Clinical Characteristics and Outcomes of Eyes with Intraocular Inflammation after Brolucizumab: Post Hoc Analysis of HAWK and HARRIER.

PURPOSE: This analysis of the pivotal phase 3 HAWK and HARRIER trials aimed to provide insights on the timing of presentation, management, and outcomes of intraocular inflammation (IOI)-related adverse events (AEs), as reported by investigators in these trials. DESIGN: Post hoc analysis of investigator-reported IOI-related AEs in HAWK and HARRIER. PARTICIPANTS: Of 1088 brolucizumab-treated eyes (3 or 6 mg), 49 eyes demonstrated at least 1 IOI-related AE and were included in this analysis. METHODS: Reports of IOI-related AEs were analyzed and descriptive statistics were provided for outcome measures. MAIN OUTCOME MEASURES: Incidence and description of eyes with IOI-related AEs, timing of presentation, management, clinical outcomes, and brolucizumab treatment after the first IOI-related AE. RESULTS: Seventy IOI-related AEs were reported in 49 eyes. Before the onset of first IOI-related AE, eyes received a mean ± standard deviation (SD) of 3.9 ± 2.2 brolucizumab injections. Median time to first IOI-related AE from the last administered brolucizumab injection was 18.0 days (interquartile range, 4.0-29.0 days). Of the 70 AEs, 61 (87.1%) were treated, most with topical corticosteroids; systemic and intraocular corticosteroids were used for 3 AEs each. Overall, inflammation resolved completely in 39 eyes (79.6%), resolved with sequelae in 5 eyes (10.2%), and did not resolve in 5 eyes (10.2%) by end-of-study (EOS). Overall, the mean ± SD best-corrected visual acuity (BCVA) change from baseline to EOS, before AE to the lowest BCVA in 3 months after AE, and from before AE to EOS were -0.84 ± 20.6 , -16.31 ± 17.6, and -0.22 ± 18.9 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, respectively. Of the 36 eyes (73.5%) that continued with brolucizumab therapy after the first IOI-related AE, 24 completed the trials and 12 discontinued; mean ± SD BCVA change in these eyes was 2.6 ± 17.6, 7.8 ± 13.2, and -7.7 ± 21.3 ETDRS letters, respectively, from baseline to EOS. The remaining 13 eyes (26.5%) were not treated with brolucizumab after first IOI-related AE and showed a mean ± SD BCVA change of -10.4 ± 25.5 ETDRS letters from baseline to EOS. CONCLUSIONS: Findings of this analysis highlight the need for continued vigilance and monitoring for any signs of IOI-related events in patients receiving brolucizumab.

Expert Opinion on Management of Intraocular Inflammation, Retinal Vasculitis, and Vascular Occlusion after Brolucizumab Treatment.

PURPOSE: Recent reports have described a spectrum of uncommon findings of intraocular inflammation (IOI), retinal vasculitis, or retinal vascular occlusion in patients with neovascular age-related macular degeneration (nAMD) treated with intravitreal injection (IVI) of brolucizumab. We present guidance on the clinical presentation of this spectrum and propose recommendations for management of these events. DESIGN: PubMed literature review and expert opinion panel. PARTICIPANTS: A working group of international medical experts and Novartis medical personnel. METHODS: The working group deliberated on the clinical presentations and used a 3-pronged approach to develop management recommendations based on (1) critical appraisal of scientific literature; (2) clinical insights from the HAWK and HARRIER trials, postmarketing reports, and assessments from an independent Safety Review Committee (SRC); and (3) their clinical experience. MAIN OUTCOME MEASURES: Management recommendations for a spectrum of ocular inflammatory events after treatment with brolucizumab or other anti-vascular endothelial growth factors (VEGFs). RESULTS: Based on insights gained from the available information and the expertise of the contributors, recommendations were proposed for ocular examinations, imaging modalities, and treatment strategies for management of this spectrum of events. Patients should be educated to promptly report any relevant or persistent symptoms after IVI to facilitate timely intervention. Patients diagnosed with IOI should be evaluated for concomitant retinal vasculitis or retinal vascular occlusive events. Clinical examination can be augmented with multimodal imaging techniques, including widefield imaging, fluorescein angiography (with peripheral sweeps), and OCT. Once confirmed, the ongoing brolucizumab treatment should be suspended and intensive treatment with potent corticosteroids (topical, subtenon, intravitreal, or systemic) is recommended, which may be supplemented with other treatment strategies depending on the severity. Based on the clinical outcome of these events, individualized treatment with locally available standard of care should be considered for the underlying nAMD. CONCLUSIONS: These recommendations emphasize the need for early diagnosis, prompt and timely intervention, intensive treatment, and frequent monitoring to minimize the risk of progression of these events. The proposed recommendations may facilitate a consistent management approach of this spectrum of ocular inflammatory events should they arise in nAMD after treatment with brolucizumab or other anti-VEGFs.

MYD88 L265P mutation in intraocular lymphoma: A potential diagnostic marker.

PURPOSE: Vitreoretinal lymphoma (VRL) is the most common intraocular lymphoma (IOL). This can be either primary or secondary to the central nervous system lymphoma. The diagnosis of primary intraocular lymphoma (PIOL) currently relies on clinical diagnosis and cytological analysis of the vitreous or subretinal biopsy. Although most cases are diagnosed without much issue, the limited amount of vitreous fluid, subjectivity in cytological reporting, and special expertise in ocular pathology make the diagnosis challenging. MYD88 L265P mutation has been implicated to have diagnostic utility in PIOL. In this study, we screened consecutive vitreous biopsies for the presence of MYD88 L265P mutation to understand its diagnostic utility compared to conventional cytological analysis. METHODS: Cytological analysis and MYD88 L265P mutation by PCR-based sequencing and restriction fragment length polymorphism (RFLP) were carried out on consecutive vitreous and subretinal biopsies collected from 21 patients. The diagnostic utility of the cytology and MYD88 L265P mutation analysis were compared. RESULTS: Out of the 21 patients, 15 had clinical suspicion of having PIOL. Out of these suspected cases of PIOL, nine were confirmed on follow-up, while six were diagnosed as other intraocular pathologies. Diagnostic utility of MYD88 L265P mutation analysis revealed a sensitivity of 88.9%, specificity of 91.6%, positive and negative predictive value of 88.9% and 91.7%, respectively. Diagnostic accuracy of 90.5% was achieved with the mutation analysis that shows the superiority of MYD88 in both ruling in and ruling out PIOL. The diagnostic utility of MYD88 L265P mutation was superior to conventional cytological analysis. CONCLUSION: The analysis of MYD88 L265P mutation is reliable and efficient in the diagnosis of PIOL.

Characterization of NCC-RbC-51, an RB cell line isolated from a metastatic site.

Retinoblastoma (RB) is a childhood eye tumor, caused by the RB1 gene mutation. Since RB is a rapidly proliferating tumor, the patient presents with a Group-D/E tumor at the time of diagnosis. Enucleation is preferred in most unilateral cases to prevent metastasis. Various cell lines have been established to study the tumor's growth pattern and target the cancer cells. The commonly used cell lines are WERI-Rb-1 and Y79, both isolated from the primary tumor of RB. Cell lines established from the metastatic site of RB have not been characterized before. In this study, we have characterized NCC-RbC-51, derived from RB tumor to cervical lymph node site and investigated its potential to represent a highly aggressive and metastatic tumor. We compared the proliferative and invasive properties of NCC-RbC-51 with a cell line isolated from the primary site, WERI-Rb-1. NCC-RbC-51 had higher rates of proliferation and apoptosis and had better invasive ability. Copy number variation analysis and the pathways predicted from these show that the pathways altered in NCC-RbC-51 could contribute to its metastatic nature. In all, the results suggest that NCC-RbC-51, a cell line isolated from metastatic site, could be a potential model to study aggressive/invasive RB.

Use of a flowable haemostat versus an oxidised regenerated cellulose agent in primary elective cardiac surgery: economic impact from a UK healthcare perspective.

BACKGROUND: Flowable haemostatic agents have been shown to be superior to non-flowable agents in terms of haemostatic control and need for transfusion products in patients undergoing cardiac surgery. We investigated the economic impact of the use of a flowable haemostatic agent (Floseal) compared with non-flowable oxidised regenerated cellulose (ORC) agent in primary elective cardiac surgery from the perspective of the UK National Health Service (NHS). METHODS: A cost-consequence framework based upon clinical data from a prospective trial and an observational trial and NHS-specific actual reference costs (2016) was developed to compare the economic impact of Floseal with that of ORC. The individual domains of care investigated comprised complications (major and minor) avoided, operating room time savings, surgical revisions for bleeding avoided and transfusions avoided. The cost impact of Floseal versus ORC on ICU days and extended bed days avoided was modelled separately. RESULTS: Compared with ORC, the use of Floseal would be associated with overall net savings to the NHS of £178,283 per 100 cardiac surgery patients who experience intraoperative bleeding requiring haemostatic therapy. Cost savings were apparent in all individual domains of care (complications avoided: £83,536; operating room time saved: £63,969; surgical revisions avoided: £34,038; and blood transfusions avoided: £22,317). Cost savings per 100 patients with Floseal over ORC in terms of ICU days avoided (n = 30) and extended bed days avoided (n = 51.7) were £57,960 and £21,965, respectively. A sensitivity analysis indicated that these findings remained robust when the model parameters representing the clinical benefit of Floseal over ORC were reduced by up to 20%. CONCLUSIONS: Despite higher initial acquisition costs, the use of flowable haemostatic agents achieves substantial cost savings over non-flowable agents in cardiac surgery. These cost savings commence during the operating theatre and appear to continue to be realised throughout the postoperative period.

Nutrient improvement for simultaneous production of exopolysaccharide and mycelial biomass by submerged cultivation of Schizophyllum commune AGMJ-1 using statistical optimization.

Exopolysaccharides (EPS) of fungal origin have attracted special attention from researchers due to their multifarious applications in the food and pharmaceutical industries. In the present study, optimization of the process parameters for the production of exopolysaccharide by Schizophyllum commune AGMJ-1 was studied using one factor at a time (OFAT) method, Plackett-Burman design (PBD) and response surface methodology (RSM). OFAT method revealed xylose and yeast extract to be the most effective carbon and nitrogen sources and pH 5.3 as an optimum for maximum EPS production. Xylose, yeast extract and KCl were screened as statistically significant variables for EPS production using PBD. RSM based on the central composite design estimated that maximum EPS (4.26 g L-1), mycelial biomass (14 g L-1) and specific yield (0.45 g g-1) were obtained when concentration of xylose, yeast extract and KCl were set at 2.5 g % (w/v), 0.83 g % (w/v) and 6.53 mg % (w/v), respectively, in the production medium.

Assessment of genetic damage among chewers of mixture containing mainly areca nut and tobacco.

UNLABELLED: Chewing mixture containing areca nut and tobacco is believed to be associated with oral cancer. Habit of chewing such mixture is prevalent among South Asian countries. This study aimed to evaluate the genotoxic effect of areca nut and tobacco on human lymphocytes. Peripheral blood from 107 subjects (nonchewers, 48; chewers, 59, including 20 subjects with oral submucous fibrosis [OSMF]) analyzed by cytokinesis-block micronucleus (CBMN) and alkaline comet assay. Nuclear anomalies, namely, binucleated cells with micronuclei (BN MN), total MN, nucleoplasmic bridge, and nuclear buds were higher in chewers whereas elevation in BN MN and total MN were significant among subjects with OSMF than nonchewers. DNA damage assessed by comet assay showed increased percentage of Tail DNA, Tail moment, and Olive tail moment among chewers as well as OSMF subjects. Significant positive correlation was observed between induction of CBMN and consumption of quids per day (r = .280, P = .033). RESULTS: suggested cytotoxic and genotoxic potential of mixture containing areca nut and tobacco.