Keratoconus International Consortium (KIC)- advancing keratoconus research.

CLINICAL RELEVANCE: The Keratoconus International Consortium (KIC) will allow better understanding of keratoconus. BACKGROUND: Keratoconus is a disorder characterised by corneal elevation and thinning, leading to reduced vision. The current gaps in understanding of this disease will be discussed and the need for a multi-pronged and multi-centre engagement to enhance our understanding of keratoconus will be highlighted. DESIGN: KIC has been established to address the gaps in our understanding of keratoconus with the aim of collecting baseline as well as longitudinal data on several fields. PARTICIPANTS: Keratoconus and control (no corneal condition) subjects from different sites globally will be recruited in the study. METHODS: KIC collects data using an online, secure database, which enables standardised data collection at member sites. Data fields collected include medical history, clinical features, quality of life and economic burden questionnaires and possible genetic sample collection from patients of different ethnicities across different geographical locations. RESULTS: There are currently 40 Australian and international clinics or hospital departments who have joined the KIC. Baseline data has so far been collected on 1130 keratoconus patients and indicates a median age of 29.70 years with 61% being male. A total of 15.3% report a positive family history of keratoconus and 57.7% self-report a history of frequent eye rubbing. CONCLUSION: The strength of this consortium is its international, collaborative design and use of a common data collection tool. Inclusion and analyses of cross-sectional and longitudinal data will help answer many questions that remain in keratoconus, including factors affecting progression and treatment outcomes.

Immune checkpoint inhibitors and tyrosine kinase inhibitors in patients with advanced hepatocellular carcinoma: Does the sequence matter?

INTRODUCTION: Combination therapy with immune checkpoint inhibitor (ICI) and antivascular endothelial growth factor (anti-VEGF) is currently the first line treatment for advanced hepatocellular carcinoma (aHCC). However, there are many patients who may not be able to receive combination therapy due to underlying comorbidities or resource limitations. For these patients, systemic treatment options include single agent tyrosine kinase inhibitors (TKIs) or ICI monotherapy. However, whether an optimal sequence of systemic therapy exists remains unknown. We aim to explore the impact of sequencing of TKI and ICI therapy in terms of response rates and to examine the safety of their use in sequential order. METHODS: Patients with aHCC treated with both ICI and TKI between December 30, 2013 and June 13, 2018 were retrospectively identified. Patients were classified into two groups: those who received TKI in the first-line (TKI1), followed by ICI (ICI2) and those who received ICI (ICI1) in the first-line followed by TKI (TKI2). The primary objective of the study was to identify differences in objective response rate (ORR) and disease control rate (DCR), as evaluated based on response evaluation criteria in solid tumor v1.1 for TKI1, TKI2, ICI1, and ICI2. Secondary objectives included comparison of progression free survival (PFS) for each line of therapy, overall survival (OS) and adverse events (AEs). RESULTS: Twenty-seven and 23 patients were classified into group 1 and 2, respectively. Objective response rates of TKI1 and TKI2 were 3.8% and 17.6%, respectively (p = .28); DCR to TKI1 versus TKI2 was 23.1% versus 35.3% (p = .49). ORRs of ICI1 and ICI2 were 8.7% and 14.3%, respectively (p = .66); DCR to ICI2 versus ICI1 was 56.5% versus 42.9% (p = .37). Median PFS was not significant between TKI1 and TKI2 (PFS 3.06 versus 1.61 months, p = .097) as well as between ICI2 and ICI1 (PFS 1.84 versus 2.37 month, p = .32). Median OS was also not significantly different between both groups (OS 20.63 versus 13.93 months, p = .20) on univariable and multivariable analysis (OS adjusted hazard ratio [HR] 2.07, 95% CI .83-5.18, p = .118). The proportion of patients who experienced adverse events of any grade was similar in both groups (TKI1 59.3% versus TKI2 52.2%; ICI1 78.3% versus ICI2 70.4%). CONCLUSION: Our study suggests that the sequence of TKI versus ICI therapy in patients with aHCC may not matter, given similar efficacy and toxicity profile when either agent is received in the first or second-line setting. This finding is of value in the real-world setting, where patients may be frail or have comorbidities that render them unable to tolerate combination therapy (ICI and TKI/anti-VEGF). For these patients, sequential exposure to both classes of drugs (ICI and TKI) may be a suitable option.

Impact of Immune-Related Adverse Events on Efficacy of Immune Checkpoint Inhibitors in Patients with Advanced Hepatocellular Carcinoma.

INTRODUCTION: Development of immune-related adverse events (irAEs) has been associated with enhanced efficacy with the use of immune checkpoint inhibitors (ICIs). It remains unknown whether such an association exists in advanced hepatocellular carcinoma (aHCC). This study aims to evaluate the association between irAEs and ICI efficacy in patients with aHCC. METHODS: We performed a retrospective cohort study on patients with aHCC who received at least one dose of an ICI between May 2015 and November 2019 at the National Cancer Centre Singapore. The primary study objectives were to compare the overall survival (OS) and progression-free survival (PFS) between patients with and without irAEs. Complementary multivariable landmark analyses were performed at the 6-week and 12-week landmarks. Data cutoff was December 31, 2020. RESULTS: One hundred and sixty-eight patients were included. Median age was 69 years, 85.7% were male, 57.7% had hepatitis B infection, 60.7% had ECOG 0, and 78.0% had Child-Pugh A liver cirrhosis. 82.7% received ICI monotherapy, while 17.3% received ICI in combination. Development and severity of irAE were correlated with survival. The median PFS for grade ≥3 irAE versus grades 1-2 irAE versus no irAE was 8.5 versus 3.6 versus 1.3 mths (p < 0.001). The median OS for grade ≥3 irAE versus grades 1-2 irAE versus no irAE was 26.9 versus 14.0 versus 4.6 mths (p < 0.001). Patients with ≥2 irAEs had a significantly longer OS on multivariable analysis (adjusted hazard ratio [aHR]0.35, p < 0.001). The presence of grade ≥3 irAEs was associated with a significantly longer OS on the multivariable analysis at the 6-week landmark (aHR0.34, p = 0.030) and 12-week landmark (aHR0.28, p = 0.011). The use of systemic corticosteroids in patients with irAE was associated with a trend toward a longer OS (20.7 vs. 14.3 mths, p = 0.064). CONCLUSION: Our study suggests that the presence of all-grade irAEs may be a potential prognostic biomarker in patients with aHCC treated with ICI. Patients with more severe irAEs and multisystem involvement have better prognosis. The prompt use of systemic corticosteroids to treat patients with irAEs is key to ensure the best long-term outcomes for these patients.

Conjunctival Stromal Tumor: Report of 2 New Cases and Review of the Literature.

Conjunctival stromal tumor (COST) is an emerging entity with only a limited number of cases reported in the literature. In this report, we describe 2 additional cases, review the accumulative clinical and histopathological features and expand on the immunophenotypic property of this entity. COST appears to have a sporadic presentation, affecting both sexes and patients of variable ethnicity and age group and predominantly occurring on the bulbar conjunctiva as a slow-growing asymptomatic or slightly tender mass-like lesion. Histopathologically, COST is characterized by singly dispersed spindle to round cells, often with some degree of degenerative nuclear atypia, within a myxomatous to collagenous stroma. Lesional cells are characteristically positive for CD34 and vimentin, negative for S100, SOX10 and STAT6 and show a normal pattern of staining with RB1 by immunohistochemistry. The reported cases to date have shown an indolent biological behavior, reliably treated by a complete surgical excision.

Real-world efficacy and safety of immune checkpoint inhibitors in advanced hepatocellular carcinoma: Experience of a tertiary Asian Center.

INTRODUCTION: Immune checkpoint inhibitor (ICI) use in advanced hepatocellular carcinoma (HCC) is increasing. Real-world data on efficacy and safety, however, are lacking. METHODS: We conducted a retrospective review of all patients with advanced HCC seen at our center who received at least one dose of an ICI between May 2015 and June 2018. Data cutoff was December 31, 2018. Responses were evaluated using Response Evaluation Criteria in Solid Tumors version 1.1 criteria. RESULTS: Of 114 patients, 88.6% were male. Median age was 66 years, 96.5% had an Eastern Cooperative Oncology Group of 0-1. 62.3% received monotherapy ICI. 18.4% of patients had Child-Pugh (CP) B disease on initiation of ICI, and 69.3% had an ALBI grade of 2. 54.4% were known to have chronic hepatitis B (HBV) or were previously infected, and 11.4% had hepatitis C. Baseline HBV viral load (VL) ranged from undetectable to 8 210 000 IU/mL. 35.1% received prior systemic treatment. 28.9% received prior sorafenib. Over a median follow-up duration of 13.8 months (10.4-15.8), ORR was 18.4%, and DCR was 50.9%. Median progression-free survival was 2.7 months (1.3-4.0), and median overall survival (OS) was 13.9 months (6.9-16.2). Thirty-one patients (27.2%) received further systemic therapy after ICI discontinuation. On multivariable analyses, lower albumin level, higher bilirubin level, diuretic-refractory ascites, and HBV-associated HCC were associated with poorer OS. 69.3% of patients experienced adverse events (AE) of any grade, 14.9% of these being grade 3-4. No grade 5 AE were observed. Use of antiviral therapy was associated with a lower risk of grade 3 or above hepatic AEs (P = 0.048), whereas high baseline HBV VL was not associated with an increased risk of reactivation or hepatic AE. DISCUSSION: We have demonstrated that the real-world performance of ICIs in advanced HCC appears comparable to that observed in clinical trials for HCC patients with CP A cirrhosis. While prognosis of patients with advanced HCC and CP B cirrhosis remains poor even with ICI, usage of ICI is likely to be safe. Patients with HBV with a baseline HBV VL ≥100 IU/mL may receive ICI safely, especially if they are on antiviral treatment.

Nephrolithiasis: Approach to Diagnosis and Management.

Although kidney stones are less common in children than in adults, incidence in children is rising. Kidney stones may lead to significant morbidity in addition to escalating medical costs. Clinical presentation is variable. Bilateral kidney stones in a younger child should prompt work-up for primary hyperoxaluria. Metabolic abnormalities are more frequent in children and can result in frequent stone recurrence. Whole exome sequencing data shows genetic defects in about 30% of stone formers. 24 h urine collection should be conducted when patient receives his usual diet and fluid intake with normal activity. Infrared spectroscopy and X-ray diffraction are used for stone analysis. Urine studies should be delayed by 4-6 wk after stone fragmentation or treatment of any stone related complications. The goal of evaluation is to identify modifiable risk factors for which targeted therapy may be instituted. Primary indications for surgical intervention include pain, infection and obstruction. Extracorporeal shockwave lithotripsy (ESWL), ureteroscopy, and percutaneous nephrolithotomy (PCNL) are most commonly used, and selection is based on stone size, anatomy, composition and anatomy. Advances in technology have allowed a shift to minimally invasive surgeries. Comprehensive management requires multidisciplinary team. Children with kidney stones require long term follow-up with periodic assessment of stone forming activity and ascertaining stone burden. High index of suspicion should be there to diagnose diseases like primary hyperoxaluria, Dent's disease, renal tubular acidosis (RTA) etc. as these diseases have ramifications on kidney function and growth.

Descemet stripping automated endothelial keratoplasty with the EndoGlide Ultrathin graft insertion device.

Endothelial keratoplasty has largely replaced penetrating keratoplasty as the preferred technique to selectively replace diseased corneal endothelium. Descemet's stripping automated endothelial keratoplasty (DSAEK) is the most common type of endothelial keratoplasty performed worldwide. One of the challenges in DSAEK is the insertion of the donor lenticule into the eye using a method so as to minimize endothelial cell loss. Various techniques have been suggested such as forceps insertion and graft insertion devices. With the trend towards using thinner DSAEK tissue and Descemet membrane endothelial keratoplasty, there are increasing challenges in inserting and manipulating even more delicate tissue. The EndoGlide Ultrathin has several new features that will enable easier insertion of thinner DSAEK tissue. This paper presents the features and surgical technique of the EndoGlide Ultrathin during DSAEK.

Ocular surface stem cell transplantation rejection: incidence, characteristics, and outcomes.

PURPOSE: To describe the incidence, characteristics, risk factors, treatment, and outcomes of ocular surface stem cell transplantation (OSST) rejection. METHODS: A chart review of patients who had OSST at a single institution between 1998 and 2010 was performed. Data were collected on patient demographics, type of OSST procedure, duration of immunosuppression, and rejection characteristics. Main outcome measures were ocular surface stability and improvement in best-corrected visual acuity. RESULTS: Two hundred twenty-two eyes of 158 patients were included with mean follow-up of 62.7 months (range, 12.0-158.3 months). The most common indications for OSST were aniridia (46.4%), chemical/thermal injury (22.1%), and Stevens-Johnson syndrome (12.2%). The most common procedures performed were keratolimbal allograft (KLAL) alone (80.6%) and combined living-related conjunctival allograft (lr-CLAL)-KLAL (11.3%). Mean time on immunosuppression was 44.3 months (range, 7.6-138.2 months). Severe rejection occurred in 43 eyes (19.4%) with mean time to rejection being 15.2 months (range, 0.2-93.1 months). Low-grade rejection occurred in 26 eyes (11.7%) with mean time to rejection being 26.2 months (range, 1.3-64.9 months). At the final follow-up, 36.6% of eyes in the rejection group achieved a stable ocular surface compared with 71.9% of eyes in the nonrejection group (P < 0.0001). Risk factors associated with increased risk of rejection were younger age (P < 0.0001), KLAL alone (P = 0.049), and noncompliance with immunosuppression (P = 0.047). CONCLUSIONS: Ocular surface outcomes for patients with OSST rejection are poor, with the majority of patients having failed ocular surfaces despite treatment with increased immunosuppression and repeat OSST. It is critical for success that OSST patients are closely monitored for rejection and for compliance with immunosuppression.

Traumatic wound rupture after Boston type 1 keratoprosthesis implantation.

OBJECTIVE: To describe the incidence, characteristics, causes, treatment, and outcomes of traumatic wound rupture in patients with Boston type 1 keratoprosthesis (KPro). DESIGN: Retrospective case series. PARTICIPANTS: We studied 136 eyes of 122 patients who underwent KPro implantation at a single institute between November 2004 and May 2011. METHODS: A chart review was performed to determine the incidence, characteristics, causes, treatments, and outcomes of traumatic wound rupture. RESULTS: The 4 eyes of 4 patients that sustained traumatic wound rupture resulted in an incidence of traumatic wound rupture of 2.9% (4/136). This complication occurred, on average, at 4.2 months (range, 1-9 months) after the KPro was implanted. All ruptures occurred at the graft-host junction. The 2 eyes that had complete keratoprosthesis extrusion experienced decreased vision postrupture, from hand motions to no light perception, and 20/300 to count-fingers vision, respectively. One eye that had 4 clock hours of superior wound rupture recovered vision postrupture from light perception to 20/40. One eye that had 2 clock hours of superior wound rupture maintained a stable vision of 20/125 after repair. CONCLUSIONS: The incidence of traumatic wound rupture after keratoprosthesis is comparable to that after penetrating keratoplasty. Patients should be aware that traumatic rupture is a lifelong concern and should use protective measures to prevent this complication from occurring.