orally once-daily in sequential escalating dose cohorts (125, 250, 500, and 750 mg) with ≥6 patients per cohort. Tumor assessments were performed every 6 weeks. Paired tumor biopsies and blood samples, before and on treatment, were collected for pharmacokinetic and pharmacodynamic characterization of the treatment.ResultsNo dose-limiting toxicities were observed, and the MTD was not reached. E7046 had an elimination half-life (t1/2) of 12 hours, and drug exposure increased dose-dependently from 125 to 500 mg. Target modulation by E7046 was supported by changes in genes downstream of EP4 with concurrent enhanced antitumoral immune responses. A best response of stable disease (per irRECIST) was reported in 23% of patients treated with E7046 (n=30) (125 mg: n=2; 250 mg: n=2; 750 mg: n=3). Over half (4/7) of the patients with stable disease had treatment duration of 18 weeks or more, and three patients (3/15; 20%) achieved metabolic responses.ConclusionsIn this first-in-human study, E7046 administered orally once daily demonstrated manageable tolerability, immunomodulatory effects, and a best response of stable disease (≥18 weeks) in several heavily pretreated patients with advanced malignancies. The 250 and 500 mg doses are proposed for further development in the combination setting.Trial registration numberNCT02540291.

Waldenstrom’s macroglobulinemia (WM) is associated with retinal findings of hyperviscosity such as venous dilation, and findings of immunogammopathy maculopathy such as serous macular detachment. The report describes a case of bilateral serous macular detachment with intraretinal schisis-like fluid in a patient with WM. Enhanced depth imaging OCT revealed a thickened choroid with hyper-reflective accumulations in the RPE layer. The ultra-widefield fundus autofluorescence demonstrated a central area of hyperautofluorescence corresponding to the area of serous macular detachment. Ultra-widefield fluorescein angiography was characteristically silent. Intravitreal bevacizumab therapy resulted in significant reduction in intraretinal fluid, but minimal change in subretinal fluid. Long-term follow-up demonstrated alterations in retinal architecture and improved serous detachments.

Objective: To describe treatment trends and outcomes of liver metastasis from uveal melanoma. Methods: Retrospective case series of 73 patients with uveal melanoma liver metastasis. Patients were treated first-line with systemic therapy (not including checkpoint inhibitors), checkpoint inhibitors, local therapy or no treatment. Time to metastasis, detection method, and survival data were collected. Time periods were divided between 2004–2011 and 2012–2016. Cox proportional hazards models were used to compare progression-free survival (PFS) and overall survival (OS). Results: Median PFS and OS for the entire cohort was 4 months (95% CI 3–5) and 15 months (95% CI 11–18), respectively. There was no statistically significant difference in PFS and OS across the two time periods. Patients who received no treatment had the shortest OS (median 4.9 months), whereas those treated with local therapy had the longest PFS (median 4.6 months) and OS (median 18.7 months). Having liver metastasis diagnosed by symptoms was associated with a greater risk of mortality (p < 0.001). Conclusion: Patients who received first-line local treatment had the longest PFS and OS, while patients who received no treatment had the shortest OS. Survival outcomes did not improve for patients including those receiving check point inhibitors.

Objective The intravitreal injection (IVI) of pharmacological agents is the most commonly performed ocular procedure and is associated with a host of complications. The majority of IVI-related complications data is derived from randomized controlled clinical trials, which report a high adverse event rate. The nature of these protocol-driven trials limit their applicability to the diverse circumstances seen in routine clinical practice. The goal of this study is to determine the prevalence of patient reported IVI-related complications, their risk factors, and the manner in which patients presented in a tertiary eye care center. Design A retrospective, IRB-approved review. Subjects, Participants and/or Controls 44,734 injections in 5,318 unique patients at the Cleveland Clinic Cole Eye Institute from 2012-2016. Methods, Intervention, or Testing Intravitreal injection. Main Outcome Measures Complication occurrence within 15 days of injection. Results From 2012-2016, a total of 44,734 injections were performed in 5,318 unique patients. Overall, complication rates were low, representing 1.9% of all injections, with 1031 unique complications in 685 (12.9%) patients. The most common minor complications, or those not requiring intervention, were irritation (n=312) and subconjunctival hemorrhage (n=284). The most common serious complications, or those requiring intervention, were corneal abrasion (n=46) and iritis (n=31). The majority of complications (66%) were adequately managed by a telephone/Epic electronic message encounter only. Importantly, no injection protocol parameter, such as type of anesthesia, preparation, or post-injection medication, increased the risk of a complication. However, patient sex, age, number of previous injections, and provider strongly influenced the risk of patient-reported complications. Conclusions Overall, complication rates seen in routine clinical practice were low compared to clinical trial reporting. Providers should feel confident in the safety and administration of IVI during times when follow-up office visits and resources may be limited. When performing an IVI, factors such as a patient’s sex, age, number of previous injections, and provider must be taken into account to ensure the best possible outcomes.

Live attenuated influenza vaccine (LAIV) candidates of the H7 subtype, A/Netherlands/219/03 (H7N7, NL03 ca) and A/chicken/British Columbia/CN-6/2004 (H7N3, BC04 ca), were evaluated for their receptor binding specificity and immunogenicity in ferrets. The BC04 ca virus exhibited α2,3-SA and α2,6-SA dual receptor binding preference while the NL03 ca virus preferentially bound to α2,3-SA. Substitution of the Q226 and G228 (Q-G) by the L226 and S228 (L-S) residues in the HA improved binding to α2,6-SA for NL03 ca. The vaccine viruses with L-S retained the attenuation phenotype. NL03 L-S ca replicated more efficiently than the original NL03 ca virus in the upper respiratory tract of ferrets, and induced higher levels of humoral and cellular immune responses. Prior vaccination with seasonal LAIV reduced H7-specific antibody responses, but did not reduce the H7N7 vaccine mediated protection against a heterologous H7N3 BC04 wt virus infection in ferrets. In addition, the H7N3 and H7N7 vaccine immunized ferret sera cross reacted with the newly emerged H7N9 virus. These data, in combination with the safety data from previously conducted Phase 1 studies, suggest that these vaccines may have a role in responding to the threat posed by the H7N9 virus.

Purpose: To describe two methods of measuring Argus II array–retina distance and to correlate array–retina distance to electrode stimulation thresholds. Methods: This was a case series of eight patients implanted with the Argus II. Spectral domain-optical coherence tomography array–retina distance was measured by two methods and correlated to corresponding electrode thresholds: (1) array–retina distance at each array corner and the largest array–retina distance and (2) using manual optical coherence tomography segmentation, the average array–retina distance was determined for each group of four electrodes. Patients 1–5 and 6–8 were analyzed separately due to a different threshold programming software. Results: The Spearman’s rank coefficient between array–retina distance and thresholds was −0.006 ( p = 0.98) for patients 1–5, and 0.16 ( p = 0.59) for patients 6–8 with the first method. The Spearman’s rank coefficient was 0.25 ( p < 0.001) for patients 1–5 and 0.36 ( p < 0.001) for patients 6–8 with the second method. Conclusion: There is a positive correlation between array–retina distance and threshold measurements when measuring the entire array but not when using a faster measurement method of four corners and largest array–retina distance.