Enhancing the utility of chromosome 6 and 8 testing in uveal melanoma biopsies.

BACKGROUND: The aim of this study was to evaluate the significance of testing the gain of chromosome 8 and the gain of chromosome 6 as prognostic markers in histopathological samples of enucleated eyes in with uveal melanoma. METHODS: This is a retrospective study of 54 enucleated eyes. The status of chromosomes 3, 8 and 6 was tested by CISH, and FISH was used in a few samples. A follow-up for the detection of metastases was conducted in all patients. The statistical significance of chromosomal abnormalities as a prognostic factor for the development of metastases was determined. RESULTS: The study group consists of 54 patients (average age 63 years), 28 men (51.9%) Monosomy 3 together with gain of chromosome 8 was found in 10 samples (18.5%). Both chromosomal abnormalities were detected in 6 (11%) patients. No chromosomal abnormality in 3 or 8 was detected in 21 (38.9%) patients. Abnormalities of chromosome 6 were present in 6 (11%) patients. Progression free survival after 5 years was 33.3% (95% CI 0.0; 83.3) in these patients. CONCLUSIONS: Our findings indicate a correlation between progression-free survival and the presence of changes in chromosome 3 and e 8 in uveal melanomas. The results underline the necessity of testing for both chromosomal aberrations.

Serum autoantibodies against hexokinase 1 manifest secondary to diabetic macular edema onset.

AIMS: Autoantibodies against hexokinase 1 (HK1) were recently proposed to be associated with diabetic macular edema (DME). We hypothesized that anti-HK1 autoantibodies can be used as DME markers and to predict DME onset. MATERIALS AND METHODS: Serum from patients with 1) DME, 2) diabetes mellitus (DM), 3) allergies or autoimmunities, and 4) control subjects was tested for anti-HK1 and anti-hexokinase 2 (HK2) autoantibodies by immunoblotting. Patients with DM were prospectively followed for up to nine years, and the association of anti-HK1 antibodies with new-onset DME was evaluated. The vitreous humor was also tested for autoantibodies. RESULTS: Among patients with DME, 32 % were positive for anti-HK1 autoantibodies (42 % of those with underlying type 1 DM and 31 % of those with underlying type 2 DM), and 12 % were positive for anti-HK2 autoantibodies, with only partial overlap of these two groups of patients. Anti-HK1 positive were also 7 % of patients with DM, 6 % of patients with allergies and autoimmunities, and 3 % of control subjects. The latter three groups were anti-HK2 negative. Only one of seven patients with DM who were initially anti-HK1 positive developed DME. CONCLUSIONS: Anti-HK1 autoantibodies can be used as DME markers but fail to predict DME onset.

Pars Plana Vitrectomy in the Treatment of Rhegmatogenous Retinal Detachment.

AIM: The aim of the study is to retrospectively evaluate the anatomical success rate and functional results of 25G+ PPV in the treatment of newly diagnosed rhegmatogenous retinal detachment (RRD). MATERIAL AND METHODS: The set consists of 152 eyes of 152 patients, of which 71 (47%) were men, average age 54 years, operated on by one surgeon for RRD at the Eye Clinic of the University Hospital and Medical Faculty of Masaryk University Brno from 1.7.2019 to 4.5.2021 using the 25G+ PPV technique. 25G+ PPV with pre-equatorial cerclage was performed on 7 patients. The patients' anamnesis included blunt ocular trauma and uncomplicated cataract surgery with implantation of a posterior chamber intraocular lens. The cause of RRD was retinal tear/s, regardless of their number and location. The transparency of the anterior segment of the eye enabled reliable visualization of the posterior segment. Preoperative proliferative vitreoretinopathy (PVR) grade A-D2 was admissible. Patients with a history of penetrating ocular trauma were excluded. The postoperative findings and functional outcomes of the patients were evaluated 1-3 months after PPV. The operation was anatomically successful if the retina was fully attached. Final visual acuity (VA) was evaluated for each patient. The final visual acuity examination was carried out typically on a Snellen optotype, either without correction, with the patient's own spectacle correction or with correction according to the current values on the autorefractometer. The arithmetic average was used for the numerical expression of the attained results, and the numerical values were also expressed in percentages. Since the different groups were not compared with each other, no statistical test was necessary to analyze the results. RESULTS: In 150 (98.7%) of the 152 patients in the group, we achieved complete retinal reattachment, in 2 (1.3%) patients the retina remained detached, and we recorded anatomical failure of the treatment. Fifty (33%) patients achieved VA ≥ 4/8. CONCLUSION: In 133 (87.5%) patients, we are able to state anatomical success even without the presence of intraocular tamponade in the operated eye. These patients can be considered completely cured. 25G+ PPV has demonstrated its contribution to resolving RRD.

Biosimilar SB11 versus reference ranibizumab in neovascular age-related macular degeneration: 1-year phase III randomised clinical trial outcomes.

BACKGROUND/AIMS: To provide longer-term data on efficacy, safety, immunogenicity and pharmacokinetics (PK) of ranibizumab biosimilar SB11 compared with the reference ranibizumab (RBZ) in patients with neovascular age-related macular degeneration (nAMD). METHODS: Setting: Multicentre. Design: Randomised, double-masked, parallel-group, phase III equivalence study. Patient population: ≥50 years old participants with nAMD (n=705), one 'study eye'. INTERVENTION: 1:1 randomisation to monthly intravitreal injection of 0.5 mg SB11 or RBZ. Main outcome measures: Visual efficacy endpoints, safety, immunogenicity and PK up to 52 weeks. RESULTS: Baseline and disease characteristics were comparable between treatment groups. Of 705 randomised participants (SB11: n=351; RBZ: n=354), 634 participants (89.9%; SB11: n=307; RBZ: n=327) completed the study until week 52. Previously reported equivalence in primary efficacy remained stable up to week 52 and were comparable between SB11 and RBZ. The adjusted treatment difference between SB11 and RBZ in full analysis set at week 52 of change from baseline in best-corrected visual acuity was -0.6 letters (90% CI -2.1 to 0.9) and of change from baseline in central subfield thickness was -14.9 µm (95% CI -25.3 to -4.5). The incidence of ocular treatment-emergent adverse events (TEAEs) (SB11: 32.0% vs RBZ: 29.7%) and serious ocular TEAE (SB11: 2.9% vs RBZ: 2.3%) appeared comparable between treatment groups, and no new safety concerns were observed. The PK and immunogenicity profiles were comparable, with a 4.2% and 5.5% cumulative incidence of antidrug antibodies up to week 52 for SB11 and RBZ, respectively. CONCLUSIONS: Longer-term results of this study further support the biosimilarity established between SB11 and RBZ.

Efficacy and Safety of a Proposed Ranibizumab Biosimilar Product vs a Reference Ranibizumab Product for Patients With Neovascular Age-Related Macular Degeneration: A Randomized Clinical Trial.

Importance: Neovascular age-related macular degeneration is the leading cause of blindness in individuals 50 years or older. The availability of a ranibizumab biosimilar product (SB11) may facilitate access to an effective alternative to this treatment. Objective: To demonstrate equivalence of efficacy, similar safety, and similar immunogenicity of SB11 compared with the reference ranibizumab. Design, Setting, and Participants: This randomized, double-masked, parallel-group phase 3 equivalence study was conducted in 75 centers in 9 countries from March 14, 2018, to December 9, 2019, among 705 participants 50 years or older with neovascular age-related macular degeneration with active subfoveal choroidal neovascularization lesions. Analysis was performed on an intent-to-treat basis. Interventions: Intravitreous injection of SB11 or ranibizumab, 0.5 mg, every 4 weeks through week 48. Main Outcomes and Measures: Preplanned interim analysis after all participants completed the week 24 assessment of primary efficacy end points at week 8 for change from baseline in best-corrected visual acuity (BCVA) and week 4 for central subfield thickness (CST), with predefined equivalence margins for adjusted treatment differences of -3 letters to 3 letters for BCVA and -36 µm to 36 µm for CST. Results: Baseline and disease characteristics among 705 randomized participants (403 women [57.2%]; mean [SD] age, 74.1 [8.5] years) were comparable between treatment groups (SB11, 351; ranibizumab, 354). Least-squares mean (SE) changes in BCVA from baseline at week 8 were 6.2 (0.5) letters in the SB11 group vs 7.0 (0.5) letters in the ranibizumab group, with an adjusted treatment difference of -0.8 letter (90% CI, -1.8 to 0.2 letters). Least-squares mean (SE) changes in CST from baseline at week 4 were -108 (5) µm in the SB11 group vs -100 (5) µm in the ranibizumab group, with an adjusted treatment difference of -8 µm (95% CI, -19 to 3 µm). Incidences of treatment-emergent adverse events (231 of 350 [66.0%] vs 237 of 354 [66.9%]), including serious treatment-emergent adverse events (44 of 350 [12.6%] vs 44 of 354 [12.4%]) and treatment-emergent adverse events leading to study drug discontinuation (8 of 350 [2.3%] vs 5 of 354 [1.4%]), were similar in the SB11 and ranibizumab groups. Immunogenicity was low, with a cumulative incidence of antidrug antibodies up to week 24 of 3.0% (10 of 330) in the SB11 group and 3.1% (10 of 327) in the ranibizumab group. Conclusions and Relevance: These findings of equivalent efficacy and similar safety and immunogenicity profiles compared with ranibizumab support the use of SB11 for patients with neovascular age-related macular degeneration. Trial Registration: ClinicalTrials.gov Identifier: NCT03150589.

An association of neovascular age-related macular degeneration with polymorphisms of CFH, ARMS2, HTRA1 and C3 genes in Czech population.

PURPOSE: We investigated associations between neovascular age-related macular degeneration (AMD) and rs10490924 polymorphism of ARMS2 gene (age-related maculopathy susceptibility 2), rs1061170 polymorphism of gene for complement factor H (CFH), rs2230199 polymorphism of gene for complement component C3 and rs11200638 polymorphism of gene for serine protease high-temperature requirement A1 (HTRA1) in the Czech population. METHODS: We analysed samples of DNA from 307 patients diagnosed with neovascular form of late AMD (average age: 73.7 ± 7.7 years) and 191 control subjects, recruited from patients awaiting cataract surgery (average age, 73.6 ± 8.7 years). RESULTS: HTRA1, CFH and ARMS2 genes polymorphisms were found to be related to neovascular AMD in the Czech population. All analysed polymorphisms were statistically significantly associated with neovascular AMD, with stronger associations in females than in males. In whole group, CC genotype of CFH gene polymorphism, TT genotype of ARMS2 gene polymorphism and AA genotype of HTRA1 gene polymorphism showed the greatest risk for neovascular AMD with odds ratios equal to 8.43, 10.07, 9.83, respectively (p < 0.0001). Only CG polymorphism of C3 gene showed statistically significant risk for neovascular AMD. In addition, we observed an association between waist circumference and neovascular AMD in both sexes, which further suggests the significance of excessive abdominal fat as a risk factor of AMD. We found a statistically significant association between polymorphisms in HTRA1, CFH and ARMS2 genes and neovascular AMS in the Czech population. The association was stronger in females than in males. CONCLUSION: We demonstrated a relationship between neovascular AMD and genes for HTRA1, CFH, ARMS2 and C3 in Czech population. To our knowledge, the relationship between these polymorphisms and neovascular AMD in Czech population has never been investigated before.

Uveal melanoma - testing of abnormalities of chromosome 3 and 8 in the Czech Republic.

AIM: The aim of this cytogenetic study is to confirm the significance of chromosome 3 loss (monosomy 3) and of the gain of chromosome 8 as prognostic markers in histopathological samples of enucleated eyes with uveal melanoma in the Czech population. METHODS: This is a retrospective study of 52 enucleated eyes. Chromosome 3 and 8 status were tested by CISH, and in a few samples FISH was used. The correlation between monosomy 3 and gain of chromosome 8 and clinical features (histopathological type, size of the tumour) were evaluated. A follow up for the detection of metastases was conducted in all patients. The statistical significance of chromosomal abnormalities as a prognostic factor for the development of metastases was calculated. RESULTS: There were 52 patients, 27 men (51.9%) and 25 women (48.1%) enrolled in our study group. The mean age was 63 ± 14 years. Loss of the one copy of chromosome 3 (monosomy 3) was detected in 26 (50.0%) patients, monosomy 8 was present in 34.6% of patients with monosomy 3. After 5 years there were no metastases in 82% of patients without monosomy 3 as opposed to 40% of patients with monosomy 3. We confirmed a statistically significant association between progression free survival (PFS) and the presence of monosomy 3 (P=0.017). The association between PFS and gain of chromosome 8 was significant as well (0.010). CONCLUSIONS: Our data showed the association of progression-free survival with the presence of monosomy 3 in uveal melanomas. We provided a good prognostic value of monosomy 3 in uveal melanoma.

CD36 gene is associated with intraocular pressure elevation after intravitreal application of anti-VEGF agents in patients with age-related macular degeneration: Implications for the safety of the therapy.

BACKGROUND: The wet form of age-related macular degeneration (AMD) is characterized by pathological vascularization of the outer retinal layers. The condition responds to treatment with antibodies against vascular endothelial growth factor (VEGF), but the patients receiving such anti-VEGF therapy sometimes show undesirable acute short-term increases in the intraocular pressure (IOP). The cause of this adverse effect is unknown, and here, we are testing a hypothesis that it is related to CD36 gene polymorphisms. MATERIALS AND METHODS: A group of 134 patients with AMD were given three therapeutic doses of anti-VEGF antibody (ranibizumab) at monthly intervals. Their IOP was measured immediately before and 30 min after each injection. Patients' DNA was analyzed, and the changes in IOP were matched against seven polymorphisms of the CD36 gene. RESULTS: Three polymorphisms were found to be associated with increases in IOP: rs1049673 (p = 0.006), rs3211931 (p = 0.01), and rs1761667 (p = 0.043) at the time of the third injection only. Pronounced elevations (IOP > 25 mmHg) were associated with rs1049673 polymorphism: GC genotype (p < 0.01) and CC genotype (p < 0.05); both increasing the risk 2.6-fold, the presence of C-allele conferring a 1.5-fold greater risk and with rs3211931 polymorphism: AG genotype (p < 0.01) and GG genotype (p < 0.05); increasing the risk 2.6-fold (AG) and 2.7-fold (GG). CONCLUSIONS: CD36 receptor may be involved in mediating the effects of VEGF on IOP. The findings will help to identify the patients at risk of acutely elevated IOP following the anti-VEGF therapy.

[The use of intravitreal ranibizumab application in the treatment of post-inflammatory neovascular membranes--a case report]. / Vyuzití intravitreální aplikace ranibizumabu v lécbe pozánetlivých neovaskulárních membrán--kazuistické sdelení.

The aim of this case report is to represent our experience with intravitreal application of ranibizumab in a patient with post-inflammatory neovascular membrane. Patient, a 46 years old male, complained about 3 months lasting metamorphopsia in the left eye. The classic post-inflammatory neovascular membrane was diagnosed by means of fluorescein angiography. The initial BCVA of the left eye was 4/6 (or 0.67). Two intravitreal injections of 0.5 mg ranibizumab each were applied. After two applications, the BCVA was 4/4 (or 1.0), there was no biomicroscopically detectable edema, and the OCT revealed reestablished foveolar depression. This condition remains stable even after 10 months after beginning of the treatment. The anti-VEGF treatment represents another possibility of the treatment of post-inflammatory neovascular membranes.

Benefits of three-month continuous glucose monitoring for persons with diabetes using insulin pumps and sensors.

BACKGROUND: The latest Paradigm 722 insulin pump, Medtronic MiniMed, USA, enables daily reading of 288 interstitial fluid glucose concentrations determined by a sensor inserted into subcutaneous tissue; the sensor signals are transmitted into the insulin pump, enabling the patient to see real-time glucose concentration on the display and adapt further treatment. AIMS: To assess the evolution of HbA1c over the course of a 3-month period in two cohorts of persons with type 1 (n=39) or type 2 (n=3) diabetes (PWD): 1) PWD on Paradigm 722 using sensors for continuous glucose monitoring (CGM group), 2) PWD on other types of insulin pumps performing intensive self-monitoring as before (3 to 6 times/d) on glucometer Linus, Wellion, Agamatrix (control group). METHODS: Compliant PWDs using insulin pump with insulin aspart for several previous months were included in the study. Seventeen were put on Paradigm 722 with CGM and 25 were included in the control group. Paired t-test and the statistical program SPSS v.15.0 were used to analyze the data. RESULTS: There was no significant difference in age between the two groups (P=0.996), in diabetes duration (P=0.482) or in daily insulin dose (P=0.469). In the CGM group (but not in the control group) HbA1c/IFCC dropped from 6.98+/-0.43 % to 5.98+/-0.36 % (P=0.006) within 1 month and remained reduced. CONCLUSION: The use of the Paradigm 722 insulin pump with CGM resulted in significant improvement in HbA1c which appeared within one month and remained throughout the whole 3-month study period. No significant improvement in HbA1c was seen in the control group.

Glycaemic index of selected foodstuffs in healthy persons.

AIMS: The aim of this study was to determine glycaemic index (GI) of 10 popular foodstuffs/mixed meals in healthy persons. METHODS: Ten tested foodstuffs and glucose standard were consumed in three replicates in the course of a defined 9-day meal plan: puffed rice squares with chocolate, dark chocolate, white bread, honey and glucose for breakfast (at 7 a.m.) and dinner (at 8 p.m.); pasta with meat, fried fish with mashed potatoes, and buttered apricot dumplings for lunch (at 12 a.m.); wafers, puffed spelt squares with chocolate, and tomato soup for snack (at 4 p.m.). Each portion contained 50 g of carbohydrates and was consumed within 30 minutes. Glucose concentrations were measured by means of the Continous Glucose Monitoring System (CGMS, Medtronic Minimed, Northridge, CA, USA). The results were processed by Solutions Software (Medtronic Minimed, Northridge, CA, USA) and DegifXL4 software, Palacký University, Olomouc, CZ. Twenty healthy persons aged 21.9 +/- 1.39 y (mean +/- SE), BMI 23.6 +/- 0.63 kg/m(2) completed the study. RESULTS: GI of tested foodstuffs ranged from 34.7 % (chocolate) to 105.3 % (puffed rice squares with chocolate). There were more than tenfold differences between minimal and maximal values of the GI for some foodstuffs. Significant interindividual differences were found between GIs of foodstuffs. CONCLUSIONS: In twenty healthy persons the glycaemic indexes of ten popular foodstuffs were determined, to be added to the nutritional labels in order to facilitate the optimum meal planning.