Dendritic cell vaccination with xenogenic polypeptide hormone induces tumor rejection in neuroendocrine cancer.

PURPOSE: No relevant breakthrough has yet been achieved in the identification of tumor antigens in many neuroendocrine cancer types that exist, such as malignant gastrinoma, insulinoma, or medullary thyroid carcinoma. The aim of this study was to proof the concept of dendritic cell immunization with a tumor cell-specific polypeptide hormone as a target molecule in a transgenic mouse model for medullary thyroid carcinoma (Ret/Cal mice). EXPERIMENTAL DESIGN: Ret/Cal mice were repeatedly immunized for up to 6 months with amino acid-modified (xenogenic) calcitonin-pulsed dendritic cells. Xenogenic calcitonin was chosen for immunization due to its higher immunogenicity as compared with murine calcitonin. RESULTS: Lymph nodes from control protein-immunized mice did not show any macroscopic abnormalities, whereas tumor peptide-treated mice revealed in general profoundly enlarged lymph nodes. In tetramer analysis of paratumorous lymph nodes, 1.9% to 3.1% of all infiltrating CD8(+) T cells were specific for one of three tumor epitopes tested. Analysis of the activated IFN-gamma-secreting component in splenic cells revealed an average of 2.8% tumor epitope-specific CD8(+) cells. Immunohistochemistry revealed strong CD8(+) tumor infiltration in calcitonin-vaccinated mice. In addition, these cells also showed strong in vitro lysis capacity at up to 63.3%. Most importantly, calcitonin-immunized mice revealed largely diminished tumor outgrowth (-74.3%) compared with control mice (P < 0.0001). Likewise, serum calcitonin levels in calcitonin-vaccinated Ret/Cal mice were lower than in the control group. CONCLUSION: These results have a major effect, as they are the first to establish a role for xenogenic polypeptide hormones as target molecules for immunotherapy in endocrine malignancies.

Amino acid-modified calcitonin immunization induces tumor epitope-specific immunity in a transgenic mouse model for medullary thyroid carcinoma.

Up to now, no relevant tumor antigen has been identified in medullary thyroid carcinoma (MTC). The aim of the present study was to prove the concept of an immunization with an amino acid-modified calcitonin (CT) for the treatment of MTC in a transgenic mouse model. Amino acid-modified (human) CT has been chosen for vaccination because of its higher binding affinity to the murine H2-Kb-MHC molecule. Mice were immunized over 6 months with monthly injections of amino acid-modified CT-pulsed dendritic cells. For enumeration of tumor epitope-specific CD8+ cytotoxic T cells, tetramer analyses were performed. CT peptide-treated mice revealed a mean 0.73 +/- 0.45 and 0.91 +/- 0.59% positive cells, depending on the two tetramers tested, whereas no increase was seen in control protein-immunized mice (0.08-0.12% tetramer-positive cells). Importantly, the subset of CT-specific CD8+ T cells also showed a high expression of interferon-gamma. In line with these results, CT-immunized mice also showed an intratumor infiltration with CD8+ T lymphocytes. Importantly, we also found a diminished tumor outgrowth of -57% and a decrease of the serum CT levels (2.0 +/- 0.1 pg/ml) compared with control protein-immunized Ret/Cal mice (3.0 +/- 0.4 pg/ml). In summary, we show that amino acid-modified CT is recognized from the immune system leading to a specific antitumor immune response and a diminished tumor outgrowth in transgenic MTC mice. The results are of potential importance because they might be applicable to patients with metastatic spread of a MTC.

[The quality of CME questions as a component part of continuing medical education--an empirical study]. / Die Qualität von CME-fragen in der arztlichen Fortbildung--eine empirische Studie.

INTRODUCTION: Changes in physician-training requirements have led to a significant increase in continuing medical education (CME) courses. Structured CME courses based on print media in combination with outcome evaluation offers one opportunity for earning credit points. On the international stage, CME courses are increasingly directed towards measurable patient benefit. Comparative assessment of quality and practical orientation in training courses is required. METHOD: Two hundred items in twenty training units from four established German medical journals were analysed for comparison-based evaluation. The criteria applied were training goals, as well as item construction, authors' requirements and question quality. The items were analyzed independently by two persons trained and experienced in preparing and reviewing items. The analyses from the two assessors were then compared, and any deviations were subjected to mutual consultation. RESULTS: Question formulation showed weaknesses in all the training units. In 52% of the items a clear question was lacking, and all of the training units contained items with concealed hints indicating the correct answer. Only 10% of the questions were preceded by a cameo case study presenting a clinical scenario, and only 14.5% of the items asked for a correct clinical decision. CONCLUSION: The CME questions from the medical journals selected show weaknesses in formulation, and mostly tested factual knowledge. Differences were revealed between publishing houses yielding insights into the requirements made of the authors by the publishers. The question preparation process is still deficient. Adherence to international standards in item construction may lead to an improvement in quality, which would also enhance the implicit transferability of content learned to actual clinical situations, thus improving the practical usefulness of training courses.

Comparison between Long-Menu and Open-Ended Questions in computerized medical assessments. A randomized controlled trial.

BACKGROUND: Long-menu questions (LMQs) are viewed as an alternative method for answering open-ended questions (OEQs) in computerized assessment. So far this question type and its influence on examination scores have not been studied sufficiently. However, the increasing use of computerized assessments will also lead to an increasing use of this question type. Using a summative online key feature (KF) examination we evaluated whether LMQs can be compared with OEQs in regard to the level of difficulty, performance and response times. We also evaluated the content for its suitability for LMQs. METHODS: We randomized 146 fourth year medical students into two groups. For the purpose of this study we created 7 peer-reviewed KF-cases with a total of 25 questions. All questions had the same content in both groups, but nine questions had a different answer type. Group A answered 9 questions with an LM type, group B with an OE type. In addition to the LM answer, group A could give an OE answer if the appropriate answer was not included in the list. RESULTS: The average number of correct answers for LMQs and OEQs showed no significant difference (p = 0.93). Among all 630 LM answers only one correct term (0.32%) was not included in the list of answers. The response time for LMQs did not significantly differ from that of OEQs (p = 0.65). CONCLUSION: LMQs and OEQs do not differ significantly. Compared to standard multiple-choice questions (MCQs), the response time for LMQs and OEQs is longer. This is probably due to the fact that they require active problem solving skills and more practice. LMQs correspond more suitable to Short answer questions (SAQ) then to OEQ and should only be used when the answers can be clearly phrased, using only a few, precise synonyms.LMQs can decrease cueing effects and significantly simplify the scoring in computerized assessment.

[Use of the internet for health care information: results from a national telephone survey]. / Verbreitung und Sozialprofil der gesundheitsthemenbezogenen Internetnutzung: Ergebnisse einer bundesweiten Telefonumfrage.

OBJECTIVES: The Internet has attracted considerable attention as a means to improve health and health care delivery, but it is not clear how prevalent internet use for health care really is. Available estimates for Germany don't exist. Without accurate estimates of use, it is difficult to focus policy discussions or design appropriate policy activities. METHODS: 2026 individuals aged 16 years or older were interviewed in Germany using computer-assisted telephone interview (CATI) in 2001. The sampling frame based on a modified RLD-Design. RESULTS: Approximately 50% of respondents with Internet access reported using the internet to look for advice or information about health or health care. The internet is differently used by the population for the health care information. There is a higher use rate of men, of younger people, of people with high socio-economic status and of the healthy ones. After controlling in multivariate analysis for the user, merely an significant age effect exists. CONCLUSIONS: The use of the internet for health care information in Germany is quite different. Questions about consequences remain unanswered. Do the differences increase or do they decrease? And which role does play the health politics? This and other questions could be answered by further studies.

The value of training in communication skills for continuing medical education.

OBJECTIVE: Question arises as to what extent communication skills are considered in continuing medical education (CME). METHODS: Analysis for CME-courses in communication skills in the area of the Chamber of Physicians North Rhine (ÄkNo), Germany. Supply Arm(A): CME events (n = 19,320) certified in 2007 were evaluated. Demand Arm(B): course participation of 850 family physicians in the period 2002-2007 was analyzed (n = 37,724). Tests were calculated to the level 0.05 using Mann-Whitney U-test. RESULTS: (A) 388 (2.0%) events were concerned with the topic communications. 59.3% involved active cooperation of the participants. 0.5% events devoted more than 50% of their duration to the topic communication. Proportions in the subjects of internal medicine, general medicine and pediatrics amounted to 0.2%. (B) 803 (2.1%) events with a focus on communication were identified. Women took part in significantly more events than men (p<0.002) and selected more interactive courses. CONCLUSION: Content on communication training was small. Increasing experience does not automatically improve communication skills but an extent of deliberate praxis seems to be necessary and must be sought and developed. PRACTICE IMPLICATIONS: Communication skills are still insufficiently provided in CME-courses and should be more directed to focus as treatment strategies and scientifically investigated for outcome improvements.

[Supply of and participation in CME activities in the area served the north rhine chamber of physicians in Germany]. / Angebot und Fortbildungsverhalten bei der Continuing Medical Education (CME) im Bereich der Ärztekammer Nordrhein.

INTRODUCTION: the study analyses the supply and the demand for Continuing Medical Education (CME) in the area served by the "Ärztekammer Nordrhein (ÄkNo)", which is one of the biggest regional Chambers of Physicians in Germany. Both the supply of all CME events certified by the ÄkNo in 2007 (n=18,932) and the participation of physicians in CME activities - using the example of family doctors (n=850), ophthalmologists (n=122) and orthopaedists (n=38) in the university towns of Cologne, Bonn and Aachen - was analysed for the period of 2002 to 2007 (n=44,760 events). METHODS: differences between groups were tested by the nonparametric Kruskal-Wallis method; adjustment for other factors was performed using Cochran-Mantel-Haenszel tests. The significance level was chosen to be 0.05. RESULTS: half of the accredited CME activities had been provided in the form of lectures accompanied by discussion. This didactic focus is reflected by the CME choices of the analysed physicians, although interactive, multimedia materials and case based formats have been demonstrated to be advantageous. Family physicians and ophthalmologists participated twice as often in CME events as orthopaedists (p<0.001). Across all the disciplines investigated, female physicians participated significantly more often in CME events than their male colleagues (p<0.03). CONCLUSION: our results show individual, group and gender specific differences in Continuing Medical Education which so far have not been adequately recognised and which warrants more research on CME.

[The effectiveness of CME -- quality improvement through differentiated advanced medical education research]. / Die Effektivität von CME Qualitätsentwicklung durch differenzierte Lehr-/Lernforschung.

Continuing medical education (CME) increasingly focuses on measurable patient outcomes. Nevertheless, international data on this issue are insufficient, and in Germany the measurable effects of CME in terms of its efficacy and utility for patient care have hardly been subjected to scientific examination. Advanced medical education as a continuation of university education is always based on scientific standards and research-oriented learning. Advanced medical training in Germany therefore requires the implementation of a kind of learning and teaching research that should be geared toward individual training needs, personal motivation and the outcomes of medical care. In addition, the definition of educational goals and the advancement of CME in terms of continuing professional development (CPD) should be considered an important component for a reevaluation of CME.

IFN-alpha skews monocytes into CD56+-expressing dendritic cells with potent functional activities in vitro and in vivo.

The antitumor effect of IFN-alpha is mediated by the activation of CTLs, NK cells, and the generation of highly potent Ag-presenting dendritic cells (IFN-DCs). In this study, we show that IFN-DCs generated in vitro from monocytes express CD56 on their surface, a marker which has been thought to be specific for NK cells. FACS analyses of CD56(+) and CD56(-) IFN-DCs showed a nearly identical pattern for most of the classical DC markers. Importantly, however, only CD56(+) IFN-DCs exhibited cytolytic activity up to 24% that could almost completely be blocked (-81%) after coincubation with anti-TRAIL. Intracytoplasmatic cytokine staining revealed that the majority of IFN-DCs independently of their CD56 expression were IFN-gamma positive as well. In contrast, CD56(+) IFN-DCs showed stronger capacity in stimulating allogenic T cells compared with CD56(-) IFN-DC. Based on these results, five patients with metastasized medullary thyroid carcinoma were treated for the first time with monocyte-derived tumor Ag-pulsed IFN-DCs. After a long term follow-up (in mean 37 mo) all patients are alive. Immunohistochemical analyses of delayed-type hypersensitivity skin reaction showed a strong infiltration with CD8(+) cells. In two patients no substantial change in tumor morphology was detected. Importantly, by analyzing PBMCs, these patients also showed an increase of Ag-specific IFN-gamma-secreting T cells. In summary, we here describe for the first time that cytotoxic activity of IFN-DCs is mainly mediated by an IFN-DC subset showing partial phenotypic and functional characteristics of NK cells. These cells represent another mechanism of the antitumor effect induced by IFN-alpha.