Carolyn Pan, MD

All Publications

• Brolucizumab: Evolution through Preclinical and Clinical Studies and the Implications for the Management of Neovascular Age-Related Macular Degeneration. Ophthalmology Nguyen, Q. D., Das, A., Do, D. V., Dugel, P., Gomes, A., Holz, F. G., Koh, A., Pan, C., Sepah, Y. J., Patel, N., MacLeod, H., Maurer, P. 2020

  Abstract

  Improving or maintaining visual acuity is the main goal for the treatment of neovascular age-related macular degeneration (nAMD). Current nAMD standard of care dictates frequent intravitreal (IVT) anti-vascular endothelial growth factor (VEGF) injections, which places a substantial burden on patients, caregivers, and physicians. Brolucizumab, a newly developed anti-VEGF molecule for nAMD treatment, has demonstrated longer durability and improvement in visual and anatomic outcomes in clinical studies in a q12-week regimen, indicating its potential to reduce treatment burden as an important therapeutic tool in nAMD management. This review focuses on the development of brolucizumab and the preclinical and clinical studies evaluating its efficacy, tolerability, and safety. Brolucizumab (also known as "RTH258" and "ESBA1008") is a humanized, single-chain variable fragment (scFv) antibody with a molecular mass of approximately 26 kDa that inhibits VEGF-A. Preclinical studies show that brolucizumab readily penetrates the retina to reach the retinal pigment epithelium (RPE)/choroid with minimal subsequent systemic exposure. The safety, tolerability, and efficacy of a single IVT brolucizumab administration in patients with treatment-naïve nAMD were first demonstrated in the SEE Phase 1/2 study. The OSPREY Phase 2 study showed brolucizumab to be as efficacious as aflibercept in a q8-week regimen with regard to best-corrected visual acuity (BCVA) and brolucizumab achieving greater fluid resolution. Brolucizumab-treated patients in the OSPREY study were subsequently challenged with a q12-week dosing interval, and the outcomes provided key information for the study design and end points of the Phase 3 studies. In the HAWK and HARRIER Phase 3 studies, after 3 monthly loading injections, brolucizumab treatment regimen (q12-week or q8-week) was guided by individual disease activity assessment using functional and anatomic parameters (central subfield thickness [CST], intraretinal fluid [IRF], or subretinal fluid [SRF]) versus aflibercept (q8-week). Fewer brolucizumab 6-mg treated eyes had disease activity versus aflibercept, and anatomic outcome results at weeks 16 and 48 demonstrate brolucizumab as a potent drying agent. Moreover, of patients treated with 6 mg brolucizumab, 55.6% and 51.0% maintained a q12-week dosing interval immediately after the loading phase until week 48 in HAWK and HARRIER, respectively. These Phase 3 studies demonstrated that the brolucizumab q12-week regimen maintains efficacy and safety while reducing treatment burden associated with regular IVT injections for patients with nAMD.

  View details for DOI 10.1016/j.ophtha.2019.12.031

  View details for PubMedID 32107066

• Questions on Rhegmatogenous Retinal Detachment and the Day of the Week of Repair or Diagnosis-Reply. JAMA ophthalmology Vail, D., Pan, C. K., Mruthyunjaya, P. 2020

  View details for DOI 10.1001/jamaophthalmol.2020.1867

  View details for PubMedID 32437496

• Association of Rhegmatogenous Retinal Detachment and Outcomes With the Day of the Week That Patients Undergo a Repair or Receive a Diagnosis. JAMA ophthalmology Vail, D., Pan, C., Pershing, S., Mruthyunjaya, P. 2019

  Abstract

  Importance: Because variation in care on weekends has been reported in many surgical fields, it is of interest if variations were noted for care patterns of rhegmatogenous retinal detachments (RRDs).Objective: To assess the association between modality of RRD repair and day of the week that patients receive a diagnosis or undergo RRD repair.Design, Setting, and Participants: A retrospective claims-based cohort analysis was performed of primary RRD surgery for 38 144 commercially insured patients in the United States who received a diagnosis of incident RRD between January 1, 2008, and December 31, 2016, and underwent repair within 14 days of diagnosis. Multinomial regression models were used to assess patients' likelihood of repair with different modalities, logistic regression models were used to assess patients' likelihood of reoperation, and linear regression models were used to assess time from diagnosis to repair. Data analysis was performed from March 9 to September 5, 2019.Exposures: Day of the week that the patient received a diagnosis of RRD or underwent RRD repair.Main Outcome and Measures: Modality of repair, time from diagnosis to repair, and 30-day reoperation rate.Results: Among the 38 144 patients in the study (23 031 men [60.4%]; mean [SD] age at diagnosis, 56.8 [13.4] years), pneumatic retinopexy (PR) was more likely to occur when patients received a diagnosis of RRD on Friday (relative risk ratio [RRR], 1.37; 95% CI, 1.17-1.60), Saturday (RRR, 1.73; 95% CI, 1.36-2.20), or Sunday (RRR, 1.53; 95% CI, 1.08-2.17) compared with Wednesday. Pneumatic retinopexy was more likely to be used for surgical procedures on Friday (RRR, 1.55; 95% CI, 1.33-1.80), Saturday (RRR, 2.03; 95% CI, 1.61-2.56), Sunday (RRR, 2.28; 95% CI, 1.55-3.35), or Monday (RRR, 1.70; 95% CI, 1.46-1.98). Patients undergoing PR on Sundays were more likely to receive another procedure (PR, scleral buckle, or pars plana vitrectomy) within 30 days (odds ratio, 1.62; 95% CI, 1.07-2.45). An association between the need for reoperation for repairs performed via scleral buckle or pars plana vitrectomy and the day of the week of the initial repair was not identified. Patients who received a diagnosis on a Friday waited a mean of 0.28 days (95% CI, 0.20-0.36 days) longer for repair than patients who received a diagnosis on a Wednesday.Conclusions and Relevance: These findings suggest that management of RRD varies according to the day of the week that diagnosis and repair occurs, with PR disproportionately likely to be used to repair RRDs during the weekend. Ophthalmologists should be aware that these results suggest that patients undergoing PR on Sundays may be more likely to require reoperation within 30 days.

  View details for DOI 10.1001/jamaophthalmol.2019.5253

  View details for PubMedID 31855233

• Nonmydriatric Photographic Screening for Diabetic Retinopathy in Pregnant Patients with Pre-existing Diabetes in a County Population Veerappan, M., Myung, D., Jelks, A., Pan, C. K. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2019

  View details for Web of Science ID 000488800705014

• ENDOGENOUS KLEBSIELLA PNEUMONIAE ENDOPHTHALMITIS IN NORTHERN CALIFORNIA. Retina (Philadelphia, Pa.) Shields, R. A., Smith, S. J., Pan, C. K., Do, D. V. 2019; 39 (3): 614–20

  Abstract

  PURPOSE: To report the clinical features, treatment modalities, and visual outcomes in 12 eyes with endogenous Klebsiella pneumoniae endophthalmitis (EKPE).METHODS: The medical records of all patients diagnosed with EKPE at Stanford Hospital (Palo Alto, CA) and Santa Clara Valley County Hospital (Santa Clara, CA) from January 2000 to March 2017 were retrospectively reviewed.RESULTS: A total of 10 patients (12 eyes) were diagnosed with EKPE. The median age at presentation was 56, 80% were male, and 30% were non-Asian. Presenting visual acuities ranged from 20/20 to no light perception. Of the 12 eyes 10 received a tap and injection (range, 1-33 injections per eye), 2 eyes underwent primary enucleation or evisceration, and 1 patient underwent pars plana vitrectomy after tap and injection. Final visual acuities ranged from no light perception (six eyes) to 20/300 or better (five eyes). Five patients eventually underwent evisceration or enucleation. All cases were associated with positive blood and/or vitreous cultures and had concurrent systemic infection.CONCLUSION: Endogenous Klebsiella pneumoniae endophthalmitis is a rare, but devastating, ocular infection. Most cases in this series resulted in light perception vision or worse, and almost half required enucleation or evisceration. In light of the virulence of EKPE, early diagnosis and treatment should be initiated in all suspected cases.

  View details for PubMedID 29232335

• ENDOGENOUS KLEBSIELLA PNEUMONIAE ENDOPHTHALMITIS IN NORTHERN CALIFORNIA RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES Shields, R. A., Smith, S. J., Pan, C. K., Do, D. V. 2019; 39 (3): 614–20

  View details for DOI 10.1097/IAE.0000000000001994

  View details for Web of Science ID 000480740100022

• Baseline characteristics associated with good visual acuity outcomes in myopic choroidal neovascularization: results from the RADIANCE trial Pan, C., Do, D. V., Hill, L., Ecoiffier, T., Stoilov, I. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2018

  View details for Web of Science ID 000442912502066

• POLYPOIDAL CHOROIDAL VASCULOPATHY: A CLINICOPATHOLOGIC STUDY. Retinal cases & brief reports Moussa, K., Bloomer, M. M., Schwartz, D. M., Pan, C. K., Toy, B. C., Crawford, J. B., Afshar, A. R. 2017; 11 Suppl 1: S128–S131

  Abstract

  PURPOSE: To present a unique case of polypoidal choroidal vasculopathy presenting as a blind, painful eye with a suspected intraocular mass, and to correlate clinical findings with histopathologic studies.METHODS: Clinical case report and literature review.RESULTS: A 58-year-old Vietnamese man presented with a blind, painful eye with concern for an intraocular mass. B-scan ultrasonography showed massive intraocular hemorrhage and could not rule out a tumor. The patient underwent enucleation and the histopathologic findings were consistent with polypoidal choroidal vasculopathy.CONCLUSION: Polypoidal choroidal vasculopathy can present with dense vitreous hemorrhage and may masquerade as an intraocular mass. It can progress rapidly and lead to profound, irreversible vision loss. A diagnosis of polypoidal choroidal vasculopathy should be considered in patients of African or East Asian origin presenting with vitreous hemorrhage.

  View details for PubMedID 27930435

• Smartphone-Based Tele-Ophthalmology Screening for Diabetic Retinopathy Toy, B. C., Prabhu, M., Pan, C., Leung, L., Blumenkranz, M. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2016

  View details for Web of Science ID 000394174004081

• SMARTPHONE-BASED DILATED FUNDUS PHOTOGRAPHY AND NEAR VISUAL ACUITY TESTING AS INEXPENSIVE SCREENING TOOLS TO DETECT REFERRAL WARRANTED DIABETIC EYE DISEASE RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES Toy, B. C., Myung, D. J., He, L., Pan, C. K., Chang, R. T., Polkinhorne, A., Merrell, D., Foster, D., Blumenkranz, M. S. 2016; 36 (5): 1000-1008

  Abstract

  To compare clinical assessment of diabetic eye disease by standard dilated examination with data gathered using a smartphone-based store-and-forward teleophthalmology platform.100 eyes of 50 adult patients with diabetes from a health care safety-net ophthalmology clinic. All patients underwent comprehensive ophthalmic examination. Concurrently, a smartphone was used to estimate near visual acuity and capture anterior and dilated posterior segment photographs, which underwent masked, standardized review. Quantitative comparison of clinic and smartphone-based data using descriptive, kappa, Bland-Altman, and receiver operating characteristic analyses was performed.Smartphone visual acuity was successfully measured in all eyes. Anterior and posterior segment photography was of sufficient quality to grade in 96 and 98 eyes, respectively. There was good correlation between clinical Snellen and smartphone visual acuity measurements (rho = 0.91). Smartphone-acquired fundus photographs demonstrated 91% sensitivity and 99% specificity to detect moderate nonproliferative and worse diabetic retinopathy, with good agreement between clinic and photograph grades (kappa = 0.91 ± 0.1, P < 0.001; AUROC = 0.97, 95% confidence interval, 0.93-1).The authors report a smartphone-based telemedicine system that demonstrated sensitivity and specificity to detect referral-warranted diabetic eye disease as a proof-of-concept. Additional studies are warranted to evaluate this approach to expanding screening for diabetic retinopathy.

  View details for Web of Science ID 000375482100029

  View details for PubMedID 26807627

• Spontaneous Resolution of Clinically Apparent Submacular Fluid After Scleral Buckling Surgery OPHTHALMIC SURGERY LASERS & IMAGING RETINA Lin, W., Pan, C. K., Tsui, I. 2014; 45 (5): 474–77

  Abstract

  A 37-year-old man presented with a chronic macula-involving rhegmatogenous retinal detachment. Despite scleral buckle surgery, the eye had clinically apparent submacular fluid for a prolonged period of time. By 1 year postoperatively, the patient had complete recovery of visual function, with residual ellipsoid layer changes on optical coherence tomography.

  View details for DOI 10.3928/23258160-20140827-01

  View details for Web of Science ID 000347297300021

  View details for PubMedID 25197928

• Morphologic features and evolution of inner retinal dimples on optical coherence tomography after internal limiting membrane peeling. Retina (Philadelphia, Pa.) Amouyal, F., Shah, S. U., Pan, C. K., Schwartz, S. D., Hubschman, J. P. 2014; 34 (10): 2096–2102

  Abstract

  To evaluate morphologic features and the evolution of inner retinal dimples using spectral domain optical coherence tomography after internal limiting membrane peeling.A single-center retrospective study of spectral domain optical coherence tomography features in 43 eyes after full-thickness macular hole surgery with internal limiting membrane peeling without adjunctive internal limiting membrane staining.Postoperatively, a total of 210 dimples were noted in 37 eyes (86%), with a mean of 5.7 dimples per eye (median, 5; range, 1-20), most frequently located in the inferotemporal quadrant (n = 122, 58%, P < 0.0001). At initial detection, mean dimple dimensions were 199 μm wide (median, 183; range, 87-442 μm) and 19 μm deep (median, 17; range, 7-35 μm). During follow-up, mean maximum dimensions were 351 μm wide (median, 305; range, 219-494 μm) and 30 μm deep (median, 31; range, 15-55 μm). Dimple dimension reached a maximum at 12 months (median, 10; range, 2-22 months) followed by a modest decline. Mean preoperative and final postoperative visual acuity were 0.70 logMAR (median, 0.54; range, 0.09-1.4 logMAR) and 0.38 logMAR (median, 0.30; range, 0-1.4 logMAR), respectively.Inner retinal dimples are common after adjunct-free internal limiting membrane peeling and evolve in the postoperative period with enlargement over the first 12 months followed by reduction in size, and have no apparent impact on the visual acuity.

  View details for DOI 10.1097/IAE.0000000000000193

  View details for PubMedID 24859477

• Embryonic stem cells as a treatment for macular degeneration. Expert opinion on biological therapy Pan, C. K., Heilweil, G., Lanza, R., Schwartz, S. D. 2013; 13 (8): 1125–33

  Abstract

  Retinal degenerations are typically characterized by loss of highly differentiated cell types within the neurosensory retina, such as photoreceptors, or retinal pigment epithelium (RPE). RPE loss is the final common pathway in a number of degenerations including the leading cause of new blindness in the developed world: age-related macular degeneration (AMD).This paper presents the pathophysiologic case for RPE transplantation with stem cell (SC)-derived tissue, a review of the preclinical data substantiating the hypothesis and the initial clinical trials safety data from early human trials.Targeting the RPE for transplantation with SC-derived tissue presents a reasonable therapeutic opportunity in a variety of important, otherwise untreatable, blinding conditions. Success of cellular replacement strategies is contingent on finding a viable source of replacement cells, establishing a safe technique for delivery and survival of transplanted cells within the host, restoration of normal retinal architecture and stabilization or improvement of vision.

  View details for DOI 10.1517/14712598.2013.793304

  View details for PubMedID 23705996

• Peripheral fluorescein angiographic findings in fellow eyes of patients with branch retinal vein occlusion. International journal of inflammation Tsui, I., Bajwa, A., Franco-Cardenas, V., Pan, C. K., Kim, H. Y., Schwartz, S. D. 2013; 2013: 464127

  Abstract

  Introduction. Branch retinal vein occlusion (BRVO) is a common retinal vascular condition that results in intraocular inflammatory changes. Ultra wide field fluorescein angiography (UWFFA) is a retinal imaging device that can capture peripheral retinal findings. The purpose of this study was to look for peripheral findings in the fellow eye of patients with BRVO using UWFFA. Methods. Retrospective imaging review of patients diagnosed with BRVO that had both eyes imaged with UWFFA. Images were graded for peripheral findings in other quadrants of the same eye as well as in all quadrants of the fellow eye. Results. Of 81 patients, 14 (17%) patients had late vascular leakage in a quadrant other than the BRVO distribution. Five (6%) findings were in the same eye, 8 (10%) findings were in the fellow eye, and 1 (1%) finding was in both the same eye and the fellow eye. Of these 14 patients, 11 (80%) patients had hypertension. Conclusion. Late peripheral retinal leakage in the fellow eye of patients with BRVO was detected in this cohort of patients with UWFFA. This novel finding may represent underlying systemic inflammation, hypertension, or bilateral BRVOs.

  View details for DOI 10.1155/2013/464127

  View details for PubMedID 23607044

  View details for PubMedCentralID PMC3626174

• Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet (London, England) Schwartz, S. D., Hubschman, J. P., Heilwell, G., Franco-Cardenas, V., Pan, C. K., Ostrick, R. M., Mickunas, E., Gay, R., Klimanskaya, I., Lanza, R. 2012; 379 (9817): 713–20

  Abstract

  It has been 13 years since the discovery of human embryonic stem cells (hESCs). Our report provides the first description of hESC-derived cells transplanted into human patients.We started two prospective clinical studies to establish the safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium (RPE) in patients with Stargardt's macular dystrophy and dry age-related macular degeneration--the leading cause of blindness in the developed world. Preoperative and postoperative ophthalmic examinations included visual acuity, fluorescein angiography, optical coherence tomography, and visual field testing. These studies are registered with ClinicalTrials.gov, numbers NCT01345006 and NCT01344993.Controlled hESC differentiation resulted in greater than 99% pure RPE. The cells displayed typical RPE behaviour and integrated into the host RPE layer forming mature quiescent monolayers after transplantation in animals. The stage of differentiation substantially affected attachment and survival of the cells in vitro after clinical formulation. Lightly pigmented cells attached and spread in a substantially greater proportion (>90%) than more darkly pigmented cells after culture. After surgery, structural evidence confirmed cells had attached and continued to persist during our study. We did not identify signs of hyperproliferation, abnormal growth, or immune mediated transplant rejection in either patient during the first 4 months. Although there is little agreement between investigators on visual endpoints in patients with low vision, it is encouraging that during the observation period neither patient lost vision. Best corrected visual acuity improved from hand motions to 20/800 (and improved from 0 to 5 letters on the Early Treatment Diabetic Retinopathy Study [ETDRS] visual acuity chart) in the study eye of the patient with Stargardt's macular dystrophy, and vision also seemed to improve in the patient with dry age-related macular degeneration (from 21 ETDRS letters to 28).The hESC-derived RPE cells showed no signs of hyperproliferation, tumorigenicity, ectopic tissue formation, or apparent rejection after 4 months. The future therapeutic goal will be to treat patients earlier in the disease processes, potentially increasing the likelihood of photoreceptor and central visual rescue.Advanced Cell Technology.

  View details for DOI 10.1016/S0140-6736(12)60028-2

  View details for PubMedID 22281388

• Ocriplasmin for Vitreoretinal Diseases JOURNAL OF BIOMEDICINE AND BIOTECHNOLOGY Tsui, I., Pan, C. K., Rahimy, E., Schwartz, S. D. 2012: 354979

  Abstract

  Fibronectin and laminin are clinically relevant plasmin receptors in the eye. Located at the vitreoretinal interface, they are cleaved by ocriplasmin (Microplasmin, ThromboGenics, Iselin, NJ), a novel ophthalmic medication. A series of clinical trials to study ocriplasmin for the treatment of vitreoretinal diseases such as vitreomacular traction, macular hole, and exudative age-related macular degeneration are underway. The results are promising and may impact patient care.

  View details for DOI 10.1155/2012/354979

  View details for Web of Science ID 000310028500001

  View details for PubMedID 23193358

  View details for PubMedCentralID PMC3496214

• Comparison of Long-Acting Bevacizumab Formulations in the Treatment of Choroidal Neovascularization in a Rat Model JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Pan, C. K., Durairaj, C., Kompella, U. B., Agwu, O., Oliver, S. C., Quiroz-Mercado, H., Mandava, N., Olson, J. L. 2011; 27 (3): 219-224

  Abstract

  The objective of this study was to compare the reduction in size of experimentally induced choroidal neovascularization (CNV) in rat eyes treated with bevacizumab, poly(ethylene-glycol) (PEG)-bevacizumab conjugate (b-PEG), and poly(lactic-co-glycolic acid) (PLGA)-encapsulated bevacizumab (b-PLGA).Forty-eight eyes from 24 rats were divided into 4 groups of 12 eyes. In each group, 3 eyes were assigned to a treatment subgroup, each receiving a different injection-control, bevacizumab, b-PEG, and b-PLGA. In all eyes, laser photocoagulation was used to rupture Bruch's membrane. In group 1, laser was followed by injection, which was then followed by harvesting the rats to assess the CNV area. All 3 steps were separated by a 2-week interval. In groups 2, 3, and 4, injection preceded laser photocoagulation by a variable interval and all rats were harvested 2 weeks postlaser treatment. In group 2, laser and injection were separated by 2 weeks. In group 3, laser followed injection by 4 weeks. In group 4, laser followed injection by 6 weeks. The CNV area was measured for each subgroup and compared against its control. Pairwise comparisons were conducted to assess for statistically significant differences between subgroups.All subgroups in groups 1, 2, and 4 showed statistically significant reduction of CNV area (P<0.05). In group 3, the b-PEG and b-PLGA subgroups showed a 9.0% (P=0.384) and 20.3% (P=0.077) reduction in CNV area versus control, whereas there was no reduction in CNV area in the bevacizumab subgroup. However, this was not found to be statistically significant. In group 4, b-PEG was more effective than bevacizumab and b-PLGA.The reduction in CNV area in all treatment subgroups, with the exception of those in group 3, suggests successful creation of the 2 bevacizumab formulations while retaining its active antiangiogenic properties. Further studies varying in dosages and timing of injection and laser are needed to evaluate the formulations' long-acting efficacy.

  View details for DOI 10.1089/jop.2010.0158

  View details for Web of Science ID 000291470700002

  View details for PubMedID 21574814