The aim of this phase I/II nonrandomized trial was to assess feasibility, safety as well as immunological and clinical responses of a mRNA-based vaccination in patients with stage IV renal cell cancer using granulocyte-macrophage colony stimulating factor (GM-CSF) as adjuvant. Intradermal injections of in vitro transcribed naked mRNA, which was generated using plasmids coding for the tumor-associated antigens mucin 1(MUC1), carcinoembryonic (CEA), human epidermal growth factor receptor 2 (Her-2/neu), telomerase, survivin, and melanoma-associated antigen 1 (MAGE-A1) were performed in 30 enrolled patients. In the first 14 patients (cohort A) vaccinations were administered on days 0, 14, 28, and 42 (20 µg/antigen) while in the consecutive 16 patients (cohort B) an intensified protocol consisting of injections at days 0-3, 7-10, 28, and 42 (50 µg/antigen) was used. In both cohorts, after this induction period, vaccinations were repeated monthly until tumor progression analyzed by Response Evaluation Criteria In Solid Tumors criteria (RECIST). Vaccinations were well tolerated with no severe side effects and induced clinical responses [six stable diseases (SD) and one partial response in cohort A and nine SD in cohort B]. In cohort A, 35.7% survived 4 years (median survival 24 months) compared to 31.25% in cohort B (median survival 29 months). Induction of CD4(+) and CD8(+) T cell responses was shown for several tumor-associated antigens (TAA) using interferon-γ (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) and Cr-release assays.
This paper is intended to demonstrate the usefulness of a psychological experimental approach in researching the underlying processes of socio-economic impacts of the effects of an eventual climate change in the field of tourism. Tourism demand for the German coasts at the North and Baltic Seas may be influenced in some way by climate change impacts, e.g. by new preferences for holiday destinations due to changing environmental conditions (especially weather) and due to the actions taken by the tourism industry to cope with these changes. A pilot study was designed and carried out in order to develop a method to measure the sensitivity of destination choice to climate change effects and to gain first ideas of whether and how destination preferences will probably change. 136 subjects in 5 experimental conditions were given scenarios describing 'positive' or 'negative' climate change effects with and without (re)actions of the regional tourism industry. The control group received a scenario describing no changes. Subjects interest in spending a holiday at the North Sea and Baltic Sea in Germany were defined as the dependent variable. One of the crucial aspects was to check whether the applied technique is appropriate for making the situation, which is only a hypothetical and future one, sufficiently clear (make it feel 'real') to the participants in the study. The methodological approach is suitable for further (and more in depth) research: subjects had no trouble imagining the scenarios. The manipulation checks indicated differences, and differences between conditions were also found in the dependent variables. Thus, the adopted procedure appears promising and can be applied in future studies. Nevertheless, some improvements are recommended. Within the restricted possibilities of a pilot study, first ideas on whether and in which direction the effects of an eventual climate change may influence destination choice of tourists are presented. According to the data, climate change can influence the preferences for vacation destinations. With respect to the North German coastal region, this effect is rather a negative one. Under the climate change conditions presented in the scenarios, possible tourists are less eager to travel there than under today's conditions. It will not be easy for the local and regional tourism industry to reduce negative effects or to use positive effects to a certain extent by appropriate action. Within limits this possibility may exist, but one has to be rather careful in defining what is 'appropriate', e.g. with respect to their target groups in tourism. The results still do not allow for predictions of destination choice or behaviour patterns during holidays. The experimental method described here may be one additional tool to the many others used to gain a clearer picture of a possible future of tourism in coastal areas under climate change conditions.
Renal cell carcinoma (RCC) is an immunogenic tumor for which immunotherapeutic approaches could be associated with clinically relevant responses. It was recently shown, that induction of T-cell responses against multiple tumor-associated antigen (TAA) epitopes results in prolonged overall survival in RCC patients. In 2003–2005, we performed a phase I/II trial testing an mRNA-based vaccine formulation consisting of a mixture of in vitro transcribed RNA coding for six different TAAs (MUC1, CEA, Her2/neu, telomerase, survivin, MAGE-A1) in 30 metastatic RCC (mRCC) patients. In the first 14 patients, vaccinations were applied i.d. on days 0, 14, 28, and 42. In the consecutive 16 patients, an intensified protocol consisting of i.d. injections (daily on days 0–3, 7–10, 28, and 42) was used. After the respective induction periods, patients in both cohorts were vaccinated monthly until tumor progression. At survival update performed in July 2015, one of the 30 patients was still alive. One patient was lost to follow-up. Median survival of 24.5 mo (all patients) and 89 mo (favorable risk patients) exceeded predicted survival according to Memorial Sloan Kettering Cancer Center (MSKCC) risk score. Impressively, long-term survivors displayed immunological responses to the applied antigens while vice versa no patient without detectable immune response had survived more than 33 mo. The current survival update shows a clear correlation between survival and immunological responses to TAAs encoded by the naked mRNA vaccine. This is one of the first vaccination studies and the only RNA trial that reports on safety and efficacy after a follow-up of more than 10 y.
Sorafenib reduces tumor perfusion and thereby induces necrosis and often hemorrhage. Malignant tumors treated with sorafenib undergo both morphologic and functional changes; however, the morphologic changes are less frequent and inadequate for early evaluation of response. Therefore, imaging tools accurately assessing hemorrhage and decrease in tumor perfusion with subsequent necrosis should be the mainstay in monitoring targeted therapy agents.
Pathologic fractures in patients with multiple myeloma undergoing bisphosphonate therapy occur independently of myeloma activity and therefore should not be considered a sign of disease progression.
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