Expansion of effector and memory T cells is associated with increased survival in recurrent glioblastomas treated with dendritic cell immunotherapy.

BACKGROUND: The efficacy of dendritic cell (DC) immunotherapy as a single therapeutic modality for the treatment of glioblastoma (GBM) patients remains limited. In this study, we evaluated in patients with GBM recurrence the immune-mediated effects of DC loaded with autologous tumor lysate combined with temozolomide (TMZ) or tetanus toxoid (TT). METHODS: In the phase I-II clinical study DENDR2, 12 patients were treated with 5 DC vaccinations combined with dose-dense TMZ. Subsequently, in eight patients, here defined as Variant (V)-DENDR2, the vaccine site was preconditioned with TT 24 hours before DC vaccination and TMZ was avoided. As a survival endpoint for these studies, we considered overall survival 9 months (OS9) after second surgery. Patients were analyzed for the generation of effector, memory, and T helper immune response. RESULTS: Four of 12 DENDR2 patients reached OS9, but all failed to show an immunological response. Five of eight V-DENDR2 patients (62%) reached OS9, and one patient is still alive (OS >30 months). A robust CD8+ T-cell activation and memory T-cell formation were observed in V-DENDR2 OS>9. Only in these patients, the vaccine-specific CD4+ T-cell activation (CD38+/HLA-DR+) was paralleled by an increase in TT-induced CD4+/CD38low/CD127high memory T cells. Only V-DENDR2 patients showed the formation of a nodule at the DC injection site infiltrated by CCL3-expressing CD4+ T cells. CONCLUSIONS: TT preconditioning of the vaccine site and lack of TMZ could contribute to the efficacy of DC immunotherapy by inducing an effector response, memory, and helper T-cell generation.

Comparison of Surgical Outcomes between Canaloplasty and Schlemm's Canal Scaffold at 24 Months' Follow-Up.

The results of canaloplasty (CP) and Hydrus Microstent (HM) implantation were retrospectively compared at 24 months' follow-up in a cohort of subjects referred to our Institution for uncontrolled IOP in primary or secondary (e.g., pseudoexfoliative and pigmentary) open-angle glaucoma. The outcome was labelled as "complete" success, "qualified" success, or "failure" if, two years after surgery, the eyes operated on needed "no" hypotensive medications, "some" hypotensive medications, or further glaucoma surgery to attain the target IOP, respectively. Both CP and HM implant allowed significant IOP reductions, with comparable rate of clinical success and safety profile. A slightly (albeit not significant) better trend for a "complete" clinical success was observed in the CP group.

Improvement of spatial contrast sensitivity threshold after surgical reduction of intraocular pressure in unilateral high-tension glaucoma.

PURPOSE: To measure the effect of a surgical reduction of IOP on the spatial contrast sensitivity threshold in eyes showing a considerably increased IOP but no glaucomatous visual field defect, on white-on-white computer-assisted static perimetry. METHODS: Prospective clinical trial, lasting 36 months; 10 consecutive subjects with untreated IOP > or = 30 mmHg in one eye and < or =18 mmHg in the fellow eye, no evidence of field damage in both eyes, best corrected visual acuity > or =20/20 in both eyes, and scheduled for a primary trabeculectomy in the eye showing a high IOP. The spatial contrast sensitivity threshold was measured before surgery and at each follow-up visit. RESULTS: Preoperative spatial contrast sensitivity was worse in those eyes bearing a high IOP relative to the normal fellow eyes (paired samples t-test, P <0.0005). An improvement of contrast sensitivity threshold, exceeding the 95% confidence limits of the preoperative test-retest variability, was observed at 3, 6, and 12 cyc/deg in each surgical eye at the end of follow-up. No change was observed in the fellow untreated normal eyes. The improvement correlated directly with the amount of decrease in pressure obtained by surgery. CONCLUSIONS: Eyes with no field defects on white-on-white computer-assisted static perimetry, but bearing a IOP > or = 30 mmHg, show a decreased spatial contrast sensitivity. A surgically obtained reduction of IOP is paralleled by an improvement of spatial contrast sensitivity.

Bronchial reactivity in healthy individuals undergoing long-term topical treatment with beta-blockers.

OBJECTIVE: To assess the impact of long-term treatment with topical timolol on bronchial reactivity in healthy individuals. METHODS: Twenty-one otherwise healthy individuals with high-pressure primary open-angle glaucoma were enrolled in a randomized controlled clinical trial. Eleven patients underwent 3 years of topical 0.5% timolol treatment followed by a 1-year washout period; 10 patients underwent primary argon laser trabeculoplasty. Functional variables and bronchial reactivity (forced expiratory volume in 1 second and metacholine challenge test results) were assessed in both groups at enrollment and after 3 and 4 years of follow-up. RESULTS: After 3 years, a measurable response to metacholine challenge was recorded in 6 of 11 otherwise symptom-free individuals treated with 0.5% timolol twice daily. A detectable response to metacholine challenge was still present in half of these individuals (3 of 6) when further washed out for 1 year from the topical beta-blocker. No significant variation in bronchial reactivity was measured in the laser-treated group during 4 years of follow-up. CONCLUSIONS: Healthy individuals who undergo long-term topical application of a nonselective beta-blocker (0.5% timolol) can develop a subclinical increase in bronchial reactivity. This phenomenon may not be completely reversible on withdrawal of the beta-blocker.

A 10-year follow-up to determine the effect of YAG laser iridotomy on the natural history of pigment dispersion syndrome: a randomized clinical trial.

IMPORTANCE: Prospective long-term analyses of the role of drug-induced mydriasis and laser peripheral iridotomy (LPI) are needed to identify and manage the eyes of patients with pigment dispersion syndrome (PDS) at risk for progressing to ocular hypertension. OBJECTIVE: To assess the 10-year incidence of increased intraocular pressure (IOP) in the 2 eyes of patients with PDS, with 1 eye that underwent LPI and the other that did not. DESIGN, SETTING, AND PARTICIPANTS: In a randomized clinical trial in the glaucoma research unit at the University Hospital of Parma, Italy, 72 patients with PDS underwent phenylephrine testing. Of these 72 patients, 29 (58 eyes) tested positive for succeeding IOP elevation, and 43 (59 eyes) tested negative. For the 29 high-risk patients (all in both eyes), one eye was randomly assigned to LPI, and the fellow eye was left untreated. For the 43 low-risk patients, the affected eyes were left untreated. MAIN OUTCOMES AND MEASURES: An IOP elevation of 5 mm Hg or higher vs baseline (daily phasing) was considered to be a significant increase (ie, an event). RESULTS: In the high-risk group, 3 of 21 eyes that underwent LPI (14.3%) and 13 of 21 untreated eyes (61.9%) showed an increase in IOP of 5 mm Hg or higher during the follow-up period; 4 of 35 low-risk eyes (11.4%) showed a similar increase. Event-free mean (SD) time was 7.99 (0.43) years for high-risk treated eyes, 3.89 (0.68) years for high-risk untreated eyes, and 7.16 (0.23) years for low-risk eyes. The log-rank test showed the following: P < .001 for treated high-risk eyes vs untreated high-risk eyes, P = .74 for treated high-risk eyes vs low-risk eyes, and P < .001 for untreated high-risk eyes vs low-risk eyes. CONCLUSIONS AND RELEVANCE: At the end of the 10-year follow-up, (1) approximately one-third of the whole PDS patient population showed an IOP increase of 5 mm Hg or higher in at least 1 eye; (2) phenylephrine testing identified eyes at high risk for developing IOP elevation; and (3) LPI, when performed on high-risk eyes, reduced the rate of IOP elevation to the same level as the low-risk eyes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01053416.