Publications by authors named "Mark Barakat"

23 Publications

  • Page 1 of 1

Effects of simulated COVID-19 cytokine storm on stent thrombogenicity.

Cardiovasc Revasc Med 2021 Apr 8. Epub 2021 Apr 8.

CVPath Institute, Inc., 19 Firstfield Road, Gaithersburg, MD 20878, United States of America. Electronic address:

Background: Cytokine storm-related hypercoagulation may be important in the pathogenesis of stent thrombosis in patients with SARS-CoV-2. Whether stent polymers behave differently under such conditions has never been explored.

Methods: Fluorinated polymer-nanocoated and uncoated COBRA stents (CeloNova), BioLinx-polymer-coated Resolute Onyx stents (Medtronic), and Synergy stents (Boston Scientific), which are abluminally coated with a bioabsorbable polymer, were exposed to human blood from healthy donors which was supplemented with 400 pg/mL IL-6 and 100 pg/mL TNF-α, similar to what is seen in cytokine storm caused by SARS-CoV-2. Platelet adhesion and neutrophil activation, assessed by immunofluorescence, were compared under cytokine storm and control conditions (untreated blood) (n = 4 experimental runs).

Results: Platelet adhesion values, defined as %platelet-covered area x staining intensity, were significantly lower in coated and uncoated COBRA and in Resolute Onyx than in Synergy under control conditions (1.28 × 10 ± 0.43 × 10 vs. 2.92 × 10 ± 0.49 × 10 vs. 3.57 × 10 ± 0.73 × 10 vs. 9.94 × 10 ± 0.99 × 10; p ≤0.0001). In cytokine storm, platelet adhesion values remained low in coated COBRA-PzF (1.78 × 10 ± 0.38 × 10) compared to all other devices (uncoated COBRA: 5.92 × 10 ± 0.96 × 10; Resolute Onyx: 7.27 × 10 ± 1.82 × 10; Synergy: 11.28 × 10 ± 1.08 × 10; p ≤ 0.0001). Although cytokine storm conditions significantly increased neutrophil activation in all stents, it was significantly less in coated and uncoated COBRA, and in Resolute Onyx than in Synergy.

Conclusions: Blood-biomaterials interactions may determine the thrombogenic potential of stents. Under simulated cytokine storm conditions, fluoropolymer-coated stents showed the most favorable anti-thrombogenic and anti-inflammatory properties.
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http://dx.doi.org/10.1016/j.carrev.2021.03.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026249PMC
April 2021

Extension study of the safety and efficacy of CLS-TA for treatment of macular oedema associated with non-infectious uveitis (MAGNOLIA).

Br J Ophthalmol 2021 Mar 12. Epub 2021 Mar 12.

Clearside Biomedical Inc, Alpharetta, Georgia, USA.

Purpose: To assess the extended efficacy and safety of suprachoroidal triamcinolone acetonide injectable suspension (CLS-TA) among patients with macular oedema (ME) secondary to non-infectious uveitis (NIU).

Methods: Patients with uveitic ME were treated with suprachoroidal CLS-TA at baseline and week 12 of the Efficacy and Safety of Suprachoroidal CLS-TA for Macular Edema Secondary to Noninfectious Uveitis: Phase 3 Randomized Trial (PEACHTREE) study. Time to rescue was evaluated over 24 additional weeks for MAGNOLIA. Safety data, visual acuity and retinal central subfield thickness (CST) reduction were also evaluated. Of the 53 eligible patients (46 CLS-TA and 7 control), 33 patients were enrolled (28 CLS-TA and 5 control).

Results: Over the entire 48-week period for PEACHTREE and MAGNOLIA, the median time to rescue therapy was 257 days versus 55.5 days for the CLS-TA and sham-control arms, respectively. Of 28 CLS-TA treated patients who participated in MAGNOLIA, 14 (50%) did not require rescue therapy through approximately 9 months after the second treatment. Among CLS-TA patients not requiring rescue, there was a mean gain of 12.1 letters and mean CST reduction of 174.5 µm at week 48. No serious adverse events related to study treatment were observed.

Conclusion: Approximately 50% of patients did not require additional treatment for up to 9 months following the last CLS-TA administration.
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http://dx.doi.org/10.1136/bjophthalmol-2020-317560DOI Listing
March 2021

Frequency of Urgent or Emergent Vitreoretinal Surgical Procedures in the United States During the COVID-19 Pandemic.

JAMA Ophthalmol 2021 04;139(4):456-463

Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, Columbia University Irving Medical Center, New York.

Importance: The American Academy of Ophthalmology (AAO) indicated that urgent or emergent vitreoretinal surgical procedures should continue during the coronavirus disease 2019 (COVID-19) pandemic. Although decreases in the frequency of critical procedures have been reported outside the field of ophthalmology, analyses are limited by volume, geography, and time.

Objective: To evaluate whether the frequency of ophthalmic surgical procedures deemed urgent or emergent by the AAO changed across the United States during the COVID-19 pandemic.

Design, Setting, And Participants: Vitreoretinal practices from 17 institutions throughout the US participated in this multicenter cross-sectional study. The frequency of 11 billed vitreoretinal Current Procedural Terminology (CPT) codes across respective weeks was obtained from each practice between January 1, 2019, and May 31, 2020. Data were clustered into intravitreal injections (code 67028), lasers and cryotherapy (codes 67141, 67145, and 67228), retinal detachment (RD) repairs (codes 67107, 67108, 67110, and 67113), and other vitrectomies (codes 67036, 67039, and 67040). Institutions were categorized by region (Northeast, Midwest, South, and West Coast), practice setting (academic [tax-exempt] or private [non-tax-exempt]), and date of respective statewide stay-at-home orders.

Main Outcomes And Measures: Nationwide changes in the frequency of billing for urgent or emergent vitreoretinal surgical procedures during the COVID-19 pandemic.

Results: A total of 526 536 CPT codes were ascertained: 483 313 injections, 19 257 lasers or cryotherapy, 14 949 RD repairs, and 9017 other vitrectomies. Relative to 2019, a weekly institutional decrease in injections was observed from March 30 to May 2, 2020, with a maximal 38.6% decrease (from a mean [SD] of 437.8 [436.3] to 273.8 [269.0] injections) from April 6 to 12, 2020 (95% CI, -259 to -69 injections; P = .002). A weekly decrease was also identified that spanned a longer interval, at least until study conclusion (March 16 to May 31, 2020), for lasers and cryotherapy, with a maximal 79.6% decrease (from a mean [SD] of 6.6 [7.7] to 1.5 [2.0] procedures) from April 6 to 12, 2020 (95% CI, -6.8 to -3.3 procedures; P < .001), for RD repairs, with a maximal 59.4% decrease (from a mean [SD] of 3.5 [4.0] to 1.6 [2.2] repairs) from April 13 to 19, 2020 (95% CI, -2.7 to -1.4 repairs; P < .001), and for other vitrectomies, with a maximal 84.3% decrease (from a mean [SD] of 3.0 [3.1] to 0.4 [0.8] other vitrectomies) from April 6 to 12, 2020 (95% CI, -3.3 to -1.8 other vitrectomies; P < .001). No differences were identified by region, setting, or state-level stay-at-home order adjustment.

Conclusions And Relevance: Although the AAO endorsed the continued performance of urgent or emergent vitreoretinal surgical procedures, the frequency of such procedures throughout the country experienced a substantial decrease that may persist after the COVID-19 pandemic's initial exponential growth phase. This decrease appears independent of region, setting, and state-level stay-at-home orders. It is unknown to what extent vitreoretinal intervention would have decreased without AAO recommendations, and how the decrease is associated with outcomes. Although safety is paramount during the COVID-19 pandemic, practices should consider prioritizing availability for managing high-acuity conditions until underlying reasons for the reduction are fully appreciated.
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http://dx.doi.org/10.1001/jamaophthalmol.2021.0036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934075PMC
April 2021

Design and rationale of a randomized trial of COBRA PzF stenting to REDUCE duration of triple therapy (COBRA-REDUCE).

Cardiovasc Revasc Med 2021 Jan 22. Epub 2021 Jan 22.

Cardiovascular Research Institute Dublin, Mater Private Hospital, Dublin, Ireland; School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons University of Medicine and Health Sciences, Dublin, Ireland. Electronic address:

Background/purpose: A coronary stent with thromboresistant and pro-healing properties such as the polymer polyzene F-coated (COBRA PzF) stent might safely allow for a very short duration of triple therapy in patients taking oral anticoagulation (OAC) who undergo coronary stenting.

Methods: The COBRA-REDUCE trial is a prospective, multinational, randomized, open-label, assessor-blinded trial. A total of 996 patients at high bleeding risk because of requirement for OAC (with a vitamin K antagonist or non-vitamin K antagonist for any indication) will be randomized at sites in the United States and Europe to treatment with the COBRA-PzF stent followed by very short duration (14 days) DAPT or a Food and Drug Administration (FDA)-approved new generation drug-eluting stent followed by guideline-recommended DAPT duration (3 or 6 months). Two co-primary endpoints will be tested at 6 months: a bleeding co-primary endpoint (bleeding academic research consortium [BARC] ≥2 bleeding beyond 14 days or after hospital discharge, whichever is later [superiority hypothesis]) and a thrombo-embolic co-primary endpoint (the composite of all-cause death, myocardial infarction, definite/probable stent thrombosis or ischaemic stroke [non-inferiority hypothesis]). The trial is registered at clinicaltrials.gov (NCT02594501).

Conclusion: The COBRA-REDUCE trial will determine whether coronary stenting with the COBRA PzF stent followed by 14 days of clopidogrel will reduce bleeding without increasing thrombo-embolic events compared with FDA-approved DES followed by 3-6 months clopidogrel in patients taking OAC and aspirin.
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http://dx.doi.org/10.1016/j.carrev.2021.01.022DOI Listing
January 2021

Suprachoroidal CLS-TA for non-infectious uveitis: an open-label, safety trial (AZALEA).

Br J Ophthalmol 2021 Feb 5. Epub 2021 Feb 5.

Clearside Biomedical Inc, Alpharetta, Georgia, USA.

Purpose: To evaluate local and systemic safety of suprachoroidal (SC) triamcinolone acetonide injectable suspension (CLS-TA) injections in subjects with non-infectious uveitis (NIU).

Design: Open-label, prospective multicentre safety study.

Participants: Thirty-eight subjects with NIU, with and without macular oedema (MO).

Methods: Treatment consisted of two suprachoroidal injections of CLS-TA 4 mg, 12 weeks apart. Best-corrected visual acuity (BCVA), adverse event (AE) assessment, ophthalmic examinations and optical coherence tomography (OCT) were conducted every 4 weeks for 24 weeks. Blood samples were analysed for plasma triamcinolone acetonide (TA) concentrations.

Main Outcome Measures: The main outcome measure was frequency of AEs. Other endpoints included plasma TA concentrations, change in signs of inflammation, BCVA and retinal central subfield thickness (CST).

Results: Based on a CST of >300 µm, 20 out of 38 subjects had MO at baseline. Mean intraocular pressure (IOP) was 13.3 mm Hg at baseline and 15.2 mm Hg at week 24 in the study eye. A total of six (15.8%) subjects had an IOP rise >10 mm Hg compared with baseline, in the study eye, and two (5.3%) subjects had IOP >30 mm Hg (maximum 34 mm Hg at week 8 and 38 mm Hg at week 20). Cataract formation AEs were reported in four study eyes; one of which was deemed treatment-related. No serious ocular AEs in the study eye occurred in the study. Quantifiable post-injection TA plasma concentration was <1 ng/mL. Efficacy parameters showed improvement over the 24-week study period.

Conclusions: Suprachoroidally administered CLS-TA was safe and well tolerated over the 24-week, open-label study in NIU subjects with and without MO.
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http://dx.doi.org/10.1136/bjophthalmol-2020-318019DOI Listing
February 2021

Successful Use of Veno-Venous Extracorporeal Membrane Oxygenation in a Patient With Severe COVID-19 Pneumonia.

Cureus 2020 Dec 6;12(12):e11938. Epub 2020 Dec 6.

Surgery, Harlem Hospital Center, New York, USA.

Lung damage in coronavirus disease 2019 (COVID-19) pneumonia may be so severe that management with lung-protective ventilation, neuromuscular blockade, and proning cannot sustain life. Extracorporeal membrane oxygenation (ECMO) may allow patients with acute respiratory distress syndrome (ARDS) to undergo a period of lung recovery before being transitioned back to mechanical ventilation. A successful outcome requires both timely initiation of ECMO before development of irreversible organ injury from severe ARDS and selection of patients with adequate physiologic reserve. We present a 40-year-old healthy male patient with severe COVID-19 pneumonia not responsive to more conservative options for ARDS management. Veno-venous extracorporeal membrane oxygenation (VV-ECMO) rescue therapy was instituted and after 34 days he was successfully decannulated and eventually discharged from the hospital in good condition. Despite needing ECMO for longer than what is reported in most case reports and series involving patients with COVID-19 pneumonia, our patient made a complete recovery. He was also followed up in an outpatient setting and seen to be doing well. With appropriate patient selection and timely initiation of ECMO, many patients stand to benefit from this treatment. Ensuring that therapy be delivered to these patients when the need arises requires meticulous planning and provision of the appropriate resources. In addition, inflammatory markers may serve as a further guide to decision-making in patients already on ECMO as has already been indicated in the literature.
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http://dx.doi.org/10.7759/cureus.11938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785490PMC
December 2020

Clinical Characterization of Suprachoroidal Injection Procedure Utilizing a Microinjector across Three Retinal Disorders.

Transl Vis Sci Technol 2020 10 22;9(11):27. Epub 2020 Oct 22.

Clearside Biomedical, Alpharetta, GA, USA.

Purpose: This study assessed physician-investigator experience with suprachoroidal (SC) injections, an investigational therapeutic administration technique using a 900 or 1100 µm microneedle to inject drugs into the SC space.

Methods: Datasets from six clinical trials across three diseases (noninfectious uveitis; diabetic macula edema, and retinal vein occlusion) were assessed. In addition to a user survey, retrospective correlations were performed between procedural variables (needle length), and demographics, and ocular characteristics.

Results: In the user survey, 84% (31/37) of physician-investigators did not perceive the SC injections to be meaningfully more challenging than other ocular injections. For the correlation analysis, the 900 µm needle was used for 71% (412/581) of baseline injections, and switching to the longer needle occured in the remaining 29% of baseline injections. No statistical correlations were found between needle lengths and age, race, disorder, refraction, visual acuity, intraocular pressure, retinal central subfield thickness, or lens status. Patient gender and needle length were statistically associated, with 76% (210/275) versus 66% (202/306) of injections administered with 900 µm needles for female and male gender, respectively. Injection quadrant correlated to needle length with 78% (214/275) of superotemporal quadrant injections administered with 900 µm needles, compared with 65% (73/113) of inferotemporal quadrant injections.

Conclusions: Both the user survey and the correlation analysis demonstrated that SC injection is well accepted by physician-investigators, and the two needle lengths accommodate a wide range of anatomic and demographic variables.

Translational Relevance: These results, along with the presented ex-vivo endoscopic imaging, suggest that SC injection could be readily adopted in clinical practice for targeted compartmentalized delivery of ocular therapeutics.
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http://dx.doi.org/10.1167/tvst.9.11.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585395PMC
October 2020

Suprachoroidal CLS-TA plus Intravitreal Aflibercept for Diabetic Macular Edema: A Randomized, Double-Masked, Parallel-Design, Controlled Study.

Ophthalmol Retina 2021 01 20;5(1):60-70. Epub 2020 Aug 20.

Clearside Biomedical, Inc., Alpharetta, Georgia.

Purpose: This study evaluated the potential safety, efficacy, and durability advantages of investigational triamcinolone acetonide suspension (CLS-TA; Clearside Biomedical, Alpharetta, GA) administered suprachoroidally in conjunction with intravitreal aflibercept compared with aflibercept monotherapy for treatment of diabetic macular edema (DME).

Design: TYBEE was a prospective, controlled, double-masked study. Patients were randomized 1:1 to CLS-TA and aflibercept (active) or aflibercept monotherapy (control), and assessed over 24 weeks.

Participants: Treatment-naive DME patients with best-corrected visual acuity (BCVA) of 20 to 70 letters and central subfield retinal thickness (CST) of more than 300 μm.

Methods: Patients in the active group (n = 36) received CLS-TA and aflibercept at baseline and week 12. Patients in the control group (n = 35) received aflibercept at baseline, week 4, week 8, and week 12. To mask both groups, sham suprachoroidal and intravitreal injections were utilized. All patients were eligible to receive aflibercept as needed at weeks 4, 8, 16, and 20 per prespecified criteria.

Main Outcome Measure: Mean change in BCVA from baseline. Treatment differences were assessed with a 2-sided significance level of 0.10.

Results: Mean BCVA changes from baseline to week 24 were not statistically different in the active and control groups (intention-to-treat [ITT] population: +11.4 letters and +13.8 letters [P = 0.288]; per protocol [PP] population: +12.3 letters and +13.5 letters [P = 0.664]; respectively). Greater improvement in CST was seen in the active versus control group (ITT population: -212.1 μm and -178.6 μm [P = 0.089]; PP population: -226.5 μm and -176.1 μm [P = 0.035]; respectively). Compared with the control group, eyes in the active group received fewer treatments (scheduled plus as-needed treatments averaging 4.6 versus 2.6, respectively). No treatment-related serious adverse events were observed. Ocular adverse events were low for both arms. Cataract events, all assessed as unrelated to treatment, and events of elevated intraocular pressure trended higher in the active group.

Conclusions: CLS-TA administered suprachoroidally in conjunction with intravitreal aflibercept for treatment of DME provides simliar visual benefit at 24 weeks' follow-up compared with aflibercept monotherapy, is well tolerated and shows modest anatomic benefit with potential to reduce treatment burden.
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http://dx.doi.org/10.1016/j.oret.2020.08.007DOI Listing
January 2021

Time Course of Reendothelialization with Polyzene-F Nanocoated Cobra PzF™ Coronary Stent on Rabbit Iliac Arteries.

Cardiovasc Revasc Med 2020 02 9;21(2):195-199. Epub 2019 Nov 9.

Department of Cardiology, CHRU Lille, Lille, France.

Purpose: Evaluation of reendothelialization with a new thin struts cobalt chromium alloy stent coated with a nano-layer of Polyzene™-F (PzF) in a rabbit iliac artery model.

Methods: Fifteen stented external rabbit iliac arteries were harvested at Day 7 for electron microscopy analysis following Cobra PzF stents implantation to assess reendothelialization and compare to historical data. Ten additional rabbits were used to assess time course of reendothelialization at 3 and 5 days.

Results: At Day 7, almost complete coverage of endothelial cells was observed with a coverage of 99.54 ± 0.25% of the stented area. No thrombus area was noted. At Day 3, more than half of examined pieces was reendothelialized and reached 78.30 ± 3.7% at Day 5 (p < .01 between each group). All stents were well expanded against the arterial wall and no struts were mal-apposed.

Conclusions: Reendothelialization was rapid and complete at Day 7. This is the fastest reendothelization process after stenting in this model. No stent occlusion was observed.
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http://dx.doi.org/10.1016/j.carrev.2019.11.005DOI Listing
February 2020

Suprachoroidal Triamcinolone Acetonide for Retinal Vein Occlusion: Results of the Tanzanite Study.

Ophthalmol Retina 2018 04 29;2(4):320-328. Epub 2017 Sep 29.

Clearside Biomedical, Alpharetta, Georgia.

Purpose: To compare the safety and efficacy of treatment with suprachoroidal triamcinolone acetonide (CLS-TA) plus intravitreal aflibercept vs. treatment with aflibercept alone in patients with macular edema due to retinal vein occlusion (RVO).

Design: Randomized masked controlled clinical trial.

Subjects: Forty-six patients with RVO.

Methods: Subjects were randomized 1:1 to suprachoroidal injection of CLS-TA plus intravitreal aflibercept (combination arm) or sham suprachoroidal injection plus aflibercept (aflibercept arm), followed by aflibercept as needed at months 1, 2, and 3 in each arm.

Main Outcome Measures: The primary efficacy end point was the number of protocol-required aflibercept re-treatments through month 3. Secondary outcomes included mean improvement from baseline best-corrected visual acuity (BCVA), central subfield thickness (CST), and the percentage of participants with CST ≤310 μm at each time point.

Results: The number of re-treatments were reduced in the combination arm compared with that in the aflibercept arm (23 vs. 9; -61%; P = 0.013) and the percentage of participants requiring no re-treatments was increased (78% vs. 30%; P = 0.003). The mean improvement from baseline BCVA letter score in combination vs. that in the aflibercept arms was 16.1 vs. 11.4 (P = 0.20) at month 1, 20.4 vs. 11.9 (P = 0.04) at month 2, and 18.9 vs. 11.3 (P = 0.09) at month 3. The mean baseline CST in the combination arm (731.1 μm) decreased into the normal range at month 1 (284.7 μm) and remained there at months 2 and 3 (272.4 μm and 285.4 μm). The mean baseline CST (727.5 μm) in the aflibercept arm decreased to 322.8 μm at month 1 and increased at months 2 and 3 (383.4 μm and 384.6 μm). Edema resolution (CST ≤ 310 μm) occurred in 87.0%, 87.0%, and 78.3% of participants in the combination arm at months 1, 2, and 3, respectively, vs. 56.5%, 47.8%, and 47.8% of participants in the aflibercept arm. In the combination arm, 1 participant had cataract progression and 4 (2 with preexistent glaucoma) had increased intraocular pressure that was controlled with topical medication.

Conclusions: Combination intravitreal aflibercept and suprachoroidal CLS-TA is well tolerated and significantly reduces the need for additional intravitreal aflibercept injections over a 3-month period in patients with RVO. Preliminary evidence suggests that combination therapy may sustain edema resolution and improve visual outcomes.
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http://dx.doi.org/10.1016/j.oret.2017.07.013DOI Listing
April 2018

Safety and Feasibility of Chemoembolization with Doxorubicin-Loaded Small Calibrated Microspheres in Patients with Hepatocellular Carcinoma: Results of the MIRACLE I Prospective Multicenter Study.

Cardiovasc Intervent Radiol 2018 Apr 22;41(4):587-593. Epub 2017 Nov 22.

Klinikum Darmstadt, Darmstadt, Germany.

Purpose: The MIRACLE I pilot study was designed as a preliminary investigation of safety and efficacy of Embozene TANDEM microspheres loaded with doxorubicin for treatment of locally untreatable (i.e., unresectable and not suitable for local thermal ablation) hepatocellular carcinoma (HCC).

Materials And Methods: Patients with locally untreatable HCC (mono- or bilobar disease, ECOG performance status 0-2, Child-Pugh score < 11) were eligible for this single-arm multicenter study. DEB-TACE was performed with 75 µm Embozene TANDEM loaded with 150 mg of doxorubicin.

Results: Twenty-five subjects with 41 tumors were treated (mean age 65 years); 16, 52, and 32% had BCLC A, B, and C status, respectively. Child-Pugh status was A for 64%, B for 32%, and C for 4%; 40% had ascites. About 92% had disease localized to one liver lobe. Most (72%) underwent ≤ 2 DEB-TACE procedures. Average doxorubicin dose was 124.5 ± 36.1 mg (median 150 mg) per procedure. Two patients had procedure-related SAE (liver necrosis, worsening of liver insufficiency) within 30 days of the first DEB-TACE procedure. Six-month freedom from procedure-related SAE or death was 68% (one hepatic encephalopathy, five deaths). Tumor response or stable disease was achieved in 95% (20/21) of subjects. Freedom from tumor progression or death at 6 months was 76%. The one-year survival rate was 56% overall and 73% among patients without ascites at baseline.

Conclusion: MIRACLE I results suggest that Embozene TANDEM microspheres loaded with doxorubicin can provide good local tumor control in a heterogeneous group of patients with locally untreatable HCC.

Level Of Evidence: Level 2b, Individual cohort study.
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http://dx.doi.org/10.1007/s00270-017-1839-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838148PMC
April 2018

9-Month Clinical and Angiographic Outcomes of the COBRA Polyzene-F NanoCoated Coronary Stent System.

JACC Cardiovasc Interv 2017 01;10(2):160-167

CeloNova BioSciences, San Antonio, Texas.

Objectives: The aim of this study was to assess the safety and effectiveness of the COBRA Polyzene-F NanoCoated Coronary Stent System (CeloNova Biosciences, San Antonio, Texas) for the treatment of de novo coronary artery lesions.

Background: Polyzene-F-coated coronary stents have shown reduced thrombogenicity and inflammation in preclinical studies.

Methods: Patients with de novo coronary artery lesions meeting eligibility criteria were enrolled in a nonrandomized, prospective clinical trial. The primary endpoint was target vessel failure (TVF) (defined as a composite of cardiac death, myocardial infarction, or clinically driven target vessel revascularization) at 9 months. A pre-specified subset was planned for routine repeat angiographic follow-up at 9 months. The powered secondary endpoint was mean late lumen loss (LL). The comparator was a performance goal derived from meta-analysis of historical bare-metal stent trials of 19.62% for TVF and 1.1 mm for LL. Other secondary endpoints were clinically driven target lesion revascularization and definite or probable stent thrombosis.

Results: Of 296 enrolled patients, 287 (97%) completed primary endpoint analysis; 130 were planned for angiographic follow-up and 115 (88%) completed. At 9 months, TVF had occurred in 33 patients (11.5%; upper 95% confidence boundary: 15.07%), including 1 (0.3%) cardiac death, 20 (7.0%) myocardial infarctions (17 periprocedural), and 17 (5.9%) target vessel revascularizations. LL was 0.84 ± 0.48 mm (upper 95% confidence boundary: 0.92). Target lesion revascularization occurred in 13 patients (4.6%). There were no stent thrombosis events.

Conclusions: The COBRA Polyzene-F stent met performance goals for TVF and LL at 9 months. There was an excellent safety profile, with infrequent late myocardial infarction and no stent thrombosis.
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http://dx.doi.org/10.1016/j.jcin.2016.10.037DOI Listing
January 2017

Preclinical evaluation of a novel polyphosphazene surface modified stent.

Int J Cardiol 2016 Nov 30;222:217-225. Epub 2016 Jul 30.

CVPath Institute, Inc., Gaithersburg, MD, United States.

Background: Treatment options for patients with coronary artery disease at high risk for bleeding complications are limited. The aim of the current preclinical study was to evaluate neointimal coverage, endothelial recovery, inflammation and thrombogenicity in a novel thin-strut (71μm thickness) Cobalt Chromium (CoCr) stent modified with a nano-thin Polyzene®-F (PzF) surface coating.

Methods And Results: Twenty-eight single PzF nano-coated stents and 20 bare metal control stents (BMS) were implanted in the coronary arteries of 24 pigs, with scheduled 5- (n=5), 28- (n=13), and 90-day (n=6) follow-up in addition to overlapping configuration (n=6 each), examined at 28-days. Histomorphometric analysis showed significantly lower neointimal thickness in PzF nano-coated stents than BMS controls at both 28- and 90-days (p=0.023 and 0.005) and reduced inflammation (p=0.06 and 0.13). Endothelial coverage over luminal surfaces at all time points was similar between nano-coated stents and BMS controls. We conducted supplementary in-vitro experiments using human monocytes and an ex-vivo swine carotid-jugular arterio-venous shunt model to better understand the healing properties afforded by the PzF nano-coating. Overall, the PzF-nano-coating showed reduced monocyte adhesion and thrombus formation compared to the un-coated controls.

Conclusions: Stents modified with a nano-thin PzF-coating implanted in healthy swine indicate favorable vascular healing properties shown by reduced neointimal hyperplasia and inflammation, along with resistance to thrombus formation in an ex-vivo shunt model over unmodified stents.
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http://dx.doi.org/10.1016/j.ijcard.2016.07.181DOI Listing
November 2016

Neovascular AMD: Where do we go from here?

Nepal J Ophthalmol 2015 Jul;7(14):97-102

Practices with Retinal Consultants of Arizona in Phoenix.

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http://dx.doi.org/10.3126/nepjoph.v7i2.14958DOI Listing
July 2015

Equine pericardium as a biological covering for the treatment of diabetic foot wounds: a prospective study.

J Am Podiatr Med Assoc 2012 Sep-Oct;102(5):352-8

Department of Orthopedic Surgery, Rush University Medical Center, Oak Park, IL, USA.

Background: Diabetic foot wounds remain a significant health-care issue. Healing these wounds in a timely manner is of paramount importance because the duration of ulceration correlates with increased rates of infection and amputation, costing billions of dollars yearly. Collagen-based matrices have been used as wound covers and have been shown to improve and expedite healing. We present our experience with equine pericardium biomatrix for the treatment of neuropathic foot wounds.

Methods: Thirty-four patients with 37 diabetic foot wounds were evaluated at two institutions prospectively. All of the wounds were debrided, and equine pericardium biomatrix was applied. Secondary dressings were changed every 48 to 72 hours until healed or for 12 weeks after application. Healing rate at 12 weeks, time to wound closure, and complications were evaluated.

Results: Twenty-two men and 12 women (mean age, 56.9 years) were treated and evaluated. Mean and median wound sizes at initial treatment were 715.8 and 440 mm(2), respectively. The overall wound healing rate by 12 weeks was 75.7% (n =28). Mean and median times to wound closure were 7.2 and 7.0 weeks, respectively. No device or procedure-related complications were reported.

Conclusions: The use of equine pericardium as a temporary biological scaffold is safe and effective for the treatment of chronic neuropathic foot wounds.
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http://dx.doi.org/10.7547/1020352DOI Listing
March 2013

Bilateral subcutaneous emphysema from pressurized infusion during pars plana vitrectomy: a case report.

Retin Cases Brief Rep 2012 ;6(1):22-4

From the *Department of Ophthalmology, Cole Eye Institute, Cleveland, Ohio; and †Department of Anesthesiology, Cleveland Clinic Foundation, Cleveland, Ohio.

Objectives: To report a case of extensive subcutaneous emphysema introduced during vitrectomy while using an advanced feedback-controlled pressurized infusion system.

Methods: Clinical case report of a 56-year-old woman undergoing pars plana vitrectomy for rhegmatogenous retinal detachment of the left eye. The clinical and radiologic findings of the patient's eyes were documented. The mechanisms of feedback-controlled pressurized infusion devices were reviewed to explain the adverse events. A search of PubMed was conducted to look for any similar cases and/or discussion.

Results: In this surgical case, vitrectomy was completed with air-fluid exchange and a formed anterior chamber was observed with an estimated pressure of high teens to low 20s by the surgeon. After the undraping, the patient was noted to have severe facial crepitus extending to the clavicles. Immediate chest X-ray was done, followed by computed tomography, confirming orbital and subcutaneous emphysema, as well as the presence of perfluoro-N-octane in the left orbit.

Conclusion: Integrated pressurized infusion devices using feedback sensors allow for a sophisticated method of maintaining intraocular pressure and globe formation. However, inadvertent or occult globe rupture may lead to disruption of feedback control and subsequent high rates of infusion. As the infused substances exit the site of rupture, they can lead to extensive extraocular gas or fluid accumulation, and we report a case of severe bilateral subcutaneous emphysema as a result.
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http://dx.doi.org/10.1097/ICB.0b013e3181f98ceaDOI Listing
November 2014

Pilot study of the delivery of microcollimated pars plana external beam radiation in porcine eyes.

Arch Ophthalmol 2011 May;129(5):628-32

Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.

Objective: To investigate the effects of a novel stereotactic radiosurgical system for pars plana delivery of microcollimated x-rays to the retina and determine the retinal radiological dose response and toxicity threshold in a pig model.

Methods: The x-rays were delivered through the pars plana to the maculae of Yucatan miniswine to verify the targeting and safety of a cornea-scleral, stabilized, office-based delivery system. Twelve eyes were randomized to receive 0, 16, 24, 42, 60, or 90 Gy in a single dose to the retina. Eye examinations, fundus photography, fluorescein angiography, and spectral-domain optical coherence tomography were obtained at days 7, 30, 60, and 90. Indocyanine green angiography was done at day 90.

Results: Through day 90 interim analysis, no abnormalities of external structures were noted. A small cortical lens opacity was noted in the 60-Gy group. Fundus evaluation revealed no abnormalities at 16 or 24 Gy. Beginning at day 30, circular pale retinal lesions with sharp margins were noted in the maculae of the eyes that received 42, 60, and 90 Gy. Higher-dose lesions showed late staining on fluorescein angiography, choroidal hypoperfusion on indocyanine green angiography, and defined photoreceptor loss and retinal thinning on spectral-domain optical coherence tomography.

Conclusion: Transscleral stereotactic radiation dosing of porcine eyes demonstrates no apparent clinical abnormalities in doses less than 24 Gy. Doses of 42 Gy or higher led to focal choroidal and retinal damage within the target area.

Clinical Relevance: Radiation can induce small-blood vessel closure and thereby has therapeutic potential in neovascular diseases such as age-related macular degeneration.
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http://dx.doi.org/10.1001/archophthalmol.2011.99DOI Listing
May 2011

Management of posteriorly dislocated endothelial keratoplasty donor lenticule.

Retin Cases Brief Rep 2011 ;5(2):163-4

From the *Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio; †Department of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio; ‡Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio; and §Department of Transplant, Cleveland Clinic, Cleveland, Ohio.

Purpose: The purpose of this study was to describe the management of a keratoplasty lenticule adhering to the retina after intraoperative dislocation.

Methods: We describe the posterior dislocation of the donor lenticule during endothelial keratoplasty in a 72-year-old woman with a transscleraly sutured intraocular lens, previous pars plana vitrectomy, and a posteriorly positioned Ahmed glaucoma tube shunt. The lenticule was retrieved through a pars plana approach 2 weeks later, at which time it was tightly adherent to the extramacular retina. Concurrent keratoplasty was performed.

Results: Six months after retrieval of the dislocated lenticule with repeat keratoplasty, the retinal examination is stable and the new graft remains attached.

Conclusion: An iris defect, the absence of capsular support, and a history of previous vitrectomy are all potential risk factors for the intraoperative migration of a keratoplasty lenticule. The surgical view 2 weeks after dislocation was not a limiting factor in the retrieval of the lenticule. However, the tight adherence of the lenticule to the retina required extensive peeling. To avoid a more difficult surgical repair and the potential for scar formation, earlier surgical repair would be preferable, especially if dealing with a macular location.
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http://dx.doi.org/10.1097/ICB.0b013e3181d4272dDOI Listing
November 2014

VEGF inhibitors for the treatment of neovascular age-related macular degeneration.

Expert Opin Investig Drugs 2009 May;18(5):637-46

Cole Eye Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.

Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world for those patients aged 50 years or older. Neovascular AMD, a subtype characterized by the growth of new, pathologic blood vessels, results in most of the cases of severe and rapid vision loss associated with AMD. A critical activator of angiogenesis in neovascular AMD is VEGF. Several therapies have been and are now being developed for neovascular AMD, with the goal of inhibiting VEGF. These VEGF inhibitors include the RNA aptamer pegaptanib, partial and full-length antibodies ranibizumab and bevacizumab, VEGF receptor decoy VEGF Trap, small interfering RNA-based therapies bevasiranib and AGN211745, sirolimus, and tyrosine kinase inhibitors including vatalanib, pazopanib, TG100801, TG101095, AG013958 and AL39324. At present, established therapies have met with great success in reducing the vision loss associated with neovascular AMD, whereas those still investigational in nature offer the potential for further advances.
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http://dx.doi.org/10.1517/13543780902855316DOI Listing
May 2009

Coats' disease, megalopapilla and Cornelia de Lange syndrome.

Ophthalmic Genet 2009 Jun;30(2):106-8

Cleveland Clinic Foundation, Cleveland Clinic, Cole Eye Institute, Cleveland, Ohio 44195, USA.

Cornelia de Lange syndrome (CdLS), a congenital disorder characterized by growth and mental retardation, hirsutism, and skeletal and cardiac anomalies, has been associated with a number of ophthalmic abnormalities including synophrys, long eyelashes, myopia, nasolacrimal duct obstruction, and ptosis. Only one case of Coats' disease has been described in the setting of this syndrome.(1) We describe a second case of Coats' disease in a five-year-old boy with this condition.
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http://dx.doi.org/10.1080/13816810902744613DOI Listing
June 2009

The use of implanted programmable infusion pumps in the management of nonmalignant, chronic low-back pain.

Neuromodulation 2007 Oct;10(4):376-80

Johns Hopkins University School of Medicine, Baltimore, MD, USA; and Codman & Shurtleff Inc., Raynham, MA, USA.

Objectives.  To assess the mode-of-use of implanted programmable infusion pumps in patients with nonmalignant, chronic low-back pain. Materials and Methods.  Charts from 101 consecutive eligible patients were analyzed retrospectively. Data were extracted relating to patient demographics, pump mode of infusion and flow rate, and medications used. Results.  Morphine was the agent most frequently used and most patients received one medication at each visit. At the last visit, 94.1% of patients were receiving constant-flow treatment; 90.1% had received such treatment for ≥ six months and 68.3% throughout the entire analysis period. For patients attaining constant-flow treatment, mean time from implantation to start of such treatment was 2.7 months. Discussion.  The results suggest that many patients with nonmalignant low-back pain could be implanted with a constant-flow pump when their programmable device needs replacing or, in some cases, at the start of intrathecal treatment. This would reduce costs and the requirement for surgery.
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http://dx.doi.org/10.1111/j.1525-1403.2007.00127.xDOI Listing
October 2007

Clinicopathologic effects of mutant GUCY2D in Leber congenital amaurosis.

Ophthalmology 2003 Mar;110(3):549-58

Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania School of Medicine, 51 North 39th Street, Philadelphia, PA 19104, USA.

Purpose: To study the retinal degeneration in an 11 -year-old patient with Leber congenital amaurosis (LCA) caused by mutation in GUCY2D.

Study Design: Comparative human tissue study.

Participants: Two subjects with LCA; postmortem eye from one LCA patient and three normal donors.

Methods: Clinical and visual function studies were performed between the ages of 6 and 10 years in the LCA eye donor and at age 6 in an affected sibling. Genomic DNA was screened for mutations in known LCA genes. The retina of the 11 -year-old subject with LCA was compared with normal retinas from donors age 3 days, 18 years, and 53 years. The tissues were processed for histopathologic studies and immunofluorescence with retinal cell-specific antibodies.

Results: Vision in both siblings at the ages examined was limited to severely impaired cone function. Mutation in the GUCY2D gene was identified in both siblings. Histopathologic study revealed rods and cones without outer segments in the macula and far periphery. The cones formed a monolayer of cell bodies, but the rods were clustered and had sprouted neurites in the periphery. Rods and cones were not identified in the midperipheral retina. The inner nuclear layer appeared normal in thickness throughout the retina, but ganglion cells were reduced in number.

Conclusions: An 11-year-old subject with LCA caused by mutant GUCY2D had only light perception but retained substantial numbers of cones and rods in the macula and far periphery. The finding of numerous photoreceptors at this age may portend well for therapies designed to restore vision at the photoreceptor level.
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http://dx.doi.org/10.1016/S0161-6420(02)01757-8DOI Listing
March 2003

The nuclear receptor NR2E3 plays a role in human retinal photoreceptor differentiation and degeneration.

Proc Natl Acad Sci U S A 2002 Jan 2;99(1):473-8. Epub 2002 Jan 2.

Scheie Eye Institute and F. M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USA.

Normal human retinal development involves orderly generation of rods and cones by complex mechanisms. Cell-fate specification involves progenitor cell lineage and external signals such as soluble factors and cell-cell interactions. In most inherited human retinal degenerations, including retinitis pigmentosa, a mutant gene causes loss of visual function, death of mature rods, and eventually death of all cone subtypes. Only one inherited retinal disorder, the enhanced S cone syndrome (ESCS), shows increased visual function, involving the minority S (blue) cones, and decreased rod and L/M (red/green) cone function. This autosomal recessive disease is caused by mutations in NR2E3, a photoreceptor nuclear receptor transcription factor, and may result from abnormal cell-fate determination, leading to excess S cones at the expense of other photoreceptor subtypes. In 16 ESCS patients with the most common NR2E3 mutation, R311Q, we documented an abnormal ratio of S to L/M cone function and progressive retinal degeneration. We studied the postmortem retina of an ESCS patient homozygous for NR2E3 R311Q. No rods were identified, but cones were increased approximately 2-fold, and 92% were S cones. Only 15% of the cones expressed L/M cone opsin, and some coexpressed S cone opsin. The retina was disorganized, with densely packed cones intermixed with inner retinal neurons. The retina was also degenerate, retaining photoreceptors in only the central and far peripheral regions. These observations suggest a key role for NR2E3 in regulation of human photoreceptor development. Degeneration of the NR2E3 retina may result from defective development, known S cone fragility, or abnormal maintenance of mature photoreceptors.
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http://dx.doi.org/10.1073/pnas.022533099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC117584PMC
January 2002