[Unmet clinical need and new therapeutic options.] / Unmet clinical need e nuovi farmaci.

The debate around unmet clinical need (UCN) is still very much alive. How do we define UCN? How does it influence the definition of clinically relevant outcomes in a therapeutic area? Who defines UCN? What are the consequences of recognizing different grading of UCN? In this paper we will address these questions and finally formulate proposals for the Italian context. The paper is based on a discussion within a panel of experts. This topic is even more stimulating as this work takes place in a historical period which, on the one hand, sees the start of a new course of negotiation rules recently published by AIFA and, on the other hand, poses unprecedented challenges that emerged during the pandemic crisis. The working group formulated suggestions and proposals to further enhance the role of the UCN in decision-making processes, also in the light of the new negotiation procedure, and to help refine the tools for grading the UCN and the value of medicines in the interests of patients and society as a whole.

Unique Features of Posterior Ocular Involvement of Whipple's Disease in a Patient with No Gastrointestinal Symptoms.

PURPOSE: To describe posterior ocular involvement features of Whipple's disease (WD) in a patient with no gastrointestinal symptoms. METHODS: Retrospective case report. OBSERVATION: A 53-year-old man with a 2-year history of seronegative arthritis presented with bilateral intraocular inflammation, optic disc edema, and cystoid macular edema (CME) in the left eye. A diagnosis of noninfectious uveitis was made and oral prednisolone was started. Despite initial improvement, after 6 weeks, CME was found in both eyes. Because of the initial response, the anti-tumor necrosis factor agent Adalimumab was started. Twelve weeks after initiation of adalimumab, fundus examination revealed widespread dot-blot retinal hemorrhages and multifocal chorioretinal lesions at the posterior pole and mid-periphery. The chorioretinal lesions appeared as hyperreflective drusen-like deposits located in the sub-retinal pigment epithelium (RPE) space on the tomographic scan. WD was considered and confirmed by polymerase chain reaction test and duodenal biopsy. CONCLUSION: Posterior ocular involvement in WD may present with a wide clinical spectrum including intraocular inflammation and unique features of sub-RPE deposits, widespread retinal hemorrhages, and optic disc edema.

Intravitreal Brolucizumab for Neovascular Age-Related Macular Degeneration in a Vitrectomized Eye.

The efficacy of intravitreal anti-VEGF may be reduced in vitrectomized eyes due to accelerated drug clearance. Given its longer durability, brolucizumab may represent a suitable therapeutic option. However, its efficacy in vitrectomized eyes remains to be explored. Herein, we describe the management of a macular neovascularization (MNV) in a vitrectomized eye with brolucizumab after unsuccessful treatment with other anti-VEGF. A 68-year-old male was treated with pars plana vitrectomy for epiretinal membrane in his left eye (LE) in 2018. After surgery, best corrected visual acuity (BCVA) improved to 20/20 with a remarkable reduction of metamorphopsia. After 3 years, the patient returned, presenting visual loss in the LE due to MNV. He was treated with intravitreal bevacizumab injections. However, after the loading phase, an increased lesion size and exudation with worsening BCVA were detected. Therefore, the treatment was switched to aflibercept. However, after three monthly intravitreal injections, further worsening was recorded. Treatment was then switched to brolucizumab. Anatomical and functional improvement was noticed 1 month after the first brolucizumab injection. Two additional injections were performed, and further improvement was recorded with BCVA recovery to 20/20. At the last follow-up visit 2 months after the third injection, no recurrence was detected. In conclusion, determining whether anti-VEGF injections are efficacious for vitrectomized eyes would be helpful for ophthalmologists managing such patients, as well as when considering pars plana vitrectomy in eyes at risk of MNV. In our case, brolucizumab was found to be effective after unsuccessful treatment with other anti-VEGF. Additional studies are required to evaluate the safety and efficacy of brolucizumab for MNV in vitrectomized eyes.

Inverted ILM Flap for the Treatment of Myopic Macular Holes: Healing Processes and Morphological Changes in Comparison with Complete ILM Removal.

PURPOSE: To investigate the microstructural changes after successful myopic macular hole (MMH) surgery, comparing inverted ILM flap and complete ILM removal techniques, and their association with visual function. METHODS: Spectral-domain optical coherence tomography (SD-OCT) was used to evaluate both external limiting membrane (ELM) and ellipsoid zone (EZ) recovery in 40 eyes of 39 patients who underwent pars plana vitrectomy with either inverted internal limiting membrane flap technique (n=27) or complete ILM removal (n=13) to achieve MH closure. The association between ELM and EZ recovery and visual acuity was also investigated. The patients were followed up at 1 year. RESULTS: ELM and EZ was recovered in 72% and 62% of cases, respectively, regardless of the surgical techniques 1 year after surgery. A strong positive association between the ELM and EZ recovery and the mean BCVA was found: regardless of the surgical technique, this was statistically significant at each time point (p < 0.05). None of the baseline variables were found to act as predictive factors for either ELM or EZ. CONCLUSION: The inverted ILM flap technique did not affect the MMH healing processes compared to complete ILM removal. Thus, the presence of the ILM plug did not interfere with the restoration of both ELM and EZ, which correlated with functional recovery.

New Insights Into the Development and Progression of Geographic Atrophy After Full Thickness Autologous Choroidal Graft.

Purpose: To investigate if the contiguity between native and transplanted retinal pigment epithelium (RPE) represents a protective factor against the progression of atrophy after autologous choroidal graft. In addition, the changes in fundus autofluorescence (FAF) in the contiguous and noncontiguous RPE areas were explored. Methods: The first postoperative reliable FAF image was selected and divided into sectors based on the characteristics of the RPE at the edge of the graft. The sectors were categorized into three groups: contiguous RPE, noncontiguous RPE, and not classifiable. The area of RPE atrophy, inside and outside the graft, was measured for each sector at baseline, one, three, and five years of follow-up. The FAF pattern outside the graft was evaluated for every sector at baseline and during the follow-up. Results: Nineteen patients met the inclusion criteria and were included in this study. Trend analysis showed that the atrophy progression outside the graft was statistically significant in areas where native and transplanted RPE were noncontiguous (P < 0.0001) yet not so in contiguous areas (P < 0.058). Inside the graft, both groups showed an increase in atrophy over time. In addition, the noncontiguous group developed more severe increased FAF patterns compared with the contiguous group. Conclusions: RPE contiguity after autologous choroidal graft seems to be a protective factor against atrophy progression, whereas any area of damaged or absent RPE tends to enlarge over time. This may suggest that the transplantation of an RPE sheet is more likely to be effective than an RPE cell suspension.

Choroidal perfusion abnormalities associated with Acute Posterior Multifocal Placoid Pigment Epitheliopathy: a case report.

BACKGROUND: Indocyanine Green Angiography (ICG-A) and Enhanced Depth Imaging Spectral-Domain Optical Coherence Tomography (EDI-OCT) are essential imaging techniques for diagnosis, management and understanding of the pathophysiology of many chorioretinal diseases. Herein, we report the ICG-A and EDI-OCT findings from a case of Acute Posterior Multifocal Placoid Pigment Epitheliopathy (APMPPE), in which these imaging techniques enable the visualization of more diagnostic details than those observable with other widely used diagnostic tools. CASE PRESENTATION: A 60-year-old white female presented with bilateral blurred vision for few days. Fundus examination showed multiple, yellow-white placoid lesions at the posterior pole of both eyes. The placoid lesions were also evident on Spectral-Domain Optical Coherence Tomography (SD-OCT), Fluorescein Angiography (FA), Fundus Autofluorescence (AF), and ICG-A. A complete ophthalmologic examination was performed and the diagnosis of APMPPE was made based on imaging and clinical features. Notably, all the lesions detected by FA, AF and OCT corresponded to focal areas of hypofluorescence seen on ICG-A, whereas several additional hypofluorescent areas that were not associated with FA, AF or OCT abnormalities, were also detected with ICG-A. On follow-up, the regression of outer retinal abnormalities detected on OCT preceded the restoration of choroidal perfusion abnormalities in the corresponding locations on ICG-A. This long-standing choroidal perfusion defect could not be detected with OCT. EDI-OCT scans revealed characteristic choriocapillaris changes beneath the placoid lesions and an increase in choroidal thickness during the acute phase, with subsequent decrease in the inactive stage of the disease. CONCLUSION: Our findings show that ICG-A and EDI-OCT provide detailed morphologic information of choroidal abnormalities in APMPPE and allow accurate evaluation of definitive resolution of the lesions. Moreover, they support the acute choroidal hypoperfusion as the primary mechanism overlying the pathogenesis of the disease, and suggest that the non-perfused areas may extend beyond the damage of the outer retina.

INVERTED INTERNAL LIMITING MEMBRANE FLAP TECHNIQUE VERSUS COMPLETE INTERNAL LIMITING MEMBRANE REMOVAL IN MYOPIC MACULAR HOLE SURGERY: A Comparative Study.

PURPOSE: To compare the results of vitrectomy with complete internal limiting membrane (ILM) removal and inverted ILM flap in the treatment of myopic macular hole (MMH). METHODS: Seventy eyes of 68 patients with MMH undergone pars-plana vitrectomy (PPV) with either complete ILM removal (n = 36, Group 1) or inverted ILM flap technique (n = 34, Group 2) were included in the study. Outcomes measured were the rate of MMH closure assessed by optical coherence tomography (OCT) and visual acuity (BCVA) at six months. RESULTS: Closure of MMH was achieved in 22 cases of Group 1 (61%) and in 32 cases of Group 2 (94%). Surgical failure was reported in 14 cases of Group 1 (39%) and in one case of Group 2 (3%). Average best-corrected visual acuity (BCVA) changed from 0.60 to 0.58 in Group 1 (P = 0.329) and from 0.70 to 0.39 in Group 2 (P < 0.01). Logistic regression analysis showed that inverted ILM flap technique was associated with 22 times higher probability of anatomic success, regardless of the MMH diameter. CONCLUSION: Inverted ILM flap should be preferred to complete ILM removal for the treatment of MMH. The outcomes reported with this technique were better than any other technique described until now.