Gianni Virgili

Verteporfin therapy of subfoveal choroidal neovascularization in pathologic myopia: 2-Year results of a randomized clinical trial - VIP report no. 3

PURPOSE To report 24-month vision and fluorescein angiographic outcomes from trials evaluating photodynamic therapy with verteporfin in patients with subfoveal choroidal neovascularization (CNV) caused by pathologic myopia. DESIGN AND SETTING Multicenter, double-masked, placebo-controlled, randomized clinical trial at 28 ophthalmology practices in Europe and North America. PARTICIPANTS Patients with subfoveal choroidal neovascular lesions caused by pathologic myopia measuring no more than 5400 micro m and best-corrected visual acuity (approximate Snellen equivalent) of 20/100 or better. METHODS Similar to methods described for 1-year results with follow-up examinations beyond 1 year, continuing every 3 months (except Photograph Reading Center evaluations only at the month 24 examination). During the second year, the same regimen (with verteporfin or placebo as applied at baseline) was used if angiography showed fluorescein leakage from CNV. MAIN OUTCOME MEASURES The primary outcome was the proportion of eyes with fewer than 8 letters (approximately 1.5 lines) of visual acuity loss at the month 24 examination, adhering to an intent-to-treat analysis and using the last observation carried forward method to impute for any missing data. RESULTS Seventy-seven of 81 patients (95%) in the verteporfin group, compared with 36 of 39 patients (92%) in the placebo group, completed the month 24 examination. At this time point, 29 of 81 verteporfin-treated patients (36%) compared with 20 of 39 placebo-treated patients (51%) lost at least 8 letters (P = 0.11). The distribution of change in visual acuity at the month 24 examination was in favor of a benefit for the cases assigned to verteporfin (P = 0.05). This included improvement by at least 5 letters (equivalent to at least 1 line) in 32 verteporfin-treated cases [40%] vs. five placebo-treated cases (13%) and improvement by at least 15 letters (equivalent to at least 3 lines) in 10 verteporfin-treated cases (12%) vs. zero placebo-treated cases. No additional photosensitivity adverse reactions or injection site adverse events were associated with verteporfin therapy in the second year of follow-up. CONCLUSIONS Verteporfin therapy for subfoveal CNV caused by pathologic myopia safely maintained a visual benefit compared with a placebo therapy through 2 years of follow-up. Although the primary outcome was not statistically significantly in favor of verteporfin therapy at 2 years as it had been at 1 year of follow-up, the distribution of change in visual acuity at the month 24 examination was in favor of the verteporfin-treated group and showed that this group was more likely to have improved visual acuity through the month 24 examination. The VIP Study Group recommends verteporfin therapy for subfoveal CNV resulting from pathologic myopia based on both the 1- and 2-year results of this randomized clinical trial.

Effect of lesion size, visual acuity, and lesion composition on visual acuity change with and without verteporfin therapy for choroidal neovascularization secondary to age-related macular degeneration: TAP and VIP report no. 1.

PURPOSE To determine whether differences in baseline lesion size and visual acuity might explain differing results found in three different lesion compositions (predominantly classic, minimally classic, and occult with no classic) among three placebo-controlled, randomized clinical trials evaluating photodynamic therapy with verteporfin (Visudyne, Novartis AG), also termed verteporfin therapy, in patients with subfoveal choroidal neovascularization (CNV) due to age-related macular degeneration (AMD). METHODS Exploratory analyses were conducted in patients with predominantly classic or minimally classic lesions at enrollment in the Treatment of AMD with Photodynamic Therapy (TAP) Investigation and in AMD patients with occult with no classic CNV in the Verteporfin In Photodynamic Therapy (VIP) Trial. Baseline characteristics of patients among these three lesion compositions were compared. In addition, multiple linear regression modeling was used to explore the effect of baseline lesion size, visual acuity, and lesion composition on mean change in visual acuity from baseline to 24 months. RESULTS At baseline, the mean size of predominantly classic lesions (3.4 disk areas) was smaller than that of minimally classic (4.7 disk areas) and occult with no classic lesions (4.3 disk areas). In the multiple linear regression model of individual lesion compositions, there was a significant treatment-by-lesion-size interaction for minimally classic and occult with no classic lesions, but not for predominantly classic lesions. Interaction between treatment and baseline visual acuity was not significant for any lesion composition. Small verteporfin-treated lesions lost less vision than large verteporfin-treated lesions in each lesion composition. In the multiple linear regression model that included all lesion compositions, lesion size was a more significant predictive factor for the magnitude of treatment benefit than either lesion composition or visual acuity. Smaller (4.0 disk areas or less) minimally classic and occult with no classic lesions had similar visual acuity outcomes to those observed in predominantly classic lesions. CONCLUSIONS Based on exploratory analyses, lesion size in the TAP Investigation and VIP Trial was an important predictor of the magnitude of treatment benefit with verteporfin therapy in occult with no classic and minimally classic lesion compositions. In patients with AMD, treating smaller rather than larger neovascular lesions, regardless of lesion composition, likely will result in a better level of visual acuity.

Timing Matters in Hip Fracture Surgery: Patients Operated within 48 Hours Have Better Outcomes. A Meta-Analysis and Meta-Regression of over 190,000 Patients

Background To assess the relationship between surgical delay and mortality in elderly patients with hip fracture. Systematic review and meta-analysis of retrospective and prospective studies published from 1948 to 2011. Medline (from 1948), Embase (from 1974) and CINAHL (from 1982), and the Cochrane Library. Odds ratios (OR) and 95% confidence intervals for each study were extracted and pooled with a random effects model. Heterogeneity, publication bias, Bayesian analysis, and meta-regression analyses were done. Criteria for inclusion were retro- and prospective elderly population studies, patients with operated hip fractures, indication of timing of surgery and survival status. Methodology/Principal Findings There were 35 independent studies, with 191,873 participants and 34,448 deaths. The majority considered a cut-off between 24 and 48 hours. Early hip surgery was associated with a lower risk of death (pooled odds ratio (OR) 0.74, 95% confidence interval (CI) 0.67 to 0.81; P<0.000) and pressure sores (0.48, 95% CI 0.38 to 0.60; P<0.000). Meta-analysis of the adjusted prospective studies gave similar results. The Bayesian probability predicted that about 20% of future studies might find that early surgery is not beneficial for decreasing mortality. None of the confounders (e.g. age, sex, data source, baseline risk, cut-off points, study location, quality and year) explained the differences between studies. Conclusions/Significance Surgical delay is associated with a significant increase in the risk of death and pressure sores. Conservative timing strategies should be avoided. Orthopaedic surgery services should ensure the majority of patients are operated within one or two days.

Biological Agents for Moderately to Severely Active Ulcerative Colitis: A Systematic Review and Network Meta-analysis

Ulcerative colitis (UC) is an idiopathic, remitting and relapsing, chronic inflammatory bowel disease. It is characterized by mucosal ulceration, rectal bleeding, diarrhea, abdominal cramps, urgency or tenesmus, fever, malaise, weight loss and fatigue, depending on the extent and severity of the disease. Worldwide, the estimated incidence of UC ranges from 1.2 to 20.3 cases per 100000 person-years and its prevalence ranges from 7.6 to 246.0 per 100000 persons (14). Pharmacologic management of UC aims at reducing inflammation and maintaining remission of symptoms and includes sulfasalazine, 5-aminosalicylates (mesalamine, olsalazine, and balsalazide), glucocorticoids, and immunosuppressants (azathioprine, 6-mercaptopurine, and cyclosporine) (5, 6). Despite progress, treatment options for moderately to severely active UC remain limited because conventional therapies inadequately control the disease in a substantial proportion of patients and often lead to adverse events (AEs). However, a series of biological agents have recently received regulatory approval or are under scrutiny; in 2013, those included the monoclonal antibodies adalimumab, golimumab, infliximab, and vedolizumab. Evidence on comparative effectiveness and harms of those treatments would be very useful to inform clinical decision making. We conducted a systematic review of randomized, controlled trials (RCTs) assessing biological agents as induction or maintenance therapy for moderately to severely active UC in adults to address this issue. We assessed their comparative clinical efficacy and harm using the method of multiple-treatment meta-analysis, also known as network meta-analysis or mixed-treatment comparison (710), based on the available evidence from RCTs. We aimed to compare the different treatment options and provide a clinically useful summary that can be used to support optimal decision making. Methods Our study protocol (11) was registered on PROSPERO (CRD42013005459). We followed standard methods for conducting and reporting systematic reviews and network meta-analyses (12, 13). Data Sources and Searches We systematically searched MEDLINE and EMBASE databases from inception to 31 December 2013. Search terms included biologic(al) agent(s), biologic(s), adalimumab, golimumab, infliximab, or vedolizumab, combined with ulcerative colitis. The search was limited to RCTs and humans. Language or age restrictions were not imposed. We also searched the Cochrane Library for any recent systematic review on the subject, the ClinicalTrials.gov database for completed but unpublished studies, and the European Medicines Agency and U.S. Food and Drug Administration Web sites to obtain details on study characteristics or outcomes if these data were missing or unclearly presented in the original articles. Study Selection The titles and abstracts of identified published articles were scanned to exclude irrelevant studies. The full text of the selected articles was retrieved and read. The bibliographies of the articles and of reviews and meta-analyses were scanned. We further asked field experts to provide additional evidence. Studies were eligible for inclusion if they were randomized, placebo-controlled or head-to-head trials assessing the efficacy or harm of biological agents for the treatment of adult patients with moderately to severely active UC. We considered only biological agents that were market-authorized by either the U.S. Food and Drug Administration or European Medicines Agency, as well as agents under review for the new drug application (United States) or marketing authorisation application (European Union). We defined moderately to severely active UC as a Mayo Clinic score (MCS) of 6 to 12 points, with an endoscopic subscore of 2 or 3. An MCS is a composite activity index ranging from 0 to 12, with higher scores indicating more severe disease activity. It is calculated as the sum of 4 items: stool frequency, rectal bleeding, endoscopic findings, and physicians global assessment (14). Randomized, controlled trials were eligible for inclusion in the network regardless of country, phase (2 or 3), or support. Data Extraction and Quality Assessment Two reviewers abstracted the data independently. The following information was collected from each study: publication data; trials acronym and identifier; first authors last name; geographic location of study; year of publication; study design; number of participants and population characteristics; and interventions variables, including drug, dose, and administration. We extracted data specific for patients who were naive to treatment with biological agents because the relative efficacy of biological agents should not be assessed by pooling patients for whom standard therapies were unsuccessful with patients for whom biological agents were unsuccessful (15, 16). Different doses of the same treatment were treated as separate interventions, and for biological agents that received regulatory approval, only data for dose and administration as approved in the respective summary of product characteristics were considered. The outcome measures were the odds ratios (ORs) for clinical response (primary outcome), clinical remission, and mucosal healing at the end of induction and at completion of each trials maintenance phase, calculated in accordance with the intention-to-treat principle (that is, total number of randomly assigned participants, regardless of how the original study investigators analyzed the data). Clinical response was defined as a decrease from baseline in the MCS of at least 3 points and at least 30%, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point, or an absolute rectal bleeding subscore of 0 or 1. Clinical remission was defined as an MCS of 2 points or lower, with no individual subscore exceeding 1 point. Mucosal healing was defined as an absolute subscore for endoscopy of 0 or 1. We also examined the occurrence of serious adverse events (SAEs), which are defined as any untoward medical occurrence that results in death, requires hospital admission or prolongation of an existing hospital stay, causes persistent or significant disability or incapacity, or is life-threatening (17); the AEs leading to discontinuation of the study drug; the total number of AEs; the total number of infectious AEs; the number of serious infections; tuberculosis; and congestive heart failure. Reviewers assessed the risk of bias in the results of included studies by using the Cochrane Collaborations tool (18), which addresses the following key domains: sequence generation, allocation concealment, blinding of participants and personnel, incomplete outcome data, selective outcome reporting, and other sources of bias. These items are considered as key domains for risk-of-bias assessment and reclassified as adequate (low risk of bias), inadequate (high risk of bias), or unclear. Studies with adequate procedures in all domains are considered to have a low risk of bias, ones with inadequate procedures in 1 or more domains are considered to have a high risk of bias, and those with unclear procedures in 1 or more domains are considered to have unclear risk of bias. Disagreements among reviewers were discussed and agreement was reached by consensus. Data Synthesis and Analysis We conducted the network meta-analysis within a Bayesian framework using Markov chain Monte Carlo methods in WinBUGS (Medical Research Council Biostatistics Unit, Cambridge, United Kingdom) (19). Analysis was based on noninformative priors for relative-effect parameters (flat normal with mean of 0 and precision of 0.001) and between-study SD (a flat uniform distribution between 0 and 2). Convergence and lack of autocorrelation were checked and confirmed after a 5000-simulation burn-in phase without any thinning and using 4 chains with different initial values. Then, a burn-in phase of 20000 iterations was used, followed by 50000 iterations to estimate parameters. We did sensitivity analyses by setting the prior on the heterogeneity equal to a uniform (0, 100) and on the precision parameter equal to a (0.001, 0.001) to check the robustness of the model to different sets of priors. Model choice was based on the deviance information criterion, and a lower deviance information criterion by 5 or more units suggested a better model fit. We report estimates only for the default model because we did not find differences in model fit according to deviance information criterion. We used the resulting ORs and 95% credible intervals (CrIs), the Bayesian equivalent to CIs, to assess treatment effects. We also calculated fixed-effects ORs and 95% CIs (frequentist approach). Given that each pairwise comparison included a limited number of RCTs, we could not formally assess statistical heterogeneity and publication bias. Role of the Funding Source This study was funded by the Centro Ricerca e Cura delle Malattie Infiammatorie Croniche Intestinali, IRCCS Istituto Clinico Humanitas. The funding source had no role in the design of the study; the collection, analysis, and interpretation of the data; or the decision to submit the manuscript for publication. Results Figure 1 summarizes the search and selection of evidence. We identified 6 publications (2025) reporting the results of 7 trials (ACT [Active Ulcerative Colitis Trial] 1, ACT 2, ULTRA [Ulcerative Colitis Long-Term Remission and Maintenance With Adalimumab] 1, ULTRA 2, PURSUIT-SC [Program of Ulcerative Colitis Research Studies Utilizing an Investigational TreatmentSubcutaneous], PURSUIT-M [Program of Ulcerative Colitis Research Studies Utilizing an Investigational TreatmentMaintenance], and GEMINI 1). One additional study, the NCT00853099 trial, was initially identified through ClinicalTrials.gov (26) and later in full-text publication (27). In total, 8 trials met the eligibility criteria, none of which were head-to-head comparisons of biological agents. Figure 1. Summ

Corneal endothelial damage after cataract surgery : Microincision versus standard technique

PURPOSE: To compare corneal endothelial changes after phacoemulsification performed with a standard technique versus a bimanual microincision cataract surgery (MICS) technique. SETTING: University ophthalmology department. METHODS: Eighty patients scheduled for routine cataract surgery were randomized into 2 groups; 40 eyes had standard stop‐and‐chop phacoemulsification (standard group) and 40 eyes had stop‐and‐chop phacoemulsification with microincision surgery (MICS group). Central corneal endothelial cell counts, coefficient of variation in cell size, hexagonality, and pachymetry were assessed preoperatively and 1 and 3 months postoperatively. RESULTS: The mean preoperative cell count in the entire sample was 2245 cells/mm2 ± 37 (SE). The mean decreased by 102 cells at 1 month (95% confidence interval [CI], −133 to −71; P<.001) and by 144 cells at 3 months (95% CI, −187 to −102; P<.001). The difference between the standard group and the MICS group was 25 cells at baseline (95% CI, −169 to 120 cells; P = .739), 19 cells at 1 month (95% CI, −163 to 126; P = .799), and 19 cells at 3 months (95% CI, −164 to 125; P = .793). There were no changes in the coefficient of variation or morphology in the overall sample, and the pattern of change did not differ between the 2 groups. Corneal thickness increased by 10.2 μm in the overall sample (95% CI, +4.5 to +16.0; P<.001) and approached baseline values by 3 months with an increase of 3.4 μm (95% CI, −4.1 to 10.8; P = .372). There was no difference in corneal thickness between the groups. CONCLUSION: No significant differences in corneal endothelial cell loss or endothelial morphology were found between MICS and standard incision techniques.

Outcome of choroidal neovascularization in angioid streaks after photodynamic therapy.

Purpose: To evaluate the visual and anatomic outcomes of photodynamic therapy for choroidal neovascularization (CNV) in patients with angioid streaks. Methods: The authors retrospectively evaluated 40 consecutive patients (48 eyes) with visual acuity of 20/200 or greater who were treated at 6 referral centers for CNV associated with angioid streaks. Main outcome measures were visual acuity, greatest linear diameter of the lesion, and, in patients with nonsubfoveal CNV, distance from the foveola. Results: Of 34 eyes with subfoveal CNV, 21 were followed up for at least 12 months (range, 5–33 months). Median visual acuity was 20/50 at baseline and 20/120 at the final examination. The 12-month estimate of the percentage of eyes with vision loss of fewer than 3 lines was 68% (95% confidence interval, 50%–85%) by using survival analysis, whereas eyes with no increase in the greatest linear diameter were 45% (95% confidence interval, 27%–62%). Fourteen eyes had extrafoveal (n = 11) or juxtafoveal (n = 3) CNV, 12 of which were followed up for at least 10 months (range, 4–36 months). Visual acuity was 20/40 or greater in all eyes with extrafoveal lesions at baseline and in 5 of 12 eyes at the last examination, when 3 cases of CNV had become subfoveal. At baseline, visual acuity was low in two eyes with juxtafoveal CNV and nearly normal in the third. It remained substantially stable at the end of follow-up (range, 10–36 months), when two lesions were subfoveal. Conclusions: Most of our patients had good baseline visual function and, thus, were at high risk for losing vision because of the poor prognosis of CNV in angioid streaks. Because most had no or limited vision loss after 1 year, the authors suggest that photodynamic therapy can be used to try to limit or delay visual damage caused by this aggressive disease.

Evolving European guidance on the medical management of neovascular age related macular degeneration

Background: Until recently, only two options were available for the treatment of choroidal neovascularisation (CNV) associated with age related macular degeneration (AMD)—thermal laser photocoagulation and photodynamic therapy with verteporfin (PDT-V). However, new treatments for CNV are in development, and data from phase III clinical trials of some of these pharmacological interventions are now available. In light of these new data, expert guidance is required to enable retina specialists with expertise in the management of AMD to select and use the most appropriate therapies for the treatment of neovascular AMD. Methods: Consensus from a round table of European retina specialists was obtained based on best available scientific data. Data rated at evidence levels 1 and 2 were evaluated for laser photocoagulation, PDT-V, pegaptanib sodium, and ranibizumab. Other treatments discussed are anecortave acetate, triamcinolone acetonide, bevacizumab, rostaporfin (SnET2), squalamine, and transpupillary thermotherapy. Results: PDT-V is currently recommended for subfoveal lesions with predominantly classic CNV, or with occult with no classic CNV with evidence of recent disease progression and a lesion size ⩽4 Macular Photocoagulation Study (MPS) disc areas (DA). The new classes of anti-angiogenic agents—namely, pegaptanib sodium and ranibizumab (the latter when peer reviewed phase III data become available) are recommended for subfoveal lesions with any proportion of classic CNV or occult with no classic CNV. For juxtafoveal classic CNV, PDT-V or anti-angiogenic therapy should be considered if the new vessels are so close to the fovea that laser photocoagulation would almost certainly extend under the centre of the foveal avascular zone. For all other well demarcated juxtafoveal lesions and for extrafoveal classic lesions, laser photocoagulation remains the standard treatment. Therapy should be undertaken within 1 week of the fluorescein angiogram on which the clinical decision to treat is based. At each follow up, fluorescein angiography should be performed and best corrected visual acuity measured as a minimum requirement. Conclusions: These recommendations provide evidence based guidance for the choice and use of non-surgical therapies for the management of neovascular AMD. Revisions of the recommendations may be required as new data become available.

Infliximab for the treatment of posterior uveitis with retinal neovascularization in Behçet disease.

Purpose To report a case of posterior uveitis with retinal neovascularization in a patient with Behçet disease treated with infliximab. Methods A 50-year-old man with a history of recurrent relapses of ocular inflammation despite immunosuppressive therapy developed retinal neovascularization near the optic disk. The patient was treated with infliximab and followed up for 12 months. Results Retinal neovascularization regressed 8 months after the first anti–tumor necrosis factor (TNF) treatment and with six infusions of infliximab. The ocular inflammation resolved almost completely. Conclusions The result suggests that anti-TNF therapy may be effective in the treatment of retinal neovascularization caused by panuveitis in Behçet disease.

Immediate intraocular pressure response to selective laser trabeculoplasty

BACKGROUND/AIMS Selective laser trabeculoplasty targets the pigmented trabecular meshwork cells without damage to the trabecular meshwork architecture in vitro. A study was conducted in vivo of eight eyes with uncontrolled open angle glaucoma to ascertain the immediate intraocular response to selective laser trabeculoplasty. METHODS The trabecular meshwork of each eye was treated 360° with a frequency doubled Q-switched Nd:YAG laser. Intraocular pressure was measured 1, 2, 24 hours and 1, 4, 6 weeks after treatment. RESULTS The average preoperative intraocular pressure was 26.6 (SD 7) mm Hg (range 18–37). Two hours and 6 weeks respectively after selective trabeculoplasty intraocular pressure was reduced in all the eyes treated with an average fall of 10.6 (5.2) mm Hg or 39.9%. A pressure spike of 10 mm Hg verified in one eye 1 hour after treatment. CONCLUSIONS Selective laser trabeculoplasty decreased intraocular pressure by an amount similar to that achieved with standard trabeculoplasty. Additional study is needed to determine whether the beneficial effect is sustained over a longer period of follow up.

MR-diffusion weighted imaging of healthy liver parenchyma: repeatability and reproducibility of apparent diffusion coefficient measurement.

To compare repeatability and reproducibility of four different methods of apparent diffusion coefficient (ADC) evaluation of liver parenchyma. In fact, repeatability and reproducibility assessment is mandatory in quantitative evaluations, however, these have not been accurately investigated in liver MR‐diffusion‐weighted studies.