Davide Poli

Prostaglandin analogs and timolol-fixed versus unfixed combinations or monotherapy for open-angle glaucoma: A systematic review and meta-analysis

PURPOSE To estimate the intraocular pressure (IOP)-lowering effect of prostaglandin analogs (PGAs) administered in combination with β-blockers. METHODS We searched the Medline and Embase databases for randomized trials comparing topical therapies with PGAs and timolol administered as monotherapy (Mt), or in fixed (FC) or unfixed combinations (UC) to patients with glaucoma or ocular hypertension. The efficacy endpoint was the mean difference (MeD) in the reduction in IOP from baseline; the tolerability endpoint was the incidence of hyperemia. RESULTS The 18 eligible trials involved 23 comparisons of FC versus Mt, and 5 of FC versus UC. The FCs were less efficacious than UCs (MeD: 0.69, 95% CI: 0.29 to 1.08). In comparison with timolol Mt, the latanoprost/timolol FC led to a greater IOP reduction (MeD: -2.74, 95% CI: -3.24 to -2.23) than the bimatoprost/timolol FC (MeD: -1.49, 95% CI: -1.86 to -1.12) or the travoprost/timolol FC (MeD: -1.93, 95%CI: -2.98 to -0.88). The FCs led to a lower hyperemia risk than UCs [relative risk (RR): 0.70, 95% CI: 0.43 to 1.14] and PGA Mt (RR: 0.61, 95% CI: 0.53 to 0.70). CONCLUSIONS FCs are more efficacious than their individual components, but less efficacious than their respective UCs. FCs lead to a lower hyperemia risk than UCs and their respective PGA Mts.

Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer

BACKGROUND Some trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential treatment of FOLFIRI [irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV)] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer. PATIENTS AND METHODS Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180 mg/m(2) day 1, LV 100 mg/m(2) as 2 h infusion and 5-FU 400 mg/m(2) as bolus, days 1 and 2 followed by 600 mg/m(2)/day as 22 h continuous infusion, q14 for four cycles) followed by docetaxel 75 mg/m(2) day 1, cisplatin 75 mg/m(2) day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm). RESULTS From February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free [hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85-1.17; P = 0.974] and overall survival (OS) (HR 0.98; 95% CI: 0.82-1.18; P = 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively. CONCLUSIONS A more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01640782.BACKGROUND Some trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential treatment of FOLFIRI [irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV)] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer. PATIENTS AND METHODS Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180mg/m2 day 1, LV 100mg/m2 as 2h infusion and 5-FU 400mg/m2 as bolus, days 1 and 2 followed by 600mg/m2/day as 22h continuous infusion, q14 for four cycles) followed by docetaxel 75mg/m2 day 1, cisplatin 75mg/m2 day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm). RESULTS From February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free [hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85-1.17; P = 0.974] and overall survival (OS) (HR 0.98; 95% CI: 0.82-1.18; P = 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively. CONCLUSIONS A more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01640782.

Impact of recent legislative bills regarding clinical research on Italian ethics committee activity

Aims and background: The present work assessed the impact of two decrees on ethics committees in Italy, aimed at bringing the national laws on the conduct of clinical trials into line with the rest of the EC, and regulating and facilitating not-for-profit research. Material and methods: Prospectively collected data from an Italian multicentre study were examined with respect to the ethics review process. Administrative and time elements of the review process were audited. Main outcome measures were time between the application submission and the ethics committee definitive opinion, type and number of application submission forms, number of ethics committees that refused fee exemption, and time between the ethics committee approval and the administrative authorisation. Results: A total of 134 local research ethics committees (LRECs) were approached. Application submission procedures and application forms varied greatly; paper submission was mandatory. The median time from submission to approval was 72 days. Only two LRECs refused the fee exemption. The median time from LREC approval to administrative agreement was 50 days and only 9.6% of local authorities came to a verbal agreement with the sponsor. Conclusions: Italian LRECs are still not sufficiently efficient in complying with the Directive 2001/20/EC requirement (60 days). Better coordination of LRECs work is needed although the optimal level of coordination between them is still not known. In the meantime, national guidelines are needed concerning the application of Directive 2001/20/EC. The behaviour of Italian LRECs towards not-for-profit research was excellent although only the fee exemption was requested.

Needle Revision With 5-fluorouracil for the Treatment of Ahmed Glaucoma Valve Filtering Blebs: 5-Fluoruracil Needling Revision can be a Useful and Safe Tool in the Management of Failing Ahmed Glaucoma Valve Filtering Blebs.

Purpose:To determine the outcome of needling with adjunctive 5-fluorouracil (5-FU) in patients with a failing Ahmed glaucoma valve (AGV) implant, and to identify predictors of long-term intraocular pressure (IOP) control. Methods:A prospective observational study was performed on consecutive patients with medically uncontrolled primary open-angle glaucoma (POAG) with AGV encapsulation or fibrosis and inadequate IOP control. Bleb needling with 5-FU injection (0.1 mL of 50 mg/mL) was performed at the slit-lamp. Patients were examined 1 week following the needling, and then at months 1, 3, and 6. Subsequent follow-up visits were scheduled at 6-month intervals for at least 2 years. Needling with 5-FU was repeated no more than twice during the first 3 months of the follow-up. Procedure outcome was determined on the basis of the recorded IOP levels. Results:Thirty-six patients with an encapsulated or fibrotic AGV underwent 67procedures (mean 1.86±0.83). Complete success, defined as IOP⩽18 mm Hg without medications, was obtained in 25% at 24 months of observation. The cumulative proportion of cases achieving either qualified (ie, IOP⩽18 mm Hg with medications) or complete success at 24 months of observation was 72.2%. In a univariate Cox proportional hazards model, age was the only variable that independently influenced the risk of failing 5-FU needling revision. Fourteen eyes (38.8%) had a documented complication. Conclusions:Needling over the plate of an AGV supplemented with 5-FU is an effective and safe choice in a significant proportion of POAG patients with elevated IOP due to encapsulation or fibrosis.

Health-related quality of life in patients with primary open-angle glaucoma. An Italian multicentre observational study

As a progressive condition, glaucoma may impair health‐related quality of life (HRQoL), due to vision loss and other factors. This study evaluated HRQoL in a cohort of patients treated for primary open‐angle glaucoma (POAG) and assessed its association with clinical features.

Impact on survival of timing and duration of adjuvant chemotherapy in radically resected gastric cancer.

Purpose Adjuvant chemotherapy improves survival of patients with gastric cancer. Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S) was a phase III study comparing sequential FOLFIRI followed by docetaxel/cisplatin versus 5-fluorouracil monotherapy. The intensive regimen was not superior in terms of disease-free survival (DFS) and overall survival (OS). Methods The treatment was to be started within 8 weeks from surgery. This analysis evaluates the impact of time from surgery to chemotherapy start (TSC) on outcomes. Results Out of 1,106 randomized, 1,072 patients without major violations of eligibility criteria and receiving at least one treatment cycle were analyzed. Median TSC was 50 days. Chemotherapy was interrupted in 201 (18.8%) cases, whereas it was completed without or with modifications in 277 (25.8%) and 594 (55.4%), respectively. At a median follow-up of 56.9 months, 513 progressions and 472 deaths occurred. A longer TSC was significantly associated with longer DFS (hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.89-1.00; p = 0.05) and OS (HR 0.91; 95% CI 0.86-0.97; p = 0.004), after adjustment for treatment arm, age, sex, primary tumor site, number of resected nodes, and tumor stage. Better treatment compliance was associated with improved survival. Conclusions Our findings suggest that longer TSC had at least no detrimental effect on DFS and OS, whereas treatment completion had a protective effect. Our findings need to be confirmed prospectively.

The Glaucoma Italian Pediatric Study (GIPSy): 1-Year Results

Purpose: To investigate the efficacy and safety of a treatment strategy with latanoprost and dorzolamide in primary pediatric glaucoma patients partially responsive to surgery. Patients and Methods: Children with primary pediatric glaucoma having postsurgical untreated intraocular pressure (IOP) between 22 and 26 mm Hg were eligible. At baseline, patients were administered latanoprost once daily. Depending on IOP reduction, patients were allocated to continuation of latanoprost monotherapy or addition of dorzolamide twice daily, or switch to dorzolamide monotherapy 3 times daily. Patients in the dorzolamide monotherapy group with IOP reduction <20% from baseline were considered nonresponders. The primary endpoint was the percentage of responders. Study treatment continued for 3 years or until treatment failure. The present article reports the 1-year analysis results. Results: A total of 35 patients (57 eyes) were analyzed. The mean age was 4.0 years (SD, 3.8). In total, 51 eyes were included in the efficacy analysis. In total, 43 eyes (84.3%; 95% confidence interval, 74.3-94.3) were considered responders: 29 on latanoprost monotherapy, 11 on the latanoprost/dorzolamide combination, and only 3 on the dorzolamide monotherapy. The efficacy of pharmacological treatment was inversely related to the age at the time of surgery. IOP reduction was 8.7 mm Hg (SD, 2.2) for latanoprost, 7.5 mm Hg (SD, 1.4) for the latanoprost/dorzolamide combination, and 8.7 mm Hg (SD, 2.1) for the dorzolamide monotherapy. Only mild or moderate local adverse events were noted. None of the patients was withdrawn due to adverse events. Conclusion: Latanoprost alone or in combination with dorzolamide is safe and highly effective in lowering IOP in children postsurgery. Nonresponders were mainly patients with early presentation of the disease.