The PAUL® glaucoma implant: 1-year results of a novel glaucoma drainage device in a paediatric cohort.

PURPOSE: The PAUL® glaucoma implant (PGI) is a novel glaucoma drainage device, which has not been previously reported in paediatric glaucoma management. This study aims to evaluate the safety and effectiveness of the PGI in a paediatric cohort. METHODS: A retrospective evaluation of 25 cases of paediatric PGI surgery (age 8 months to 16 years) was performed at Manchester Royal Eye Hospital between September 2019 and July 2020. Primary outcome measures included failure (intraocular pressure (IOP) > 21 mmHg or < 20% reduction of IOP, removal of the implant, further glaucoma intervention or visual loss. Secondary outcomes included mean IOP, mean number of medications, logMAR visual acuity and complications. RESULTS: Eleven eyes (48%) had a complete success and achieved an unmedicated IOP < 21 mmHg, and 21 eyes (84%) had a qualified success (with or without medications). Four failures were observed, 2 due to hypotony and 2 underwent further surgery (gonioscopy-assisted transluminal trabeculotomy). The mean preop IOP was 30.9 ± 5.9 mmHg (n = 25), falling to 13.5 ± 6.8 mmHg at 1 month, 17.9 ± 7.2 mmHg at 3 months, 13.4 ± 5.1 mmHg at 6 months, 13.2 ± 4.9 mmHg at 12 months and 11.8 ± 4.6 mmHg at 24 months. The mean change in IOP from the preoperative visit to the last visit was a reduction of 19.1 ± 7.7 mmHg. A significant reduction in the number of medications and IOP was demonstrated after PGI (p < 0.0001). Nine patients required removal of the intraluminal Prolene stent from the PGI for further pressure lowering. CONCLUSION: The one- to two-year results demonstrate paediatric PGI has high qualified success rates and effectively reduces IOP and the need for glaucoma medical therapy.

Circulating tumor DNA dynamics reveal KRAS G12C mutation heterogeneity and response to treatment with the KRAS G12C inhibitor divarasib in solid tumors.

PURPOSE: To inform prognosis, treatment response, disease biology, and KRAS G12C mutation heterogeneity, we conducted exploratory circulating tumor DNA (ctDNA) profiling on 134 patients with solid tumors harboring a KRAS G12C mutation treated with single-agent divarasib (GDC-6036) in a phase 1 study. EXPERIMENTAL DESIGN: Plasma samples were collected for serial ctDNA profiling at baseline (Cycle 1 Day 1 prior to treatment) and multiple on-treatment time points (Cycle 1 Day 15 and Cycle 3 Day 1). RESULTS: KRAS G12C ctDNA was detectable from plasma samples in 72.9% (43/59) and 92.6% (50/54) of patients with non-small cell lung cancer and colorectal cancer, respectively, the majority of whom were eligible for study participation based on a local test detecting the KRAS G12C mutation in tumor tissue. Baseline ctDNA tumor fraction was associated with tumor type, disease burden, and metastatic sites. A decline in ctDNA level was observed as early as Cycle 1 Day 15. Serial assessment showed a decline in ctDNA tumor fraction associated with response and progression-free survival. Except for a few cases of KRAS G12C sub-clonality, on-treatment changes in KRAS G12C variant allele frequency mirrored changes in the overall ctDNA tumor fraction. CONCLUSION: Across tumor types, the KRAS G12C mutation likely represents a truncal mutation in the majority of patients. Rapid and deep decline in ctDNA tumor fraction was observed in patients responding to divarasib treatment. Early on-treatment dynamics of ctDNA were associated with patient outcomes and tumor response to divarasib treatment.

Surgical technique, perioperative management and early outcome data of the PAUL® glaucoma drainage device.

OBJECTIVES: To describe a surgical technique and early post-operative outcomes for a novel glaucoma drainage device-the PAUL® glaucoma implant (PGI). METHODS: A consecutive cohort study of subjects who had PGI surgery between February 2019 and May 2020 with a minimum of 6-month follow-up. Primary outcome measures included failure (intraocular pressure (IOP) > 21 mmHg or a <20% reduction of IOP, removal of the implant, further glaucoma intervention or visual loss to no light perception). Secondary outcomes included mean IOP, mean number of medications, logMAR visual acuity (VA) and complications. RESULTS: Ninety-nine eyes of 97 patients had a preoperative IOP (mean ± standard deviation) of 28.1 ± 9.0 mmHg, falling to 18.2 ± 6.8 mmHg at 1 month, 17.9 ± 6.7 mmHg at 3 months and 13.6 ± 4.7 mmHg at 6 months. 52 patients had a 12-month mean IOP of 13.3 ± 4.4 mmHg. The mean change in number of medications was a reduction of 2.38 ± 1.48. A significant reduction in the number of medications and intraocular pressure was demonstrated after PGI (p < 0.0001). No significant change was demonstrated in VA (p = 0.1158). A total of nine cases were deemed failures (six had <20% IOP reduction from baseline and three had IOP >21 mmHg). Thirty-eight (38.4%) of eyes had complete success and achieved an unmedicated IOP <21 mmHg. Ninety (90.1%) of eyes were qualified successes (with or without topical medications). Seventy-four (74.7%) eyes have achieved an intraocular pressure of <15 mmHg. Two cases of hypotony were observed. CONCLUSION: This study presents a safe surgical technique, which significantly reduces IOP and number of medications with minimal complications.

Removal of a migrated dexamethasone implant (Ozurdex) from the anterior chamber using an intravenous cannula.

Ozurdex is a dexamethasone intravitreal implant used for the treatment of macular oedema. A rare but serious complication is the migration of the implant into the anterior chamber (AC) in eyes with absent or incomplete posterior capsules that may lead to corneal decompensation. We report the case of a 75-year-old woman who presented with a 1-day history of decreased vision in her left eye. She had a history of complicated cataract surgery and had received multiple Ozurdex implants for postoperative cystoid macular oedema in the same eye. She had significant left corneal decompensation and a mobile Ozurdex implant in the AC. We report a simple but novel surgical technique for removing an Ozurdex implant from the AC using an intravenous cannula (Venflon). This technique can also be applied to removing a fluocinolone acetonide (Iluvien) implant in similar situations.

Molecular classification of melanomas and nevi using gene expression microarray signatures and formalin-fixed and paraffin-embedded tissue.

Melanoma may be difficult to identify histologically and relatively high rates of misdiagnosis leads to many malpractice claims. Currently separation of melanomas from nevi is based primarily on light microscopic interpretation of hematoxylin and eosin stained sections with limited assistance from immunohistology. To increase the accuracy of discrimination of benign and malignant melanocytic lesions we identified DNA microarray-derived gene expression profiles of different melanocytic lesions and evaluated the performance of these gene signatures as molecular diagnostic tools in the molecular classification and separation of melanomas and nevi. Melanocyte-derived cells were isolated by laser capture microdissection from 165 formalin-fixed and paraffin-embedded melanocytic nevi and melanoma tissue sections. RNA was isolated, amplified, labeled, and hybridized to a custom DNA microarray. In all 120 samples were used to identify differentially expressed genes and generate a gene expression classifier capable of distinguishing between melanomas and nevi. These classifiers were tested by the leave-one-out method and in a blinded study. RT-PCR verified the results. Unsupervised hierarchical clustering identified two distinct lesional groups that closely correlated with the histopathologically identified melanomas and nevi. Analysis of gene expression levels identified 36 significant differentially expressed genes. In comparison with nevi, melanomas expressed higher levels of genes promoting signal transduction, transcription, and cell growth. In contrast, expression of L1CAM (homolog) was reduced in melanomas relative to nevi. Genes differentially expressed in melanomas and nevi, on the basis of molecular signal, sub classified a group of unknown melanocytic lesions as melanomas or nevi and had high concordance rates with histopathology. Gene signatures established using DNA microarray gene expression profiling can distinguish melanomas from nevi, indicating the feasibility of using molecular classification as a supplement to standard histology. Our successful use of a standard formalin-fixed and paraffin-embedded tissue further supports the practicability of combining molecular diagnostic testing with histopathology in evaluation of difficult melanocytic lesions.

Incidence, management and outcome of raised intraocular pressure in childhood-onset uveitis at a tertiary referral centre.

BACKGROUND/AIMS: To investigate the incidence, management and outcome of uveitis and raised intraocular pressure (IOP) in children treated at the Manchester Uveitis Clinic (MUC). METHODS: This was a retrospective, observational study of patients who presented with uveitis under the age of 16 to the MUC from July 2002 to June 2016. RESULTS: A total of 320 children were included in the study. Out of these, 55 (17.2%) patients (75 eyes) were found to have raised IOP requiring treatment. The mean age at diagnosis of uveitis and at first recorded raised IOP was 8.2±4.3 and 10.8±3.6 years, respectively. The pre-treatment IOP was 32.3±6.6 mm Hg and the IOP at the final visit was 15.5±3.7 mm Hg (median follow-up period, 43.7 months) on a median number of 0 medications. Twenty-eight eyes (37.3%) required glaucoma drainage surgery, and eight eyes (12.5%) had cyclodiode laser before this. Kaplan-Meier analysis showed that 11.5% of eyes required glaucoma surgery at 1 year after diagnosis of raised IOP, increasing to 50.0% by 5 years. The best-corrected visual acuity at diagnosis of uveitis was 0.26±0.42 logMAR, which remained stable at 0.28±0.65 logMAR at final follow-up visit. Four eyes (5.3%) from four patients fulfilled the definition of blindness by the WHO criteria. The mean cup:disc ratio at final follow-up was 0.4. CONCLUSION: Our cohort of children with raised IOP appeared to have a good outcome overall through aggressive medical and surgical management. Regular long-term follow-up is recommended, and early surgical intervention in eyes with uncontrolled IOP can prevent loss of vision.

Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis.

BACKGROUND: Cholinesterase inhibitors (ChEIs) are the only drugs marketed for the treatment of Alzheimer's disease. Despite numerous randomized controlled trials, the efficacy and safety of this group of medications has not been quantified. Our objective was to quantitatively summarize data on the efficacy and safety of ChEIs in Alzheimer's disease in a format useful to clinicians. METHODS: We performed a meta-analysis of randomized, double-blind, placebo-controlled, parallel-group trials of currently marketed ChEIs (donepezil, rivastigmine and galantamine), used in therapeutic doses for at least 12 weeks, from which a cognitive outcome was reported. Studies were identified through 3 electronic databases searched to May 2002, pharmaceutical companies and journals. We extracted the proportions of subjects who responded, experienced adverse events, discontinued treatment for any reason or discontinued treatment because of adverse events. RESULTS: In the 16 identified trials that met the inclusion criteria, 5159 patients were treated with a ChEI and 2795 received a placebo. The pooled mean proportion of global responders to ChEI treatment in excess of that for placebo treatment was 9% (95% confidence interval [95% CI] 6%-12%). The rates of adverse events, dropout for any reason and dropout because of adverse events were also higher among the patients receiving ChEI treatment than among those receiving placebo, the excess proportions being 8% (95% CI 5%-11%), 8% (95% CI 5%-11%) and 7% (95% CI 3%-10%), respectively. The numbers needed to treat for 1 additional patient to benefit were 7 (95% CI 6-9) for stabilization or better, 12 (95% CI 9-16) for minimal improvement or better and 42 (95% CI 26-114) for marked improvement; the number needed to treat for 1 additional patient to experience an adverse event was 12 (95% CI 10-18). INTERPRETATION: Treatment with ChEIs results in a modest but significant therapeutic effect and modestly but significantly higher rates of adverse events and discontinuation of treatment. The numbers needed to treat to benefit 1 additional patient are small.