Uncovering students' misconceptions by assessment of their written questions.

BACKGROUND: Misconceptions are ideas that are inconsistent with current scientific views. They are difficult to detect and refractory to change. Misconceptions can negatively influence how new concepts in science are learned, but are rarely measured in biomedical courses. Early identification of misconceptions is of critical relevance for effective teaching, but presents a difficult task for teachers as they tend to either over- or underestimate students' prior knowledge. A systematic appreciation of the existing misconceptions is desirable. This explorative study was performed to determine whether written questions generated by students can be used to uncover their misconceptions. METHODS: During a small-group work (SGW) session on Tumour Pathology in a (bio)medical bachelor course on General Pathology, students were asked to write down a question about the topic. This concerned a deepening question on disease mechanisms and not mere factual knowledge. Three independent expert pathologists determined whether the content of the questions was compatible with a misconception. Consensus was reached in all cases. Study outcomes were to determine whether misconceptions can be identified in students' written questions, and if so, to measure the frequency of misconceptions that can be encountered, and finally, to determine if the presence of such misconceptions is negatively associated with the students' course formal examination score. A subgroup analysis was performed according to gender and discipline. RESULTS: A total of 242 students participated in the SGW sessions, of whom 221 (91 %) formulated a question. Thirty-six questions did not meet the inclusion criteria. Of the 185 questions rated, 11 % (n = 20) was compatible with a misconception. Misconceptions were only found in medical students' questions, not in biomedical science students' questions. Formal examination score on Tumour Pathology was 5.0 (SD 2.0) in the group with misconceptions and 6.7 (SD 2.4) in the group without misconceptions (p = 0.003). CONCLUSIONS: This study demonstrates that misconceptions can be uncovered in students' written questions. The occurrence of these misconceptions was negatively associated with the formal examination score. Identification of misconceptions creates an opportunity to repair them during the remaining course sessions, in advance of the formal examination.

Challenging students to formulate written questions: a randomized controlled trial to assess learning effects.

BACKGROUND: Underutilization of dialogue among students during small-group work is a threat to active meaningful learning. To encourage small-group learning, we challenged students to generate written questions during a small-group work session. As gender differences have been shown to affect learning, these were also inventoried. METHODS: Prospective randomized study during a bachelor General Pathology course including 459 (bio) medical students, 315 females and 144 males. The intervention was to individually generate an extra written question on disease mechanisms, followed by a selection, by each student group, of the two questions considered to be most relevant. These selected questions were open for discussion during the subsequent interactive lecture. Outcome measure was the score on tumour pathology (range 1-10) on the course examination; the effect of gender was assessed. RESULTS: The mean score per student was 7.2 (intervention) and 6.9 (control; p = 0.22). Male students in the intervention group scored 0.5 point higher than controls (p = 0.05). In female students, this was only 0.1 point higher (p = 0.75). CONCLUSIONS: Formulating and prioritizing an extra written question during small-group work seems to exert a positive learning effect on male students. This is an interesting approach to improve learning in male students, as they generally tend to perform less well than their female colleagues.

Diffusion tensor characteristics of gyrencephaly using high resolution diffusion MRI in vivo at 7T.

Gyrification of the human cerebral cortex allows for the surface expansion that accommodates many more cortical neurons in comparison to other mammals. For neuroimaging, however, it forms a feature that complicates analysis. For example, it has long been established that cortical layers do not occupy the same depth in gyri and sulci. Recently, in vivo diffusion imaging has provided insights into the fibre architecture of the cortex, usually showing radial tensor orientations. This makes it relevant to investigate whether cortical diffusion tensor metrics depend on the gyral pattern. High-resolution (1mm isotropic) diffusion weighted MRI of the medial wall of the hemispheres was performed at 7 T. Diffusion data were resampled to surfaces in the cortex and underlying white matter, where the cortical surfaces obeyed the equivolume principle for cortical laminae over the cortical curvature. Diffusion tensor metrics were averaged over bins of curvature to obtain maps of characteristic patterns in the gyrus. Diffusivity, anisotropy and radiality varied with curvature. Radiality was maximal in intermediate layers of the cortex next to the crown of the gyrus, not in white matter or on the crown. In the fundus, the deep cortical layers had tangential tensor orientations. In the white matter, tensor orientation changed from radial on the crown to tangential under the banks and fundus. White matter anisotropy gradually increased from the crown to the fundus. The characteristic pattern in the gyrus demonstrated here is in accordance with ex vivo diffusion MR microscopy and histological studies. The results indicate the necessity of taking into account the gyral pattern when cortical diffusion data is analysed. Additionally, the data suggest a confound for tractography approaches when reaching the gyrus, resulting in a possible bias towards the gyral crown. The implications for mechanisms that could drive cortical folding are discussed.

Building on prior knowledge: schema-dependent encoding processes relate to academic performance.

The acquisition and retention of conceptual knowledge is more effective in well-structured curricula that provide an optimal conceptual framework for learning new material. However, the neural mechanisms by which preexisting conceptual schemas facilitate learning are not yet well understood despite their fundamental importance. A preexisting schema has been shown to enhance memory by influencing the balance between activity within the medial-temporal lobe and the medial pFC during mnemonic processes such as encoding, consolidation, and retrieval. Specifically, correctly encoding and retrieving information that is related to preexisting schemas appears rather related to medial prefrontal processing, whereas information unrelated or inconsistent with preexisting schemas rather relates to enhanced medial temporal processing and enhanced interaction between these structures. To further investigate interactions between these regions during conceptual encoding in a real-world university setting, we probed human brain activity and connectivity using fMRI during educationally relevant conceptual encoding carefully embedded within two course programs. Early second-year undergraduate biology and education students were scanned while encoding new facts that were either related or unrelated to the preexisting conceptual knowledge they had acquired during their first year of study. Subsequently, they were tested on their knowledge of these facts 24 hr later. Memory scores were better for course-related information, and this enhancement was associated with larger medial-prefrontal, but smaller medial-temporal subsequent memory effects. These activity differences went along with decreased functional interactions between these regions. Furthermore, schema-related medial-prefrontal subsequent memory effects measured during this experiment were found to be predictive of second-year course performance. These results, obtained in a real-world university setting, reveal brain mechanisms underlying acquisition of new knowledge that can be integrated into preexisting conceptual schemas and may indicate how relevant this process is for study success.

Differential roles for medial prefrontal and medial temporal cortices in schema-dependent encoding: from congruent to incongruent.

Information that is congruent with prior knowledge is generally remembered better than incongruent information. This effect of congruency on memory has been attributed to a facilitatory influence of activated schemas on memory encoding and consolidation processes, and hypothesised to reflect a shift between processing in medial temporal lobes (MTL) towards processing in medial prefrontal cortex (mPFC). To investigate this shift, we used functional magnetic resonance imaging (fMRI) to compare brain activity during paired-associate encoding across three levels of subjective congruency of the association with prior knowledge. Participants indicated how congruent they found an object-scene pair during scanning, and were tested on item and associative recognition memory for these associations one day later. Behaviourally, we found a monotonic increase in memory performance with increasing congruency for both item and associative memory. Moreover, as hypothesised, encoding-related activity in mPFC increased linearly with increasing congruency, whereas MTL showed the opposite pattern of increasing encoding-related activity with decreasing congruency. Additionally, mPFC showed increased functional connectivity with a region in the ventral visual stream, presumably related to the binding of visual representations. These results support predictions made by a recent neuroscientific framework concerning the effects of schema on memory. Specifically, our findings show that enhanced memory for more congruent information is mediated by the mPFC, which is hypothesised to guide integration of new information into a pre-existing schema represented in cortical areas, while memory for more incongruent information relies instead on automatic encoding of arbitrary associations by the MTL.

Consolidation differentially modulates schema effects on memory for items and associations.

Newly learned information that is congruent with a preexisting schema is often better remembered than information that is incongruent. This schema effect on memory has previously been associated to more efficient encoding and consolidation mechanisms. However, this effect is not always consistently supported in the literature, with differential schema effects reported for different types of memory, different retrieval cues, and the possibility of time-dependent effects related to consolidation processes. To examine these effects more directly, we tested participants on two different types of memory (item recognition and associative memory) for newly encoded visuo-tactile associations at different study-test intervals, thus probing memory retrieval accuracy for schema-congruent and schema-incongruent items and associations at different time points (t = 0, t = 20, and t = 48 hours) after encoding. Results show that the schema effect on visual item recognition only arises after consolidation, while the schema effect on associative memory is already apparent immediately after encoding, persisting, but getting smaller over time. These findings give further insight into different factors influencing the schema effect on memory, and can inform future schema experiments by illustrating the value of considering effects of memory type and consolidation on schema-modulated retrieval.

Explicit feedback to enhance the effect of an interim assessment: a cross-over study on learning effect and gender difference.

In a previous study we demonstrated by a prospective controlled design that an interim assessment during an ongoing small group work (SGW) session resulted in a higher score in the course examination. As this reflects the so-called testing effect, which is supposed to be enhanced by feedback, we investigated whether feedback following an interim assessment would have an effect on the score of the course exam, and whether the effect is influenced by the gender of the student. During a General Pathology bachelor course all 386 (bio) medical students took an interim assessment on the topics cell damage (first week) and tumour pathology (fourth week). The intervention consisted of immediate detailed oral feedback on the content of the questions of the interim assessment by the tutor, including the rationale of the correct and incorrect answers. It concerned a prospective randomized study using a cross-over design. Outcome measures were: (1) the difference in the normalized scores (1-10) of the course examination multiple choice questions related to the two topics, (2) effect of gender, and (3) gender-specific scores on formal examination. The effect of feedback was estimated as half the difference in the outcome between the two conditions. Mixed-model analysis was used whereby the SGW group was taken as the study target. The scores of the questions on cell damage amounted to 7.70 (SD 1.59) in the group without and 7.78 (SD 1.39) in the group with feedback, and 6.73 (SD 1.51) and 6.77 (SD 1.60), respectively, for those on tumour pathology. No statistically significant effect of feedback was found: 0.02 on a scale of 1-10 (95 % CI: -0.20; 0.25). There were no significant interactions of feedback with gender. Female students scored 0.43 points higher on the formal examination in comparison with their male colleagues. No additional effect of immediate explicit feedback following an interim assessment during an SGW session in an ongoing bachelor course could be demonstrated in this prospective randomized controlled study. Gender analysis revealed a higher performance of female students on the formal examination, which could not be explained by the effect of feedback in the current study. In this particular learning environment, SGW, explicit feedback may have little added value to the interactive learning that includes implicit feedback.

Loosely-guided, self-directed learning versus strictly-guided, station-based learning in gross anatomy laboratory sessions.

Anatomy students studying dissected anatomical specimens were subjected to either a loosely-guided, self-directed learning environment or a strictly-guided, preformatted gross anatomy laboratory session. The current study's guiding questions were: (1) do strictly-guided gross anatomy laboratory sessions lead to higher learning gains than loosely-guided experiences? and (2) are there differences in the recall of anatomical knowledge between students who undergo the two types of laboratory sessions after weeks and months? The design was a randomized controlled trial. The participants were 360 second-year medical students attending a gross anatomy laboratory course on the anatomy of the hand. Half of the students, the experimental group, were subjected without prior warning to station-based laboratory sessions; the other half, the control group, to loosely-guided laboratory sessions, which was the course's prevailing educational method at the time. The recall of anatomical knowledge was measured by written reproduction of 12 anatomical names at four points in time: immediately after the laboratory experience, then one week, five weeks, and eight months later. The strictly-guided group scored higher than the loosely-guided group at all time-points. Repeated ANOVA showed no interaction between the results of the two types of laboratory sessions (P = 0.121) and a significant between-subject effect (P ≤ 0.001). Therefore, levels of anatomical knowledge retrieved were significantly higher for the strictly-guided group than for the loosely-guided group at all times. It was concluded that gross anatomy laboratory sessions with strict instructions resulted in the recall of a larger amount of anatomical knowledge, even after eight months.

How schema and novelty augment memory formation.

Information that is congruent with existing knowledge (a schema) is usually better remembered than less congruent information. Only recently, however, has the role of schemas in memory been studied from a systems neuroscience perspective. Moreover, incongruent (novel) information is also sometimes better remembered. Here, we review lesion and neuroimaging findings in animals and humans that relate to this apparent paradoxical relationship between schema and novelty. In addition, we sketch a framework relating key brain regions in medial temporal lobe (MTL) and medial prefrontal cortex (mPFC) during encoding, consolidation and retrieval of information as a function of its congruency with existing information represented in neocortex. An important aspect of this framework is the efficiency of learning enabled by congruency-dependent MTL-mPFC interactions.

How to achieve synergy between medical education and cognitive neuroscience? An exercise on prior knowledge in understanding.

A major challenge in contemporary research is how to connect medical education and cognitive neuroscience and achieve synergy between these domains. Based on this starting point we discuss how this may result in a common language about learning, more educationally focused scientific inquiry, and multidisciplinary research projects. As the topic of prior knowledge in understanding plays a strategic role in both medical education and cognitive neuroscience it is used as a central element in our discussion. A critical condition for the acquisition of new knowledge is the existence of prior knowledge, which can be built in a mental model or schema. Formation of schemas is a central event in student-centered active learning, by which mental models are constructed and reconstructed. These theoretical considerations from cognitive psychology foster scientific discussions that may lead to salient issues and questions for research with cognitive neuroscience. Cognitive neuroscience attempts to understand how knowledge, insight and experience are established in the brain and to clarify their neural correlates. Recently, evidence has been obtained that new information processed by the hippocampus can be consolidated into a stable, neocortical network more rapidly if this new information fits readily into a schema. Opportunities for medical education and medical education research can be created in a fruitful dialogue within an educational multidisciplinary platform. In this synergetic setting many questions can be raised by educational scholars interested in evidence-based education that may be highly relevant for integrative research and the further development of medical education.

Challenging medical students with an interim assessment: a positive effect on formal examination score in a randomized controlled study.

Until now, positive effects of assessment at a medical curriculum level have not been demonstrated. This study was performed to determine whether an interim assessment, taken during a small group work session of an ongoing biomedical course, results in students' increased performance at the formal course examination. A randomized controlled trial was set up, with an interim assessment without explicit feedback as intervention. It was performed during a regular biomedical Bachelor course of 4 weeks on General Pathology at the Radboud University Nijmegen Medical Centre. Participants were 326 medical and 91 biomedical science students divided into three study arms: arm Intervention-1 (I-1) receiving one interim assessment; arm I-2 receiving two interim assessments, and control arm C, receiving no interim assessment. The study arms were stratified for gender and study discipline. The interim assessment consisted of seven multiple-choice questions on tumour pathology. Main outcome measures were overall score of the formal examination (scale 1-10), and the subscore of the questions on tumour pathology (scale 1-10). We found that students who underwent an interim assessment (arm I) had a 0.29-point (scale 1-10) higher score on the formal examination than the control group (p = 0.037). For the questions in the formal examination on tumour pathology the score amounted to 0.47 points higher (p = 0.007), whereas it was 0.17 points higher for the questions on topics related to the previous 3 weeks. No differences in formal examination score were found between arms I-1 and I-2 (p = 0.817). These findings suggest that an interim assessment during a small group work session in a randomized study setting stimulates students to increase their formal examination score.

Retrieval of associative information congruent with prior knowledge is related to increased medial prefrontal activity and connectivity.

We remember information that is congruent instead of incongruent with prior knowledge better, but the underlying neural mechanisms related to this enhancement are still relatively unknown. Recently, this memory enhancement due to a prior schema has been suggested to be based on rapid neocortical assimilation of new information, related to optimized encoding and consolidation processes. The medial prefrontal cortex (mPFC) is thought to be important in mediating this process, but its role in retrieval of schema-consistent information is still unclear. In this study, we regarded multisensory congruency with prior knowledge as a schema and used this factor to probe retrieval of consolidated memories either consistent or inconsistent with prior knowledge. We conducted a visuotactile learning paradigm in which participants studied visual motifs randomly associated with word-fabric combinations that were either congruent or incongruent with common knowledge. The next day, participants were scanned using functional magnetic resonance imaging while their memory was tested. Congruent associations were remembered better than incongruent ones. This behavioral finding was parallelized by stronger retrieval-related activity in and connectivity between medial prefrontal and left somatosensory cortex. Moreover, we found a positive across-subject correlation between the connectivity enhancement and the behavioral congruency effect. These results show that successful retrieval of congruent compared to incongruent visuotactile associations is related to enhanced processing in an mPFC-somatosensory network, and support the hypothesis that new information that fits a preexisting schema is more rapidly assimilated in neocortical networks, a process that may be mediated, at least in part, by the mPFC.

An altar in honor of the anatomical gift.

On All Saints Day 2009 a monument for body donors was unveiled by the Department of Anatomy, at the Radboud University Nijmegen Medical Centre (RUNMC). Although body donation to medical science contributes substantially to the quality of medical education, the ceremony was only the first time that the RUNMC publicly reciprocated the anatomical gift. By means of the monument the department of Anatomy endeavors to express gratitude for the gift of body donors and raise awareness among students to value the gift and treat donor bodies with the proper respect. Furthermore, the large attendance of bereaved at the unveiling ceremony, revealed another equally important meaning of the monument, which is the significance of the monument to the donor kin. The wish of a body donor has large implications for the way bereaved can take leave of the donor; there is limited time to bade the deceased farewell, the body will not be available for a funeral, and the donor kin stay behind empty handed without even a grave or ashes. Therefore the monument can be meaningful by facilitating the bereaved with a place of commemoration. The design of the monument anticipates on these multiple meanings and symbolisms by placing an old marble dissection table in the shape of an altar and fixing a bronze sculpture of a phoenix as symbol of imperishableness.

HRAS-mutated Spitz tumors: A subtype of Spitz tumors with distinct features.

It is often very difficult to confidently distinguish benign and malignant Spitz lesions, and a diagnosis of Spitz tumor of unknown malignant potential (STUMP) is rendered. To address this problem, we performed molecular genetic analysis in a large group of Spitz tumors (93 Spitz nevi and 77 STUMPs) and identified a subgroup of 24 lesions harboring a HRAS mutation. This subgroup lay predominantly in the dermis, had a relatively low cellularity, showed desmoplasia (with single cells interspersed between the collagen bundles), and had an infiltrating base. In 7 of these 24 cases (29%) melanoma had been the initial diagnosis, or an important differential diagnostic consideration, mainly based on the presence of multiple or deeply located mitotic figures, especially in adult patients. In our series none of the patients with the HRAS-mutated lesions developed recurrences or metastases (mean and median follow-up: 10.5 y). This was in accordance with the literature: review showed that no HRAS mutations had so far been reported in Spitzoid melanomas. We therefore conclude that HRAS mutation analysis may be a useful diagnostic tool to help differentiate between Spitz nevus and Spitzoid melanoma, thereby reducing the frequency of overdiagnosis of melanoma, and to help predict the biological behavior of a STUMP. Moreover, this might be a first step toward a more reproducible classification of Spitz tumors combining histological and genetic data.

Soluble adhesion molecules in human cancers: sources and fates.

Adhesion molecules endow tumor cells with the necessary cell-cell contacts and cell-matrix interactions. As such, adhesion molecules are involved in cell signalling, proliferation and tumor growth. Rearrangements in the adhesion repertoire allow tumor cells to migrate, invade and form metastases. Besides these membrane-bound adhesion molecules several soluble adhesion molecules are detected in the supernatant of tumor cell lines and patient body fluids. Truncated soluble adhesion molecules can be generated by several conventional mechanisms, including alternative splicing of mRNA transcripts, chromosomal translocation, and extracellular proteolytic ectodomain shedding. Secretion of vesicles (ectosomes and exosomes) is an alternative mechanism mediating the release of full-length adhesion molecules. Soluble adhesion molecules function as modulators of cell adhesion, induce proteolytic activity and facilitate cell signalling. Additionally, adhesion molecules present on secreted vesicles might be involved in the vesicle-target cell interaction. Based on currently available data, released soluble adhesion molecules contribute to cancer progression and therefore should not be regarded as unrelated and non-functional side products of tumor progression.

Molecular cytogenetics of cutaneous melanocytic lesions - diagnostic, prognostic and therapeutic aspects.

This review intends to update current knowledge regarding molecular cytogenetics in melanocytic tumours with a focus on cutaneous melanocytic lesions. Advantages and limitations of diverse, already established methods, such as (fluorescence) in situ hybridization and mutation analysis, to detect these cytogenetic alterations in melanocytic tumours are described. In addition, the potential value of more novel techniques such as multiplex ligation-dependent probe amplification is pointed out. This review demonstrates that at present cytogenetics has mainly increased our understanding of the pathogenesis of melanocytic tumours, with an important role for activation of the mitogen-activated protein kinase (MAPK) signalling pathway in the initiation of melanocytic tumours. Mutations in BRAF (in common naevocellular naevi), NRAS (congenital naevi), HRAS (Spitz naevi) and GNAQ (blue naevi) can all cause MAPK activation. All these mutations seem early events in the development of melanocytic tumours, but by themselves are insufficient to cause progression towards melanoma. Additional molecular alterations are implicated in progression towards melanoma, with different genetic alterations in melanomas at different sites and with varying levels of sun exposure. This genetic heterogeneity in distinct types of naevi and melanomas can be used for the development of molecular tests for diagnostic purposes. However, at the moment only few molecular tests have become of diagnostic value and are performed in daily routine practice. This is caused by lack of large prospective studies on the diagnostic value of molecular tests including follow-up, and by the low prevalence of certain molecular alterations. For the future we foresee an increasing role for cytogenetics in the treatment of melanoma patients with the increasing availability of targeted therapy. Potential targets for metastatic melanoma include genes involved in the MAPK pathway, such as BRAF and RAS. More recently, KIT has emerged as a potential target in melanoma patients. These targeted treatments all need careful evaluation, but might be a promising adjunct for treatment of metastatic melanoma patients, in which other therapies have not brought important survival advantages yet.

Type I collagen expression contributes to angiogenesis and the development of deeply invasive cutaneous melanoma.

Tumors are complex tissues composed of neoplastic cells, soluble and insoluble matrix components and stromal cells. Here we report that in melanoma, turn-over of type I collagen (Col(I)), the predominant matrix protein in dermal stroma affects melanoma progression. Fibroblasts juxtaposed to melanoma cell nests within the papillary dermis display high levels of Col(I) mRNA expression. These nests are enveloped by collagen fibers. In contrast, melanoma-associated fibroblasts within the reticular dermis express Col(I) mRNA at a level that is comparable to its expression in uninvolved dermis and reduced amount of collagen protein can be observed. To determine the significance of Col(I) expression in melanoma, we pharmacologically inhibited its transcription in a porcine cutaneous melanoma model by oral administration of halofuginone. When administered before melanoma development, it reduced melanoma incidence and diminished the transition from microinvasive toward deeply invasive growth by limiting the development of a tumor vasculature. Whereas invasive melanoma growth has been correlated with increased blood vessel density previously, our data for the first time demonstrate that the proangiogenic effect of Col(I) expression by fibroblasts and vascular cells precedes the development of invasive melanomas in a de novo tumor model.

Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial.

BACKGROUND: Individuals affected by melanoma with thick primary tumours or regional node involvement have a poor outlook, with only 30-50% alive at 5 years. High-dose and low-dose interferon alfa have been assessed for the treatment of these patients, with the former having considerable toxicity and a consistent effect on disease free survival, but not on overall survival, and the latter no consistent effect on either. Our aim was, therefore, to assess the effect of two regimens of interferon of intermediate dose versus observation alone on distant metastasis-free interval (DMFI) and overall survival in such patients. METHODS: We did a randomised controlled trial in 1388 patients who had had a thick primary tumour (thickness > or = 4 mm) resected (stage IIb) or regional lymph node metastases dissected (stage III) and had been assigned to 13-months (n=553) or 25 months (n=556) of treatment with subcutaneous interferon alfa 2b, or observation (n=279). Treatment comprised 4 weeks of 10 million units (MU) of interferon alfa (5 days per week) followed by either 10 MU three times a week for 1 year or 5 MU three times a week for 2 years, to a total dose of 1760 MU. Our primary endpoint was DMFI. Analyses were by intent to treat. FINDINGS: After a median follow-up of 4.65 years, we had recorded 760 distant metastases and 681 deaths. At 4.5 years, the 25-month interferon group showed a 7.2% increase in rate of DMFI (hazard ratio 0.83, 97.5% CI 0.66-1.03) and a 5.4% improvement in overall survival. The 13-month interferon group showed a 3.2% increase in rate of DMFI at 4.5 years (0.93, 0.75-1.16) and no extension of overall survival. Toxicity was acceptable, with 18% (195 of 1076) of patients going off study because of toxicity or as a result of refusal of treatment because of side-effects. INTERPRETATION: Interferon alfa as used in the regimens studied does not improve outcome for patients with stage IIb/III melanomas, and cannot be recommended. With respect to efficacy of the drug, duration of treatment seemed more important than dose, and should be assessed in future trials.

Immunomonitoring tumor-specific T cells in delayed-type hypersensitivity skin biopsies after dendritic cell vaccination correlates with clinical outcome.

PURPOSE: Tumor-specific immunomonitoring is essential to evaluate the efficacy of vaccination against cancer. In this study, we investigated the predictive value of the presence or absence of antigen-specific T cells in biopsies from delayed-type hypersensitivity (DTH) sites. PATIENTS AND METHODS: In our ongoing clinical trials, HLA-A2.1+ melanoma patients were vaccinated with mature dendritic cells (DC) pulsed with melanoma-associated peptides (gp100 and tyrosinase) and keyhole limpet hemocyanin. RESULTS: After intradermal administration of a DTH challenge with gp100- and tyrosinase peptide-loaded DC, essentially all patients showed a positive induration. In clinically responding patients, T cells specific for the antigen preferentially accumulated in the DTH site, as visualized by in situ tetramer staining. Furthermore, significant numbers of functional gp100 and tyrosinase tetramer-positive T cells could be isolated from these DTH biopsies, in accordance with the applied antigen in the DTH challenge. We observed a direct correlation between the presence of DC vaccine-related T cells in the DTH biopsies of stage IV melanoma patients and a positive clinical outcome (P = .0012). CONCLUSION: These findings demonstrate the potency of this novel approach in the monitoring of vaccination studies in cancer patients.