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Background: Adoptive cell therapy with peripheral blood T cells expressing transgenic T-cell receptors (TCRs) is an innovative therapeutic approach for solid malignancies. We investigated the safety and feasibility of adoptive transfer of autologous T cells expressing melanoma antigen recognized by T cells 1 (MART-1)-specific TCR, cultured to have less differentiated phenotypes, in patients with metastatic melanoma. Materials and methods: In this phase I/IIa trial, peripheral blood T cells from HLA-A2∗02:01-positive patients with unresectable stage IIIC/IV melanoma expressing MART-1 were selected and stimulated with anti-CD3/CD28 beads, transduced with a modified MART-1(26-35)-specific 1D3 TCR (1D3HMCys) and expanded in interleukin (IL)-7 and IL-15. Patients received a single infusion of transgenic T cells in a dose-escalating manner. Feasibility, safety and objective response rate were assessed. Results: Twelve pretreated metastatic cutaneous (n = 7) and uveal (n = 5) melanoma patients were included. Patient 1 received 4.6 × 109 1D3HMCys T cells and experienced grade 5 toxicity after 9 days. Subsequent patients received 5.0 × 107 [n = 3; cohort (c) 2], 2.5 × 108 (n = 2; c3) and 1.0 × 108 (n = 6; c4) 1D3HMCys T cells. The study was prematurely terminated because of dose-dependent toxicity, concerning skin (10/12), eyes (3/12), ears (4/12) and cytokine release syndrome (5/12), with 7 patients experiencing grade 3-5 toxicity. Partial responses were seen in 2/11 (18%) assessable patients and persistence of 1D3HMCys T cells corresponded to infused cell dose. Conclusions: Production of TCR-modified cells as described leads to highly potent T cells. Partial responses were seen in 18% of patients with dose-dependent 'on-target, off-tumor' toxicity and a maximum tolerated dose of 1.0 × 108 cells.
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BACKGROUND: Telephone-assisted instructions for cardiopulmonary resuscitation (T-CPR) are highly recommended by the current European Resuscitation Council (ERC) guidelines for resuscitation 2010. AIM: The aim of this study was to analyze the adherence of laypersons to T-CPR instructions given by dispatchers in a mock scenario. The dispatchers adapted international T-CPR instructions to local requirements. MATERIAL AND METHODS: An emergency "collapse in the office" with subsequent T-CPR was simulated for 10 volunteer, untrained administrative staff, as the only single emergency witness and 4 emergency medical service (EMS) dispatchers. Each volunteer was sent to a "colleague" who simulated a sudden cardiovascular event and collapsed unconscious during the description of symptoms. The local lay responder made an emergency call by landline telephone and was connected to the dispatcher. In the course of the simulation the "victim" was replaced by a CPR manikin. RESULTS: Every participant, i.e. 10 out of 10, assessed the victim, recognized the situation and telephoned for help. On the orders of the dispatchers 9 out of the 10 activated the loudspeaker of the telephone but 4 still continued to use the handset. The instructions for positioning were followed by all 10. Correct positioning of the victim required a median of 33[Symbol: see text]s with an interquartile range (IQR) of 30-39[Symbol: see text]s. Breathing control including instructions lasted a median of 54[Symbol: see text]s (IQR 49-60[Symbol: see text]s). Breathing was assessed by 8 out of 10 but only 2 out of 8 achieved a duration of 10[Symbol: see text]s as recommended by the ERC guidelines for resuscitation 2010. After a median of 202[Symbol: see text]s (IQR 196-241[Symbol: see text]s) chest compressions were started by 9 out of 10 and were performed for a median of 63[Symbol: see text]s (IQR 60-69[Symbol: see text]s). A correct technique was used by 7 but with a low rate of 80 compressions/min (IQR 72-86/min). The instructions for ventilation were understood by 9 out of 10. Mouth-to-mouth resuscitation was performed by 7 participants and technically correct by 5 of them. The ventilation cycle of the 7 active participants lasted for a mean of 25[Symbol: see text]s (IQR 24-30[Symbol: see text]s). The mean total duration of the timeframe analyzed was 340[Symbol: see text]s (IQR 334-368[Symbol: see text]s). CONCLUSION: The results demonstrate that the local T-CPR concept for untrained laypersons is feasible in a mock scenario. No substantial errors were observed for the majority of the untrained responders but the simulation also showed that not every emergency witness implemented the instructions according to the dispatcher's expectations. The T-CPR procedure was also more time-consuming than expected; therefore, every standardized T-CPR concept should be tested for local practicability. In accordance with current studies, the results suggest that the focus should be on compression-only CPR instructions in urban settings. Dispatcher education in T-CPR should incorporate videotaped mock-up scenarios with untrained local laypersons.
