Pina Fortunato

Oral propranolol for retinopathy of prematurity: Risks, safety concerns, and perspectives

OBJECTIVE To evaluate safety and efficacy of oral propranolol administration in preterm newborns affected by an early phase of retinopathy of prematurity (ROP). STUDY DESIGN Fifty-two preterm newborns with Stage 2 ROP were randomized to receive oral propranolol (0.25 or 0.5 mg/kg/6 hours) added to standard treatment or standard treatment alone. To evaluate safety of the treatment, hemodynamic and respiratory variables were continuously monitored, and blood samples were collected weekly to check for renal, liver, and metabolic balance. To evaluate efficacy of the treatment, the progression of the disease (number of laser treatments, number of bevacizumab treatments, and incidence of retinal detachment) was evaluated by serial ophthalmologic examinations, and plasma soluble E-selectin levels were measured weekly. RESULTS Newborns treated with propranolol showed less progression to Stage 3 (risk ratio 0.52; 95% CI 0.47-0.58, relative reduction of risk 48%) or Stage 3 plus (relative risk 0.42 95% CI 0.31-0.58, relative reduction of risk 58%). The infants required fewer laser treatments and less need for rescue treatment with intravitreal bevacizumab (relative risk 0.48; 95% CI 0.29-0.79, relative reduction of risk 52 %), a 100% relative reduction of risk for progression to Stage 4. They also had significantly lower plasma soluble E-selectin levels. However, 5 of the 26 newborns treated with propranolol had serious adverse effects (hypotension, bradycardia), in conjunction with episodes of sepsis, anesthesia induction, or tracheal stimulation. CONCLUSION This pilot study suggests that the administration of oral propranolol is effective in counteracting the progression of ROP but that safety is a concern.

Study protocol: safety and efficacy of propranolol in newborns with Retinopathy of Prematurity (PROP-ROP): ISRCTN18523491

BackgroundDespite new therapeutic approaches have improved the prognosis of newborns with retinopathy of prematurity (ROP), an unfavourable structural and functional outcome still remains high. There is high pressure to develop new drugs to prevent and treat ROP. There is increasing enthusiasm for anti-VEGF drugs, but angiogenic inhibitors selective for abnormal blood vessels would be considered as an optimal treatment.In an animal experimental model of proliferative retinopathy, we have recently demonstrated that the pharmacological blockade of beta-adrenoreceptors improves retinal neovascularization and blood retinal barrier breakdown consequent to hypoxia. The purpose of this study is to evaluate the propranolol administration in preterm newborns suffering from a precocious phase of ROP in terms of safety and efficacy in counteracting the progression of retinopathy.Methods/DesignPreterm newborns (gestational age at birth lower than 32 weeks) with stage 2 ROP (zone II-III without plus) will be randomized, according to their gestational age, to receive propranolol added to standard treatment (treatment adopted by the ETROP Cooperative Group) or standard treatment alone. Propranolol will be administered until retinal vascularization will be completely developed, but not more than 90 days. Forty-four participants will be recruited into the study. To evaluate the safety of propranolol administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of propranolol, the progression of the disease, the number of laser treatments or vitrectomies, the incidence of retinal detachment or blindness, will be evaluated by serial ophthalmologic examinations. Visual function will be evaluated by means of behavioural standardized tests.DiscussionThis pilot study is the first research that explores the possible therapeutic role of beta blockers in ROP. The objective of this research is highly ambitious: to find a treatment simple, inexpensive, well tolerated and with few adverse effects, able to counteract one of the major complications of the prematurity. Any favourable results of this research could open new perspectives and original scenarios about the treatment or the prevention of this and other proliferative retinopathies.Trial RegistrationCurrent Controlled Trials ISRCTN18523491; ClinicalTrials.gov Identifier NCT01079715; EudraCT Number 2010-018737-21

Texture Classification of Retinal Layers in Optical Coherence Tomography

This work investigates the ability of texture analysis to yield discrimination of retinal tissue layers in the images provided by Optical Coherence Tomography (OCT). In fact, this relatively new imaging technology allows noninvasive visualization of retinal layers. Their segmentation is a prerequisite for any computer method that aims to objectively extract valuable information, regarding the condition and the progression of disease and therapy. Since the regularities of biological tissue can be captured by texture analysis in a straightforward way, a computer approach is proposed based on co-occurence matrices and artificial neural networks (ANN) for the classification and analysis of single retinal layers. A subset of ten normal eyes has been used for the training phase, and another subset of ten normal eyes has been used for testing the system performance. For inner retinal layers, accuracy was 79%, specificity about 71% and sensibility was 87%. Slightly lower values were obtained for outer retinal layers. These preliminary results suggest that this approach may be useful as a prototype system for a quantitative characterization of retinal tissue.

Intravitreal bevacizumab for retinopathy of prematurity as first line or rescue therapy with focal laser treatment. A case series

Objectives: Laser therapy is effective in the treatment of severe forms of retinopathy of prematurity (ROP), and aggressive posterior ROP (APROP), but always damages the retina. We report our preliminary findings in seven premature infants with complicated ROP or APROP who were treated with intravitreal bevacizumab (IVB) as first line monotherapy or rescue therapy combined with laser treatment. Methods: We studied retrospectively seven preterm infants, who were affected by APROP (n = 4) or pre-threshold ROP (n = 3). Infants were treated with IVB (0.625 mg; Avastin®, Roche, Basel, Switzerland) monotherapy (n = 2) when they were too sick to undergo lengthy laser treatment. Results: Monotherapy IVB (n = 3 eyes) and IVB combined with laser therapy (n = 3 eyes) of APROP cases were followed by regression of the ROP and complete peripheral vascularization. The combined therapy with IVB and laser therapy of pre-threshold ROP (5 eyes) produced a regression of neovascularization and good retinal anatomical outcome. Conclusions: In our series, IVB was successful in treating ROP in a small cohort of extremely preterm infants with APROP or pre-threshold ROP, both as monotherapy or rescue treatment after laser therapy, without the development of ocular and systemic short- and long-term adverse effects.

Irresponsiveness of two retinoblastoma cases to conservative therapy correlates with up- regulation of hERG1 channels and of the VEGF-A pathway

BackgroundTreatment strategies for Retinoblastoma (RB), the most common primary intraocular tumor in children, have evolved over the past few decades and chemoreduction is currently the most popular treatment strategy. Despite success, systemic chemotherapeutic treatment has relevant toxicity, especially in the pediatric population. Antiangiogenic therapy has thus been proposed as a valuable alternative for pediatric malignancies, in particolar RB. Indeed, it has been shown that vessel density correlates with both local invasive growth and presence of metastases in RB, suggesting that angiogenesis could play a pivotal role for both local and systemic invasive growth in RB. We present here two cases of sporadic, bilateral RB that did not benefit from the conservative treatment and we provide evidence that the VEGF-A pathway is significantly up-regulated in both RB cases along with an over expression of hERG1 K+ channels.Case presentationTwo patients showed a sporadic, bilateral RB, classified at Stage II of the Reese-Elsworth Classification. Neither of them got benefits from conservative treatment, and the two eyes were enucleated. In samples from both RB cases we studied the VEGF-A pathway: VEGF-A showed high levels in the vitreous, the vegf-a, flt-1, kdr, and hif1-α transcripts were over-expressed. Moreover, both the transcripts and proteins of the hERG1 K+ channels turned out to be up-regulated in the two RB cases compared to the non cancerous retinal tissue.ConclusionsWe provide evidence that the VEGF-A pathway is up-regulated in two particular aggressive cases of bilateral RB, which did not experience any benefit from conservative treatment, showing the overexpression of the vegf-a, flt-1, kdr and hif1-α transcripts and the high secretion of VEGF-A. Moreover we also show for the first time that the herg1 gene transcripts and protein are over expressed in RB, as occurs in several aggressive tumors. These results further stress the relevance of the VEGF-A pathway in RB and the correlation with hERG1, making aggressive and recurrent RB cases good candidates for antiangiogenesis therapies based on the targeting of VEGF-A.

Propranolol 0.1% eye micro-drops in newborns with retinopathy of prematurity: a pilot clinical trial.

Background:Oral propranolol reduces retinopathy of prematurity (ROP) progression, although not safely. This study evaluated safety and efficacy of propranolol eye micro-drops in preterm newborns with ROP.Methods:A multicenter open-label trial, planned according to the Simon optimal two-stage design, was performed to analyze safety and efficacy of propranolol micro-drops in newborns with stage 2 ROP. To this end, hemodynamic and respiratory parameters were monitored, and blood samples were collected weekly, for 3 wk. Propranolol plasma levels were also monitored. The progression of the disease was evaluated with serial ophthalmologic examinations.Results:Twenty-three newborns were enrolled. Since the fourth of the first 19 newborns enrolled in the first stage of the study showed a progression to stage 2 or 3 with plus, the second stage was prematurely discontinued. Even though the objective to complete the second stage was not achieved, the percentage of ROP progression (26%) was similar to that obtained previously with oral propranolol administration. However, no adverse effects were observed and propranolol plasma levels were significantly lower than those measured after oral administration.Conclusion:Propranolol 0.1% eye micro-drops are well tolerated, but not sufficiently effective. Further studies are required to identify the optimal dose and administration schedule.

Validation of a Computer Aided Segmentation System for Retinography

In spite of the huge literature on angiography, some problems are still open to discussion, such as segmentation of entire vascular networks. In the present work a new computer approach is developed in two stages, with the aim of improving the analysis and comparison of retina vessel images in the follow up of patients. The first stage adopts multiscale filtering to detect objects of different sizes: a two scale Laplacian of Gaussian scheme is used with the related sigma values chosen according to the smallest and greatest vessel widths. An approximate segmentation is achieved simply by means of the Laplacian sign. The interpretation stage is application-specific and accomplishes classification and quantitative analysis. The skeleton of the binary structures is subdivided in vessel segments, their features (intensity, position, length and width) are fed into an artificial neural network (ANN), after back-propagation training. The segments classified as vessels are assembled into the retinal vascular tree by rule-based tracking, starting from optic disc (OD). Results are evaluated on STARE and DRIVE data bases. Accuracy is 95% and the false positive rate is decreased to about 1%, lower than literature values.

Macular diseases: update on diagnostic and therapeutic techniques

Purpose of this course is to review the principles that guide the diagnosis and the classification of macular diseases, and the new options available for this purpose. Among new treatments modalities, photodynamic therapy (PDT) has been recently introduced in the clinical practice for treating subfoveal choroidal neovascularization (CNV). In age-related macular degeneration (AMD), eyes in which the classic CNV components covers at least 50% of the entire lesion, called predominantly classic lesions, benefit from a substantial reduction of the rate of moderate visual loss during the first year. Preliminary results in other types of CNV also indicate a possible efficacy. We will present the theoretical basis and mechanisms of action of PDT and then comment on the main results of the TAP study; the preliminary results available from the VIP will also be displayed. Numerous cases treated with PDT, one year after its introduction in the clinical practice, will be shown and discussed. The introduction of PDT has probably reduced the applicability of surgical techniques for treating CNV. Yet, surgeons are developing less invasive techniques to minimize the complications associated with membrane removal and the various types of translocation. This innovation will be illustrated, as well as the criteria for patients selection in the era of PDT.

Vitreo-retinal interface: diagnosis and medical-surgical treatment

Despite insightful studies of various researchers, vitreous physiophathology is still only partially explored as a field of study for modern ophthalmology. There is much to be learned about the mechanisms that maintain the integrity of vitreo-retinal interface and, more deeply, about the biochemical relationship between retinal pigment epithelium and Bruchs membrane; an imbalance between the physical and biological homeostasis at these levels may determine the onset of vitreo-retinal interface disease. Despite the unclear relationship between internal limiting membrane (ILM) and hyaloid, and between pathogenesis and effect of vitreous detachment, surgical techniques are being developed that promise a resolution of most diseases associated with vitreous and retinal anomalies. Optical coherence tomography (OCT) is the main diagnostic technique supporting this advances. The authors, after briefly introducing vitreous physiology and pathology, will discuss the main indications to this type of surgery, which is guided by OCT.