ARTIFICIAL INTELLIGENCE'S ROLE IN DIFFERENTIATING THE ORIGIN FOR SUBRETINAL BLEEDING IN PATHOLOGIC MYOPIA.

PURPOSE: To identify salient imaging features to support human-based differential diagnosis between subretinal hemorrhage (SH) due to choroidal neovascularization (CNV) onset and SH without CNV (simple bleeding [SB]) in pathologic myopia eyes using a machine learning (ML)-based step-wise approach. METHODS: Four different methods for feature extraction were applied: GradCAM visualization, reverse engineering, image processing, and human graders' measurements. GradCAM was performed on a deep learning model derived from Inception-ResNet-v2 trained with OCT B-scan images. Reverse engineering consisted of merging U-Net architecture with a deconvolutional network. Image processing consisted of the application of a local adaptive threshold. Available OCT B-scan images were divided in two groups: the first group was classified by graders before knowing the results of feature extraction and the second (different images) was classified after familiarization with the results of feature extraction. RESULTS: Forty-seven and 37 eyes were included in the CNV group and the simple bleeding group, respectively. Choroidal neovascularization eyes showed higher baseline central macular thickness ( P = 0.036). Image processing evidenced in CNV eyes an inhomogeneity of the subretinal material and an interruption of the Bruch membrane at the margins of the SH area. Graders' classification performance improved from an accuracy of 76.9% without guidance to 83.3% with the guidance of the three methods ( P  = 0.02). Deep learning accuracy in the task was 86.0%. CONCLUSION: Artificial intelligence helps identifying imaging biomarkers suggestive of CNV in the context of SH in myopia, improving human ability to perform differential diagnosis on unprocessed baseline OCT B-scan images. Deep learning can accurately distinguish between the two causes of SH.

Comparison of Dasatinib, Nilotinib, and Imatinib in the Treatment of Chronic Myeloid Leukemia.

To overcome the drug resistance phenomenon induced by Imatibib (IM), in clinical practice, are often used second generation of tyrosine kinase inhibitors as Nilotinib (NIL); a such potent inhibitor of the BCR/ABL kinase and Dasatinib (DAS), a inhibitor of BCR/ABL kinase, and inhibitor SrC family kinase. In this study we evaluated the in vivo effect of DAS, NIL, and IM on intracellular calcium concentration, oxidative stress, and apoptosis in peripheral blood leukocytes of 45 newly diagnosed patients with chronic myeloid leukaemia (CML-PBM). Our data demonstrated that treatment with DAS and NIL showed an higher modulating potential than IM on intracellular calcium concentration by inhibiting the thapsigargin, a sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor, and Lithium (Li) an inositol 1,4,5-triphosphate (InsP3) receptor inhibitor activities. Moreover our data demonstrated that NIL and DAS have significantly increased apoptosis more than IM by involving both intracellular calcium signaling as well as oxidative stress. The acquisition of the oxidative stress and calcium channels receptors values data could help the hematologist to modulate and improve the treatment of chronic myeloid leukaemia (CML) pathology.

SRC family kinase inhibition through a new pyrazolo[3,4-d]pyrimidine derivative as a feasible approach for glioblastoma treatment.

Glioblastoma (GB) is the most common and aggressive primary tumor of the central nervous system. The current standard of care for GB consists of surgical resection, followed by radiotherapy combined with temozolomide chemotherapy. However, despite this intensive treatment, the prognosis remains extremely poor. Therefore, more effective therapies are urgently required. Recent studies indicate that SRC family kinases (SFKs) could represent promising molecular targets for GB therapy. Here, we challenged four GB cell lines with a new selective pyrazolo[3,4-d]pyrimidine derivative SFK inhibitor, called SI221. This compound exerted a significant cytotoxic effect on GB cells, without significantly affecting non-tumor cells (primary human skin fibroblasts), as evaluated by MTS assay. We also observed that SI221 was more effective than the well-known SFK inhibitor PP2 in GB cells. Notably, despite the high intrinsic resistance to apoptosis of GB cells, SI221 was able to induce this cell death process in all the GB cell lines, as observed through cytofluorimetric analysis and caspase-3 assay. SI221 also exerted a long-term inhibition of GB cell growth and was able to reduce GB cell migration, as shown by clonogenic assay and scratch test, respectively. Moreover, through in vitro pharmacokinetic assays, SI221 proved to have a high metabolic stability and a good potential to cross the blood brain barrier, which is an essential requirement for a drug intended to treat brain tumors. Therefore, despite the need of developing strategies to improve SI221 solubility, our results suggest a potential application of this selective SFK inhibitor in GB therapy.

The Protective Effect of Apocynin on Cyclosporine A-Induced Hypertension and Nephrotoxicity in Rats.

Cyclosporine A (CsA) is the prototype of immunosuppressant drugs that has provided new perspectives in human and veterinary medicine to prevent organ transplant rejection and to treat certain autoimmune diseases and dermatologic diseases. Unfortunately, the treatment with CSA is often limited by severe adverse effects such as hypertension and nephrotoxicity. Some data suggest that reactive oxygen species (ROS) and the oxidative stress play an important role in its pathogenesis, in particular the superoxide (O2 (-)) that is the most powerful free radical generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase present mainly in the kidney. The present study has been designed to investigate the role of Apocynin a selective inhibitor of NADPH oxidase activity on cyclosporine-induced adverse effect. In this study, we have evaluated the effect of CsA, used alone or in association with Apocynin on blood pressure (BP), on glomerular filtration rate (GFR), on absoluted fluid reabsorption (Jv) in proximal tubule (PT), on O2 (-) concentration, and on nitric oxide (NO) production. We have demonstrated that CsA administration increases superoxide concentration in the aorta, decreases the NO concentration, reduces GFR and the Jv in PT, and induces a significant increase in BP. Moreover, we have shown that Apocynin treatment restores these hemodynamic alterations, as well as NO and superoxide productions. In conclusion, the reported data indicate that CsA induced nephrotoxicity and hypertension are related to NADPH oxidase activity, in fact Apocynin protects the kidney function and BP from toxic effects induced by CsA through the inhibition of NADPH oxidase activity.

Macular Neovascularization Secondary to Subclinical Angioid Streaks in Age-Related Macular Degeneration: Treatment Response to Anti-VEGF at 2-Year Follow-up.

INTRODUCTION: To characterize the response to antivascular endothelial growth factor (VEGF) treatment of macular neovascularization (MNV) secondary to age-related macular degeneration (AMD) with subclinical angioid streaks (AS) during a 2-year follow-up. METHODS: Retrospective, longitudinal, case-control, and multicentric study. Among a cohort of neovascular AMD population, we selected patients with subclinical AS and treatment-naïve MNV treated with anti-VEGF for a 2-year follow-up. An age- and sex-matched control group with treatment-naïve MNV secondary to AMD without subclinical AS was selected. Demographics and differences in treatment response (i.e., number of injections needed, anatomical and functional outcomes) between the two groups were analyzed. RESULTS: Among 102 eyes of 102 patients with neovascular AMD, 34 eyes of 34 patients (82 ± 6 years old) were included in the subclinical AS group, whereas 68 eyes of 68 patients (81 ± 6 years old, p = 0.342) in the control group. All eyes with subclinical AS presented RPD compared to 56% of eyes without subclinical AS (p < 0.001). During the 2-year follow-up, eyes with subclinical AS needed more injections (10.6 ± 3.2 vs 8.3 ± 3.1 injections for eyes with and without subclinical AS, respectively, p < 0.001). Visual acuity (VA) decreased during the treatment (from 0.53 ± 0.37 at the baseline to 0.69 ± 0.45 LogMAR at 2-year follow-up, p = 0.044) in eyes with subclinical AS; no VA changes were observed in the control group (p = 0.798). RPE atrophy at the end of the 2-year follow-up affected 74% of cases with subclinical AS and 29% of cases of the control group (p < 0.001). CONCLUSIONS: MNVs secondary to AMD with subclinical AS are characterized by worse functional and anatomical outcomes after 2-year anti-VEGF treatment compared to MNV secondary to AMD without subclinical AS, supporting the different pathophysiological mechanisms involved in this recently described AMD phenotype.

Hypertensive choroidopathy in atypical hemolytic-uremic syndrome.

PURPOSE: We present the case of a 22-year-old woman, diagnosed as having atypical hemolytic uremic syndrome with a hypertensive crisis, who presented a bilateral serous retinal detachment. CASE DESCRIPTION: A 22-year-old woman, diagnosed as having atypical hemolytic uremic syndrome, was referred for blurred vision in both eyes, evolving over 7 days. Treatment including hemodialysis, plasma exchange, systemic steroids, antihypertensive medications and eculizumab was started 1 month prior to referral. At presentation, best-corrected visual acuity was 20/40 in the right eye and 20/25 in the left eye. Retinal examination revealed bilateral serous retinal detachment in the posterior pole and some small, flat, variably pigmented lesions. Optical coherence tomography confirmed marked serous retinal detachment in both eyes. Fluorescein and indocyanine green angiography was performed. Treatment for systemic hypertension was changed. Seven days later, dilated fundus examination and optical coherence tomography demonstrated a significant regression of the serous retinal detachment. Her visual acuity improves in both eyes at the last control, showing at fundus examination a complete resolution of the exudative detachment but a persistence of variable flat pigmented lesion. CONCLUSION: Although multiple organ systems are commonly affected in hemolytic uremic syndrome, ocular involvement has only been described in very few cases. Ocular manifestations in atypical hemolytic uremic syndrome include retinal, choroidal and vitreal hemorrhages, retina and/or ischemic signs. Bilateral serous retinal detachment may also be a sign of atypical hemolytic uremic syndrome or even the first manifestation of a hypertensive event.

Automated Quantification of Pathological Fluids in Neovascular Age-Related Macular Degeneration, and Its Repeatability Using Deep Learning.

Purpose: To develop a reliable algorithm for the automated identification, localization, and volume measurement of exudative manifestations in neovascular age-related macular degeneration (nAMD), including intraretinal (IRF), subretinal fluid (SRF), and pigment epithelium detachment (PED), using a deep-learning approach. Methods: One hundred seven spectral domain optical coherence tomography (OCT) cube volumes were extracted from nAMD eyes. Manual annotation of IRF, SRF, and PED was performed. Ninety-two OCT volumes served as training and validation set, and 15 OCT volumes from different patients as test set. The performance of our fluid segmentation method was quantified by means of pixel-wise metrics and volume correlations and compared to other methods. Repeatability was tested on 42 other eyes with five OCT volume scans acquired on the same day. Results: The fully automated algorithm achieved good performance for the detection of IRF, SRF, and PED. The area under the curve for detection, sensitivity, and specificity was 0.97, 0.95, and 0.99, respectively. The correlation coefficients for the fluid volumes were 0.99, 0.99, and 0.91, respectively. The Dice score was 0.73, 0.67, and 0.82, respectively. For the largest volume quartiles the Dice scores were >0.90. Including retinal layer segmentation contributed positively to the performance. The repeatability of volume prediction showed a standard deviations of 4.0 nL, 3.5 nL, and 20.0 nL for IRF, SRF, and PED, respectively. Conclusions: The deep-learning algorithm can simultaneously acquire a high level of performance for the identification and volume measurements of IRF, SRF, and PED in nAMD, providing accurate and repeatable predictions. Including layer segmentation during training and squeeze-excite block in the network architecture were shown to boost the performance. Translational Relevance: Potential applications include measurements of specific fluid compartments with high reproducibility, assistance in treatment decisions, and the diagnostic or scientific evaluation of relevant subgroups.

The Pupil Diameter as a Possible Indicator of Neurodegenerative Diseases and Response to Acetylcholinesterase Inhibitors Therapy: In-Depth Measurements Following Topical Administration of Tropicamide and Pilocarpine.

BACKGROUND: The aim of this study is to assess whether pupillary modifications following ocular anticholinergic and cholinergic drugs can identify subjects with neurodegenerative diseases from early stages. METHODS: 51 subjects were divided into 3 groups, according to different neurodegenerative diseases, and compared with a control group of 10 patients. Pupil diameter has been measured at different times after topical administration of tropicamide 0.01% in the right eye. Then, topical administration of pilocarpine 0.06% has been performed, followed by pupillary constriction measurement. Pupillary response rates were stratified according to acetylcholinesterase inhibitors intake. RESULTS: Observed mydriasis and pupillary constriction was similar in all study groups at all evaluation times. Patients without acetylcholinesterase inhibitors intake presented greater mydriasis. CONCLUSIONS: Although it was not possible to observe significant differences among groups in terms of pupillary response, the analysis of pupillary features may become an useful tool to detect efficacy of acetylcholinesterase inhibitors.

Exogenous Fungal Endophthalmitis: Clues to Aspergillus Aetiology with a Pharmacological Perspective.

Exogenous fungal endophthalmitis (EXFE) represents a rare complication after penetrating ocular trauma of previously unresolved keratitis or iatrogenic infections, following intraocular surgery such as cataract surgery. The usual latency period between intraocular inoculation and presentation of symptoms from fungal endophthalmitis is several weeks to months as delayed-onset endophthalmitis. Aspergillus spp., is the most common causative mould pathogen implicated in this ocular infection and early diagnosis and prompt antimicrobial treatment, concomitantly in most cases with expert surgical attention, reduce unfavorable complications and increase the possibility of eye function preservation. Topical, intravitreal and systemic antifungal molecules are the mainstay of a medical approach to the disease and azoles, polyenes and in particular cases echinocandins are the pharmacological classes most commonly used in clinical practice. This review discusses pharmacokinetics and pharmacodynamic of antifungal agents in their principal modes of administration with a focus on their ability to achieve high drug concentration in the vitreous and ocular tissues.

Baseline SD-OCT characteristics of diabetic macular oedema patterns can predict morphological features and timing of recurrence in patients treated with dexamethasone intravitreal implants.

AIMS: To evaluate the timing and spectral-domain optical coherence tomography (SD-OCT) features of diabetic macular oedema (DME) recurrence according to baseline OCT patterns in patients treated with dexamethasone implant (DEX-I). METHODS: This is a retrospective observational study (72 eyes/65 patients). Best-corrected visual acuity, timing of DME recurrence, and SD-OCT pattern [intraretinal cysts (IRC), IRC plus subretinal fluid (mixed), external limiting membrane (ELM), ellipsoid (IS/OS) layer integrity] were assessed at baseline and monthly until first DME recurrence. RESULTS: Forty-two (58.3%) and 30 (41.6%) DME eyes had an IRC and mixed DME pattern at baseline, respectively. Twenty-four out of thirty mixed eyes (80%) relapsed without subretinal fluid. At baseline, mixed eyes showed similar changes in ELM and IS/OS (60 and 76.6% of eyes, respectively) versus IRC eyes (42.8 and 80.9% of eyes). After DME recurrence, more mixed eyes at baseline showed ELM and IS/OS changes (63.3 and 86.6%) than IRC eyes (50 and 76.2%). 33.3% of mixed eyes had DME recurrence at ≥ 6 months from first DEX-I implant versus 19% of IRC eyes. CONCLUSIONS: Mixed DME eyes were treated with DEX-I relapse later and more frequently without subretinal fluid than IRC eyes. SD-OCT characteristics of different DME patterns at baseline can predict morphological features and timing of DME recurrence.

Vitreomacular interface alterations following peripheral laser retinopexy: Interface changes after laser.

AIM: To demonstrate the morphological outcomes of macular hole following prophylactic peripheral laser retinopexy (PPLR). METHODS: Our retrospective case-control analysis included 92 eyes, 55 in the laser group and 37 in the non-laser group. Fifty-five patients were subjected to prophylactic peripheral laser retinopexy in preparation for pars plana vitrectomy for macular hole, with and without vitreomacular adhesion (laser group). Before and after prophylactic peripheral laser retinopexy, we evaluated any changes in vitreomacular anatomy by optical coherence tomography. Optical coherence tomography changes were also analyzed in the visits preceding pars plana vitrectomy in 37 macular hole eyes not subjected to prophylactic peripheral laser retinopexy (non-laser group). RESULTS: In the laser group, 7 out of 55 eyes (12.7%) showed macular hole closure (6 out of 18 macular hole eyes with vitreomacular adhesion (33.3%) and 1 out of 37 eyes without vitreomacular adhesion (2.7%)), while no patients showed macular hole closure in the non-laser group (p < 0.05). The mean width of the seven closed macular hole was 191.4 µm (range: 59-282 µm). In all except one of the six macular hole eyes with vitreomacular adhesion, the macular hole closed without vitreomacular adhesion release. In our analysis of the patient subgroup with vitreomacular adhesion, we observed a release of vitreomacular adhesion in 3 out of 18 eyes (16.6%) in the laser group and in 1 out of 13 eyes (7.6%) in the non-laser group (p > 0.05). CONCLUSION: These findings support a possible beneficial role for prophylactic peripheral laser retinopexy in selected individuals with macular hole.

Impact of intraoperative topical hydroxypropyl methylcellulose 2% versus sodium hyaluronate 1.2% on corneal reepithelialization after intentional epithelial debridement during vitrectomy.

PURPOSE: The aim of this study was to assess the impact of the intraoperative use of topical hydroxypropyl methylcellulose (HPMC) 2% versus sodium hyaluronate 1.2% on corneal reepithelialization time and final corneal status after intentional epithelial debridement during vitrectomy for proliferative vitreoretinopathy. METHODS: Forty eyes of 40 patients were included in the study, divided into 2 groups of 20 eyes. HPMC 2% and sodium hyaluronate 1.2% were used as corneal protectors in the first and second group, respectively. Patients' charts were reviewed to determine any differences between the HPMC 2% and sodium hyaluronate 1.2% groups in relation to the preoperative, intraoperative, and postoperative factors that could impact postoperative corneal reepithelialization. Postoperative reepithelialization time and final corneal status were recorded. RESULTS: No significant between-group differences in preoperative, intraoperative, and postoperative factors were found. Reepithelialization time was significantly shorter in the sodium hyaluronate 1.2% group than in the HPMC 2% group, although reepithelialization was eventually achieved in every patient in both groups. Corneal sequelae were significantly more frequent in the HPMC 2% group than in the sodium hyaluronate 1.2% group. CONCLUSIONS: The choice of the ophthalmic viscosurgical device for intraoperative corneal protection may significantly influence the postoperative corneal status after complicated retinal detachment.