Fungal Infections in Boston Keratoprosthesis Patients: Lessons Learned and Novel Developments on the Horizon.

The Boston Keratoprosthesis (B-KPro) is a widely accepted modality of corneal restoration in eyes where traditional penetrating keratoplasty has little chance of success. It is the most commonly used keratoprosthesis worldwide. While the introduction of broad-spectrum antibiotic prophylaxis has virtually eliminated cases of bacterial endophthalmitis, fungal colonization and infections are a growing concern. This review of the literature summarizes risk factors for fungal infections in KPro eyes, rates of fungal infection and colonization, clinical presentation, causative organisms, management, and outcomes. We also focus on current recommendations for antifungal prophylaxis, and highlight the role of translational research at the Massachusetts Eye and Ear Infirmary (MEEI, Boston, USA) with its aim of developing novel strategies for reducing rates of fungal infections in KPro patients.

Fungal Infections After Boston Type 1 Keratoprosthesis Implantation: Literature Review and In Vitro Antifungal Activity of Hypochlorous Acid.

PURPOSE: To review the current literature describing cases of fungal keratitis and endophthalmitis after Boston keratoprosthesis (KPro) implantation and to characterize the antifungal activity of 0.01% hypochlorous acid against medically relevant fungi. METHODS: A literature review of fungal keratitis or endophthalmitis in KPro patients from January 2001 to April 2015, and an in vitro time kill assay characterizing the fungicidal activity of 0.01% hypochlorous acid against fungi causing ocular infections. RESULTS: Fifteen publications, predominantly retrospective case series, were identified. Infection rates after KPro implantation ranged from 0.009 to 0.02 fungal infections per patient-year of follow-up. The largest single-surgeon series reported an incidence of 2.4% for fungal endophthalmitis during a 10-year period. Causative organisms included both yeasts and molds. Outcomes were favorable if infections were caught early and treated appropriately; less favorable outcomes were reported in developing countries where fungal species are endemic and resources are limited. 0.01% hypochlorous acid is rapidly fungicidal, reducing the number of viable yeast cells or mold conidia by at least 99.99% within 60 seconds. The antifungal activity extended to all molds (Acremonium kiliense, Aspergillus flavus, Aspergillus fumigatus, Fusarium solani, and Mucor indicus) and yeast species (Candida albicans and Candida parapsilosis) tested. CONCLUSIONS: Fungal infections remain a lifelong concern in patients after KPro implantation. There is a growing need for a standard antifungal prophylaxis regimen, especially in the developing world. The rapid broad-spectrum in vitro fungicidal activity of 0.01% hypochlorous acid against all fungi tested makes it an attractive candidate as an antifungal prophylaxis in KPro patients.

Epoxy cross-linked collagen and collagen-laminin Peptide hydrogels as corneal substitutes.

A bi-functional epoxy-based cross-linker, 1,4-Butanediol diglycidyl ether (BDDGE), was investigated in the fabrication of collagen based corneal substitutes. Two synthetic strategies were explored in the preparation of the cross-linked collagen scaffolds. The lysine residues of Type 1 porcine collagen were directly cross-linked using l,4-Butanediol diglycidyl ether (BDDGE) under basic conditions at pH 11. Alternatively, under conventional methodology, using both BDDGE and 1-Ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC)/N-hydroxysuccinimide (NHS) as cross-linkers, hydrogels were fabricated under acidic conditions. In this latter strategy, Cu(BF4)2·XH2O was used to catalyze the formation of secondary amine bonds. To date, we have demonstrated that both methods of chemical cross-linking improved the elasticity and tensile strength of the collagen implants. Differential scanning calorimetry and biocompatibility studies indicate comparable, and in some cases, enhanced properties compared to that of the EDC/NHS controls. In vitro studies showed that human corneal epithelial cells and neuronal progenitor cell lines proliferated on these hydrogels. In addition, improvement of cell proliferation on the surfaces of the materials was observed when neurite promoting laminin epitope, IKVAV, and adhesion peptide, YIGSR, were incorporated. However, the elasticity decreased with peptide incorporation and will require further optimization. Nevertheless, we have shown that epoxy cross-linkers should be further explored in the fabrication of collagen-based hydrogels, as alternatives to or in conjunction with carbodiimide cross-linkers.

Infliximab for the treatment of refractory progressive sterile peripheral ulcerative keratitis associated with late corneal perforation: 3-year follow-up.

PURPOSE: To report a case of refractory progressive sterile peripheral ulcerative keratitis (PUK) that resulted in late corneal perforation, despite good initial response to tumor necrosis factor-alpha inhibitor infliximab. METHODS: Review of the clinical course of a patient with progressive PUK treated with infliximab infusions of 3 mg/kg intravenously. RESULTS: A 72-year-old man presented with a visual acuity of 20/200 and a 5-month history of a progressive sterile PUK. More than 90% of the surface area previously unresponsive to 8 weeks of high-dose systemic steroid therapy healed within 1 week of the first infusion. After his second infusion, best-corrected visual acuity improved to 20/30(+2), with 2 small epithelial defects remaining. However, the remaining unhealed cornea thinned to an area of microperforation 6 weeks after his third dose, prompting an increase in dose frequency to every 4 weeks. One month after his fifth infusion, the area of ulceration healed completely. After his seventh infusion, the patient developed a deep venous thrombosis and infliximab was discontinued. After 10 months of remission, clear corneal cataract surgery was performed. Three years after initial presentation, he remains in remission with a corrected visual acuity of 20/20. CONCLUSIONS: Infliximab was effective in rapidly arresting the progression of a sterile PUK in our patient. Optimal dosing for infliximab in PUK has not been established, and increasing dose frequency to every 4 weeks may be necessary. Despite a progressive PUK resulting in corneal perforation, treatment with infliximab and subsequent visual rehabilitation can result in sustained remission and an excellent visual outcome.

Same-day sequential cataract surgery.

PURPOSE OF REVIEW: Simultaneous bilateral cataract surgery (SBCS) is gaining in popularity worldwide. Whereas 5 or 10 years ago, it was only performed by scattered individual surgeons, it is now rapidly becoming accepted and mainstream. RECENT FINDINGS: Cataract surgery is generally performed on older patients. The reduction in medical visits, avoidance of interprocedural anisometropia and decreased stereopsis, and very rapid rehabilitation made possible by SBCS make the surgery much easier on the patients and their families. The fears of SBCS, most notably bilateral postoperative endophthalmitis, seem unfounded, as long as established precautions are followed. Some jurisdictions continue to penalize surgeons financially for performing SBCS, thus discouraging its spread. Unlike the Royal College of Ophthalmologists, UK, Surgery Guidelines, the American Academy of Ophthalmology's 2006 Preferred Practice Patterns do not include relative indications for SBCS. SUMMARY: SBCS will likely become rapidly more common around the world during the coming decade, to the great benefit of patients, institutions, and funding agencies.

Second instrument tip breaks during phacoemulsification.

BACKGROUND: Second instrument tip breaks during phacoemulsification are complications that are anecdotally recalled, yet little information exists on why and how often they occur, whether they are consistently tracked, and how they are managed. They may be an underreported, but potentially serious, complication of phacoemulsification. METHODS: We surveyed 114 cataract surgeons in Ontario to determine reported rates of second instrument tip breaks, their management, and presumed etiology. We reviewed 4 Toronto cataract centres for incident reports, instrument sterilization processes, and purchase histories. Using scanning electron microscopy (SEM), we compared the characteristics of a broken Sweeney tip to new and used second instruments. RESULTS: Of the 35 surgeons responding to the survey, 34% had experienced a second instrument tip break during their careers. Approximately 73% (16 cases) of the 22 cases reported were managed successfully during the procedure by the primary surgeon, 14% (3 cases) required imaging by computerized tomography or x-ray, and another 14% (3 cases) required pars plana vitrectomy for tip retrieval. Purchase histories revealed that 1 Sweeney hook was exchanged monthly, equivalent to 100 to 150 surgeries. SEM of new and used second instruments revealed signs of metal fatigue on both new and used second instruments. INTERPRETATION: Although both physicians and hospitals lack a method for ensuring quality control of second instruments, approximately one third of cataract surgeons encounter second instrument tip breaks during the course of their careers. Although most cases are managed intraoperatively, consistent hospital tracking records and standardized instrument inspection by institutions and surgeons are needed to determine how these complications occur and to establish protocols for complication reporting and management.

Activation of Notch signaling in human colon adenocarcinoma.

Notch and Wnt signaling function together to regulate colonic progenitor cell division and differentiation. Studies in mice have also shown that Notch signaling is required for adenoma formation in response to elevated Wnt-pathway signaling that occurs in the APCMin mouse model of human adenomatous polyposis coli. We therefore used in situ hybridization to analyze expression of Notch ligands, receptors and fringe genes, as well as the Notch target gene, HES1, in human colorectal cancer (CRC). In a small cohort of tumors, JAGGED ligands, NOTCH1, LFNG and HES1 were expressed at levels similar to, or higher than, levels observed in the crypt. To explore the possibility that Notch signaling may play a quantitative role in human CRC we next analyzed HES1 mRNA expression in 130 tumors, each associated with outcome data. The vast majority of these tumors expressed HES1, although at varying levels. Absolute expression levels did not correlate with patient survival. These results establish that JAG ligands and NOTCH1, as well as Notch receptor activation are consistent features of human CRC and support the notion that many of these tumors, like the APCMin mouse, may respond to anti-Notch therapeutic regimes.

High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival.

Aberrant activation of Notch receptors has been shown to cause mammary tumors in mice. We therefore used in situ hybridization to analyze expression of Notch ligands and receptors in human breast cancer. High levels of JAG1 and NOTCH1 were noted in a subset of tumors with poor prognosis pathologic features (P < 0.05). We therefore used tissue microarrays to analyze the expression of these genes in a collection of breast cancers from patients representing a wide spectrum of clinical stages, and from whom associated follow-up survival data was available (n = 184). Patients with tumors expressing high levels of JAG1 or NOTCH1 had a significantly poorer overall survival compared with patients expressing low levels of these genes [5-year survival rate of 42% versus 65% and median survival of 50 versus 83 months, respectively, for JAG1(Hi vs. Lo) (P = 0.01); 49% versus 64% and 53 versus 91 months, respectively, for NOTCH1(Hi vs. Lo) (P = 0.02)]. Moreover, a synergistic effect of high-level JAG1 and high-level NOTCH1 coexpression on overall survival was observed (5-year survival rate of 32% and median survival of 40 months; P = 0.003). These data (a) identify novel prognostic markers for breast cancer, (b) suggest a mechanism whereby Notch is activated in aggressive breast tumors, and (c) may identify a signaling pathway activated in poor prognosis breast cancer which can be therapeutically targeted.