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BACKGROUND/OBJECTIVES: To investigate if the visual and anatomic response to the first dexamethasone implant (DEX) predicts the 12-month clinical outcome after shifting to fluocinolone acetonide (FAc) implant in patients with diabetic macular oedema (DMO). METHODS: Retrospective cohort study including pseudophakic patients with previously treated DMO, undergone one or more DEX injections before FAc. Functional and morphologic response to DEX was defined based on the best-corrected visual acuity (BCVA) and central macular thickness (CMT) changes after the first DEX, respectively. Steroid-response was defined as intraocular pressure (IOP) elevation ≥5 mmHg or IOP > 21 mmHg after any previous DEX exposure. Pairwise comparisons for BCVA, CMT, and IOP after FAc were performed with linear mixed models and a repeated-measure design. RESULTS: Forty-four eyes of 33 patients were included. Patients were shifted to FAc after a mean ± standard deviation of 4.6 ± 3.2 DEX injections. Overall, BCVA and CMT improved during the first 12 months after switching to FAc (p = 0.04 and p

Background/Objectives: To investigate if the visual and anatomic response to the first dexamethasone implant (DEX) predicts the 12-month clinical outcome after shifting to fluocinolone acetonide (FAc) implant in patients with diabetic macular oedema (DMO). Methods: Retrospective cohort study including pseudophakic patients with previously treated DMO, undergone one or more DEX injections before FAc. Functional and morphologic response to DEX was defined based on the best-corrected visual acuity (BCVA) and central macular thickness (CMT) changes after the first DEX, respectively. Steroid-response was defined as intraocular pressure (IOP) elevation ≥5 mmHg or IOP > 21 mmHg after any previous DEX exposure. Pairwise comparisons for BCVA, CMT, and IOP after FAc were performed with linear mixed models and a repeated-measure design. Results: Forty-four eyes of 33 patients were included. Patients were shifted to FAc after a mean ± standard deviation of 4.6 ± 3.2 DEX injections. Overall, BCVA and CMT improved during the first 12 months after switching to FAc (p = 0.04 and p < 0.001, respectively). Only eyes with a good morphologic response to DEX had a significant CMT reduction after FAc (p < 0.001), while no significant relationship was found between BCVA improvement after DEX and after FAc. IOP elevation occurred in 9 eyes (20%) following DEX implant. These eyes carried a 20-fold increased risk of having an IOP rise after FAc (p < 0.001), with a non-linear relationship between the IOP increase after DEX and the one after FAc. Conclusion: The response to previous DEX may anticipate the morphologic response to subsequent FAc. Eyes with steroid-induced IOP elevation after DEX are at a high risk of IOP increase after FAc. The visual response after FAc was not associated with the visual response to previous steroids, indicating that FAc may have a role also in patients refractory to DEX implant. © 2021, The Author(s), under exclusive licence to The Royal College of Ophthalmologists.

The primary objective of this study was to assess whether the topical administration of two neuroprotective drugs (brimonidine and somatostatin) could prevent or arrest retinal neurodysfunction in patients with type 2 diabetes. For this purpose, adults aged between 45 and 75 years with a diabetes duration ≥5 years and an Early Treatment of Diabetic Retinopathy Study (ETDRS) level of ≤35 were randomly assigned to one of three arms: placebo, somatostatin, or brimonidine. The primary outcome was the change in implicit time (IT) assessed by multifocal electroretinography between baseline and at the end of follow-up (96 weeks). There were 449 eligible patients allocated to brimonidine (n = 152), somatostatin (n = 145), or placebo (n = 152). When the primary end point was evaluated in the whole population, we did not find any neuroprotective effect of brimonidine or somatostatin. However, in the subset of patients (34.7%) with preexisting retinal neurodysfunction, IT worsened in the placebo group (P < 0.001) but remained unchanged in the brimonidine and somatostatin groups. In conclusion, the topical administration of the selected neuroprotective agents appears useful in preventing the worsening of preexisting retinal neurodysfunction. This finding points to screening retinal neurodysfunction as a critical issue to identify a subset of patients in whom neuroprotective treatment might be of benefit.

Over the past decade, great strides have been made in the management of diabetic macular edema (DME). Therapeutic alternatives now include focal/grid laser photocoagulation, vitreo-retinal surgery, and intraocular injection of anti-angiogenic and steroid molecules. Intravitreal administration of steroids represents a fundamental alternative for recalcitrant and naive eyes with DME, especially in those cases when anti-vascular endothelial growth factor (VEGF) agents are contraindicated or a treatment regimen with fewer intravitreal injections is required. Currently, 3 intravitreal corticosteroid options for DME treatment are available: the dexamethasone delivery system, the fluocinolone acetonide insert, and off-label intravitreal triamcinolone acetonide. All 3 agents are associated with risk of cataract progression and intraocular pressure elevation, but they maintain a good safety profile. In patients who remain unresponsive to anti-VEGF therapy, are pseudophakic, at low risk for glaucoma, or who have significant cardiovascular risk, treatment with long-lasting intraocular steroids is suggested. There still remain many unanswered questions about intravitreal drugs, regarding dose, frequency, the correct regimen of each treatment, and the potential long-term side effects.

Optical coherence tomography (OCT) angiography (OCT-A) represents an innovative imaging technique which can delineate the retinal and choroidal vascular networks. OCT-A in the assessment of chorio-retinal dystrophies reveal alterations especially located at the level of the deep capillary plexus and the choriocapillaris. This information can have a direct implication on the understanding of the pathogenesis of dystrophies and for their future therapeutic management.

Dexamethasone intravitreal implant 0.7 mg (DEX 0.7) was approved for treatment of diabetic macular edema (DME) after demonstration of its efficacy and safety in the MEAD registration trials. We performed subgroup analysis of MEAD study results to evaluate the efficacy and safety of DEX 0.7 treatment in patients with previously treated DME. Three-year, randomized, sham-controlled phase 3 study in patients with DME, best-corrected visual acuity (BCVA) of 34–68 Early Treatment Diabetic Retinopathy Study letters (20/200–20/50 Snellen equivalent), and central retinal thickness (CRT) ≥300 μm measured by time-domain optical coherence tomography. Patients were randomized to 1 of 2 doses of DEX (0.7 mg or 0.35 mg), or to sham procedure, with retreatment no more than every 6 months. The primary endpoint was ≥15-letter gain in BCVA at study end. Average change in BCVA and CRT from baseline during the study (area-under-the-curve approach) and adverse events were also evaluated. The present subgroup analysis evaluated outcomes in patients randomized to DEX 0.7 (marketed dose) or sham based on prior treatment for DME at study entry. Baseline characteristics of previously treated DEX 0.7 (n = 247) and sham (n = 261) patients were similar. In the previously treated subgroup, mean number of treatments over 3 years was 4.1 for DEX 0.7 and 3.2 for sham, 21.5 % of DEX 0.7 patients versus 11.1 % of sham had ≥15-letter BCVA gain from baseline at study end (P = 0.002), mean average BCVA change from baseline was +3.2 letters with DEX 0.7 versus +1.5 letters with sham (P = 0.024), and mean average CRT change from baseline was −126.1 μm with DEX 0.7 versus −39.0 μm with sham (P

Purpose: To analyze the presence of hyperreflective foci in Type 1 and Type 2 diabetic patients, separately, without clinically significant diabetic macular edema and visual impairment. Methods: Noninvasive, observational prospective study. Seventeen and 19 consecutive Type 1 and Type 2 diabetic patients (33 and 38 eyes), respectively, were recruited. All patients had no clinically significant diabetic macular edema or visual impairment. Two age-and sex-matched control groups were also included. Patients underwent an ophthalmologic examination including spectral domain optical coherence tomography. Hyperreflective foci were counted considering horizontal B-scan passing through the fovea. Results: On spectral domain optical coherence tomography, patients affected by Type 1 and Type 2 diabetes had a mean of 7.5 +/- 4.6 and 9.9 +/- 4.5 hyperreflective foci, respectively. Subjects of control groups had a mean of 0.9 +/- 0.8 and 1.7 +/- 1.5 hyperreflective foci, respectively. Hyperreflective foci amount was statistically different between Type 1 and Type 2 diabetic groups (P = 0.032) and significantly higher in diabetic patients than in controls (P < 0.001). Hyperreflective foci amount was significantly higher in diabetic patients with a poor quality glycometabolic control (P < 0.001 and P = 0.016) or affected by hypertension (P = 0.008). Conclusion: We reported the presence of hyperreflective foci in diabetic patients without diabetic macular edema and visual impairment. This spectral domain optical coherence tomography finding might be a useful marker for the diagnosis and the follow-up in the early stage of diabetic retinopathy.

Frizzled receptors mediate Wnt ligand signalling, which is crucially involved in regulating tissue development and differentiation, and is often deregulated in cancer. In this study, we found that the gene encoding the Wnt receptor frizzled 6 (FZD6 ) is frequently amplified in breast cancer, with an increased incidence in the triple‐negative breast cancer (TNBC ) subtype. Ablation of FZD6 expression in mammary cancer cell lines: (1) inhibited motility and invasion; (2) induced a more symmetrical shape of organoid three‐dimensional cultures; and (3) inhibited bone and liver metastasis in vivo. Mechanistically, FZD6 signalling is required for the assembly of the fibronectin matrix, interfering with the organization of the actin cytoskeleton. Ectopic delivery of fibronectin in FZD6 ‐depleted, triple‐negative MDA‐MB ‐231 cells rearranged the actin cytoskeleton and restored epidermal growth factor‐mediated invasion. In patients with localized, lymph node‐negative (early) breast cancer, positivity of tumour cells for FZD6 protein identified patients with reduced distant relapse‐free survival. Multivariate analysis indicated an independent prognostic significance of FZD6 expression in TNBC tumours, predicting distant, but not local, relapse. We conclude that the FZD6 –fibronectin actin axis identified in our study could be exploited for drug development in highly metastatic forms of breast cancer, such as TNBC .

It is now well established that the enzymes phosphoinositide 3-kinases (PI3Ks) have a key role in the development and progression of many cancer types and indeed PI3Ks inhibitors are currently being tested in clinical trials. Although eight distinct PI3K isoforms exist, grouped into three classes, most of the evidence currently available are focused on one specific isoform with very little known about the potential role of the other members of this family in cancer. Here we demonstrate that the class II enzyme PI3K-C2β is overexpressed in several human breast cancer cell lines and in human breast cancer specimens. Our data indicate that PI3K-C2β regulates breast cancer cell growth in vitro and in vivo and that PI3K-C2β expression in breast tissues is correlated with the proliferative status of the tumor. Specifically we show that downregulation of PI3K-C2β in breast cancer cell lines reduces colony formation, induces cell cycle arrest and inhibits tumor growth, in particular in an estrogen-dependent in vivo xenograft. Investigation of the mechanism of the PI3K-C2β-dependent regulation of cell cycle progression and cell growth revealed that PI3K-C2β regulates cyclin B1 protein levels through modulation of microRNA miR-449a levels. Our data further demonstrate that downregulation of PI3K-C2β inhibits breast cancer cell invasion in vitro and breast cancer metastasis in vivo. Consistent with this, PI3K-C2β is highly expressed in lymph-nodes metastases compared to matching primary tumors. These data demonstrate that PI3K-C2β plays a pivotal role in breast cancer progression and in metastasis development. Our data indicate that PI3K-C2β may represent a key molecular switch that regulates a rate-limiting step in breast tumor progression and therefore it may be targeted to limit breast cancer spread.

Purpose: To evaluate the precision of the IcareONE rebound tonometer, which was developed for self-measuring intraocular pressure (IOP) and to compare IcareONE measurement with Goldmann applanation tonometry (GAT). Methods: Twenty-four healthy eyes and 81 glaucomatous eyes were enrolled. IOP measurements (three times per session) with IcareONE were made in a random order by an ophthalmologist (Icare(O)) and by the subject (Icare(S)). Intraclass correlation coefficients (CCs), kappa values and mean values of IOP were compared among the two types of Icare recordings and GAT. Bland–Altman analysis was used to assess agreement between methods. Multiple regression analysis was performed to identify the subject factors that influenced the discordant measurements between IcareONE and GAT. Results: The mean value of Icare(O) and Icare(S) measurements was 13.5 ± 5.2 and 13.5 ± 5.4 mmHg, respectively, neither of which was significantly different from GAT (13.8 ± 4.4). The intrarater CC of Icare(O) and Icare(S) was 0.968 and 0.885, respectively. The intermethod CC and weighted kappa between Icare(O) and Icare(S) were 0.907 and 0.684, respectively. All pairwise correlations between the two types of IOP measurement showed coefficients of determination >0.8. Bland–Altman analysis did not show any proportional biases. Multiple regression analysis revealed that the differences between GAT and Icare(O) or Icare(S) were positively correlated with central corneal thickness (CCT) and negatively correlated with age. Conclusions: Intraocular pressure measurements with IcareONE by a physician and by the subject showed excellent agreement with GAT measurements; IcareONE measurements between a physician and the subject had high intrarater reliability, and good agreement thicker CCT led IcareONE measurement to overestimate IOP, while higher age caused it to underestimate IOP compared with GAT.

© 2015 Augustin et al. Background: Dexamethasone intravitreal implant 0.7 mg (DEX 0.7) was approved for treatment of diabetic macular edema (DME) after demonstration of its efficacy and safety in the MEAD registration trials. We performed subgroup analysis of MEAD study results to evaluate the efficacy and safety of DEX 0.7 treatment in patients with previously treated DME. Methods: Three-year, randomized, sham-controlled phase 3 study in patients with DME, best-corrected visual acuity (BCVA) of 34.68 Early Treatment Diabetic Retinopathy Study letters (20/200.20/50 Snellen equivalent), and central retinal thickness (CRT) ≥300 μm measured by time-domain optical coherence tomography. Patients were randomized to 1 of 2 doses of DEX (0.7 mg or 0.35 mg), or to sham procedure, with retreatment no more than every 6 months. The primary endpoint was ≥15-letter gain in BCVA at study end. Average change in BCVA and CRT from baseline during the study (area-under-the-curve approach) and adverse events were also evaluated. The present subgroup analysis evaluated outcomes in patients randomized to DEX 0.7 (marketed dose) or sham based on prior treatment for DME at study entry. Results: Baseline characteristics of previously treated DEX 0.7 (n = 247) and sham (n=261) patients were similar. In the previously treated subgroup, mean number of treatments over 3 years was 4.1 for DEX 0.7 and 3.2 for sham, 21.5 % of DEX 0.7 patients versus 11.1 % of sham had ≥15-letter BCVA gain from baseline at study end (P = 0.002), mean average BCVA change from baseline was +3.2 letters with DEX 0.7 versus +1.5 letters with sham (P = 0.024), and mean average CRT change from baseline was -126.1 μm with DEX 0.7 versus -39.0 μm with sham(P < 0.001). Cataract-related adverse events were reported in 70.3 % of baseline phakic patients in the previously treated DEX 0.7 subgroup; vision gains were restored following cataract surgery. Conclusions: DEX 0.7 significantly improved visual and anatomic outcomes in patients with DME previously treated with laser, intravitreal anti-vascular endothelial growth factor, intravitreal triamcinolone acetonide, or a combination of these therapies. The safety profile of DEX 0.7 in previously treated patients was similar to its safety profile in the total study population.