Purpose
A randomized, double-masked, multicenter, phase 2 trial to evaluate the long-term safety and efficacy of travoprost intraocular implant, an extended-release drug delivery system designed to ...provide uninterrupted sustained intraocular pressure (IOP)-lowering therapy, thereby reducing patient treatment burden and improving adherence with IOP-lowering medication.
Methods
Patients with open-angle glaucoma or ocular hypertension were administered a fast-eluting implant (FE implant,
n
= 51) and received twice-daily (BID) placebo eye drops, a slow-eluting (SE implant,
n
= 54) and received BID placebo eye drops, or underwent a sham surgical procedure and received BID timolol 0.5% (
n
= 49). IOP was measured at baseline, day 1–2, day 10, week 4, week 6, month 3, and every 3 months thereafter through 36 months. Efficacy was evaluated by mean change from 8:00 AM unmedicated baseline IOP through month 36, and the percentage of patients receiving the same or fewer topical IOP-lowering medications as at screening (pre-study). Safety was evaluated by adverse events and ophthalmic parameters.
Results
Clinically and statistically relevant IOP-lowering treatment effects were observed through month 36 after a single administration of the travoprost implant compared with BID timolol with mean IOP reductions ranging from 7.6 to 8.8 mmHg for the FE implant group, from 7.3 to 8.0 mmHg for the SE implant group, and from 7.3 to 7.9 for the timolol group at the 8:00 AM timepoint (
P
< 0.0001 for all treatment groups at all visits). At months 12, 24, and 36, a greater percentage of FE and SE implant patients versus timolol patients were well controlled on the same or fewer topical IOP-lowering medications compared with screening with 63 and 69% for the FE and SE implants groups, respectively, versus 45% for the timolol group at month 36. The safety profile of the implant was favorable; there were no dislodgements, no explantations, no adverse events of conjunctival hyperemia or periorbital fat atrophy, no discontinuations due to study eye adverse events, nor any serious adverse events in the study eye. Comparable changes from baseline in corneal endothelial cell counts were observed in the three treatment groups over the 36 months.
Conclusion
The travoprost intraocular implant demonstrated robust IOP-lowering and substantially reduced topical IOP-lowering medication burden for up to 36 months following a single administration, while maintaining a favorable safety profile. The travoprost intraocular implant promises to be a meaningful addition to the interventional glaucoma armamentarium by addressing the key shortcomings of topical IOP-lowering medications, including low adherence and topical side effects while controlling IOP for up to 36 months.
Trial Registry
ClinicalTrials.gov identifier NCT02754596 registered 28 April 2016.
To compare the efficacy of different microinvasive glaucoma surgery (MIGS) devices for reducing intraocular pressure (IOP) and medications in open-angle glaucoma (OAG).
Prospective, multicenter, ...randomized clinical trial.
One hundred fifty-two eyes from 152 patients aged 45 to 84 years with OAG, Shaffer angle grade III-IV, best-corrected visual acuity (BCVA) 20/30 or better, and IOP 23 to 39 mmHg after washout of all hypotensive medications. Eyes with secondary glaucoma other than pseudoexfoliative or pigmentary glaucoma, angle closure, previous incisional glaucoma surgery, or any significant ocular pathology other than glaucoma were excluded.
Study eyes were randomized 1:1 to standalone MIGS consisting of either 1 Hydrus Microstent (Ivantis, Inc, Irvine, CA) or 2 iStent Trabecular Micro Bypass devices (Glaukos Inc, San Clemente, CA). Follow-up was performed 1 day, 1 week, and 1, 3, 6, and 12 months postoperatively.
Within-group and between-group differences in IOP and medications at 12 months and complete surgical success defined as freedom from repeat glaucoma surgery, IOP 18 mmHg or less, and no glaucoma medications. Safety measures included the frequency of surgical complications, changes in visual acuity, slit-lamp findings, and adverse events.
Study groups were well matched for baseline demographics, glaucoma status, medication use, and baseline IOP. Twelve-month follow-up was completed in 148 of 152 randomized subjects (97.3%). At 12 months, the Hydrus had a greater rate of complete surgical success (P < 0.001) and reduced medication use (difference = -0.6 medications, P = 0.004). More Hydrus subjects were medication free at 12 months (difference = 22.6% P = 0.0057). Secondary glaucoma surgery was performed in 2 eyes in the 2-iStent group (3.9%) and in none of the Hydrus eyes. Two eyes in the Hydrus group and 1 in the 2-iStent group had BCVA loss of ≥2 lines.
Standalone MIGS in OAG with the Hydrus resulted in a higher surgical success rate and fewer medications compared with the 2-iStent procedure. The 2 MIGS devices have similar safety profiles.
To compare the clinical performance of the TECNIS Synergy multifocal (model ZFR00V) intraocular lens (IOL) with that of the AcrySof PanOptix Trifocal (model TFNT00) IOL in patients undergoing ...bilateral cataract surgery.
Multicenter clinical setting.
Prospective randomized comparative study.
Patients aged 22 years or older were randomly assigned (2:1) to bilateral implantation with ZFR00V or TFNT00 IOLs. End points included the mean binocular distance-corrected near visual acuity (DCNVA) at 40 cm, photopic and mesopic DCNVAs at 33 cm, photopic low-contrast corrected distance visual acuity (CDVA) and mesopic CDVA, nondirected patient responses to an ocular/visual symptoms questionnaire, and safety.
Of the 150 patients implanted with IOLs, 95 of the 97 patients with ZFR00V IOLs and 52 of the 53 patients with TFNT00 IOLs completed the 3-month follow-up. Most patients in the ZFR00V and TFNT00 groups achieved 20/25 or better binocular CDVA (100% vs 96.2%) and DCNVA measured at 40 cm (88.4% vs 75.0%) and 33 cm (78.9% vs 51.9%). The mean between-group difference in binocular DCNVA at 40 cm favored ZFR00V IOLs (0.5 lines Snellen; 95% CI, 0.012 to 0.089; P ≤ .05). Similarly, the mean binocular photopic and mesopic DCNVAs at 33 cm (0.8 lines Snellen each; both P ≤ .05 vs TFNT00) and photopic high-contrast and low-contrast CDVA (0.5 lines Snellen each; both P ≤ .05 vs TFNT00) favored ZFR00V IOLs. Patient-reported ocular/visual symptoms and safety were generally similar between the 2 IOLs.
The ZFR00V IOL showed an extensive range of vision, particularly through near distances, and better mesopic performance than the TFNT00 IOL in patients undergoing cataract surgery.
The spindle checkpoint prevents chromosome mis-segregation by delaying sister chromatid separation until all chromosomes have achieved bipolar attachment to the mitotic spindle. Its operation is ...essential for accurate chromosome segregation, whereas its dysregulation can contribute to birth defects and tumorigenesis. The target of the spindle checkpoint is the anaphase-promoting complex (APC), a ubiquitin ligase that promotes sister chromatid separation and progression to anaphase. Using a short hairpin RNA screen targeting components of the ubiquitin-proteasome pathway in human cells, we identified the deubiquitinating enzyme USP44 (ubiquitin-specific protease 44) as a critical regulator of the spindle checkpoint. USP44 is not required for the initial recognition of unattached kinetochores and the subsequent recruitment of checkpoint components. Instead, it prevents the premature activation of the APC by stabilizing the APC-inhibitory Mad2-Cdc20 complex. USP44 deubiquitinates the APC coactivator Cdc20 both in vitro and in vivo, and thereby directly counteracts the APC-driven disassembly of Mad2-Cdc20 complexes (discussed in an accompanying paper). Our findings suggest that a dynamic balance of ubiquitination by the APC and deubiquitination by USP44 contributes to the generation of the switch-like transition controlling anaphase entry, analogous to the way that phosphorylation and dephosphorylation of Cdk1 by Wee1 and Cdc25 controls entry into mitosis.
Severe infections are a major stress on haematopoiesis, where the consequences for haematopoietic stem cells (HSCs) have only recently started to emerge. HSC function critically depends on the ...integrity of complex bone marrow (BM) niches; however, what role the BM microenvironment plays in mediating the effects of infection on HSCs remains an open question. Here, using a murine model of malaria and combining single-cell RNA sequencing, mathematical modelling, transplantation assays and intravital microscopy, we show that haematopoiesis is reprogrammed upon infection, whereby the HSC compartment turns over substantially faster than at steady-state and HSC function is drastically affected. Interferon is found to affect both haematopoietic and mesenchymal BM cells and we specifically identify a dramatic loss of osteoblasts and alterations in endothelial cell function. Osteo-active parathyroid hormone treatment abolishes infection-triggered HSC proliferation and-coupled with reactive oxygen species quenching-enables partial rescuing of HSC function.
Introduction
This prospective, multicenter, randomized, double-masked pivotal phase 3 trial evaluated the efficacy and safety of the travoprost intracameral SE-implant (slow-eluting implant, the ...intended commercial product) and FE-implant (fast-eluting implant, included primarily for masking purposes) compared to twice-daily (BID) timolol ophthalmic solution, 0.5% in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT).
Methods
The trial enrolled adult patients with OAG or OHT with an unmedicated mean diurnal intraocular pressure (IOP) of ≥ 21 and unmedicated IOP ≤ 36 mmHg at each diurnal timepoint (8
a.m.
, 10
a.m.
, and 4
p.m.
) at baseline. The eligible eye of each patient was administered an SE-implant, an FE-implant or had a sham administration procedure. Patients who received an implant were provided placebo eye drops to be administered BID and patients who had the sham procedure were provided timolol eye drops to be administered BID. The primary efficacy endpoint, for which the study was powered, was mean change from baseline IOP at 8
a.m.
and 10
a.m.
at day 10, week 6, and month 3. Non-inferiority was achieved if the upper 95% confidence interval (CI) on the difference in IOP change from baseline (implant minus timolol) was < 1.5 mmHg at all six timepoints and < 1 mmHg at three or more timepoints. The key secondary endpoint was mean change from baseline IOP at 8
a.m.
and 10
a.m.
at month 12. Non-inferiority at month 12 was achieved if the upper 95% CI was < 1.5 mmHg at both timepoints. Safety outcomes included treatment-emergent adverse events (TEAEs) and ophthalmic assessments.
Results
A total of 590 patients were enrolled at 45 sites and randomized to one of three treatment groups: 197 SE-implant (the intended commercial product), 200 FE-implant, and 193 timolol. The SE-implant was non-inferior to timolol eye drops in IOP lowering over the first 3 months, and was also non-inferior to timolol at months 6, 9, and 12. The FE-implant was non-inferior to timolol over the first 3 months, and also at months 6 and 9. Of those patients who were on glaucoma medication at screening, a significantly greater proportion of patients in the SE- and FE-implant groups (83.5% and 78.7%, respectively) compared to the timolol group (23.9%) were on fewer topical glaucoma medications at month 12 compared to screening (
P
< 0.0001, chi-square test). TEAEs, mostly mild, were reported in the study eyes of 39.5% of patients in the SE-implant group, 34.0% of patients in the FE-implant group and 20.1% of patients in the timolol group.
Conclusions
The SE-travoprost intracameral implant demonstrated non-inferiority to timolol over 12 months whereas the FE-implant demonstrated non-inferiority over 9 months. Both implant models were safe and effective in IOP lowering in patients with OAG or OHT.
Trial Registration
ClinicalTrials.gov identifier, NCT03519386.
Purpose: To evaluate the postoperative rotational stability of two prototype intraocular lens (IOL) designs (subsequently termed version 1 and version 2). Patients and Methods: A prospective, ...multicenter, randomized, paired-eye, 6-month study evaluated the version 1 and version 2 IOLs. Results were compared with a control IOL (TECNISR toric 1-piece monofocal IOL) evaluated in a separate, similarly designed study. Participants aged greater than or equal to22 years and scheduled to undergo bilateral cataract extraction were randomly assigned 1:1 to receive the version 1 or version 2 IOL in the first operative eye; the alternate test IOL was then implanted in the second operative eye. Results: Mean absolute IOL rotation at postoperative week 1 was the primary effectiveness end point. Additional end points included the percentage of eyes with postoperative IOL rotation >5degrees/>10degrees, direction of lens rotation, surgeon-reported ease of IOL handling during implantation, and safety. At postoperative week 1, mean (+ or - standard deviation) absolute IOL rotation was significantly lower for both version 1 and version 2 versus control (0.88degrees + or -0.94 and 0.71degrees + or -0.69 vs 2.24degrees + or -3.21, respectively; both P < 0.001). For both study lenses, absolute rotation was <5degrees for all eyes at postoperative week 1, and no cases of rotation >10degrees were observed at any postoperative time point. From postoperative week 1 onward, version 2 had a statistically significant clockwise bias in the direction of rotation (P = 0.03); similar findings were observed for version 1. Surgeons reported acceptable ease of IOL handling during implantation for both version 1 and version 2. No device-related adverse events were reported. Conclusion: Both the version 1 and version 2 IOLs, each with frosted, squared haptics, demonstrated improved postoperative rotational stability compared with a control lens without frosted haptics. Because version 2 had the same overall geometry as the current TECNIS toric IOL, this design was selected for commercialization. Trial Registration: German Clinical Trials Register, DRKS00015287. Keywords: astigmatism, cataract, IOL rotation, surgery, toric IOL
To compare size, circularity, and centration outcomes of continuous curvilinear capsulorhexis (CCC) performed with or without assistance from the VERUS ophthalmic caliper (Mile High Ophthalmics, ...Denver, CO).
This was a multicenter retrospective consecutive case controlled series review.
Data from 40 consecutive cases using the VERUS device for CCC were compared to 40 consecutive cases with standard manual CCC. VERUS-assisted CCC size, circularity, and centration were closer to target compared to that of manual only procedures (P < .05). The average time from initiation to completion of the capsulotomy was shorter with manual (40 ± 11 seconds) compared to VERUS-assisted (71 ± 13 seconds) cases (P < .0001).
The VERUS ophthalmic caliper is effective at improving size, circularity, and centration of the CCC in a time-efficient manner when compared to manual procedures performed without VERUS guidance. J Refract Surg. 2016;32(10):654-658..
AIM:To assess NY-ESO-1 expression in a cohort of esophageal adenocarcinomas.METHODS:A retrospective search of our tissue archive for esophageal resection specimens containing esophageal ...adenocarcinoma was performed,for cases which had previously been reported for diagnostic purposes,using the systematised nomenclature of human and veterinary medicine coding system.Original haematoxylin and eosin stained sections were reviewed,using light microscopy,to confirm classification and tumour differentiation.A total of 27 adenocarcinoma resection specimens were then assessed using immunohistochemistry for NY-ESO-1 expression:4 well differentiated,14 moderately differentiated,4 moderatepoorly differentiated,and 5 poorly differentiated.RESULTS:Four out of a total of 27 cases of esophageal adenocarcinoma examined(15%)displayed diffuse cytoplasmic and nuclear expression for NY-ESO-1.They displayed a heterogeneous and mosaic-type pattern of diffuse staining.Diffuse cytoplasmic staining was not identified in any of these structures:stroma,normal squamous epithelium,normal submucosal gland and duct,Barrett’s esophagus(goblet cell),Barrett’s esophagus(non-goblet cell)and high grade glandular dysplasia.All adenocarcinomas showed an unexpected dot-type pattern of staining at nuclear,paranuclear and cytoplasmic locations.Similar dot-type staining,with varying frequency and size of dots,was observed on examination of Barrett’s metaplasia,esophageal submucosal gland acini and the large bowel negative control,predominantly at the crypt base.Furthermore,a prominent pattern of apical(luminal)cytoplasmic dot-type staining was observed in some cases of Barrett’s metaplasia and also adenocarcinoma.A further morphological finding of interest was noted on examination of haematoxylin and eosin stained sections,as aggregates of lymphocytes were consistently noted to surround submucosal glands.CONCLUSION:We have demonstrated for the first time NY-ESO-1 expression by esophageal adenocarcinomas,Barrett’s metaplasia and normal tissues other than germ cells.
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