A phase I, dose-escalation study of TB-403, a monoclonal antibody directed against PlGF, in patients with advanced solid tumours

BACKGROUND: TB-403 (RO 5323441), a humanised monoclonal antibody, is a novel antiangiogenesis agent directed against placental growth factor. The safety, pharmacokinetics (PK), and antitumour activity of TB-403 were assessed in a phase I, dose-escalation study in patients with advanced solid tumours. METHODS: Patients in sequential dose groups received either weekly doses of 1.25, 5.0, or 10 mg kg(−1) or doses of 20 or 30 mg kg(−1) every third week. RESULTS: Twenty-three patients were enrolled and received TB-403. The most common adverse events (AEs) were fatigue, constipation, pyrexia, dyspnoea, and nausea. One serious AE, a lung embolus in a patient with non-small cell lung cancer treated with 10 mg kg(−1) weekly, was deemed possibly related to TB-403. No dose-limiting toxicities were observed, and a maximum-tolerated dose was not reached. The PK parameters were dose linear and the terminal half-life values ranged from 9 to 14 days. Six patients exhibited stable disease for at least 8 weeks. Two patients, (oesophageal squamous cell carcinoma and pancreatic adenocarcinoma) both treated with 5 mg kg(−1) weekly, remained stable for 12 months. CONCLUSION: TB-403 treatment in this patient population is well tolerated, with a safety profile distinct from that of vascular endothelial growth factor-axis inhibitors

Efficacy of Intravitreal Ocriplasmin for Treatment of Vitreomacular Adhesion

PURPOSE: To evaluate the efficacy of a single intravitreal injection of ocriplasmin 125 μg across relevant subpopulations of patients with symptomatic vitreomacular adhesion (VMA)/vitreomacular traction (VMT), including when associated with macular hole. DESIGN: Two multicenter, randomized, placebo-controlled, double-masked, 6-month studies. PARTICIPANTS: A total of 652 randomized patients (464 receiving ocriplasmin; 188 receiving placebo). METHODS: A single intravitreal injection of ocriplasmin 125 μg or placebo in the study eye. MAIN OUTCOME MEASURES: Prespecified subgroup analyses were conducted to evaluate the effects on the proportion of patients with nonsurgical resolution of focal VMA at day 28, nonsurgical full-thickness macular hole (FTMH) closure at month 6, and categoric improvement in best-corrected visual acuity (BCVA) at month 6. RESULTS: Resolution of VMA at day 28 was achieved more often in younger patients (<65 years), eyes without epiretinal membrane, eyes with FTMH, phakic eyes, and eyes with a focal VMA ≤ 1500 μm. Eyes with FTMH width ≤ 250 μm were more likely to achieve nonsurgical FTMH closure. Categoric ≥ 2-line and ≥ 3-line improvement in BCVA occurred more often in younger patients (<65 years) and in patients with a lower baseline BCVA (<65 letters). Treatment differences in favor of ocriplasmin were generally observed across each subgroup of subpopulations studied. CONCLUSIONS: Subgroup analyses confirmed the positive effect of ocriplasmin across relevant subpopulations.status: publishe

ASSOCIATION BETWEEN ANATOMICAL RESOLUTION AND FUNCTIONAL OUTCOMES IN THE MIVI-TRUST STUDIES USING OCRIPLASMIN TO TREAT SYMPTOMATIC VITREOMACULAR ADHESION/VITREOMACULAR TRACTION, INCLUDING WHEN ASSOCIATED WITH MACULAR HOLE

To evaluate visual function in patients with symptomatic vitreomacular adhesion (VMA)/vitreomacular traction including when associated with macular hole after ocriplasmin treatment, and the association between resolution of the underlying condition and improvement in visual function.status: publishe

Improving the cytotoxic response of tumor-infiltrating lymphocytes towards advanced stage ovarian cancer with an oncolytic adenovirus expressing a human vIL-2 cytokine

While the presence of tumor-infiltrating lymphocytes (TILs) associates with improved survival prognosis in ovarian cancer (OvCa) patients, TIL therapy benefit is limited. Here, we evaluated an oncolytic adenovirus coding for a human variant IL-2 (vIL-2) cytokine, Ad5/3-E2F-d24-vIL2 (vIL-2 virus), also known as TILT-452, as an immunotherapeutic strategy to enhance TIL responsiveness towards advanced stage OvCa tumors. Fragments of resected human OvCa tumors were processed into single-cell suspensions, and autologous TILs were expanded from said samples. OvCa tumor specimens were co-cultured with TILs plus vIL-2 virus, and cell killing was assessed in real time through cell impedance measurement. Combination therapy was further evaluated in vivo through a patient-derived xenograft (PDX) ovarian cancer murine model. The combination of vIL-2 virus plus TILs had best cancer cell killing ex vivo compared to TILs monotherapy. These results were supported by an in vivo experiment, where the best OvCa tumor control was obtained when vIL-2 virus was added to TIL therapy. Furthermore, the proposed therapy induced a highly cytotoxic phenotype demonstrated by increased granzyme B intensity in NK cells, CD4+ T, and CD8+ T cells in treated tumors. Our results demonstrate that Ad5/3-E2F-d24-vIL2 therapy consistently improved TILs therapy cytotoxicity in treated human OvCa tumors.Peer reviewe

Medico-legal assessment of disability in narcolepsy: an interobserver reliability study

none11noneF. Ingravallo; L. Vignatelli; M. Brini; C. Brugaletta; C. Franceschini; F. Lugaresi; M.C. Manca; S. Garbarino; P. Montagna; A. Cicognani; G. PlazziF. Ingravallo; L. Vignatelli; M. Brini; C. Brugaletta; C. Franceschini; F. Lugaresi; M.C. Manca; S. Garbarino; P. Montagna; A. Cicognani; G. Plazz